Infectious disease a clinical short courseDocument Transcript
Infectious DiseasesA Clinical Short Course
NoticeMedicine is an ever-changing science. As new research and clinical experience broadenour Despite dire warnings that we are approaching the end of the antibiotic era, the inci-dence of antibiotic-resistant bacteria continues to rise. The proportions of penicillin-resis-tant Streptococcus pneumoniae, hospital-acquired methicillin-resistant Staphylococcusaureus (MRSA), and vancomycin-resistant Enterococcus (VRE) strains continue toincrease. Community-acquired MRSA (cMRSA) is now common throughout the world.Multiresistant Acinetobacter and Pseudomonas are everyday realities in many of our hos-pitals. The press is now warning the lay public of the existence of “dirty hospitals.” Asnever before, it is critical that health care providers understand the principles of properanti-infective therapy and use anti-infective agents judiciously. These agents need to bereserved for treatable infections-not used to calm the patient or the patients family. Toooften, patients with viral infections that do not warrant anti-infective therapy arrive at thephysicians ofﬁce expecting to be treated with an antibiotic. And health care workers toooften prescribe antibiotics to fulﬁll those expectations. Physicians unschooled in the prin-ciples of microbiology utilize anti-infective agents just as they would more conventionalmedications, such as anti-inﬂammatory agents, anti-hypertensive medications, and car-diac drugs. They use one or two broad-spectrum antibiotics to treat all patients with.They use one or two broad-spectrum antibiotics to treat all patients with.
Infectious Diseases A Clinical Short Course Second EditionFREDERICK S. SOUTHWICK, M.D. Professor of Medicine Chief of Infectious Diseases Vice Chairman of Medicine University of Florida College of Medicine Gainesville, Florida McGraw-Hill Medical Publishing DivisonNew York Chicago San Fracisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto
For more information about this title, click here ContentsContributors ixPreface xiAcknowledgments xiii1 ANTI-INFECTIVE THERAPY 12 THE SEPSIS SYNDROME 573 THE FEBRILE PATIENT 664 PULMONARY INFECTIONS 795 EYE, EAR NOSE, AND THROAT INFECTIONS 1206 CENTRAL NERVOUS SYSTEM INFECTIONS 1397 CARDIOVASCULAR INFECTIONS 1678 GASTROINTESTINAL AND HEPATOBILIARY INFECTIONS 1909 GENITOURINARY TRACT INFECTIONS AND SEXUALLY TRANSMITTED DISEASES (STDs) 23110 SKIN AND SOFT TISSUE INFECTIONS 25611 BONE AND JOINT INFECTIONS 27312 PARASITIC INFECTIONS 28813 ZOONOTIC INFECTIONS 32214 BIOTERRORISM 34915 SERIOUS ADULT VIRAL ILLNESSES OTHER THAN HIV 36516 INFECTIONS IN THE IMMUNOCOMPROMISED HOST 38417 HIV INFECTION 397Index 435
xii / PREFACEthe clinician should know when managing each improve healthcare providers understanding of infec-infection. When possible simple diagrams summarize tious diseases and provide them with the latestmanagement approaches, as well as principles of approaches managing infections. It is our ﬁrm beliefpathogenesis. All chapters have been updated to that only through a concerted educational campaignreﬂect the current treatment and diagnostic guide- to teach the principles of infectious diseases and thelines of the Infectious Disease Society of America judiciously use anti-infective agents we can help to(IDSA) and up-to-date references have been prevent the “End of the Antibiotic Era”.included at the end of each chapter. Our goal is to
2 / CHAPTER 1 KEY POINTS About Anti-Infective Therapy 1. Too often, antibiotics are prescribed to fulﬁll the patient’s expectations, rather than to treat a true bacterial infection. 2. A single antibiotic cannot meet all infectious disease needs. 3. Physicians ignore the remarkable adaptability of bacteria, fungi, and viruses at their patient’s peril. 4. Anti-infective therapy is dynamic and requires a basic understanding of microbiology. 5. The “shotgun” approach to infectious diseases must end, or we may truly experience the end of the antibiotic era.■ ANTIBIOTIC RESISTANCEGENETIC MODIFICATIONS LEADING TO Figure 1–1. Mechanisms by which bacteria transferANTIMICROBIAL RESISTANCE antibiotic resistance genes.To understand why antibiotics must be used judi-ciously, the physician needs to understand how bacte-ria are able to adapt to their environment. Point second bacterium and serves as bridge for themutations can develop in the DNA of bacteria as they transfer of the plasmid DNA from the donor toreplicate. These mutations occur in the natural envi- the recipient bacterium. Using this mechanism, aronment, but are of no survival advantage unless the single resistant bacterium can transfer resistancebacteria are placed under selective pressures. In the to other bacteria.case of a mutation that renders a bacterium resistant to 2. Transduction. Bacteriophages are protein-coateda speciﬁc antibiotic, exposure to the speciﬁc antibiotic DNA segments that attach to the bacterial wall andallows the bacterial clone that possesses the antibiotic inject DNA in a process called “transduction.”resistance mutation to grow, while bacteria without the These infective particles can readily transfer resis-mutation die and no longer compete for nutrients. tance genes to multiple bacteria.Thus the resistant strain becomes the dominant bacte- 3. Transformation. Donor bacteria can also releaserial ﬂora. In addition to point mutations bacteria can linear segments of chromosomal DNA, which isalso use three major mechanisms to transfer genetic then taken up by recipient bacteria and incorpo-material among themselves: rated into the recipient’s genome. This process is1. Conjugation. Bacteria often contain circular, called “transformation,” and the naked DNA double-stranded DNA structures called plasmids. capable of incorporating into the genome of recip- These circular DNA structures lie outside the bac- ient bacteria is called a transposon (Figure 1.1). terial genome (Figure 1.1). Plasmids often carry Natural transformation most commonly occurs in resistance (“R”) genes. Through a mechanism Streptococcus, Haemophilus, and Neisseria species. called “conjugation,” plasmids can be transferred Transposons can transfer multiple antibiotic resis- from one bacterium to another. The plasmid tance genes in a single event and have been shown encodes for the formation of a pilus on the donor to be responsible for high-level vancomycin resis- bacteria’s outer surface. The pilus attaches to a tance in enterococci.
ANTI-INFECTIVE THERAPY / 3 -lactamase activity occurs primarily through plasmids KEY POINTS and transposons. Multiple classes of -lactamases exist. Some preferen- About Antibiotic Resistance tially break down penicillins; others preferentially destroy speciﬁc cephalosporins or carbenicillin. Extended-spec- 1. Bacteria can quickly alter their genetic makeup by trum -lactamases (ESBLs) readily destroy most cepha- losporins. Another class of -lactamase is resistant to a) point mutation. clavulanate, an agent added to numerous antibiotics to b) transfer of DNA by plasmid conjugation. inhibit -lactamase activity. Some bacteria are able to pro- c) transfer of DNA by bacteriophage trans- duce -lactamases called carbapenemases that are capable duction. of inactivating imipenem and meropenem. d) transfer of naked DNA by transposon trans- Gram-negative bacilli produce a broader spectrum formation. of -lactamases than do gram-positive organisms, and 2. The ability of bacteria to share DNA provides a therefore infections with gram-negative organisms survival advantage, allowing them to quickly more commonly arise in patients treated for pro- adapt to antibiotic exposure. longed periods with broad-spectrum antibiotics. In 3. Biochemical alterations leading to antibiotic some instances, -lactamase activity is low before the resistance include bacterium is exposed to antibiotics; however, follow- a) degradation or modiﬁcation of the antibiotic. ing exposure, -lactamase activity is induced. b) reduction of the bacterial antibiotic concen- Enterobacter is a prime example. This gram-negative tration by inhibiting entry or by efflux bacterium may appear sensitive to cephalosporins on pumps. initial testing. Following cephalosporin treatment, c) modiﬁcation of the antibiotic target. -lactamase activity increases, resistance develops, and the patient’s infection relapses. For this reason, 4. Under the selection pressure of antibiotics, the third-generation cephalosporins are not recom- question is not whether, but when resistant bacteria will take over. mended for serious Enterobacter infections. OTHER ENZYME MODIFICATIONS OF ANTIBIOTICS Erythromycin is readily inactivated by an esterase that hydrolyzes the lactone ring of the antibiotic. This Thus bacteria possess multiple ways to transfer their esterase has been identiﬁed in Escherichia coli. OtherDNA, and they promiscuously share genetic informa- plasmid-mediated erythromycin inactivating enzymestion. This promiscuity provides a survival advantage, have been discovered in Streptococcus species andallowing bacteria to quickly adapt to their environment. S. aureus. Chloramphenicol is inactivated by chloram- phenicol acetyltransferase, which has been isolated from both gram-positive and gram-negative bacteria. Simi-BIOCHEMICAL MECHANISMS FOR larly, aminoglycosides can be inactivated by acetyltrans-ANTIMICROBIAL RESISTANCE ferases. Bacteria also inactivate this class of antibiotics byWhat are some of the proteins that these resistant genes phosphorylation and adenylation.encode for, and how do they work? These resistance enzymes are found in many gram- The mechanisms by which bacteria resist antibiotics negative strains and are increasingly detected in entero-can be classiﬁed into three major groups: cocci, S. aureus and S. epidermidis.• Degradation or modiﬁcation of the antibiotic Reduction of the Bacterial• Reduction of the bacterial antibiotic concentration Antibiotic Concentration• Modiﬁcation of the antibiotic target INTERFERENCE WITH ANTIBIOTIC ENTRY For an antibiotic to work, it must be able to penetrateDegradation or Modiﬁcation the bacterium and reach its biochemical target. Gram-of the Antibiotic negative bacteria contain an outer lipid coat that impedes penetration by hydrophobic reagents (such as -LACTAMASES most antibiotics). The passage of hydrophobic antibi-Many bacteria synthesize one or more enzymes called otics is facilitated by the presence of porins—small -lactamases that inactivate antibiotics by breaking the channels in the cell walls of gram-negative bacteria thatamide bond on the -lactam ring. Transfer of allow the passage of charged molecules. Mutations
4 / CHAPTER 1leading to the loss of porins can reduce antibiotic pene- Ribosomal resistance to gentamicin, tobramycin, andtration and lead to antibiotic resistance. amikacin is less common because these aminoglyco- sides have several binding sites on the bacterial ribo-PRODUCTION OF EFFLUX PUMPS some and require multiple bacterial mutations beforeTransposons have been found that encode for an their binding is blocked.energy-dependent pump that can actively pumptetracycline out of bacteria. Active efﬂux of antibiotics CONCLUSIONShas been observed in many enteric gram-negativebacteria, and this mechanism is used to resist Bacteria can readily transfer antibiotic resistance genes.tetracycline, macrolide, and fluoroquinolone Bacteria have multiple mechanisms to destroy antibi-antibiotic treatment. S. aureus, S. epidermidis, otics, lower the antibiotic concentration, and interfereS. pyogenes, group B streptococci, and S. pneumoniae with antibiotic binding. Under the selective pressures ofalso can utilize energy-dependent efflux pumps to prolonged antibiotic treatment, the question is notresist antibiotics. whether, but when resistant bacteria will take over.Modiﬁcation of the Antibiotic TargetALTERATIONS OF CELL WALL PRECURSORS ■ ANTI-INFECTIVE AGENT DOSINGAlteration of cell wall precursors is the basis for VRE.Vancomycin and teicoplanin binding requires that D- The characteristics that need to be considered whenalanine-D-alanine be at the end of the peptidoglycan cell administering antibiotics include absorption (when deal-wall precursors of gram-positive bacteria. Resistant ing with oral antibiotics), volume of distribution, metab-strains of Enterococcus faecium and Enterococcus faecalis olism, and excretion. These factors determine the dose ofcontain the vanA plasmid, which encodes a protein that each drug and the time interval of administration. Tosynthesizes D-alanine-D-lactate instead of D-alanine-D- effectively clear a bacterial infection, serum levels of thealanine at the end of the peptidoglycan precursor. Loss antibiotic need to be maintained above the minimumof the terminal D-alanine markedly reduces vancomycin inhibitory concentration (MIC) for a signiﬁcant period.and teicoplanin binding, allowing the mutant bac- For each pathogen, the MIC is determined by seriallyterium to survive and grow in the presence of these diluting the antibiotic into liquid medium containing 104antibiotics. bacteria per milliliter. Inoculated tubes are incubated overnight until broth without added antibiotic hasCHANGES IN TARGET ENZYMES become cloudy or turbid as a result of bacterial growth.Penicillins and cephalosporins bind to speciﬁc proteins The lowest concentration of antibiotic that preventscalled penicillin-binding proteins (PBPs) in the bacter- active bacterial growth—that is, the liquid media remainsial cell wall. Penicillin-resistant S. pneumoniae demon- clear—constitutes the MIC (Figure 1.2). Automatedstrate decreased numbers of PBPs or PBPs that bind analyzers can now quickly determine, for individualpenicillin with lower afﬁnity, or both. Decreased peni- pathogens, the MICs for multiple antibiotics, and thesecillin binding reduces the ability of the antibiotic to kill data serve to guide the physician’s choice of antibiotics.the targeted bacteria. The mean bactericidal concentration (MBC) is deter- The basis for antibiotic resistance in MRSA is pro- mined by taking each clear tube and inoculating a plateduction of a low afﬁnity PBP encoded by the mecA of solid medium with the solution. Plates are then incu-gene. Mutations in the target enzymes dihydropteroate bated to allow colonies to form. The lowest concentra-synthetase and dihydrofolate reductase cause sulfon- tion of antibiotic that blocks all growth of bacteria—thatamide and trimethoprim resistance respectively. Single is, no colonies on solid medium—represents the MBC.amino-acid mutations that alter DNA gyrase function Successful cure of an infection depends on multiplecan result in resistance to ﬂuoroquinolones. host factors in addition to serum antibiotic concentration. However, investigators have attempted to predict success-ALTERATIONS IN RIBOSOMAL BINDING SITE ful treatment by plotting serum antibiotic levels againstTetracyclines, macrolides, lincosamides, and amino- time. Three parameters can be assessed (Figure 1.3): timeglycosides all act by binding to and disrupting the above the MIC (T>MIC), ratio of the peak antibiotic con-function of bacterial ribosomes (see the descriptions centration to the MIC (Cmax/MIC), and the ratio of theof individual antibiotics later in this chapter). A num- area under the curve (AUC) to the MIC (AUC/MIC).ber of resistance genes encode for enzymes that Cure rates for -lactam antibiotics are maximized bydemethylate adenine residues on bacterial ribosomal maintaining serum levels above the MIC for >50% ofRNA, inhibiting antibiotic binding to the ribosome. the time. Peak antibiotic concentrations are of less
ANTI-INFECTIVE THERAPY / 5 exceed the MIC. High peak levels of these antibiotics may be more effective than low peak levels at curing infec- tions. Therefore, for treatment with aminoglycosides and ﬂuoroquinolones Cmax/MIC and AUC/MIC are more helpful for maximizing effectiveness. In the treatment of gram-negative bacteria, aminoglycosides have been sug- gested to achieve maximal effectiveness when Cmax/MIC is 10 to 12. For ﬂuoroquinolones, best outcomes in com- munity-acquired pneumonia may be achieved when the AUC/MIC is 34. To prevent the development of ﬂuo- roquinolone resistance to S. pneumoniae, in vitro studies have suggested that AUC/MIC should be 50. For P. aeruginosa, an AUC/MIC of 200 is required. In vitro studies also demonstrate that aminoglycosides and ﬂuoroquinolones demonstrate a post-antibiotic effect: when the antibiotic is removed, a delay in the recovery of bacterial growth occurs. Gram-negative bacteria demon- strate a delay of 2 to 6 hours in the recovery of active growth after aminoglycosides and ﬂuoroquinolones, but no delay after penicillins and cephalosporins. But peni- cillins and cephalosporins generally cause a 2-hour delay in the recovery of gram-positive organisms. Investigators suggest that antibiotics with a signiﬁcant post-antibioticFigure 1–2. Understanding the minimum inhibitory effect can be dosed less frequently; those with no post-concentration and the minimal bactericidal antibiotic effect should be administered by constantconcentration. infusion. Although these in vitro effects suggest certain therapeutic approaches, it must be kept in mind that con- centration-dependent killing and post-antibiotic effect areimportance for these antibiotics, and serum concentra- both in vitro phenomena, and treatment strategies basedtions above 8 times the MIC are of no beneﬁt other than on these effects have not been substantiated by controlledto enhance penetration into less permeable body sites. human clinical trials. Unlike -lactam antibiotics, aminoglycosides and ﬂu-oroquinolones demonstrate concentration-dependentkilling. In vitro studies show that these antibioticsdemonstrate greater killing the more their concentrations KEY POINTS About Antibiotic Dosing 1. Absorption, volume of distribution, metabolism, and excretion all affect serum antibiotic levels. 2. Mean inhibitory concentration (MIC) is helpful in guiding antibiotic choice. 3. To maximize success with -lactam antibiotics, serum antibiotic levels should be above the MIC for at least 50% of the time (T>MIC 50%). 4. To maximize success with aminoglycosides and fluoroquinolones, high peak concentration, Cmax/MIC, and high AUC/MIC ratio are recom- mended. 5. The clinical importance of concentration- dependent killing and post-antibiotic effect for aminoglycosides and ﬂuoroquinolones remain to be proven by clinical trials.Figure 1–3. Pharmacokinetics of a typical antibiotic.
6 / CHAPTER 1BASIC STRATEGIES Does the Patient have aFOR ANTIBIOTIC THERAPY Bacterial Infection? WBC with DifferentialThe choice of antibiotics should be carefully consi- Assess Severity of Illnessdered. A step-by-step logical approach is helpful(Figure 1.4).1. Decide Whether The Patient Has a No,Bacterial Infection Yes Observe Closely Obtain Cultures.One test that has traditionally been used to differentiatean acute systemic bacterial infection from a viral illness isthe peripheral white blood cell (WBC) count. In patientswith serious systemic bacterial infections, the peripheral Obtain Cultures If Patient worsensWBC count may be elevated and may demonstrate an including blood clinicallyincreased percentage of neutrophils. On occasion, lessmature neutrophils such as band forms and, less com-monly, metamyelocytes are observed on peripheral bloodsmear. Most viral infections fail to induce a neutrophil Decide onresponse. Viral infections, particularly Epstein–Barr virus, Probable Site ofinduce an increase in lymphocytes or monocytes (or Infection & Beginboth) and may induce the formation of atypical mono- Empiric Therapycytes. Unfortunately, the peripheral WBC count is only arough guideline, lacking both sensitivity and speciﬁcity.Recently, serum procalcitonin concentration has beenfound to be a far more accurate test for differentiating At 3 Days Review Culturebacterial from viral infection. In response to bacterial and Graminfection, this precursor of calcitonin is synthesized and Stain Resultsreleased into the serum by many organs of the body; pro-duction of interferon in response to viral infectioninhibits its synthesis. The serum procalcitonin test mayalso be of prognostic value, serum procalcitonin levels Positive & Gram stainbeing particularly high in severe sepsis (see Chapter 2). consistent with Infection Negative or Colonization Review sensitivities and2. Make a Reasonable Statistical Guess Return to top streamline antibioticsas to the Possible Pathogens (narrowest spectrum and fewest drugs possible)Based on the patient’s symptoms and signs, as well as onlaboratory tests, the anatomic site of the possible infec- Figure 1.4. Algorithm for the initial use oftion can often be determined. For example, burning on anti-infective therapy.urination, associated with pyuria on urinalysis, suggests aurinary tract infection. The organisms that cause uncom-plicated urinary tract infection usually arise from thebowel ﬂora. They include E. coli, Klebsiella, and Proteus. ﬂora associated with the hospital and the ﬂoor where theAntibiotic treatment needs to cover these potential patient became ill. Many hospitals have a high incidencepathogens. Later chapters review the pathogens com- of MRSA and therefore empiric antibiotic treatment formonly associated with infections at speciﬁc anatomic a possible staphylococcal infection must include van-sites and the recommended antibiotic coverage for those comycin, pending culture results. Other hospitals have apathogens. large percentage of Pseudomonas strains that are resistant to gentamicin, eliminating that antibiotic from consid-3. Be aware of the Antibiotic Susceptibility Patterns eration as empiric treatment of possible gram-negativein Your Hospital and Community sepsis. In many communities, individuals who have never been hospitalized are today presenting with soft-In patients that develop infection while in hospital tissue infections caused by cMRSA, and physicians in(“nosocomial infection), empiric therapy needs to take these communities must adjust their empiric antibioticinto account the antibiotic susceptibility patterns of the selection (see Chapter 10).
ANTI-INFECTIVE THERAPY / 74. Take into Account Previous Antibiotic Treatment tic. The use of rifampin combined with oxacillin is antagonistic in some strains of S. aureus, for exam-The remarkable adaptability of bacteria makes it ple. Many combination regimens have not beenhighly likely that a new pathogen will be resistant to completely studied, and the natural assumption thatpreviously administered antibiotics. If the onset of the more antibiotics lead to more killing power oftennew infection was preceded by a signiﬁcant interval does not apply.when antibiotics were not given, the resident ﬂora mayhave recolonized with less resistant ﬂora. However, the b. Use of multiple antibiotics increases the risk ofre-establishment of normal ﬂora can take weeks, and adverse reactions. Drug allergies are common.patients in hospital are likely to recolonize with highly When a patient on more than one antibiotic devel-resistant hospital ﬂora. ops an allergic reaction, all antibiotics become potential offenders, and these agents can no longer5. Take into Consideration Important Host Factors be used. In some instances, combination therapy can increase the risk of toxicity. The combination ofa. Penetration into the site of infection. For example, gentamicin and vancomycin increases the risk of patients with bacterial meningitis should not be nephrotoxicity, for example. treated with antibiotics that fail to cross the c. Use of multiple antibiotics often increases costs blood–brain barrier (examples include 1st-generation and the risk of administration errors. Administra- cephalosporins, gentamicin, and clindamycin). tion of two or more intravenous antibiotics requiresb. Peripheral WBC count. Patients with neutropenia multiple intravenous reservoirs, lines, and pumps. have a high mortality rate from sepsis. Immediate Nurses and pharmacists must dispense each antibi- broad-spectrum, high-dose intravenous antibiotic otic dose, increasing labor costs. The more drugs a treatment is recommended as empiric therapy for patient receives, the higher the probability of an these patients. administration error. Use of two or more drugs usu-c. Age and underlying diseases (hepatic and renal ally increases the acquisition costs. dysfunction). Elderly patients tend to metabolize d. Use of multiple antibiotics increases the risk of and excrete antibiotics more slowly; longer dosing infection with highly resistant organisms. Pro- intervals are therefore often required. Agents with longed use of broad-spectrum antibiotic coverage significant toxicity (such as aminoglycosides) increases the risk of infection with MRSA, VRE, should generally be avoided in elderly patients multiresistant gram-negative bacilli, and fungi. because they exhibit greater toxicity. Antibiotics When multiple antibiotics are used, the spectrum metabolized primarily by the liver should generally of bacteria killed increases. Killing most of the be avoided or reduced in patients with signiﬁcant normal ﬂora in the pharynx and gastrointestinal cirrhosis. In patients with significant renal dys- tract is harmful to the host. The normal flora function, antibiotic doses need to be modiﬁed. compete for nutrients, occupy binding sites thatd. Duration of hospitalization. Patients who have could otherwise be used by pathogenic bacteria, just arrived in the hospital tend to be colonized with and produce agents that inhibit the growth of community-acquired pathogens; patients who have competitors. Loss of the normal ﬂora allows resis- been in the hospital for prolonged periods and have tant pathogens to overgrow. received several courses of antibiotics tend to be col- onized with highly resistant bacteria and with fungi. 7. Switch to Narrower-Spectrum Antibiotic Coveragee. Severity of the patient’s illness. The severely ill Within 3 Days patient who is toxic and hypotensive requires broad- (Table 1.1, Figure 1.5). Within 3 days following the spectrum antibiotics; the patient who simply has a administration of antibiotics, sequential cultures of new fever without other serious systemic complaints mouth ﬂora reveal that the numbers and types of bac- can usually be observed off antibiotics. teria begin to change signiﬁcantly. The normal ﬂora6. Use the Fewest Drugs Possible die, and resistant gram-negative rods, gram-positive cocci, and fungi begin to predominate. The morea. Multiple drugs may lead to antagonism rather quickly the selective pressures of broad-spectrum than synergy. Some regimens, such as penicillin antibiotic coverage can be discontinued, the lower the and an aminoglycoside for Enterococcus, have been risk of selecting for highly resistant pathogens. Broad shown to result in synergy—that is, the combined coverage is reasonable as initial empiric therapy until effects are greater than simple addition of the MBCs cultures are available. By the 3rd day, the microbiology of the two agents would suggest. In other instances, laboratory can generally identify the pathogen or certain combinations have proved to be antagonis- pathogens, and a narrower-spectrum, speciﬁc antibiotic
8 / CHAPTER 1Table 1.1. Classiﬁcation of Antibiotics by Spectrum of Activity Narrow Moderately Broad Broad Very Broad Penicillin Ampicillin Ampicillin–sulbactam Ticarcillin–clavulinate Oxacillin/Nafcillin Ticarcillin Amoxicillin–clavulanate Piperacillin–tazobactam Cefazolin Piperacillin Ceftriaxone, Cefepime Cephalexin/Cephradine Cefoxitin Cefotaxime Imipenem Aztreonam Cefotetan Ceftizoxime Meropenem Aminoglycosides Cefuroxime–axetil Ceftazidime Ertapenem Vancomycin Cefaclor Ceﬁxime Gatiﬂoxacin Macrolides Ciproﬂoxacin Cefpodoxime proxetil Moxiﬂoxacin Clindamycin Azithromycin Tetracycline Tigecycline Linezolid Clarithromycin Doxycycline Quinupristin/dalfopristin Talithromycin Chloramphenicol Daptomycin Trimethoprim– Levoﬂoxacin sulfamethoxazole Metronidazoleregimen can be initiated. Despite the availability of cul- gentamicin is low, but when blood-level monitoring,ture results, clinicians too often continue the same the requirement to closely follow blood urea nitrogenempiric broad-spectrum antibiotic regimen, and thatbehavior is a critical factor in explaining subsequentinfections with highly resistant superbugs. Figure 1.5graphically illustrates the spectrum of available antibi- KEY POINTSotics as a guide to the antibiotic choice.Obey the 3-day rule. Continuing broad-spectrum About the Steps Required to Designantibiotics beyond 3 days drastically alters the host’s an Antibiotic Regimenresident ﬂora and selects for resistant organisms. After3 days, streamline antibiotic coverage. Use narrower-spectrum antibiotics to treat the specific pathogens 1. Assess the probability of bacterial infection.identiﬁed by culture and Gram stain. (Antibiotics should be avoided in viral infections.) 2. Be familiar with the pathogens primarily8. All Else Being Equal, Choose The Least responsible for infection at each anatomic site.Expensive Drug 3. Be familiar with the bacterial ﬂora in the local hospital and community.As is discussed in later chapters, more than one antibi- 4. Take into account previous antibiotic treatment.otic regimen can often be used to successfully treat aspeciﬁc infection. Given the strong economic forces dri- 5. Take into account the speciﬁc host factors (age,ving medicine today, the physician needs to consider the immune status, hepatic and renal function, duration of hospitalization, severity of illness).cost of therapy whenever possible. Too often, new, moreexpensive antibiotics are chosen over older generic 6. Use the minimum number and narrowest spec-antibiotics that are equally effective. In this book, the trum of antibiotics possible.review of each speciﬁc antibiotic tries to classify that 7. Switch to a narrower-spectrum antibiotic regi-antibiotic’s cost range to assist the clinician in making men based on culture results.cost-effective decisions. 8. Take into account acquisition cost and the costs However, in assessing cost, factoring in toxicity is of toxicity.also important. For example, the acquisition cost of
Figure 1–5. Antibiogram of all major antibiotics.9
10 / CHAPTER 1and serum creatinine, and the potential for an culture). However, because the sputum culture wasextended hospital stay because of nephrotoxicity are positive for a resistant E. coli, the physician switchedfactored into the cost equation, gentamicin is often to a broader-spectrum antibiotic. The correct decisionnot cost-effective. should have been to continue cefazolin.Obey the 3-day rule. Continuing broad-spectrum One of the most difﬁcult and confusing issues forantibiotics beyond 3 days drastically alters the host’s nor- many physicians is the interpretation of culture results.mal ﬂora and selects for resistant organisms. After Wound cultures and sputum cultures are often misin-3 days streamline the antibiotics. Use narrower-spectrum terpreted. Once a patient has been started on an antibi-antibiotics to treat the speciﬁc pathogens identiﬁed by otic, the bacterial ﬂora on the skin and in the mouthculture and Gram stain. and sputum will change. Often these new organisms do not invade the host, but simply represent new ﬂora that have colonized these anatomic sites. Too often, physi-COLONIZATION VERSUS INFECTION cians try to eradicate the new ﬂora by adding new more- powerful antibiotics. The result of this strategy is to select for organisms that are multiresistant. The eventual CASE 1.1 outcome can be the selection of a bacterium that is resis- tant to all antibiotics.Following a motor vehicle accident, a 40-year-old No definitive method exists for differentiatingman was admitted to the intensive care unit with between colonization and true infection. However, several clinical findings are helpful in guiding the4 fractured ribs and a severe lung contusion on the physician. Evidence supporting the onset of a newright side. Chest X-ray (CXR) demonstrated an inﬁl- infection include a new fever or a change in fever pat-trate in the right lower lobe. Because of depressed tern, a rise in the peripheral WBC with a increase inmental status, this man required respiratory the percentage of PMNs and band forms (left shift),support. Gram stain demonstrating an increased number of Initially, Gram stain of the sputum demonstrated PMNs in association with predominance of bacteriafew polymorphonuclear leukocytes (PMNs) and no that are morphologically consistent with the cultureorganisms. On the third hospital day, this patient results. In the absence of these ﬁndings, colonizationdeveloped a fever to 103 F (39.5 C), and his periph- is more likely, and the current antibiotic regimeneral WBC increased to 17,500 from 8000 (80% PMNs, should be continued.15% band forms). A new CXR demonstrated exten-sion of the right lower lobe inﬁltrate. Gram stain ofsputum revealed abundant PMNs and 20 to 30gram-positive cocci in clusters per high-power ﬁeld. KEY POINTSHis sputum culture grew methicillin-sensitiveS. aureus. Intravenous cefazolin (1.5 g every 8 hours) About Differentiating Colonizationwas initiated. He defervesced, and secretions from from Infectionhis endotracheal tube decreased over the next 3days. On the fourth day, a repeat sputum samplewas obtained. Gram stain revealed a moderate 1. Growth of resistant organisms is the rule in thenumber of PMNs and no organisms; however, patient on antibiotics.culture grew E. coli resistant to cefazolin. The physi- 2. Antibiotics should be switched only on evi-cian changed the antibiotic to intravenous cefepime dence of a new infection.(1 g every 8 hours). 3. Evidence for a new superinfection includes a) new fever or a worsening fever pattern, b) increased peripheral leukocyte count with left shift, c) increased inﬂammatory exudate at the origi- Case 1.1 represents a very typical example of how nal site of infection,antibiotics are misused. The initial therapy for a prob- d) increased polymorphonuclear leukocytes onable early S. aureus pneumonia was appropriate, and Gram stain, andthe patient responded (fever resolved, sputum pro- e) correlation between bacterial morphologyduction decreased, gram-positive cocci disappeared and culture on Gram stain.from the Gram stain, and S. aureus no longer grew on
ANTI-INFECTIVE THERAPY / 11 new anti-infectives are frequently being introduced, pre-■ SPECIFIC ANTI-INFECTIVE scribing physicians should also take advantage of hand- held devices, online pharmacology databases, and AGENTS antibiotic manuals so as to provide up-to-date treatment (see Further Reading at the end of the current chapter).ANTIBIOTICS When the proper therapeutic choice is unclear, on-the-Before prescribing a speciﬁc antibiotic, clinicians should job training can be obtained by requesting a consulta-be able to answer these questions: tion with an infectious disease specialist. Anti-infective agents are often considered to be safe; however, the mul-• How does the antibiotic kill or inhibit bacterial growth? tiple potential toxicities outlined below, combined with• What are the antibiotic’s toxicities and how should the likelihood of selecting for resistant organisms, they be monitored? emphasize the dangers of over-prescribing antibiotics.• How is the drug metabolized, and what are the dosing recommendations? Does the dosing schedule need to -Lactam Antibiotics be modiﬁed in patients with renal dysfunction?• What are the indications for using each specific CHEMISTRY AND MECHANISMS OF ACTION antibiotic? The -Lactam antibiotics have a common central• How broad is the antibiotic’s antimicrobial spectrum? structure (Figure 1.6) consisting of a -lactam ring and a thiazolidine ring [in the penicillins and carbapenems,• How much does the antibiotic cost? Figure 1.6(A)] or a -lactam ring and a dihydrothiazine Clinicians should be familiar with the general classes of ring [in the cephalosporins, Figure 1.6(B)]. The sideantibiotics, their mechanisms of action, and their major chain attached to the -lactam ring (R1) determinestoxicities. The differences between the speciﬁc antibiotics many of the antibacterial characteristics of the speciﬁcin each class can be subtle, often requiring the expertise of antibiotic, and the structure of the side chain attachedan infectious disease specialist to design the optimal to the dihydrothiazine ring (R2) determines the phar-anti-infective regimen. The general internist or physician- macokinetics and metabolism.in-training should not attempt to memorize all the facts The -lactam antibiotics bind to various PBPs.outlined here, but rather should read the pages that follow The PBPs represent a family of enzymes important foras an overview of anti-infectives. The chemistry, mecha- bacterial cell wall synthesis, including the car-nisms of action, major toxicities, spectrum of activity, boxypeptidases, endopeptidases, transglycolases, andtreatment indications, pharmacokinetics, dosing regimens, transpeptidases. Strong binding to PBP-1, a celland cost are reviewed. The speciﬁc indications for each wall transpeptidase and transglycolase causes rapidanti-infective are brieﬂy covered here. A more complete bacterial death. Inhibition of this transpeptidasediscussion of speciﬁc regimens is included in the later prevents the cross-linking of the cell wall peptido-chapters that cover infections of speciﬁc anatomic sites. glycans, resulting in a loss of integrity of the bacterial Upon prescribing a speciﬁc antibiotic, physicians cell wall. Without its protective outer coat, theshould reread the speciﬁc sections on toxicity, spectrum hyperosmolar intracellular contents swell, and theof activity, pharmacokinetics, dosing, and cost. Because bacterial cell membrane lyses. Inhibition of PBP-3, a Figure1.6. Basic structure of the A penicillins and B the cephalosporins.
12 / CHAPTER 1 and bacterial death. Inhibition of other PBPs blocks KEY POINTS cell wall synthesis in other ways, and activates bacter- ial lysis. About -Lactam Antibiotics The activity of all -lactam antibiotics requires active bacterial growth and active cell wall synthesis. There- fore, bacteria in a dormant or static phase will not be 1. Penicillins, cephalosporins, and carbapenems are all b-lactam antibiotics: killed, but those in an active log phase of growth are quickly lysed. Bacteriostatic agents slow bacterial a) All contain a -lactam ring. growth and antagonize -lactam antibiotics, and there- b) All bind to and inhibit penicillin-binding pro- fore, in most cases, bacteriostatic antibiotics should not teins, enzymes important for cross-linking be combined with -lactam antibiotics. bacterial cell wall peptidoglycans. c) All require active bacterial growth for bacte- TOXICITY riocidal action. Table 1.2 summarizes the toxicities of the -lactam d) All are antagonized by bacteriostatic anti- antibiotics. biotics. Hypersensitivity reactions are the most common side effects associated with the -lactam antibiotics. Penicillins are the agents that most commonly cause allergic reactions, at rates ranging from 0.7% to 10%.transpeptidase and transglycolase that acts at the sep- Allergic reactions to cephalosporins have beentum of the dividing bacterium, causes the formation reported in 1% to 3% of patients, and similar percent-of long filamentous chains of non-dividing bacteria ages have been reported with carbapenems. However,Table 1.2. Toxicities of -Lactam Antibiotics Clinical symptom Antibiotic Meropenem Ceftriaxone Aztreonam Imipenem Penicillins Cefotetan Cefepime Cefazolin Allergic skin rash Anaphylaxis Steven–Johnson Seizures Encephalopathy a Diarrhea (Clostridium difﬁcile) Cholelithiasis Phlebitis Laboratory tests: Coagulation Creatinine↑ Cytopenias Eosinophilia AST/ALT↑a Encephalopathy associated with myoclonus has been reported in elderly patients.Black = principal side effect; dark gray = less common side effect; light gray = rare side effect; white = not reported or veryrare; ↑ = rise; AST/ALT = aspartate aminotransferase/ alanine transaminase.
ANTI-INFECTIVE THERAPY / 13the incidence of serious, immediate immunoglobulin Other less common toxicities are associated withE (IgE)–mediated hypersensitivity reactions is much individual -lactam antibiotics. Natural penicillins andlower with cephalosporins than with penicillins. imipenem lower the seizure threshold and can result inApproximately 1% to 7% of patients with penicillin grand mal seizures. Ceftriaxone is excreted in high con-allergies also prove to be allergic to cephalosporins and centrations in the bile and can crystallize, causing biliarycarbapenems. sludging and cholecystitis. Antibiotics containing a spe- Penicillins are the most allergenic of the -lactam ciﬁc methylthiotetrazole ring (cefamandole, cefopera-antibiotics because their breakdown products, partic- zone, cefotetan) can induce hypoprothrombinemia and,ularly penicilloyl and penicillanic acid, are able to in combination with poor nutrition, may increase post-form amide bonds with serum proteins. The resulting operative bleeding. Cefepime has been associated withantigens increase the probability of a host immune encephalopathy and myoclonus in elderly individuals.response. Patients who have been sensitized by previ- All broad-spectrum antibiotics increase the risk ofous exposure to penicillin may develop an immediate pseudomembranous colitis (see Chapter 8). In combi-IgE-mediated hypersensitivity reaction that can result nation with aminoglycosides, cephalosporins demon-in anaphylaxis and urticaria. In the United States, strate increased nephrotoxicity.penicillin-induced allergic reactions result in 400 to800 fatalities annually. Because of the potential dan-ger, patients with a history of an immediate hypersen- Penicillinssitivity reaction to penicillin should never be given Tables 1.3 and 1.4, together with Figure 1.5, summarizeany -lactam antibiotic, including a cephalosporin or the characteristics of the various penicillins.carbapenem. High levels of immunoglobulin G anti- Penicillins vary in their spectrum of activity. Naturalpenicillin antibodies can cause serum sickness, a syn- penicillins have a narrow spectrum. The aminopeni-drome resulting in fever, arthritis, and arthralgias, cillins have an intermediate spectrum, and combinedurticaria, and diffuse edema. with -lactamase inhibitors, the carboxy/ureidopeni- cillins have a very broad spectrum of activity. NATURAL PENICILLINS KEY POINTS Pharmacokinetics—All natural penicillins are rapidly excreted by the kidneys, resulting in short half-lives About -Lactam Antibiotic Toxicity (Table 1.3). As a consequence, the penicillins must be dosed frequently, and dosing must be adjusted in patients with renal dysfunction. Probenecid slows renal excretion, 1. Allergic reactions are most common toxicity, and this agent can be used to sustain higher serum levels. and they include both delayed and immediate hypersensitivity reactions. 2. Allergy to penicillins (PCNs) seen in 1% to 10% of patients; 1% to 3% are allergic to KEY POINTS cephalosporins and carbapenems. 1% to 7% of patients with a PCN allergy are also allergic to cephalosporins and carbapenems. About the Natural Penicillins 3. Seizures are associated with PCNs and imipenem, primarily in patients with renal dys- 1. Very short half-life (15–30 minutes). function. 2. Excreted renally; adjust for renal dysfunction; 4. Ceftriaxone is excreted in the bile and can crys- probenecid delays excretion. tallize to form biliary sludge. 3. Penetrates most inﬂamed body cavities. 5. Cephalosporins with methylthiotetrazole rings 4. Narrow spectrum. Indicated for Streptococcus (cefamandole, cefoperazone, moxalactam, pyogenes, S. viridans Gp., mouth ﬂora, Clostridia cefotetan) can interfere with vitamin K and perfringens, Neisseria meningitidis, Pasteurella, increase prothrombin time. and spirochetes. 6. Pseudomembranous colitis can develop as a 5. Recommended for penicillin-sensitive S. pneu- result of overgrowth of Clostridium difﬁcile. moniae [however, penicillin resistant strains are 7. Nephrotoxicity sometimes occurs when now frequent ( 30%)]; infections caused by cephalosporins are given in combination with mouth flora; Clostridium perfringens or spiro- aminoglycosides. chetes.
14 / CHAPTER 1Table 1.3. Penicillins: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Half-life Dose Dose for reduced Costa Spectrum (trade name) (h) creatinine clearance (mL/min) Natural penicillins (PCNs) PCN G 0.5 2 4 106 U IV q4h <10: Half dose $ Narrow Procaine PCN G 0.6 1.2 106 U IM q24h $ Narrow 6 Benzathine PCN G 2.4 10 U IM weekly $ Narrow PCN V–K 0.5 250–500 mg PO q6–8h $ Narrow Aminopenicillins Ampicillin 1 Up to 14 g IV daily, 30–50: q8h $ Moderate (Omnipen) given q4–6h <10: q12h Amoxicillin 1 500 mg PO q8h or <10: q24h $ Moderate (Amoxil) 875 mg q12h Amoxicillin–clavulanate Same as amoxicillin PO Same as $$$$ Broad (Augmentin) amoxicillin Ampicillin–sulbactam 1 1.5–2 g q6h IV 30–50: q8h $$$$ Broad (Unasyn) <10: q12h Penicillinase–resistant PCNs Oxacillin 0.5 1–2 g q4h IV None $ Narrow (Prostaphlin) Nafcillin 0.5 0.5–2 g q4h IV None $$$$ Narrow (Unipen) Cloxacillin/dicloxacillin 0.5 0.25–1 g q6h None $ Narrow (Dynapen) Carboxy/ureido–PCNs Ticarcillin–clavulanate 1 3.1 g q4–6h IV 10–50: 3.1 g q6–8h $ Very broad (Timentin) <10: 2 g q12h Piperacillin–tazobactam 1 3.375 g q6h or 10–50: 2.25 g q6h $$ Very broad (Zosyn) 4.5 g q8h <10: 2.5 g q8ha Intravenous preparations (daily cost dollars): $ = 20 to 60; $$ = 61 to 100; $$$ = 101 to 140; $$$$ = 140 to 180; $$$$$ = more than180; oral preparations (10-day course cost dollars): $ = 10 to 40; $$ = 41 to 80; $$$ = 81 to 120; $$$$ = 121 to 160; $$$$$ ≥ 160.Depending on the speciﬁc drug, penicillins can be given treatment of infections caused by mouth ﬂora. Penicillinintravenously or intramuscularly. Some penicillins have G is also primarily recommended for Clostridium perfrin-been formulated to withstand the acidity of the stomach gens, C. tetani, Erysipelothrix rhusiopathiae, Pasteurellaand are absorbed orally. Penicillins are well distributed in multocida, and spirochetes including syphilis and Lep-the body and are able to penetrate most inﬂamed body tospira. This antibiotic also remains the primary recom-cavities. However, their ability to cross the blood–brain mended therapy for S. pneumoniae sensitive to penicillinbarrier in the absence of inﬂammation is poor. In the pres- (MIC < 0.1 g/mL). However, in many areas of theence of inﬂammation, therapeutic levels are generally United States, more than 30% of strains are moderatelyachievable in the cerebrospinal ﬂuid. resistant to penicillin (MIC = 0.1–1 g/mL). In these Spectrum of Activity and Treatment Recommenda- cases, ceftriaxone, cefotaxime, or high-dose penicillintions—Pencillin G (Table 1.4) remains the treatment of ( 12 million units daily) can be used. Moderatelychoice for S. pyogenes (“group A strep”) and the S. viridans resistant strains of S. pneumoniae possess a lower-group. It also remains the most effective agent for the afﬁnity PBP, and this defect in binding can be overcome
ANTI-INFECTIVE THERAPY / 15Table 1.4. Organisms That May Be Susceptible to Penicillins Natural Aminopenicillins Anti-staphylococcal Carboxy/ureidopenicillins penicillins (with or without penicillin plus clavulanate or (PCNs) clavulanate) (nafcillin/oxacillin) tazobactam Streptococcus pyogenes Covers same Narrower spectrum Covers same S. pneumoniae organisms as than natural penicillins, organisms as (increasing numbers of natural penicillins No activity against natural penicillins PCN-resistant strains) plus: Escherichia coli anaerobes, Enterococcus, or plus: MSSA S. viridans Proteus gram-negative organisms. E. coli PCN-sensitive enterococci PCN-sensitive enterococci Drug of choice for MSSA. Proteus mirabilis Salmonella spp. Klebsiella Mouth ﬂora including: Actinomyces israelli, Shigella spp. pneumoniae Capnocytophaga canimorsus, Addition of Enterobacter spp. Fusobacterium nucleatum, clavulanate adds Citrobacter freundii Eikenella corrodens susceptibility to: Serratia spp. Clostridium perfringens H. inﬂuenzae Morganella spp. Clost. tetani ( -lactamase strains) Pseudomonas aeruginosa Pasteurella multocida Moraxella catarrhalis Bacteroides fragilis Erysipelothrix rhusiopathiae Methicillin-sensitive Spirochetes: Staph. aureus Treponema pallidum, (MSSA) Borrelia burgdorferi, Leptospira interrogans Neisseria gonorrhoeae Neiss. meningitidis Listeria monocytogenesby high serum levels of penicillin in the treatment of Haemophilus influenzae. Aminopenicillins are alsopneumonia, but not of meningitis. Infections with high- effective against Shigella ﬂexneri and sensitive strains oflevel penicillin-resistant S. pneumoniae (MIC nontyphoidal Salmonella. Amoxicillin can be used to2 g/mL) require treatment with vancomycin or another treat otitis media and air sinus infections. Whenalternative antibiotic. combined with a -lactamase inhibitor (clavulanate or sulbactam), aminopenicillins are also effectiveAMINOPENICILLINS against methicillin-sensitive S. aureus (MSSA),Pharmacokinetics—In aminopenicillins, a chemical mod- -lactamase-producing strains of H. influenzae, andiﬁcation of penicillin increases resistance to stomach acid, Moraxella catarrhalis. The latter two organisms areallowing these products to be given orally (Table 1.3). commonly cultured from middle ear and air sinusThey can also be given intramuscularly or intravenously. infections (see Chapter 5). However, the superiority ofAmoxicillin has excellent oral absorption: 75% as com- amoxicillin–clavulanate over amoxicillin for middle earpared with 40% for ampicillin. Absorption is not impaired and air sinus infections has not been proven.by food. The higher peak levels achievable withaminopenicillins allow for a longer dosing interval, mak- PENICILLINASE-RESISTANT PENICILLINSing them a more convenient oral antibiotic than ampi- Pharmacokinetics—The penicillinase-resistant peni-cillin. As observed with the natural penicillins, the half-life cillins have the same half-life as penicillin (30 minutes)is short (1 hour) and these drugs are primarily excreted and require dosing at 4-hour intervals or constantunmodiﬁed in the urine. intravenous infusion (Table 1.3). Unlike the natural Spectrum of Activity and Treatment Recommenda- penicillins, these agents are cleared hepatically, andtions—The spectrum of activity in the aminopenicillins doses of nafcillin and oxacillin usually do not need tois slightly broader than in the natural penicillins be adjusted for renal dysfunction. But the efficient(Table 1.4). Intravenous ampicillin is recommended for hepatic excretion of nafcillin means that the dosetreatment of Listeri monocytogenes, sensitive enterococci, needs to be adjusted in patients with significantProteus mirabilis, and non– -lactamase-producing hepatic dysfunction. The liver excretes oxacillin less
16 / CHAPTER 1 dicloxacillin should not be used to treat S. aureus bac- KEY POINTS teremia. These oral agents are used primarily for mild soft-tissue infections or to complete therapy of a resolv- About the Aminopenicillins ing cellulitis. CARBOXYPENICILLINS AND UREIDOPENICILLINS 1. Short half-life (1 hour), and clearance similar to natural penicillins. Pharmacokinetics—The half-lives of ticarcillin and piperacillin are short, and they require frequent dosing 2. Slightly broader spectrum of activity. (Table 1.3). Sale of ticarcillin and piperacillin alone has 3. Parenteral ampicillin indicated for Listeria been discontinued in favor of ticarcillin–clavulanate and monocytogenes, sensitive enterococci, Proteus piperacillin–tazobactam. mirabilis, and non–b-lactamase-producing Dosing every 6 hours is recommended for Haemophilus inﬂuenzae. piperacillin–tazobactam to prevent accumulation of 4. Ampicillin plus an aminoglycoside is the treat- tazobactam. In P. aeruginosa pneumonia, the dose ment of choice for enterococci.Whenever possi- of piperacillin–tazobactam should be increased from ble, vancomycin should be avoided. 3.375 g Q6h to 4.5 g Q8h to achieve cidal levels of 5. Amoxicillin has excellent oral absorption; it is piperacillin in the sputum. In combination with an the initial drug of choice for otitis media and aminoglycoside, piperacillin–tazobactam often demon- bacterial sinusitis. strates synergy against P. aeruginosa. However, the 6. Amoxicillin–clavulanate has improved cover- administration of the piperacillin–tazobactam needs to age of Staphylococcus, H. inﬂuenzae, and Mora- be separated from the administration of the aminogly- xella catarrhalis, but it is expensive and has a coside by 30 to 60 minutes. high incidence of diarrhea. Increased efﬁcacy Spectrum of Activity and Treatment Recommenda- compared with amoxicillin is not proven in tions—Ticarcillin and piperacillin are able to resist otitis media. However, covers amoxicillin- -lactamases produced by Pseudomonas, Enterobacter, resistant H. inﬂuenzae, a common pathogen in that disease. Morganella, and Proteus–Providencia species. At high doses, ticarcillin and piperacillin can also kill many strains of Bacteroides fragilis and provide effective anaerobic cov- erage. These antibiotics can be used for empiric coverage of moderate to severe intra-abdominal infections. Theyefficiently, and so dose adjustment is usually not have been combined with a -lactamase inhibitor (clavu-required in liver disease. lanate or tazobactam) to provide effective killing of MSSA. Spectrum of Activity and Treatment Recommenda- These agents are reasonable alternatives to nafcillintions–The synthetic modiﬁcation of penicillin to ren- or oxacillin when gram-negative coverage is alsoder it resistant to the -lactamases produced byS. aureus reduces the ability of these agents to killanaerobic mouth ﬂora and Neisseria species (Table 1.4).These antibiotics are strictly recommended for thetreatment of MSSA. They are also used to treat cellulitis KEY POINTSwhen the most probable pathogens are S. aureus andS. pyogenes. Because oral preparations result in consid- About Carboxypenicillins and Ureidopenicillinserably lower serum concentration levels, cloxacillin or 1. More effective resistance to gram-negative -lactamases. 2. Carboxypenicillin or ureidopenicillin combined KEY POINTS with aminoglycosides demonstrate synergistic killing of Pseudomonas aeruginosa. About Penicillinase-Resistant Penicillins 3. Ticarcillin–clavulanate and piperacillin–tazobac- tam have excellent broad-spectrum coverage, including methicillin-sensitive Staphylococcus 1. Short half-life, hepatically metabolized. aureus and anaerobes. They are also useful for 2. Very narrow spectrum, poor anaerobic activity. intra-abdominal infections, acute prostatitis, in- 3. Primarily indicated for methicillin-sensitive hospital aspiration pneumonia, and mixed soft- Staphylococcus aureus and cellulitis. tissue and bone infections.
ANTI-INFECTIVE THERAPY / 17Table 1.5. Cephalosporins: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Half-life Dose Dose for reduced Costa Spectrum (trade name) (h) creatinine clearance (mL/min) 1st generation Cefazolin 1.8 1–1.5 g IV or 10–50: 0.5–1 g q8–12h $ Narrow (Ancef) IM q6–8h <10: 0.25–0.75 g q18–24h Cephalexin 0.9 0.25–1 g PO q6–8h $ Narrow (Keﬂex) Cephradine 0.7 0.25–1 g PO q6h $–$$ (Velocef) Cefadroxil 1.2 0.5–1 g PO q12h $$–$$$$ Narrow (Duricef) 2nd generation Cefoxitin 0.8 1–2 g IV or IM q4–6h, 50–80: q8–12h $$ Moderately (Mefoxin) not to exceed 10–50: q12–24h broad 12 g daily <10: 0.5–1 g q12–24h Cefotetan 3.5 1–2 g IV or IM q12h 10–50: q24h $ Moderately (Cefotan) <10: q48h broad Cefuroxime 1.3 0.75–1.5 g IV q8h 10–50: q12h $ Moderately (Zinacef) <10: 0.75 g q24h broad Cefuroxime–axetil 1.5 0.25–0.5 g PO q12h <10: 0.25 g q12h $$$$ Moderately (Ceftin) broad Cefaclor 0.8 0.25–0.5 g PO q8h No change required $$$$ Moderately (Ceclor) broad 3rd generation Ceftriaxone 8 1–2 g IV q12–24h No change required $$ Broad (Rocephin) Cefotaxime 1.5 2 g IV q4–8h 10–30: q8–12h $$ Broad (Claforin) (maximum 12 g daily) <10: q12–24h Ceftizoxime 1.7 1–4 g IV q8–12h 10–30: q12h $$ Broad (Ceﬁzox) (maximum 12 g daily) <10: q24h Ceftazidime 1.9 1–3 g IV or IM q8h, 10–50: 1 g q12–24h $$ Broad (Fortaz) up to 8 g daily <10: 0.5 q24–48h Ceﬁxime 3.7 400 mg PO q12h 10–30: 300 mg q24h $$$$ Broad (Suprax) or q24h <10: 200 mg q24h Cefpodoxime proxetil 2.2 200–400 g PO q12h 10–30: 3 weekly $$$ Broad (Vantin) <10: 1 weekly 4th generation Cefepime 2.1 0.5–2 g IV q12h 10–30: 0.5–1 g q24h $–$$ Very broad (Maxipime) <10: 250–500 mg q24h q12h Cefpirome 2 1–2 g IV q12h Same as cefepime $$ Very broad (IV–Cef) Monobactams Aztreonam 2 1–2 g IV q6h 10–30: q12–18h $$–$$$$ Narrow (Azactam) <10: q24hIntravenous preparations (daily cost dollars): $ = 20–70; $$ = 71–110; $$$ = 111–150; $$$$ = 150–200; $$$$$ ≥ 200; oralpreparations (10-day course cost dollars): $ = 10–50; $$ = 51–100; $$$ = 101–140; $$$$ = 141–180; $$$$$ ≥ 180.
18 / CHAPTER 1Table 1.6. Organisms That May Be Susceptible to Cephalosporins 1st generation 2nd generation 3rd generation 4th generation (cefazolin) (cefoxitin, cefotetan) (ceftriaxone, cefotaxime) (cefepime) Methicillin-sensitive Covers same organisms Covers same organisms Covers same organisms Staphylococcus aureus as cefazolin, but as cefazolin, but as cefazolin and ceftriaxone. (best activity) weaker gram-positive often weaker gram- Excellent gram-positive and Streptococcus pyogenes activity. positive and gram-negative activity. Penicillin (PCN)–sensitive Also covers: stronger gram-negative Also covers: Haemophilus inﬂuenzae activity. Intermediate S. pneumoniae Moraxella catarrhalis Also covers: PCN-resistant Escherichia coli (some species) Neisseria gonorrhoeae H. inﬂuenzae S. pneumoniae Klebsiella pneumoniae N. meningitidis M. catarrhalis Enterobacter spp. (some species) Bacteroides fragilis N. gonorrhoeae Pseudomonas aeruginosa Proteus mirabilis (some strains) N. meningitidis Serratia spp. (some species) Citrobacter freundii Morganella spp. Salmonella spp. Shigella spp.required. Both agents can be used for in-hospital that, for many infections, earlier-generation, narrower-aspiration pneumonia to cover for mouth flora and spectrum cephalosporins are preferred to the moregram-negative rods alike, and they can also be used for recently developed broader-spectrum cephalosporins.serious intra-abdominal, gynecologic,and acute prostateinfections. They have been used for skin and bone infec- FIRST-GENERATION CEPHALOSPORINStions thought to be caused by a combination of gram- Pharmacokinetics—Cefazolin, the preferred parenteralnegative and gram-positive organisms. first-generation cephalosporin, has a longer half-life than penicillin, and it is primarily excreted by theCephalosporins kidneys (Table 1.5). The ﬁrst-generation cephalosporins penetrate most body cavities, but they fail to cross theTables 1.5 and 1.6, together with Figure 1.5, summarize blood–brain barrier. Oral preparations (cephalexin,the characteristics of the various cephalosporins. cephradine, cefadroxil) are very well absorbed, achieving In an attempt to create some semblance of order, the excellent peak serum concentrations (0.5 g cephalexincephalosporins have been classified into generations results in a 18 g/mL peak). Absorption is not affectedbased on spectrum of activity (Table 1.5). First-generation cephalosporins are predominantly effectiveagainst gram-positive cocci. Second-generation cepha-losporins demonstrate increased activity against aerobic KEY POINTSand anaerobic gram-negative bacilli, but have variableactivity against gram-positive cocci. The third-genera- About First-Generation Cephalosporinstion cephalosporins demonstrate even greater activityagainst gram-negative bacilli, but only limited activity 1. Excellent gram-positive coverage, some gram-against gram-positive cocci. Finally, the fourth-genera- negative coverage.tion cephalosporins demonstrate the broadest spectrumof activity, being effective against both gram-positive 2. Do not cross the blood–brain barrier.cocci and gram-negative bacilli. 3. Inexpensive. Classiﬁcation of the cephalosporins by generation nat- 4. Useful for treating soft-tissue infections and forurally leads to the assumption that newer, later- surgical prophylaxis. Can often be used as angeneration cephalosporins are better than the older alternative to oxacillin or nafcillin.cephalosporins. However, it is important to keep in mind
ANTI-INFECTIVE THERAPY / 19by food. The half-lives of cephalexin and cephradine are the newer penicillins, second-generation cephalosporinsshort, requiring frequent administration. These agents are rarely recommended as primary therapy.need to be corrected for renal dysfunction. Because cefoxitin and cefotetan demonstrate increased Spectrum of Activity and Treatment Recommenda- anaerobic coverage, including many strains of B. fragilis,tions—The first-generation cephalosporins are very and also cover gonococcus, these two agents are used asactive against gram-positive cocci, including MSSA, and part of ﬁrst-line therapy in pelvic inﬂammatory disease.they also have moderate activity against some commu- They are also used for the treatment of moderately severenity-acquired gram-negative bacilli (Table 1.6). They intra-abdominal infections and mixed aerobic–anaerobicare active against oral cavity anaerobes, but are soft-tissue infections, including diabetic foot infections.ineffective for treating B. fragilis, H. influenzae, The oral preparation cefuroxime achieves serum levelsL. monocytogenes, MRSA, penicillin-resistant S. pneumo- that are approximately one tenth that of intravenousniae, and Enterococcus. preparations, and this agent is recommended for the out- First-generation cephalosporins are an effective alter- patient treatment of uncomplicated urinary tract infec-native to nafcillin or oxacillin for soft-tissue infections tions and otitis media. Other less costly oral antibioticsthought to be caused by MSSA or S. pyogenes. Cefazolin effectively cover the same pathogens.is also the antibiotic of choice for surgical prophylaxis. Cefaclor, the other second-generation oral prepara-Because of its inability to cross the blood–brain barrier, tion, is inactivated by -lactamases produced bycefazolin should never be used to treat bacterial menin- H. influenzae and M. catarrhalis. Although cefaclorgitis. Oral preparations are commonly used to treat less has been recommended for otitis media, other oralsevere soft-tissue infections, including impetigo, early antibiotics are generally preferred.cellulitis, and mild diabetic foot ulcers. THIRD-GENERATION CEPHALOSPORINSSECOND-GENERATION CEPHALOSPORINS Pharmacokinetics—With the exception of ceftriaxone,Pharmacokinetics—The second-generation cephalo- the third-generation cephalosporins are excreted by thesporins are cleared primarily by the kidney (Table 1.5). kidneys (Table 1.5). Ceftriaxone is cleared primarily byThey have half-lives that range from 0.8 to 3.5 hours, the liver, but high concentrations of the drug are alsoand they penetrate all body cavities. excreted in the biliary system. The half-lives of these Spectrum of Activity and Treatment Recommenda- agents vary, being as short as 1.5 hours (cefotaxime) andtions—The second-generation cephalosporins possess as long as 8 hours (ceftriaxone). They penetrate mostincreased activity against some gram-negative strains, body sites effectively.and they effectively treat MSSA and non-enterococcal Spectrum of Activity and Treatment Recommenda-streptococci (Table 1.6). Given the availability of the tions—As compared with the ﬁrst- and second-ﬁrst-, third-, and fourth-generation cephalosporins and generation, third-generation cephalosporins have enhanced activity against many aerobic gram-negative bacilli, but they do not cover Serratia marcescens, Acineto- bacter, and Enterobacter cloacae. With the exceptions of KEY POINTS ceftazidime and cefoperazone, third-generation cepha- losporins are ineffective against P. aeruginosa. About Second-Generation Cephalosporins These agents have excellent cidal activity against S. pneumoniae (including moderately penicillin-resistant strains), S. pyogenes, and other streptococci. All members 1. Improved activity against Haemophilus inﬂuen- of this generation are ineffective for treating Enterococ- zae, Neisseria species, and Moraxella catarrhalis. cus, MRSA, highly penicillin-resistant pneumococcus, 2. Cefoxitin and cefotetan have anaerobic activity and L. monocytogenes. and are used in mixed soft-tissue infections and The ESBLs are increasing in frequency, and they pelvic inﬂammatory disease. promise to reduce the effectiveness of the third- and 3. Cefotetan and cefamandole have a methylth- fourth-generation cephalosporins. A large number of iotetrazole ring that decreases prothrombin third-generation cephalosporins are available, all with production. Vitamin K prophylaxis is recom- similar indications. Small deﬁciencies in coverage and mended in malnourished patients. less-desirable pharmacokinetics have affected the popu- 4. Cefuroxime–axetil is a popular oral cephalo- larity of a number of these drugs. sporin; less expensive alternative oral antibi- Ceftriaxone and cefotaxime are recommended for otics are available, however. empiric treatment of community-acquired pneumonia 5. Overall, this generation is of limited usefulness. and community-acquired bacterial meningitis (see Chap- ters 4 and 6). Third-generation cephalosporins can be used
20 / CHAPTER 1in combination with other antibiotics to empirically treat FOURTH-GENERATION CEPHALOSPORINSthe septic patient. Ceftriaxone is recommended for treat- Pharmacokinetics—Clearance of the fourth-generationment of N. gonorrhoeae. Cefotaxime is cleared renally and cephalosporins is renal, and the half-lives of these agentsdoes not form sludge in the gallbladder. For this reason, are similar to the renally cleared third-generationthis agent is preferred over ceftriaxone by some pediatri- cephalosporins (Table 1.5). The R2 substitution of thecians, particularly for the treatment of bacterial meningitis fourth-generation cephalosporins contains both a posi-in children—where high-dose therapy has been associated tively and negatively charged group that, together, havewith symptomatic biliary sludging. Ceftazidime is the zwitterionic properties that permit these antibiotics toonly third-generation cephalosporin that has excellent penetrate the outer wall of gram-negative bacteria andactivity against P. aeruginosa; however, the fourth- concentrate in the periplasmic space. This characteristicgeneration cephalosporin cefepime (and the monobactam also allows for excellent penetration of all body com-aztreonam) are now more commonly utilized for anti- partments, including the cerebrospinal ﬂuid.Pseudomonas therapy in many institutions. Spectrum of Activity and Treatment Recommenda- The oral third-generation cephalosporin ceﬁxime has a tions—The fourth-generation cephalosporins are resis-long half-life, allowing for once-daily dosing. Ceﬁxime tant to most -lactamases, and they only weakly induceprovides effective coverage for S. pneumoniae (penicillin- -lactamase activity (Table 1.6, Figure 1.5). Thesesensitive), S. pyogenes, H. inﬂuenzae, M. catarrhalis, Neisse- agents also bind gram-positive PBPs with high afﬁnity.ria species, and many gram-negative bacilli, but it is inef- The only agent currently available in the Unitedfective against S. aureus. Its absorption is not affected by States is cefepime. In addition to having broad antimi-food. This agent is a potential second-line therapy for crobial activity against gram-negative bacilli, includingcommunity-acquired pneumonia, and it is an alternative P. aeruginosa, cefepime provides excellent coverage forto penicillin for the treatment of bacterial pharyngitis. The S. pneumoniae (including strains moderately resistant toother oral preparation, cefpodoxime proxetil, has an penicillin), S. pyogenes, and MSSA. Cefepime and cef-antimicrobial spectrum similar to that of ceﬁxime. In tazidime provide comparable coverage for P. aeruginosa.addition, it has moderate activity against S. aureus. The To maximize the likelihood of cure of serious P. aerugi-indications for use are similar to those for ceﬁxime, and nosa infection, more frequent dosing (q8h) has been rec-cefpodoxime proxetil has also been recommended as an ommended.alternative treatment for acute sinusitis. Cefepime is not effective against L. monocytogenes, MRSA, or B. fragilis. As compared with third-genera- tion cephalosporins, cefepime is more resistant to KEY POINTS -lactamases, including the ESBLs. It has been effec- tively used to treat gram-negative meningitis. Cefepime is effective as a single agent in the febrile neutropenic About the Third-Generation Cephalosporins 1. Improved gram-negative coverage. 2. Excellent activity against Neisseria gonor- KEY POINTS rhoeae, N. meningitidis, Haemophilus inﬂuen- zae, and Moraxella catarrhalis. About Fourth-Generation Cephalosporins 3. Ceftriaxone has a long half-life that allows for once-daily dosing. In children, acalculous chole- cystitis can occur with large doses. 1. Zwiterionic properties allow for excellent pene- 4. Cefotaxime has a shorter half-life but activity tration of the bacterial cell wall and of human identical to that of ceftriaxone; does not cause tissues and ﬂuids. biliary sludging. 2. Weakly induce -lactamases. 5. Ceftazidime has excellent activity against most 3. More resistant to extended-spectrum -lacta- Pseudomonas aeruginosa strains, but reduced mases and chromosomal -lactamases. activity against Staphylococcus aureus. 4. Excellent gram-positive (including methicillin- 6. Extended spectrum -lactamases are increas- sensitive Staphylococcus aureus) and gram- ing in frequency and endangering the effective- negative coverage (including Pseudomonas ness of third-generation cephalosporins. aeruginosa). 7. Recommended for community-acquired pneu- 5. Excellent broad-spectrum empiric therapy. Use- monia and bacterial meningitis ful in nosocomial infections.
ANTI-INFECTIVE THERAPY / 21patient, and it is an excellent agent for initial empiriccoverage of nosocomial infections. KEY POINTS Cefpirome is available in Europe. It has an antimi-crobial spectrum similar to that of cefepime, although it About Aztreonamis somewhat less active against P. aeruginosa. 1. A distinctly different structure than that of theMonobactams cephalosporins.AZTREONAM 2. No cross-reactivity with penicillin,Chemistry and Pharmacokinetics—Aztreonam was 3. Binds the penicillin-binding proteins of gram-originally isolated from Chromobacterium violaceum and negative, but not of gram-positive bacteria.subsequently modiﬁed. This antibiotic has a distinctly 4. Narrow spectrum, with excellent activity againstdifferent structure from the cephalosporins, and it is the aerobic gram-negative rods.only available antibiotic in its class. Rather than a cen- 5. Marketed as a non-nephrotoxic replacement fortral double ring, aztreonam has a single ring (“mono- aminoglycosides. However, as compared withcyclic -lactam structure”), and has been classiﬁed as a aminoglycosides, itmonobactam. a) has no synergy with penicillins in enterococ- Because of its unique structure, aztreonam exhibits no cal infections.cross-reactivity with other -lactam antibiotics. It can be b) is not helpful for treating Streptococcus viri-used safely in the penicillin-allergic patient. The drug pen- dans endocarditis.etrates body tissue well and crosses the blood–brain barrier 6. Excellent empiric antibiotic when combined withof inﬂamed meninges. Aztreonam is renally cleared and an antibiotic with good gram-positive activity.has a half-life similar to to that of the renally cleared third- Useful for the treatment of pyelonephritis.and fourth-generation cephalosporins. Spectrum of Activity and Treatment Recommenda-tions—Aztreonam does not bind to the PBPs of gram-positive organisms or anaerobes; rather, it binds with aztreonam is its restricted antimicrobial spectrum, whichhigh afﬁnity to PBPs, particularly PBP-3 (responsible allows for survival of the normal gram-positive and anaer-for septum formation during bacterial division), of obic ﬂora that can compete with more resistant pathogens.gram-negative bacilli including P. aeruginosa. Gram- Aztreonam can be used for the treatment of most infec-negative organisms exposed to aztreonam form long tions attributable to gram-negative bacilli. It has been usedﬁlamentous structures and are killed. effectively in pyelonephritis, nosocomial gram-negative Aztreonam is effective against most gram-negative pneumonia, gram-negative bacteremia, and gram-negativebacilli, and this agent has been marketed as a non-nephro- intra-abdominal infections. Importantly, though, aztre-toxic replacement for aminoglycosides. However, unlike onam provides no gram-positive or anaerobic coverage.aminoglycosides, aztreonam does not provide synergy Therefore, when it is used for empiric treatment of poten-with penicillins for Enterococcus. A major advantage of tial gram-positive pathogens in the seriously ill patient,Table 1.7. Carbapenems: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Half-life Dose Dose for reduced Costa Spectrum (trade name) (h) creatinine clearance (mL/min) Imipenem–cilastin 1 0.5–1 g IV q6h 50–80: 0.5 g q6–8h $$$–$$$$$ Very broad (Primaxin) 10–50: 0.5 g q8–12h 10: 0.25–0.5 g q12h Meropenem 1 1 g IV q8h 10–50: 0.5 g q8h $$$$ Very broad (Merrem) 10: 0.5 g q24h Ertapenem 4 1 g IV or IM q24h 30: 500 mg q24h $ Very broad (Invanz)Intravenous preparations (daily cost dollars): $ = 20–70; $$ 71–110; $$$ = 111–150; $$$$ = 150–200; $$$$$ ≥ 200.
22 / CHAPTER 1aztreonam should be combined with vancomycin, clin- istration with cilastatin. These drugs are all primarilydamycin, erythromycin, or a penicillin. cleared by the kidneys. SPECTRUM OF ACTIVITY ANDCarbapenems TREATMENT RECOMMENDATIONSTable 1.7, together with Figure 1.5, summarizes the char- The carbapenems have a very broad spectrum of activity,acteristics of the various carbapenems. effectively killing most strains of gram-positive and gram- negative bacteria, including anaerobes. Overall, imipenemCHEMISTRY AND PHARMACOKINETICS has slightly better activity against gram-positive organisms.The carbapenems have both a modiﬁed thiazolidine Meropenem and ertapenem have somewhat better activityring and a change in the conﬁguration of the side chain against gram-negative pathogens (except Pseudomonas, asthat renders the -lactam ring highly resistant to cleav- described later in this subsection).age. Their hydroxyethyl side chain is in a trans rather These agents are cidal not only against S. pneumoniae,than cis conformation, and this conﬁguration is thought S. pyogenes, and MSSA, but also against organisms that areto be responsible for the group’s remarkable resistance to not covered by the cephalosporins, including Listeria, -lactamase breakdown. At physiologic pH, these Nocardia, Legionella, and Mycobacterium avium intracellu-agents have zwitterionic characteristics that allow them lare (MAI). They have static activity against penicillin-to readily penetrate tissues. The carbapenems bind with sensitive enterococci; however, many penicillin-resistanthigh afﬁnity to the high molecular weight PBPs of both strains are also resistant to carbapenems. MRSA, somegram-positive and gram-negative bacteria. penicillin-resistant strains of S. pneumoniae, C. difﬁcile, Imipenem is combined in a 1:1 ratio with cilastatin Stenotrophomonas maltophilia, and Burkholderia cepacia areto block rapid breakdown by renal dehydropeptidase I. also resistant. Resistance in gram-negative bacilli is mostMeropenem and ertapenem are not significantly often secondary to loss of an outer membrane proteindegraded by this enzyme and do not require co-admin- called D2 that is required for intracellular penetration of the carbapenems. Increasing numbers of gram-negative strains can also produce -lactamases called carbapene- KEY POINTS mases that can hydrolyze these drugs. Imipenem and meropenem can be used as empiric therapy for sepsis, and they are particularly useful if About the Carbapenems polymicrobial bacteremia is a strong possibility. They can also be used to treat severe intra-abdominal infections and 1. -Lactam ring is highly resistant to cleavage. complicated pyelonephritis. Infections attributable to gram-negative bacilli resistant to cephalosporins and 2. Have zwitterionic characteristics, and penetrate all tissues. aminoglycosides may be sensitive to imipenem or meropenem. Imipenem or meropenem are recommended 3. Frequent cross-reactivity in penicillin-allergic as primary therapy for Serratia. Meropenem can be used patients (7%). for meningitis, achieving therapeutic levels in the cere- 4. Imipenem causes seizures at high doses; be cau- brospinal ﬂuid. Imipenem is not recommended for this tious in renal failure patients. Meropenem is less purpose because of its propensity to cause seizures. In gen- epileptogenic. eral, imipenem and meropenem should be reserved for the 5. Bind penicillin binding proteins of all bacteria seriously ill patient or the patient infected with a highly with high afﬁnity. resistant bacterium that is sensitive only to this antibiotic. 6. Very broad cidal activity for aerobic and anaero- Ertapenem has a longer half-life and can be given bic gram-positive and gram-negative bacteria. just once daily, making it a useful agent for home intra- Also covers Listeria monocytogenes and Nocardia. venous therapy. This agent is not effective against 7. Imipenem and meropenem are useful for P. aeruginosa, but otherwise it has a spectrum similar to empiric therapy of suspected mixed aerobic that of meropenem. It is recommended for complicated and anaerobic infection or a severe nosocomial intra-abdominal infections, postpartum and postopera- infection, pending culture results. Reserve for tive acute pelvic infections, and complicated soft-tissue the severely ill patient. infections. 8. Ertapenem can be given once daily. Lacks Because the carbapenems are extremely broad- Pseudomonas aeruginosa coverage. spectrum agents, they kill nearly all normal ﬂora. The 9. Treatment markedly alters the normal bacterial loss of normal ﬂora increases the risk of nosocomial ﬂora. infections with resistant pathogens including MRSA, Pseudomonas, and Candida.
ANTI-INFECTIVE THERAPY / 23Aminoglycosides often rise before a signiﬁcant rise in serum creati- nine can be detected.Tables 1.8 and 1.9, together with Figure 1.5, summarizethe characteristics of the various aminoglycosides. 2. Ototoxicity. Aminoglycosides enter the inner earCHEMISTRY AND MECHANISM OF ACTION ﬂuid and damage outer hair cells important to the detection of high-frequency sound. Loss of high-Aminoglycosides were originally derived from frequency hearing occurs in 3% to 14% ofStreptomyces species. These agents have a characteristic patients treated with aminoglycosides. The risk of6-member ring with amino-group substitutions, and hearing loss is greater after prolonged treatment,they are highly soluble in water. At neutral pH, they are with most cases developing after 9 or more dayspositively charged, and this positive charge contributes of therapy. Hearing loss is irreversible and canto their antibacterial activity. At a low pH, the charge is occur weeks after therapy has been discontinued.reduced, impairing antimicrobial activity. Their positive A genetic predisposition has been observed, withcharge also causes aminoglycosides to bind to and certain families having a high incidence of deaf-become inactivated by -lactam antibiotics. Therefore ness after receiving aminoglycosides. The risk ofaminoglycosides should never be in the same solution hearing loss depends on the speciﬁc aminoglyco-with -lactam antibiotics. side. Neomycin has the highest risk of toxicity, Upon entering the bacterium, the antibiotic molecules followed in order of decreasing frequency by gen-interact with and precipitate DNA and other anionic tamicin, tobramycin, amikacin, and netilmicin.components. Aminoglycosides also bind to the 30S sub- Concomitant use of furosemide or vancomycin,unit of bacterial 16S ribosomal RNA and interfere with and exposure to loud noises increase the risk. Astranslation. These combined effects are bactericidal. compared with dosing at 8-hour intervals, once-TOXICITY daily dosing reduces the toxic risk.The aminoglycosides have a narrow ratio of therapeutic Less commonly, aminoglycosides can cause neuro-effect to toxic side effect, and monitoring serum levels is muscular blockade; they should be avoided in myas-generally required to prevent toxicity. These agents are thenia gravis. Given the high risk of toxicity, amino-among the most toxic drugs prescribed today, and they glycosides should be used only when alternativeshould be avoided whenever safer alternative antibiotics antibiotics are unavailable. When aminoglycosides areare available (Table 1.10). required, the duration of therapy should be as brief as Two major toxicities are observed: possible. Pretreatment and periodic testing of high- frequency hearing should be performed, and serum1. Nephrotoxicity. Injury to the proximal convo- creatinine and aminoglycoside serum levels should be luted tubules of the kidney leads to a reduction in monitored. creatinine clearance. The brush border cells of the proximal tubule take up aminoglycosides by PHARMACOKINETICS endocytosis, and intracellular entry is associated Following intravenous infusion, aminoglycosides take with cell necrosis. Aminoglycosides cause signiﬁ- 15 to 30 minutes to distribute throughout the body. cant reductions of glomerular ﬁltration in 5% to Therefore, to determine peak serum level, blood samples 25% of patients. Patient characteristics associated should be drawn 30 minutes after completion of the with an increased risk of nephrotoxicity include intravenous infusion. The half-life of aminoglycosides is older age, pre-existing renal disease, hepatic dys- 2 to 5 hours, and these agents are cleared by the kidneys. function, volume depletion, and hypotension. Re- Proper dosing of aminoglycosides is more compli- exposure to aminoglycosides increases risk, as do cated than for most other antibiotics, and these agents the use of larger doses, more frequent dosing require close monitoring. In many hospitals, a pharma- intervals, and treatment for more than cist is consulted to assist in dose management. For daily 3 days. The risk of renal failure is also associated multiple-dose therapy, a loading dose is ﬁrst given to with co-administration of vancomycin, ampho- rapidly achieve a therapeutic serum level; maintenance tericin B, clindamycin, piperacillin, cephalos- doses are then administered. Doses are calculated based porins, foscarnet, or furosemide. Because renal on ideal body weight. In the setting of renal dysfunc- tubular cells have regenerative power, renal dys- tion, dosing must be carefully adjusted, and peak and function usually reverses on discontinuation of trough serum levels monitored. As renal impairment the aminoglycoside. Because aminoglycosides are worsens, the dosage interval should be extended. primarily renally cleared, aminoglycoside serum Once-daily aminoglycoside dosing is now the pre- levels are useful for detecting worsening renal ferred therapy in nearly all instances. As compared with function. Trough aminoglycoside serum levels multidose therapy, once-daily administration reduces
24 / CHAPTER 1Table 1.8. Aminoglycosides: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Half-life Dose Dose for reduced Costa Spectrum (trade name) (h) creatinine clearance (mL/min) Gentamicin 2 2 mg/kg load, 0.03 mg/kg CrCl q8h, $$$$– Narrow and then adjusting peak to $$$$$ tobramycin 1.7–2 mg/kg 5–10 g/mL (Garamycin and q8h; or and trough 1–2 g/mL; or Nebcin) 5 mg/kg q24h 60–79: 4 mg/kg q24h 50: 3.5 mg/kg q24h 40: 2.5 mg/kg q24h <30: Conventional dosing, adjusting trough to <0.5 g/mL Amikacin 2 8 mg/kg load, 0.12 mg/kg CrCl q8h, $$$$– Narrow (Amikin) then adjusting peak to $$$$$ 7.5–8 mg/kg 20–40 g/mL, and q8h, or trough 5–10 g/mL, or 15 mg/kg daily 60–79: 12 mg/kg q24h 50: 7.5 mg/kg q24h 40: 4.0 mg/kg q24h <30: Conventional dosing, adjusting trough to <5 g/mL Netilmicin 2.5 2 mg/kg load, Same as gentamicin $$$$– Narrow then and tobramycin $$$$$ 2 mg/kg q8h Streptomycin 2–5 7.5 mg/kg load, 50–80: 15 mg/kg q24–72h $$$$– Narrow then 10–40: 15 mg/kg q72–96h $$$$$ 7.5 mg/kg q12h <10: 7.5 mg/kg q72–96h, adjusting peak to 15–25 g/mL and trough to 5–10 g/mLIntravenous preparations (daily cost dollars): $ = 20–70; $$ = 71–110; $$$ = 111–150; $$$$ = 150–200; $$$$$ ≥ 200. Includescosts of monitoring and toxicity.Table 1.9. Organisms That May Be Susceptible to Aminoglycosides Gentamicin Tobramycin Amikacin Streptomycin Most Enterobacteriaceae Most Enterobacteriaceae Most Enterobacteriaceae Yersinia pestis (see Figure 1.5) (see Figure 1.5) (see Figure 1.5) Francisella tularensis Francisella tularensis Pseudomonas aeruginosa Mycobacterium avium Brucella spp. Brucella spp. (synergy with complex (combined with doxy (combined with doxycycline) anti-Pseudomonas penicillin cycline) Synergy with penicillins, or cephalosporins) M. tuberculosis vancomycin, and ceftriaxone for S. viridans Synergy with penicillins and vancomycin for Enterococcus
ANTI-INFECTIVE THERAPY / 25Table 1.10. Toxicities of Miscellaneous Antibiotics Clinical symptom Antibiotic Quinu/dalfopristin Chloramphenicol Aminoglycosides Meronidazole Tetracyclines Clindamycin Daptomycin Vancomycin Macrolides Quinolons Linezolid Sulfas Allergic skin rash a b c Steven–Johnson Diarrhea (Clost. difﬁcile) Gastrointestinal intolerance Hearing loss Dizziness Neurotoxicity Seizure Musculoskeletal Phlebitis Laboratory tests: Coagulation Creatinine↑ Cytopenias Eosinophilia AST/ALT↑ d Bilirubin↑ QT prolonged Glucose↑ or ↓ Amylase↑a “Red man syndrome” common, but not a true allergic reaction (see text).b Also photosensitivity.c Gemiﬂoxacin is associated with frequent skin rash in women under 40 years of age.d Severe and occasionally fatal hepatitis associated with talithromycin.Black = principle side effect; dark gray less common side effect; light gray rare side effect; white not reported or veryrare; ↑ rise; AST/ALT aspartate aminotransferase/alanine transaminase.the concentration of the aminoglycoside that accumu- adjust for renal impairment, the daily dose should belates in the renal cortex and lowers the incidence of reduced.nephrotoxicity. Because aminoglycosides demonstrate Monitoring of serum levels is recommended forconcentration-dependent killing, the high peak levels both multidose and once-daily regimens. With multi-achieved with this regimen increase the bactericidal rate dose therapy, blood for a peak level determinationand prolong the post-antibiotic effect. In addition, a should be drawn 30 minutes after intravenous infu-once-daily regimen is simpler and less expensive to sion is complete, and for a trough level, 30 minutesadminister. This regimen has not been associated with a before the next dose. Blood for peak and trough deter-higher incidence of neuromuscular dysfunction. To minations should be drawn after the third dose of
26 / CHAPTER 1 advantage of this characteristic. Aminoglycosides also KEY POINTS demonstrate persistent suppression of bacterial growth for 1 to 3 hours after the antibiotic is no longer present. About Aminoglycoside Toxicity The higher the concentration of the aminoglycoside, the longer the post-antibiotic effect. Aminoglycosides also demonstrate synergy with antibiotics that act on 1. Very low ratio of therapeutic benefit to toxic side effect. the cell wall ( -lactam antibiotics and glycopeptides). The effect of these combinations is greater than the 2. Monitoring of serum levels usually required. sum of the anti-microbial effects of each individual 3. Nephrotoxicity commonly occurs (usually agent. Synergy has been achieved in the treatment of reversible). Incidence is higher in enterococci, S. viridans, S. aureus, coagulase-negative a) elderly individuals, staphylococci, P. aeruginosa, L. monocytogenes, and JK b) patients with pre-existing renal disease, corynebacteria. c) patients with volume depletion and hypoten- An aminoglycoside in combination with other sion, and antibiotics is generally recommended for treatment of d) patients with liver disease. the severely ill patients with sepsis syndrome to assure 4. Higher incidence with co-administration of broad coverage for gram-negative bacilli. An amino- vancomycin, cephalosporins, clindamycin, pipe- glycoside combined with penicillin is recommended racillin, foscarnet, or furosemide. for empiric coverage of bacterial endocarditis. 5. The loss of high-frequency hearing and vestibular Tobramycin combined with an anti-pseudomonal dysfunction resulting from ototoxicity is often penicillin or an anti-pseudomonal cephalosporin is devastating for elderly individuals. recommended as primary treatment of P. aeruginosa. 6. Neuromuscular blockade is rare. Streptomycin or gentamicin is the treatment of choice for tularemia and Yersinia pestis, and either agent can 7. Once-daily therapy may be less toxic. KEY POINTSantibiotic to assure full equilibration within the dis-tribution volume. In the critically ill patient, bloodfor a peak level determination should be drawn after About Dosing and Serumthe first dose to assure achievement of an adequate Monitoring of Aminoglycosidestherapeutic level. For once-daily dosing, trough levels need to be moni- 1. Aminoglycosides take 15 to 30 minutes to equi-tored to assure adequate clearance. Serum level at 18 hours librate in the body.should be <1 g/mL. Alternatively, blood for a level deter- 2. For multidose therapy, blood for a peak serummination can be drawn between 6 and 14 hours, and the level determination should be drawn 30 min-value applied to a nomogram to help decide on subse- utes after infusion.quent doses. In the seriously ill patient, blood for a peak 3. Blood for trough serum level determinationslevel determination should also be drawn 30 minutes after should be drawn just before the next dose.completion of the infusion to assure that a therapeuticlevel is being achieved (for gentamicin–tobramycin, a tar- 4. Conventionally, aminoglycosides are given 3 times daily. Dosing should be based on leanget concentration of 16 to 24 g/mL should be achieved). body weight.Once-daily dosing is not recommended for the treatmentof enterococcal endocarditis and has not been sufﬁciently 5. Once-daily dosing takes advantage ofstudied in pregnancy or in patients with osteomyelitis or concentration-dependent killing and the post-antibiotic effects of aminoglycosides.cystic ﬁbrosis. 6. Once-daily dosing reduces, but does not elimi-SPECTRUM OF ACTIVITY AND nate, nephrotoxicity.TREATMENT RECOMMENDATIONS 7. In most cases, trough serum levels need to beThe aminoglycosides are cidal for most aerobic gram- monitored only during once-daily dosing.Toxicitynegative bacilli, including Pseudomonas species. These correlates with high trough levels.agents kill rapidly, and the killing is concentration- 8. Once-daily dosing is not recommended fordependent—that is, the rate increases as the concentra- enterococcal endocarditis or pregnant women.tion of the antibiotic increases. Once-daily dosing takes
ANTI-INFECTIVE THERAPY / 27 KEY POINTS KEY POINTS About Aminoglycoside Antibacterial Activity About Glycopeptide Antibacterial Activity 1. 6-Member ring, soluble in water, positively 1. Act on the cell wall of gram-positive bacteria by charged; never with cephalosporins or acidic binding to the D-alanine–D-alanine peptidogly- solutions. can precursor. 2. Cause temporary holes in bacterial membranes, 2. Require active bacterial growth. bind to ribosomal RNA, and interfere with trans- 3. Also interfere with RNA synthesis. lation. 4. Have a 2-hour post-antibiotic effect. 3. Killing is concentration-dependent. 4. The higher the concentration, the longer the post-antibiotic effect. 5. Excellent gram-negative coverage; strepto- usually prevents this reaction. There is less experience mycin for tularemia and plague. with teicoplanin; however, this agent does not cause 6. Synergy with penicillins in S. viridans, Enterococ- signiﬁcant thrombophlebitis, and skin ﬂushing after cus, and Pseudomonas aeruginosa infections. rapid infusion is uncommon. Ototoxicity has been reported. PHARMACOKINETICSalso be used to treat Brucella. Gentamicin combined The half-lives of vancomycin (4 to 6 hours) andwith penicillin is the treatment of choice for both teicoplanin (40 to 70 hours) are prolonged Table 1.11).S. viridans and Enterococcus faecalis. Both drugs are excreted primarily by the kidneys, and in the anuric patient, the half-life of vancomycin increases to 7 to 9 days. For vancomycin, peak levelsGlycopeptide Antibiotics should reach 20 to 50 g/mL, with trough levels beingTable 1.11, together with Figure 1.5, summarizes the char- maintained at 10 to 12 g/mL. Vancomycin penetratesacteristics of the glycopeptide antibiotics. most tissue spaces, but does not cross the blood–brain barrier in the absence of inﬂammation. TherapeuticCHEMISTRY AND MECHANISM OF ACTION cerebrospinal levels are achieved in patients withVancomycin and teicoplanin are complex glycopeptides meningitis. Unlike vancomycin, which is minimallyof approximately 1500 Da molecular weight. These bound to protein, teicoplanin is 90% protein-bound,agents act primarily at the cell wall of gram-positive accounting for its slow renal clearance. Tissue penetra-organisms by binding to the D-alanine–D-alanine tion has not been extensively studied, and little data areprecursor and preventing it from being incorporated available on penetration of bone, peritoneal, or cere-into the peptidoglycan. The binding of vancomycin to brospinal ﬂuid.this cell wall precursor blocks the transpeptidase andtransglycolase enzymes, interfering with cell wall for-mation and increasing permeability of the cell. Theseagents may also interfere with RNA synthesis. Theybind rapidly and tightly to bacteria and rapidly kill KEY POINTSactively growing organisms. They also have a 2-hourpost-antibiotic effect. About Vancomycin ToxicityTOXICITY 1. Rapid infusion associated with “red man syn-The most common side effect of the glycopeptide drome.”antibiotics is “red man syndrome,” which occurs mostoften when vancomycin is infused rapidly (Table 2. Phlebitis is common.1.10). The patient experiences flushing of the face, 3. Ototoxicity leading to deafness uncommon,neck, and upper thorax. This reaction is thought to be preceeded by tinnituscaused by sudden histamine release secondary to local 4. Rarely nephrotoxic, potentiates aminoglycosidehyperosmolality and not to be a true hypersensitivity nephrotoxicityreaction. Infusing vancomycin over a 1-hour period
28 / CHAPTER 1Table 1.11. Glycopeptides, Macrolides, Clindamycin, Tetracyclines, and Chloramphenicol: Half-Life,Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Half-life Dose Dose for reduced Costa Spectrum (trade name) (h) creatinine clearance (mL/min) Vancomycin 4–6 15 mg/kg IV q12h 40–60: 1 g q12–24h $ Narrow (Vancocin) (usual dose: 1 g q12h) 20–40: q24–48h 10–20: q48–72h <10: q3–7d Exact dose based on levels: peak: 25–50 g/mL; trough: 10–12 g/mL Teicoplanin 40–70 6 mg/kg IV or IM 10–50: Half the dose Not sold in Narrow (Targocid) followed by <10: One third the dose United 3 mg/kg q24h States Erythromycin 1.2–1.6 250-500 mg PO q6h No change required $ Narrow 1 g IV q6h Clarithromycin 4 250–500 mg PO q12h <10: 250–500 mg q24h $–$$ Narrow (Biaxin, Biaxin XL) XL: 1 g PO q24h Azithromycin 68 500 mg PO, Probably no change $ Narrow (Zithromax) followed by required 250 mg PO q24h, or <10: Not studied 500 mg IV q24h Talithromycin 10 800 mg PO q24h <30: 600 mg q24h $$ Narrow (Ketek) Clindamycin 2.5 150–300 mg PO q6h No change required PO: $$$$$ Narrow (Cleocin) 300–900 mg IV q6–8h IV: $ Tetracycline 8 250–500 mg PO 50–80: q12h $ Broad twice daily 10–50: q12–24h <10: q24h Doxycycline 18 100 mg PO No change required $ Broad (Vibramycin, Doxy) twice daily Minocycline 16 200 mg PO No change required $ Broad (Minocin, Dynacin) twice daily Tigecycline 42 100 mg IV, No change required. $$ Very (Tygecil) followed by For severe hepatic broad 50 mg IV q12h dysfunction, maintenance dose: 25 mg IV q12h Chloramphenicol 4 0.25–1 g IV q6h No change required. $ Broad (Chloromycetin) Serum levels should be monitored in hepatic failure.a Intravenous preparations (daily cost dollars): $ = 20–70; $$ 5 71–110; $$$ = 111–150; $$$$ = 150–200; $$$$$ ≥ 200; oralpreparations (10-day course cost dollars): $ = 10–50; $$ = 51–100; $$$ = 101–140; $$$$ = 141–180; $$$$$ ≥ 180.
ANTI-INFECTIVE THERAPY / 29ANTIMICROBIAL SPECTRUM AND TREATMENTRECOMMENDATIONS KEY POINTSVancomycin and teicoplanin both cover MRSA andMSSA, and they are the recommended treatment for About the Treatment RecommendationsMRSA. These agents also kill most strains of coagulase- for Vancomycinnegative staphylococci (S. epidermidis), which are usuallymethicillin-resistant. They are recommended for the 1. Treatment of choice for methicillin-resistanttreatment of coagulase-negative staphylococcal line sepsis Staphylococcus aureus; vancomycin-tolerantand bacterial endocarditis. For the latter infection, the strains have been reported.glycopeptide antibiotic should be combined with one or 2. Treatment of choice for coagulase-negativemore additional antibiotics (see Chapter 7). Vancomycin- staphylococci.intermediately-resistant strains of S. aureus were ﬁrstdiscovered in Japan and have also been identiﬁed in 3. Excellent activity against high-level penicillin-Europe and the United States. These strains have MICs of resistant Streptococcus pneumoniae.8 to 16 g/mL and are cross-resistant to teicoplanin. The 4. In the penicillin-allergic patient, vancomycin isincreasing use of vancomycin has selected for these strains recommended for Strep. pyogenes, Gp B strepto-and warns us that the indiscriminant use of the glycopep- cocci, Strep. viridans, and Strep. bovis.tide antibiotics must be avoided. 5. Excellent activity against some strains of Ente- Vancomycin and teicoplanin not only have excellent rococcus; however,van A gene–mediatedactivity against Staphylococcus, but also against penicillin- vancomycin-resistant enterococci (VRE) areresistant and susceptible strains of S. pneumoniae, and they increasing in frequency.are recommended for empiric treatment of the seriously ill 6. Vancomycin use must be restricted to reducepatient with pneumococcal meningitis to cover for highly the likelihood of selecting for VRE and van-penicillin-resistant strains. The glycopeptide antibiotics comycin-tolerant Staph. aureus.also effectively treat S. pyogenes, GpB streptococci,S. viridans, and S. bovis, and they are recommended fortreatment of these infections in the penicillin-allergicpatient. Corynebacterium jeikeium (previously called JK CHEMISTRY AND MECHANISM OF ACTIONdiphtheroids) is sensitive to vancomycin, and that antibi- The founding member of the macrolide family, ery-otic is recommended for its treatment. Oral vancomycin thromycin, was originally purified from a soil bac-clears C. difﬁcile from the bowel, and in the past it was terium. It has a complex 14-member macrocyclicrecommended for C. difﬁcile toxin–associated diarrhea. lactone ring (which gives rise to the class nameHowever, because of the increased risk of developing VRE “macrolides”) attached to two sugars. Azithromycin hasfollowing oral vancomycin, this regimen is recommended a 15-member lactone ring and a nitrogen substitution.only for cases that are refractory to metronidazole or for Clarithromycin has a methoxy group modiﬁcation atpatients who are very seriously ill. carbon 6 of the erythromycin molecule. These modiﬁ- Vancomycin is frequently used to treat Enterococcus cations enhance oral absorption and broaden thefaecalis and faecium; however, an increasing number of antimicrobial spectrum.strains have become resistant. Three gene complexes The newest class of macrolide-like agents are thetransfer resistance. The van A gene cluster directs peptido- semisynthetic derivatives of erythromycin calledglycan cell wall synthesis and coverts D-alanine–D-alanine ketolides. The ketolides, represented by talithro-(the site of vancomycin action) to D-alanine–D-lactate, mycin, have a 14-member macrolactone ring with amarkedly reducing vancomycin and teicoplanin binding. keto group at position 3, with the hydroxyls atThe other two resistance gene clusters, van B and van C, positions 11 and 12 replaced by a cyclic carbamate.result in vancomycin resistance, but do not impair These agents all inhibit protein biosynthesis by block-teicoplanin activity. ing the passage of nascent proteins through the ribosome exit tunnel. In the case of conventionalMacrolides and Ketolides macrolides, inhibition is accomplished by binding toTables 1.11 and 1.12, together with Figure 1.5, summa- a single domain of the 50S ribosomal subunitrizes the chracteristics of the macrolides and ketolides. (domain V of the 23 rRNA molecule). As compared
30 / CHAPTER 1Table 1.12. Organisms That May Be Susceptible to Macrolides and Ketolides Erythromycin Clarithromycin Azithromycin Talithromycin Streptococcus pyogenes More active against Less active against Most active against Penicillin (PCN)–sensitive S. pyogenes S. pyogenes S. pyogenes S. pneumoniae More active against Less active against Active against some PCN-sensitive PCN-sensitive erythromycin-resistant strains Mouth ﬂora including anaerobes, but not S. pneumoniae S. pneumoniae Active against multiresistant Bacteroides fragilis All pathogens covered all pathogens covered S. pneumoniae Neisseria gonorrhoeae by erythromycin, plus: by erythromycin, plus: All pathogens covered Neisseria meningitides Haemophilus inﬂuenzae more active against by erythromycin, plus: H. inﬂuenzae Most active against Campylobacter jejuni Moraxella catarrhalis Moraxella catarrhalis erythromycin-sensitive Bordetella pertussis Borrelia burgdorferi Most active against S. aureus Legionella pneumophilia Mycoplasma leprae Legionella pneumophilia Good activity against Mycoplasma pneumoniae Mycobacterium avium M. avium complex Enterococcus faecalis, Ureaplasma urealyticum complex but not Enterococcus faecium Helicobacter pylori Chlamydia trachomatis Toxoplasma gondii H. inﬂuenzae Plasmodium falciparum Helicobacter pylori Moraxella catarrhalis Chlamydophila pneumoniae Poor activity against Corynebacterium diphtheriae M. avium complex Bartonella quintanawith the macro-lides, talithromycin binds to the 50S ally fatal hepatitis. All patients receiving this agent shouldsubunit with higher afﬁnity, binding to two regions of therefore be warned of this potential side effect, and thethe 23S rRNA molecule (domains II and V) rather drug should be prescribed only for cases of pneumonia inthan one region. This unique binding mode explains which the incidence of penicillin-resistant S. pneumoniaethe enhanced antimicrobial activity of ketolides is high. Under these circumstance a ﬂuoroquinolone withagainst macrolide-resistant pathogens. gram-positive coverage may be preferred. Macrolides and ketolides may exacerbate myastheniaTOXICITY gravis and should be avoided in patients with that ill-Macrolides and ketolides are among the safer classes ness. Macrolides prolong the QT interval, and ery-of antibiotics (Table 1.10). The primary adverse reac- thromycin administration has, on rare occasions, beentions are related to these agents’ ability to stimulate associated with ventricular tachycardia.bowel motility. In fact, erythromycin can be used to These agents are metabolized by the cytochrometreat gastric paresis. Particularly in younger patients, P450 3A4 system, and they cause an increase in serumabdominal cramps, nausea, vomiting, diarrhea, and levels of other drugs metabolized by that system, includ-gas are common with erythromycin. These symptoms ing many of the statins, short-acting benzodiazepines,are dose-related and are more common with oral such as midazolam (Versed), cisapride (Propulsid),preparations, but can also occur with intravenous ritonavir (Norvir), and tacrolimus (Prograf ).administration. Gastrointestinal toxicity can be debil-itating, forcing the drug to be discontinued. PHARMACOKINETICSAzithromycin and clarithromycin at the usual recom- The stearate, ethylsuccinate, and estolate forms of ery-mended doses are much less likely to cause these thromycin are reasonably well absorbed on an emptyadverse reactions. stomach, reaching peak serum levels 3 hours after inges- Talithromycin administration has been accompanied tion. Clarithromycin, azithromycin, and talithromycinby difﬁculty with accommodation, resulting in blurred are better absorbed orally than erythromycin is, result-vision. Patients have also experienced diplopia following ing in peak concentrations within 1 hour. Erythromycinadministration of this agent. Talithromycin treatment has and azithromycin should be taken on an empty stom-also resulted in the sudden onset of severe and occasion- ach. If cost is not a primary issue, the improved
ANTI-INFECTIVE THERAPY / 31 bacteria. Erythromycin can be bacteriostatic or bacterici- KEY POINTS dal. Cidal activity increases when antibiotic concentra- tions are high and bacteria are growing rapidly. About Macrolide Chemistry, Mechanism These drugs are recommended for the treatment of of Action, and Toxicity community-acquired pneumonia (see Chapter 4). How- ever S. pneumoniae resistance to macrolides has steadily increased and now ranges between 10% and 15%. 1. Complex 14- to 15-member lactone ring struc- Resistance is more likely in intermediately penicillin- ture. resistant strains (40% macrolide resistant) and highly 2. Inhibit RNA-dependent protein synthesis, bind penicillin-resistant strains (60% macrolide resistance). to 50S ribosomal subunit; talithromycin binds Multiresistant S. pneumoniae can be treated with tal- with higher afﬁnity, binding to two sites rather ithromycin as a consequence of that agent’s different than just one, ribosomal binding sites. 3. Can be bacteriostatic or cidal. In most countries, including the United States, 95% 4. Gastrointestinal irritation, particularly with ery- of S. pyogenes are sensitive to macrolides. However, in thromycin, is the major toxicity. Japan, where macrolides are commonly used, 60% are 5. Hypersensitivity reactions can occur. resistant. Because S. aureus can develop resistance after a 6. Transient hearing loss with high doses, mainly single mutation, macrolides are generally not recom- in elderly individuals. mended in their treatment. The macrolides and 7. Talithromycin can cause blurred vision and ketolides are effective against mouth ﬂora, including diplopia. Also can result in fatal hepatitis. anaerobes, but they do not cover the bowel anaerobe B. fragilis. The macrolides are also the treatment of 8. Can exacerbate myasthenia gravis. choice for Legionella pneumophilia, with talithromycin, 9. Prolonged QT interval; occasionally causes ven- azithromycin, and clarithromycin being more potent tricular tachycardia. than erythromycin. 10.Metabolized by the cytochrome P450 3A4 sys- Macrolides are the primary antibiotics used to treat tem; increase serum concentrations of other the two major pathogens associated with atypical pneu- drugs metabolized by that system. monia: Mycoplasma pneumoniae and Chlamydophila pneumoniae (see Chapter 4). Talithromycin is also approved for acute bacterial sinusitis. In many instances the erythromycins can be used as an alternative to peni-absorption and lower incidence of gastrointestinal toxi- cillin in the penicillin-allergic patient.city make the three newer agents preferable to ery- Clarithromycin is one of the primary antibioticsthromycin in most instances (Table 1.11). used for the treatment of atypical mycobacterial infec- Most of the macrolides and ketolides are metabolized tions, particularly MAI complex. Azithromycin in com-and cleared primarily by the liver. Azithromycin is not bination with other antibiotics is also recommended formetabolized, being excreted unchanged in the bile. Small the treatment of MAI complex, and it can be used alonepercentages of these drugs are also excreted in the urine. for MAI prophylaxis in HIV-infected patients withThese agents are widely distributed in tissues, achieving CD4 cell counts below 100 cells/mL.concentrations that are several times the peak concentra- In combination with antacid therapy, effective regi-tion achieved in serum in most areas the body, including mens for curing peptic ulcer disease caused by Heli-the prostate and middle ear. Clarithromycin levels in cobacter pylori include azithromycin or clarithromycinmiddle ear ﬂuid have been shown to be nearly 10 times combined with bismuth salts and either amoxicillin,serum levels. Azithromycin concentrations in tissue metronidazole, or tetracycline. Single high-doseexceed serum levels by a factor of 10 to 100, and its aver- azithromycin (1 g) effectively treats chancroid, as well asage half-life in tissues is 2 to 4 days. Therapeutic levels of Chlamydia trachomatis urethritis and cervicitis. Single-azithromycin have been estimated to persist for 5 days dose therapy also cures male Ureaplasma urealyticumafter the completion of a 5-day treatment course. With urethritis.the exception of intravenous erythromycin, these agentsfail to achieve signiﬁcant levels in the cerebrospinal ﬂuid. ClindamycinSPECTRUM OF ACTIVITY AND CHEMISTRY AND MECHANISM OF ACTIONTREATMENT RECOMMENDATIONS Although clindamycin is structurally different fromMacrolides demonstrate excellent activity against erythromycin, many of its biologic characteristics aremost gram-positive organisms and some gram-negative similar. Clindamycin consists of an amino acid linked
32 / CHAPTER 1 ANTIMICROBIAL SPECTRUM AND KEY POINTS TREATMENT RECOMMENDATIONS Clindamycin is similar to erythromycin in its activity About the Spectrum and Treatment Indications against streptococci and staphylococci (Figure 1.5). for Macrolides and Ketolides Moderately penicillin-resistant S. pneumoniae are often sensitive to clindamycin. In the penicillin-allergic patient, clindamycin is a reasonable alternative for 1. Gram-positive coverage, plus mouth anaerobes. S. pyogenes pharyngitis. Because its activity against 2. Recommended for treatment of community- H. influenzae is limited, clindamycin is not recom- acquired pneumonia. mended for the treatment of otitis media. 3. Increased use of macrolides selects for resistant Clindamycin distinguishes itself from the macrolides by strains of Streptococcus pyogenes and S. pneu- possessing excellent activity against most anaerobic bacte- moniae. Penicillin-resistant strains of S. pneumo- ria. It is used effectively in combination with an aminogly- niae are often resistant to macrolides. coside, aztreonam, or a third-generation cephalosporin to 4. Talithromycin is effective against multi-resistant treat fecal soilage of the peritoneum. However, other less- S. pneumoniae. toxic regimens have proved to be equally effective. Clin- 5. Recommended for treatment of Legionella damycin in combination with a ﬁrst-generation pneumophilia. cephalosporin can be used to block toxin production in 6. Recommended for Mycoplasma, Ureaplasma, severe cellulitis and necrotizing fasciitis caused by MSSA or and Chlamydia. S. pyogenes. It is also effective for the treatment of anaerobic 7. Clarithromycin or azithromycin can used for pulmonary and pleural infections. Clindamycin also has treatment of Helicobacter pylori. signiﬁcant activity against Toxoplasma gondii and is recom- 8. Clarithromycin is a primary drug for treatment mended as alternative therapy in the sulfa-allergic patient. of Mycobacterium avium intracellulare (MAI), and azithromycin is useful for MAI prophylaxis Tetracyclines in HIV patients with low CD4 cell counts. CHEMISTRY AND MECHANISMS OF ACTION The tetracyclines consist of four 6-member rings with substitutions at the 4, 5, 6, and 7 positions that alterto an amino sugar, and it was derived by modifyinglincomycin. It binds to the same 50S ribosomal bind-ing site used by the macrolides, blocking bacterialprotein synthesis. KEY POINTSTOXICITY About ClindamycinDiarrhea is a major problem seen in 20% of patientstaking clindamycin (Table 1.10). The incidence is high-est with oral administration. In up to half of the affected 1. Binds to the 50S ribosomal binding site used by the macrolides.patients, the cause of diarrhea is pseudomembranouscolitis, a disease caused by overgrowth of the anaerobic 2. Diarrhea is a common side effect, with Clostrid-bacteria C. difﬁcile (see Chapter 8). ium difﬁcile toxin found in half of cases. 3. Pseudomembranous colitis can lead to toxicPHARMACOKINETICS megacolon and death. If C. difficile toxin isClindamycin is well absorbed orally; however, the detected, clindamycin should be discontinued.drug can also be administered intravenously and the 4. Active against most gram-positive organismsintravenous route can achieve higher peak serum including MSSA; covers many intermediatelevels. Clindamycin penetrates most tissues, but it penicillin-resistant Streptococcus pneumoniae,does not enter the cerebrospinal ﬂuid. Clindamycin is but is not a ﬁrst-line therapy.metabolized primarily by the liver and is excreted in 5. Excellent anaerobic coverage, including Bac-the bile. Therapeutic concentrations of clindamycin teroides fragilis.persist in the stool for 5 or more days after the antibi- 6. Used to reduce toxin production by S. pyogenesotic is discontinued, and the reduction of clin- and Staphylococcus aureus.damycin-sensitive flora persists for up to 14 days. 7. Used to treat anaerobic lung abscesses andSmall percentages of clindamycin metabolites are also toxoplasmosis in the sulfa-allergic patient.excreted in the urine.
ANTI-INFECTIVE THERAPY / 33the pharmacokinetics of the various preparations; tract. Calcium- or magnesium-containing antacids,however, with the exception of tigecycline, these milk, or multivitamins markedly impair absorption ofchanges have no effect on the antimicrobial spectrum. all tetracycline preparations, and simultaneous inges-The tetracyclines enter gram-negative bacteria by pas- tion of these products should be avoided. Tigecyclinesively diffusing through porins. They bind to the 30S can be administered only intravenously. Tetracyclineribosomal subunit and block tRNA binding to the is cleared primarily by the kidneys; other agents,mRNA ribosome complex. This blockade primarily including doxycycline and tigecycline are cleared pri-inhibits protein synthesis in bacteria, but to a lesser marily by the liver.extent, it also affects mammalian cell protein synthe-sis, particularly mitochondria. The inhibition of bac- ANTIMICROBIAL SPECTRUM ANDterial protein synthesis stops bacterial growth, but TREATMENT RECOMMENDATIONSdoes not kill the bacterium. Therefore, tetracycline is The tetracyclines are able to inhibit the growth of atermed a bacteriostatic agent. broad spectrum of bacteria (Table 1.13, Figure 1.5). However, for most conventional pathogens, otherTOXICITY agents are more effective. High concentrations of tetra-Photosensitivity reactions consisting of a red rash over cycline are achieved in the urine, and this agent can besun-exposed areas can develop (Table 1.10). Hypersensi- used for uncomplicated urinary tract infections. Doxy-tivity reactions are less common than with the penicillins, cycline combined with gentamicin is the treatment ofbut they do occur. Tetracyclines interfere with enamel for- choice for brucellosis. Tetracyclines are also recom-mation, and in children, teeth often become permanently mended for the treatment of Lyme disease (Borreliadiscolored. Therefore these agents are not recommended burgdorferi), and chlamydia infections (includingfor children 8 years of age or younger, or for pregnant Chlamydia pneumonia, psittacosis, epididymitis, ure-women. Because the tetracyclines inhibit protein synthe- thritis, and endocervical infections). Tetracyclines aresis, they increase azotemia in renal failure patients. the treatment of choice for rickettsial infections (includ-Minocycline can cause vertigo, and that side effect has ing Rocky Mountain spotted fever, ehrlichiosis, Q fever,limited its use. Benign intracranial hypertension (pseudo- and typhus fever). They are also often used in combina-tumor cerebri) is another rare neurologic side effect. tion with other antibiotics for the treatment of pelvic inﬂammatory disease.PHARMACOKINETICS The most recently developed member of thisTetracycline is reasonably well absorbed (70% to family, tigecycline, was derived from minocycline.80%) by the gastrointestinal tract (see Table 1.11). Tigecycline has a broader spectrum of activity. ItFood interferes with its absorption. Doxycycline is effectively inhibits the growth of many resistantnearly completely absorbed in the gastrointestinal gram-positive bacteria (Table 1.13). This agent also Table 1.13. Organisms That May Be Susceptible to the Tetracyclines Tetra-, Doxy-, and Minocycline Tigecycline Vibrio spp. Methicillin-resistant Mycobacterium marinum Staphylococcus aureus (MRSA) Borrelia burgdorferi Vancomycin intermediately resistant Leptospira S. aureus (VISA) Chlamydia spp. Vancomycin-resistant enterococci (VRE) Rickettsia spp. Penicillin-resistant S. pneumoniae Brucella Acinetobacter baumannii Stenotrophomonas maltophilia Enterobacteriaceae, including those with extended-spectrum -lactamases Bacteroides fragilis Clostridium perfringens and difﬁcile
34 / CHAPTER 1 The first form is dose-related and is commonly KEY POINTS observed in patients receiving chloramphenicol 4 g or more daily. The reticulocyte count decreases, and ane- About the Tetracyclines mia develops in association with elevated serum iron. Leukopenia and thrombocytopenia are also com- monly encountered. These changes reverse when the 1. Bind to the 30S subunit of the ribosome, block- ing tRNA binding and inhibiting protein synthe- antibiotic is discontinued. The second form of mar- sis. Bacteriostatic for most gram-positive and row toxicity, irreversible aplastic anemia, is rare, but gram-negative bacteria. usually fatal. This complication can occur weeks or months after the antibiotic is discontinued. Any 2. Toxicities include photosensitivity, interference with dental enamel formation in children, gas- patient receiving chloramphenicol requires twice- trointestinal discomfort, fatty liver changes, weekly monitoring of peripheral blood counts. If the exacerbation of azotemia, vertigo (minocy- WBC drops below 2500/mm3, the drug should be cline), and pseudotumor cerebri. discontinued. 3. Tetracycline can be used for uncomplicated uri- PHARMACOKINETICS nary tract infections. As a result of the much higher incidence of idiosyn- 4. Recommended for brucellosis, Lyme disease, cratic aplastic anemia associated with oral administra- chlamydia, and rickettsial infections tion as compared with intravenous administration, 5. Recommended, in combination with other oral preparations of chloramphenicol are no longer antibiotics, for pelvic inﬂammatory disease. available in the United States. The drug is well 6. Oral absorption blocked by calcium- and absorbed, and therapeutic serum levels can be magnesium-containing antacids, milk, and achieved orally (Table 1.11). Chloramphenicol is multivitamins. metabolized by the liver. It diffuses well into tissues 7. Tigecycline has improved gram-positive and and crosses the blood–brain barrier in uninﬂamed as gram-negative coverage, with the exception of well as inﬂamed meninges. A serum assay is available, Pseudomonas aeruginosa and Proteus. It is and serum levels should be monitored in patients with approved for complicated intra-abdominal and hepatic disease, maintaining the serum concentration soft-tissue infections. between 10 and 25 g/mL. ANTIMICROBIAL SPECTRUM AND TREATMENT RECOMMENDATIONSdemonstrates improved activity against many highly Chloramphenicol has excellent activity against mostresistant nosocomial gram-negative bacteria, but it gram-positive organisms with the exception of entero-does not effectively cover P. aeruginosa or Proteus cocci and S. aureus, as well as many gram-negativespecies. Tigecycline is approved for complicated intra-abdominal and soft-tissue infections.Chloramphenicol KEY POINTSCHEMISTRY AND MECHANISMS OF ACTION About ChloramphenicolChloramphenicol consists of a nitro group on a benzenering and a side chain containing ﬁve carbons. Chloram-phenicol uses an energy-dependent mechanism to enter 1. Binds to 50S subunit of the ribosome, blockingbacteria, and once in the cell, binds to the larger 50S protein synthesis; is bacteriostatic.subunit of the 70S ribosome, blocking attachment of 2. Idiosyncratic aplastic anemia has limited thetRNA. It inhibits bacterial protein synthesis, making it use of chloramphenicol; dose-related bonebacteriostatic for most bacteria; however, chlorampheni- marrow suppression is another concern.col is cidal for H. influenzae, S. pneumoniae, and 3. Broad spectrum of activity, including Salmo-N. meningitidis. nella, Brucella, Bordetella, anaerobes, Rick- ettsiae, Chlamydiae, Mycoplasma, and spiro-TOXICITY chetes.Probably as result of its binding to human mitochon- 4. Can be used as alternative therapy in thedrial ribosomes, this agent has signiﬁcant bone mar- penicillin-allergic patient.row toxicity (see Table 1.10). Two forms are observed.
ANTI-INFECTIVE THERAPY / 35pathogens (Figure 1.5). Chloramphenicol also is veryactive against spirochetes, as well as Rickettsiae,Chlamydiae, and mycoplasmas. Because of its bone marrow toxicity, chlorampheni-col is not considered the treatment of choice for anyinfection. Alternative, less-toxic agents are available foreach indication. For the penicillin-allergic patient,chloramphenicol can be used for bacterial meningitis.Chloramphenicol can also be used as alternative ther-apy for brain abscess, C. perfringens, psittacosis, rick-ettsial infections including Rocky Mountain spottedfever, Vibrio vulniﬁcus, and typhoid fever. Figure 1–7. Basic structure of the quinolones.QuinolonesTables 1.14 and 1.15, together with Figure 1.5, summa-rizes the characteristics of the quinolone antibiotics. formed DNA into daughter cells. The loss of these activi-CHEMICAL STRUCTURE AND MECHANISMS OF ACTION ties blocks DNA synthesis and results in rapid bacterial death. Killing is concentration-dependent.The quinolones all contain two 6-member rings (seeFigure 1.7) with a nitrogen at position 1, a carbonyl TOXICITYgroup at position 4, and a carboxyl group attached to The most common side effects are mild anorexia, nau-the carbon at position 3. Potency of the quinolones is sea, vomiting, and abdominal discomfort (Table 1.10).greatly enhanced by adding ﬂuorine at position 6, and Quinolones can result in arthropathy because of carti-gram-negative activity is enhanced by addition of a lage damage and tendonitis. Although rare, this compli-nitrogen-containing piperazine ring at position 7. cation can be debilitating, but it usually reverses weeks The quinolones inhibit two enzymes critical for DNA to months after the quinolone is discontinued. Becausesynthesis: DNA gyrase, which is important for regulating of concerns about cartilage damage in children,the superhelical twists of bacterial DNA, and topoiso- quinolones are not recommended for routine adminis-merase IV, which is responsible for segregating newly tration in pediatric patients. Gatiﬂoxacin administra- tion can be associated with severe dysregulation of glucose homeostasis and can result in either severe KEY POINTS hypo- or hyperglycemia. Fluoroquinolones are associ- ated with a concentration-dependent delay in cardiac repolarization, causing a prolongation of the QT inter- About the Chemistry, Mechanisms of Action, val—a condition that can predispose to ventricular and Toxicity of Quinolones tachycardia. In combination with other agents that effect repolarization, moxiﬂoxacin has occasionally been associated with life-threatening cardiac arrhythmias. 1. Inhibit bacterial DNA gyrase (important for coiling DNA) and topoisomerase (required to PHARMACOKINETICS segregate DNA to daughter cells). Rapidly cidal, with concentration-dependent killing. The quinolones are readily absorbed orally, but can also 2. Main side effects are be given intravenously. Ciproﬂoxacin, levoﬂoxacin, and gatiﬂoxacin are cleared primarily by the kidneys. Moxi- a) nausea and anorexia. ﬂoxacin is also partially metabolized by the liver, and b) allergic reactions (most common with gemiﬂoxacin is metabolized primarily by the liver. All gemifloxacin; less common with other quinolones demonstrate similar tissue penetration, quinolones). being concentrated in prostate tissue, feces, bile, and c) Arthropathy and tendonitis. May damage lung tissue. These drugs tend to be very highly concen- cartilage. Not routinely recommended in trated in macrophages and neutrophils. children. d) Gatifloxacin can cause hypo- or hyper- SPECTRUM OF ACTIVITY AND glycemia. TREATMENT RECOMMENDATIONS e) Moxiﬂoxacin prolongs the QT interval. Ciproﬂoxacin—Ciproﬂoxacin is the most potent quinolone for P. aeruginosa (Table 1.15, Figure 1.5). As a
36 / CHAPTER 1Table 1.14. Quinolones, Linezolid, Quinupristin/Dalfopristin, Daptomycin, Metronidazole, and Sulfano-mides: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Half- Dose Dose for reduced Costa Spectrum (trade name) life (loading/ creatinine clearance (h) maintenance) (mL/min) Ciproﬂoxacin 4 250–750 mg 10–50: q18h PO: $$$ Moderately (Cipro) PO q12h, or <10: q24h IV: $–$$ broad 200–400 mg IV q12h Levoﬂoxacin 6–8 500 mg PO or IV q24h 10–50: 250 mg q24h PO: $$$ Broad (Levoquin) <10: 250 mg q48h IV: $ Gatiﬂoxacin 6–8 400 mg PO or IV q24h 10–50: 200 mg q24h PO: $$ Very broad (Tequin) <10: 200 mg q24h IV: $ Moxiﬂoxacin 6–8 400 mg PO q24h No change required PO: $$ Very broad (Avelox) IV: $ Gemiﬂoxacin 7 320 mg PO q24h 10–50: 160 mg q24h $$$$$ Broad (Factive) <10: 160 mg q24h Linezolid 5 600 mg PO or IV q12h No change required PO: $$$$$ Narrow (Zyvox) IV: $$$$ Quinupristin/ 1.5 7.5 mg/kg IV q8–12h No change required $$$$$ Narrow dalfopristin (Synercid) Daptomycin 8–9 4 mg/kg IV q24h <30: q48h $$$$–$$$$$ Narrow (Cubicin) (soft-tissue infection) 6 mg/kg IV q24h (Staphylococcus aureus bacteremia) Metronidazole 6–14 500 mg PO q8h, or No change required. $ Narrow (Flagyl, 500 mg–1 g PO q12h In severe hepatic failure, Protostat, 15 mg/kg followed by half the dose. Metronid) 7.5 mg/kg IV q6h or 15 mg/kg q12h (not to exceed 4 g) Sulﬁsoxazole 1–2 g PO q6h 10–50: 1 g $ Moderately q8–12h Broad <10: 1 g q12–24h Sulfadiazine 0.5–1.5 g PO q 4–6h 10–50: 0.5– $$ Moderately 1.5 g q8–12h Broad <10: 0.5–1.5 g q12–24h Trimethoprim– 2–4 tablets q24h or Half the oral dose, and $ Moderately sulfamethoxazole 1–2 DS PO q24h reduce the IV dose to Broad Trimethoprim: 10–50: 3–5 mg/kg q12–24h 3–5 mg/kg IV q6–12h <10: Don’t givea Intravenous preparations (daily cost dollars): $ = 20–70; $$ = 71–110; $$$ = 111–150; $$$$ = 150–200; $$$$$ ≥ 200; oralpreparations (10-day course cost dollars): $ = 10–50; $$ = 51–100; $$$ = 101–140; $$$$ = 141–180; $$$$$ ≥ 180.
ANTI-INFECTIVE THERAPY / 37 Table 1.15. Organisms That May Be Susceptible to the Quinolones Ciproﬂoxacin Levoﬂoxacin, Gemiﬂoxacin, Gatiﬂoxacin, Moxiﬂoxacin Pseudomonas aeruginosa Same as ciproﬂoxacin, plus: Escherichia coli Methicillin-sensitive Enterobacter cloacae Staphylococcus aureus Proteus spp. Streptococcus pneumoniae Providencia Vancomycin-sensitive Enterococcus Salmonella, including Sal. typhi Strep. pyogenes Shigella spp. Gatiﬂoxacin and moxiﬂoxacin: anaerobes Yersinia spp. Campylobacter spp. Bacillus anthracis Mycoplasma pneumoniae Chlamydia spp. Ureaplasma urealyticum Bartonella henselae Neisseria gonorrhoeaeresult of an excellent gram-negative spectrum, thought to include anaerobes. The exact indicationsciproﬂoxacin is one of the primary antibiotics recom- for these agents are currently evolving. Fear of select-mended for treatment of urinary tract infections. It ing for resistant pathogens has led to their use beingconcentrates in the prostate and is recommended for treat- restricted in some hospitals.ment of prostatitis. For gonococcal urethritis, it is a usefulalternative to ceftriaxone. Ciproﬂoxacin has been used Oxazolidones (Linezolid)effectively for traveler’s diarrhea most commonly causedby enterotoxigenic E. coli and Shigella. It is the drug of CHEMISTRY AND MECHANISMS OF ACTIONchoice for Salmonella typhi (typhoid fever), and it also is The oxazolidones have a unique ring structure con-recommended for treatment of Salmonella gastroenteritis sisting of a 5-member ring containing an oxygen andwhen antibiotic treatment is necessary. Ciproﬂoxacin is a nitrogen. The nitrogen connects to a 6-memberthe recommended treatment for cat scratch disease caused ring, and each specific compound has side chainsby Bartonella henselae. added to both rings at positions A and B (Figure 1.8). Levofloxacin, Moxifloxacin, Gatifloxacin, and These agents bind to the 50S ribosome at a site simi-Gemiﬂoxacin—These agents all demonstrate impro- lar to that used by chloramphenicol. However, unlikeved gram-positive coverage (Table 1.15, Figure 1.5) chloramphenicol, they do not inhibit the attachmentand have been recommended as one of the ﬁrst-line of tRNA, but instead block the initiation of proteintreatments for community-acquired pneumonia in the synthesis by preventing the nearby 30S subunit fromotherwise healthy adult who does not require hospital-ization. With the exception of gemifloxacin, theseagents can also be used in soft-tissue infection in whicha combination of gram-positive and gram-negativeorganisms is suspected. Given the worse toxicityproﬁles of the three newer agents (moxiﬂoxacin, gati-floxacin, and gemifloxacin), levofloxacin shouldprobably be the ﬂuoroquinolone of choice for thoseinfections. Gatiﬂoxacin and moxiﬂoxacin demonstratemoderate in vitro activity against anaerobes and may Figure 1–8. Basic structure of thebe considered for the treatment of mixed infections oxazolidones.
38 / CHAPTER 1 KEY POINTS KEY POINTS About the Speciﬁc Quinolones About Linezolid 1. Ciproﬂoxacin: 1. Like chloramphenicol, binds to the 50S ribo- a) Excellent coverage of Pseudomonas. Also some subunit; inhibits the initiation of protein covers many other gram-negative organisms synthesis. including Esch. coli, Salmonella, Shigella, Neis- 2. Thrombocytopenia common with treatment seria, and Legionella. exceeding 2 weeks; inhibitor of monoamine oxi- b) Kills Mycoplasma, Chlamydia, and Ure- dase; avoid tyramine, pseudoephedrine, sero- aplasma. tonin uptake inhibitors. c) Recommended for urinary tract infections 3. Strictly gram-positive activity; bacteriostatic and prostatitis, gonococcal urethritis, trav- activity for vancomycin-resistant enterococci eler’s diarrhea, typhoid fever, and Salmonella (VRE), and methicillin-resistant Staphylococcus gastroenteritis; used for cat scratch disease. aureus. Also has activity against penicillin-resis- 2. Levoﬂoxacin, gatiﬂoxacin, moxiﬂoxacin, gemi- tant Streptococcus pneumoniae. ﬂoxacin 4. Recommended for the treatment of VRE. a) Greater activity against Streptococcus pneu- moniae, covers highly penicillin-resistant strains. b) Also cover methicillin-sensitive Staphylococ- does not lower peak levels. An intravenous preparation cus aureus. is also available. Linezolid achieves excellent penetration c) Recommended for community-acquired of all tissue spaces, including the cerebrospinal ﬂuid. pneumonia (levoﬂoxacin preferred). The drug is partly metabolized by the liver and excreted d) Levoﬂoxacin, gatiﬂoxacin, and moxiﬂoxacin in the urine. recommended for mixed skin infections. ANTIMICROBIAL ACTIVITY AND e) Gatifloxacin and moxifloxacin have some- what improved anaerobic coverage. TREATMENT RECOMMENDATIONS f ) Gatiﬂoxacin and moxiﬂoxacin recommended Linezolid demonstrates activity only against gram-positive for mixed skin infections. organisms. It has bacteriostatic activity against both vancomycin-resistant Enterococcus faecium and Enterococ- cus faecalis (VRE). This agent is also active against MSSA and MRSA, and has activity against penicillin-resistantforming the 70S initiation complex. The oxazolidones S. pneumoniae. Linezolid is recommended primarily forare bacteriostatic against staphylococcal species and the treatment of VRE.enterococci. StreptograminsTOXICITYLinezolid is the only agent in this class released for use. CHEMICAL STRUCTURE AND MECHANISM OF ACTIONReversible thrombocytopenia has been reported in asso- The streptogramins belong to the macrolide family.ciation with prolonged therapy, and monitoring of They are derived from pristinamycin. Quinupristin isplatelet count is recommended for patients receiving a peptide derived from pristinamycin IA and dalfo-two or more weeks of linezolid. Leukopenia and hepatic pristin is derived from pristinamycin IIB. A combina-enzyme elevations have also been reported. Because this tion of 30:70 quinupristin:dalfopristin has synergisticagent is a weak inhibitor of monoamine oxidase, hyper- activity and has been named Synercid. These twotension has been reported in association with ingestion agents inhibit bacterial protein synthesis by bindingof large amounts of tyramine. Pseudoephedrine and to the 50S bacterial ribosome. Quinupristin inhibitsselective serotonin reuptake inhibitors should be pre- peptide chain elongation, and dalfopristin interferesscribed with caution. with peptidyl transferase activity.PHARMACOKINETICS TOXICITYLinezolid is well-absorbed orally, and peak serum levels Myalgias and arthralgias are the most common and severeare achieved in 1 to 2 hours. Food slows absorption, but adverse reaction, and they can force discontinuation of
ANTI-INFECTIVE THERAPY / 39 in creatine phosphokinase (CPK; Table 1.10). The KEY POINTS patient’s CPK levels should be monitored weekly, and the drug should be discontinued if CPK exceeds 1000 About Synercid in association with symptoms of myopathy, or if CPK exceeds 2000 in the absence of symptoms. Other drugs associated with rhabdomyolysis, specifically 1. Combination of two pristinamycin derivatives: quinupristin and dalfopristin. Together, they HMG-CoA reductase inhibitors (statins), should not synergistically block protein synthesis. Both be administered with daptomycin. Less commonly, bind to the 50S ribosomal subunit. daptomycin administration has resulted in neuropa- thy associated with a slowing of nerve conduction 2. Myalgias and arthralgias can force discontinua- tion of the drug. Nausea, vomiting, and diarrhea velocity. The peripheral or cranial nerves can be also occur. affected. Patients may experience paresthesia or Bell’s palsy. This rare toxicity has also been observed in ani- 3. Spectrum of activity: covers primarily gram- mal studies. positive bacteria. Active against vancomycin- resistant enterococci (VRE) and methicillin- PHARMACOKINETICS resistant Staphylococcus aureus. Daptomycin is given intravenously, and a 4-mg/kg dose 4. Recommended for the treatment of VRE. achieves peak serum levels of 58 g/mL (Table 1.14). Daptomycin is 92% protein-bound and is excreted by the kidneys. Its ability penetrate various tissue compart- ments including the cerebrospinal ﬂuid has not beenthe drug (Table 1.10). Administration has also been asso- extensively studied.ciated with hyperbilirubinemia. SPECTRUM OF ACTIVITY ANDPHARMACOKINETICS TREATMENT RECOMMENDATIONSThe streptogramins are administered intravenously, Daptomycin kills aerobic and facultative gram-and they are metabolized primarily in the liver positive organisms, including Enterococcus faecium and(Table 1.14). faecalis (including VREs), S. aureus (including MRSA), S. epidermidis (including methicillin-resistant strains),ANTIMICROBIAL ACTIVITY AND TREATMENT INDICATIONSSynercid is active primarily against gram-positive organ-isms (Figure 5.1). It has proved to be efﬁcacious in thetreatment of VRE and MRSA. Synercid or linezolid are KEY POINTSthe treatments of choice for VRE. About DaptomycinDaptomycinCHEMICAL STRUCTURE AND MECHANISM OF ACTION 1. Large, cyclic lipopeptide that binds to andDaptomycin is a large cyclic lipopeptide (C72H101N17O26) depolarizes bacterial membranes.with a molecular weight of 1620 that was derived from 2. Rapidly cidal, concentration-dependent killing;Streptomyces roseosporus. Daptomycin has a mechanism of post-antibiotic effect.action that is distinctly different from that of other antibi- 3. Toxicities include muscle pain and weaknessotics. It binds to bacterial membranes and causes rapid associated with creatine phosphokinase leak;depolarization of the membrane potential. As a result, pro- no co-administration of statins. Less common:tein, DNA, and RNA synthesis is inhibited. This antibi- peripheral or cranial nerve neuropathy.otic is cidal and causes rapid concentration-dependent 4. Kills enterococci (including VRE), Staphylococcuskilling, but it does not result in the systemic release of cell aureus (including MRSA), Staphylcoccusmembrane or cell wall contents. It also demonstrates sig- epidermidis, Streptococcus pyogenes, andniﬁcant post-antibiotic effect. Synergy with aminoglyco- corynebacteria.sides, -lactam antibiotics, and rifampin has been 5. Approved to treat complicated skin andobserved. soft-tissue infections, and S. aureus (including MRSA) bacteremia and right-sided endocarditis.TOXICITY 6. Inactivated by surfactant; should not be used toMuscle pain and weakness are reported in less than treat pneumonia.5% of patients. This drug is also associated with a rise
40 / CHAPTER 1S. pyogenes, and Corynebacterium jeikeium (Figure 1.5). PHARMACOKINETICSIt is approved for the treatment of complicated skin and This agent is rapidly and completely absorbed orally,soft?tissue infections by susceptible strains and for but it can also be given intravenously. Therapeutic levelsS. aureus (including MRSA) bacteremia and right-sided are achieved in all body fluids, including the cere-endocarditis. It is not currently approved for VRE, brospinal ﬂuid and brain abscess contents. Metronida-because of insufﬁcient clinical data. Daptomycin is inac- zole is metabolized primarily in the liver.tivated by surfactant and should not be used for thetreatment of pneumonia. SPECTRUM OF ACTIVITY AND TREATMENT RECOMMENDATIONSMetronidazole Metronidazole was originally used primarily for Trichomonas vaginitis, being effective both topically andCHEMICAL STRUCTURE AND MECHANISM OF ACTION orally. It is also effective for treating amoebic abscesses andMetronidazole is a nitroimidazole with a low molecular giardiasis. Metronidazole is cidal for most anaerobic bac-weight that allows it to readily diffuse into tissues. teria, and it is the antibiotic of choice for covering anaer-Within a bacterium, this antibiotic acts as an electron obes. Because metronidazole has no signiﬁcant activityacceptor and is quickly reduced. The resulting free rad- against aerobes, it is usually administered in combinationicals are toxic to the bacterium, producing damage to with a cephalosporin for aerobic coverage. MetronidazoleDNA and to other macromolecules. Metronidazole has is the drug of choice for treatment of pseudomembranoussigniﬁcant activity against anaerobes. colitis attributable to overgrowth of C. difﬁcile. Metron- idazole is also recommended as part of the regime forTOXICITY Helicobacter pylori gastric and duodenal infection.Metronidazole is usually well tolerated, but it can resultin a disulﬁram (Antabuse–like) reaction with alcoholconsumption (Table 1.10). Concern about the muta- Sulfonamides and Trimethoprimgenic potential of this agent has resulted in multiple CHEMICAL STRUCTURE AND MECHANISMS OF ACTIONmammalian studies that, overall, have failed to demon- The sulfonamides all have a structure similar to para-strate signiﬁcant DNA abnormalities. Metronidazole is aminobenzoic acid (PABA), a substrate required for bac-not recommended in pregnancy, and it should usually terial folic acid synthesis (Figure 1.9). All sulfonamidesbe avoided in patients on Coumadin, because it impairs inhibit bacterial folic acid synthesis by competitivelymetabolism of that drug. inhibiting PABA incorporation into tetrahydropteroic acid. These agents are bacteriostatic. A sulfonyl radical is attached to carbon 1 of the 6-member ring, increasing PABA inhibition. Alterations in the sulfonyl radical determine many of the pharma- KEY POINTS cokinetic properties of the compounds. Trime-thoprim consists of two 6-member rings, one of which has two About Metronidazole nitrogens and two amino groups, the other having three methoxybenzyl groups. This agent strongly inhibits 1. Electron acceptor; produces free radicals that dihydrofolate reductase and complements sulfonamide damage bacterial DNA. inhibition of folate metabolism (Figure 1.9). Inhibition of bacterial dihydrofolate reductase by trimethoprim is 2. Antabuse-like reaction can occur; mutagenic effects not proven in mammals, but the drug 100,000 times that of the agent’s inhibition of the should be avoided in pregnancy. Impairs mammalian enzyme, minimizing toxicity to the patient. Coumadin metabolism. 3. Excellent activity against anaerobes, amoebae, Giardia, and Trichomonas. Penetrates tissues well, including abscesses. 4. Indicated in combination with other antibiotics for mixed bacterial infections. Has no activity against aerobic bacteria. 5. Treatment of choice for Clostridium difficile– induced diarrhea. Used as part of combination treatment for Helicobacter pylori. Figure 1–9. Effects of sulfonamides and trimetho- prim on the bacterial folate pathway.
ANTI-INFECTIVE THERAPY / 41 Table 1.16. Organisms That May Be Susceptible to Trimethoprim/Sulfa Usually susceptible Some susceptible Streptococcus pyogenes Staphylococcus aureus Listeria monocytogenes (including community-acquired Bacillus anthracis methicillin-resistant strains) Shigella spp. Strepococcus pneumoniae Haemophilus inﬂuenzae Proteus mirabilis Neisseria meningitidis Klebsiella spp. Chlamydia trachomatis Salmonella Burkholderia cepacia Neisseria gonorrhoeae Stenotrophomonas maltophilia Yersinia enterocolitica Nocardia spp.TOXICITY effective for the empiric treatment of uncomplicated uri-Hypersensitivity reactions represent the most severe toxic- nary tract infections; however, because of widespread resis-ity (Table 1.10). Maculopapular drug rashes, erythema tance, they are seldom used as empiric therapy in othermultiforme, Steven–Johnson syndrome, vasculitis (includ- infections. Sulfonamides are the treatment of choice foring drug-induced lupus), serum sickness-like syndrome, Nocardia asteroides, and are useful in combination withand anaphylaxis have been reported. Hemolytic anemia other agents for the treatment of M. kansasii.can be associated with glucose-6-phosphate dehydroge- Trimethoprim is generally administered in combina-nase (G6PD) deﬁciency. Sulfonamides should be avoided tion with sulfamethoxazole. This combination oftenin the last month of pregnancy because they displacebilirubin bound to plasma albumin and increase fetalblood levels of unconjugated bilirubin. KEY POINTSPHARMACOKINETICSSulfonamides are classiﬁed as short-, medium-, or About Sulfonamideslong?acting, depending on half-life. Sulﬁsoxazole is in theshort-acting class, having a half-life of 5 to 6 hours. 1. Competitively inhibit para-aminobenzoic acidSulfamethoxazole and sulfadiazine are medium-acting. incorporation, blocking folic acid synthesis;All of these agents are generally well absorbed orally. trimethoprim inhibits dihydrofolate reductase,Intravenous preparations are available for some agents. potentiating sulfonamide activity.All are metabolized by the liver, undergoing acetylation 2. Hypersensitivity reactions (including Steven–and glucuronidation, with the metabolites being excreted Johnson syndrome) are common; hemolyticin the urine. Trimethoprim is excreted primarily by the anemia seen in G6PD-deﬁcient patients. Agran-renal tubules, and very high concentrations of active drug ulocytosis and thrombocytopenia are lessare found in the urine. Some trimethoprim is also common.excreted in bile. The half-life of trimethoprim is 9 to 11 3. Broad spectrum of activity for gram-positivehours matching the half-life of sulfamethoxazole. The and gram-negative organisms, but resistance isratio of trimethoprim to sulfamethoxazole supplied is 1:5. common. 4. Used for initial therapy of uncomplicated uri-SPECTRUM OF ACTIVITY AND nary tract infections. Treatment of choice forTREATMENT RECOMMENDATIONS Nocardia.The sulfonamides demonstrate activity against gram-posi- 5. Trimethoprim–sulfamethoxazole combinationtive and gram-negative organisms; however, resistance in is the drug of choice for Pneumocystis prophy-both community and nosocomial strains is widespread laxis and treatment.(Table 1., Figure 1.5). Sulfonamides have proved to be
42 / CHAPTER 1results in significantly improved activity. Trimetho-prim–sulfamethoxazole (TMP-SMX) demonstrates KEY POINTSexcellent activity against Listeria monocytogenes, and it isthe antibiotic of choice in the penicillin-allergic patient About the Mechanism of Action andwith listeriosis. It can be used to treat a number of other Spectrum of Amphotericin Bgram-positive and gram-negative pathogens. However,plasmid-mediated resistance is common, and treatmentfor most pathogens should be initiated only after sensi- 1. Polyene compound forms rod-like structurestivity is conﬁrmed by microbiologic testing. This com- that bind to ergosterol in the fungal membrane,bination is highly effective for killing Pneumocystis forming pores that result in a leak of intracellu-carinii, and TMP-SMX is the drug of choice for treat- lar potassium.ment or prophylaxis of that infection in immunocom- 2. Rapidly cidal; does not require active growth.promised hosts, including patients with AIDS.ANTIFUNGAL AGENTS intracellular potassium and in fungal cell death. ThisFungi are eukaryotes, and they share many of the struc- fungicidal action is rapid and does not require activetural and metabolic characteristics of human cells. As a growth.result, designing agents that affect fungi without harming Toxicity—Nephrotoxicity is the major complicationhuman cells has proved difﬁcult. One major difference associated with the conventional deoxycholate form ofbetween the two cell types is the primary sterol building amphotericin B. This agent causes vasoconstriction ofblock used to form the plasma membrane. The fungal renal arterioles, resulting in a reduction in glomerularplasma membrane consists of ergosterols; the major sterol ﬁltration rate. Vasoconstriction also impairs proximalcomponent of the human plasma membrane is choles- and distal tubular reabsorption, causing potassium,terol. This difference has been exploited in the develop- magnesium, and bicarbonate wasting. These effects arement of two classes of drugs. The polyenes act by binding reversible. However, permanent loss of nephrons andto ergosterol and disrupting the fungal membrane. These permanent damage to tubular basement membranes areagents are fungicidal. The azoles inhibit ergosterol synthe- also observed and correlate with the total dose adminis-sis, and lowered ergosterol levels results in fungal mem- tered. Renal dysfunction is observed in virtually allbrane breakdown. These agents are usually fungistatic. patients receiving this drug, and serum creatinine levels of 2 to 3 mg/dL are to be expected. Hydration with nor- mal saline before infusion reduces nephrotoxicity. Fever is commonly associated with administration of THE MAJOR DIFFERENCE amphotericin B, and fever can be associated with chills BETWEEN MAMMALIAN and tachypnea, particularly if the drug is infused too AND FUNGAL CELLS rapidly. This agent should be infused slowly [2 to 3 hours for the deoxycholate form (ABD) and under 2 hours for the lipid preparations]. Fever and chills usually diminish Like mammals, fungi are eukaryotes. Drug therapy with each subsequent dose. However, if those reactions takes advantage of fact that fungi use ergosterols persist, the patient can be premedicated with aceta- rather than cholesterol as the major building block minophen or 25 to 50 mg hydrocortisone can be added to of their plasma membrane. the solution. This febrile reaction does not represent an allergic reaction and should not be misinterpreted as ana- phylaxis. A 1 mg test dose preceding administration of the full dose has not proved to be helpful, and use of a test dose delays achievement of therapeutic antifungal serumAgents for Treatment of Systemic and tissue levels. Because of a high incidence of phlebitis,Fungal Infections amphotericin B should be administered through a cen- trally placed intravenous line.AMPHOTERICIN B Pharmacokinetics—At physiologic pH, ABD isChemical Structure, Mechanism of Action, and Spec- insoluble in water (Table 1.17). It is stored as a powdertrum of Activity—Amphotericin B is a long, cyclic that is dispersed as colloidal suspension in a 5% dex-polyene compound that forms a large rod-like struc- trose solution. Following intravenous infusion, ampho-ture. Multiple molecules bind to ergosterol in the fun- tericin B is bound to lipoproteins in the serum andgal membrane, forming pores that result in leakage of then leaves the circulation. The drug is stored in the
ANTI-INFECTIVE THERAPY / 43Table 1.17. Toxicities of Systemic Antifungal Agents Clinical symptom Antifungal agent Amphotericin B lipid Amphotericin B Posaconazole Ketoconazole Voriconazole Caspofungin Itraconazole Fluconazole Flucytosine Allergic skin rash Anaphylaxis Stevens–Johnson Pruritus Hypotension Fever and chills Nausea and vomiting Diarrhea Headache Seizures Visual disturbances Other neurotoxicity Phlebitis Alopecia (reversible) Adrenal insufﬁciency Gynecomastia Impotence Leg edema Laboratory tests: Renal tubular acidosis Proteinuria Hypokalemia Creatinine↑ Anemia Other cytopenias Eosinophilia AST/ALT↑ ALP↑ Drug–drug interactionsBlack = principle side effect; dark gray = less common side effect; light gray = rare side effect; white = not reported or veryrare; ↑ = rise; AST/ALT = aspartate aminotransferase/alanine transaminase; ALP = alkaline phosphatase.
44 / CHAPTER 1liver and other organs and subsequently released into effective agent for systemic fungal infections. Clinicalthe circulation. resistance to amphotericin B has been demonstrated Lipid-associated amphotericin B is ingested by among Candida lusitaniae, Fusarium species, andmacrophages, resulting in high intracellular levels in Pseudalles-cheria boydii. C. lusitaniae initially is suscepti-that cell type. This drug shows poor penetration of the ble to amphotericin B, but develops resistance duringblood–brain barrier and brain. Therapeutic levels are treatment. The alterations in sterol structure requireddetectable in inﬂamed pleural ﬂuid, peritoneum, and for amphotericin B resistance often reduce tissue inva-joint fluid. Amphotericin B is degraded slowly, and siveness, such strains being capable of growing only ondegradation is not affected by hepatic or renal dysfunc- mucosal surfaces or in the urine.tion. Serum concentrations of the drug are detectable Efﬁcacy of Various Amphotericin B Preparations—7 weeks after therapy is discontinued. Lipid-associated preparations of amphotericin B are pre- Spectrum of Activity—Amphotericin B is effective ferred because of their lower nephrotoxicity. However,against most fungal infections and remains the most these preparations are very expensive (Table 1.18) andTable 1.18. Systemic Antifungal Agents: Half-Life, Dosing, Renal Dosing, and Cost Antifungal Half-life Dose Dose for reduced Costa (trade name) (h) creatinine clearance (mL/min) Amphotericin B 15 d 0.3–1.0 mg/kg IV q24h No change required $ deoxycholate (infuse over 4–6 h) (Fungizone) Amphotericin B 7d 3–5 mg/kg IV q24h No change required $$$$$ lipid preparations (Abelcet, Amphotec, AmBisome) Fluconazole 20–50 100–200 mg PO 10–50: Half the dose $$–$$$ (Diﬂucan) q12–24h 10: One quarter to half 200–400 mg IV q24h the dose Ketoconazole 1–4 200–400 mg PO q12–24h No change required $–$$$ (Nizoral) Itraconazole 20–60 100–200 mg PO q12–24h 30: Contraindicated $$$$–$$$$$ (Sporanox) 200 mg IV q12h 4, then 200 mg q24h Posaconazole 35 200 mg PO q6h, or No change required $$$$$ (Noxaﬁl) 400 mg PO q12h Voriconazole Nonlinear 200 mg PO q12h 50: IV not $$$$$ (Vfend) kinetics 6 mg/kg IV q12h 2, recommended; then 4 mg/kg q12h switch to oral Anidulafungin 10–15 200 mg IV, then No change required $$$$ (Eraxis) 100 mg q24h Caspofungin 9–11 70 mg IV, then No change required $$$$$ (Cancidas) 50 mg q24h Micafungin 14–17 150 mg IV q24h No change required $$$$$ (Mycamine) Flucytosine 3–6 25–33 mg/kg PO q6h 10–50: 25 mg/kg $$$$$ (Ancobon) q12–24h 25 mg/kg q24h (<10)a Intravenous preparations (daily cost dollars): $ = 20–70; $$ >71–110; $$$ = 111–150; $$$$ = 150–200; $$$$$ ≥ 200; oralpreparations (10-day course cost dollars): $ = 10–50; $$ = 51–100; $$$ = 101–140; $$$$ = 141–180; $$$$$ ≥ 180.
ANTI-INFECTIVE THERAPY / 45 renal dysfunction (50% increase in baseline creatinine KEY POINTS to a minimum of 2 mg/ml) is associated with a 6.6-fold increased risk of death. About the Toxicity of Amphotericin B AZOLES Chemical Structure and Mechanism of Action—The 1. Nephrotoxicity is observed with virtually all azoles are chemically synthesized agents that come in patients receiving amphotericin B deoxycholate two classes. The ﬁrst to be synthesized were the imi- (ABD); reduced by hydration using normal saline. dazoles (miconazole and ketoconazole). Those com- Reversible in most cases. Permanent damage with prolonged therapy. pounds are now seldom used for systemic infections, being primarily reserved for topical treatment of 2. Fever is common with all preparations. Slow superﬁcial fungal infections. The second class, the tri- infusion (2 to 3 hours with ABD, less than azoles, are preferred for systemic fungal infection; 2 hours with liposomal preparations) reduces severity. Premedication with corticosteroids or they are well absorbed orally and have excellent toxic- acetaminophen, or both, often reduce fever. ity proﬁles. All azoles inhibit a cytochrome P450–dependent 3. Phlebitis is common, requiring administration demethylation system that results in decreased produc- by central intravenous line. tion of ergosterol and accumulation of intermediate sterols. The loss of ergosterol results in altered fungal membrane permeability, disturbed activity of mem-in most clinical trials have comparable efficacy to brane surface enzymes, and retention of metabolites.amphotericin-B deoxycholate. Liposomal amphotericin These agents have broad antifungal activity, but theyB was shown to be superior to ABD for the treatment of demonstrate fungistatic rather than fungicidal activity.pulmonary histoplasmosis. The lipid-associated prepa- Itraconazole can antagonize amphotericin B activity byrations are recommended in patients with signiﬁcant reducing its binding target, ergosterol.preexisting renal dysfunction or in patients who develop Toxicity—Ketoconazole not only interferes withprogressive renal failure (serum creatinine above fungal sterol metabolism, but at higher doses it also2.5 mg/dl) while being treated ABD. Clinicians also interferes with testosterone and cortisone productionneed to be aware of the observation that ABD-related (Table 1.17). Gynecomastia and loss of libido are com- monly observed. Severe hepatitis can develop during treatment with this agent. As a result of its many toxic- ities, ketoconazole is rarely prescribed today. KEY POINTS The triazoles (ﬂuconazole, itraconazole, posacona- zole, voriconazole) demonstrate minimal toxicity. Side About Amphotericin Spectrum of effects include headache, gastrointestinal intolerance, and asymptomatic increases in serum transaminase lev- Activity and Preparations els. Voriconazole infusion can be associated with tran- sient loss of light perception. This symptom resolves 1. Preferred antifungal agent for severe systemic with subsequent doses. Visual hallucinations less com- fungal infections. monly occur. 2. Effective against most fungi except Candida lusitaniae, Fusarium, and Pseudallescheria boydii. 3. Lipid-associated preparations reduce nephro- KEY POINTS toxicity, but similar incidence of fever, with efﬁ- cacy comparable to conventional amphotericin B deoxycholate (ABD). About the Mechanism of Action of the Azoles 4. Higher doses of lipid-associated preparations required: 3 to 5 mg/kg daily as compared with 1. Inhibit cytochrome P450–dependent demethy- 0.3 to 1.4 mg/kg for ABD. lation, resulting in decreased ergosterol produc- 5. Very high cost. Recommended for patients with tion and altered fungal membrane permeability. significant pre-existing renal dysfunction or 2. Azoles are usually fungistatic. those who develop progressive renal dysfunc- 3. Itraconazole can antagonize amphotericin B tion on ABD (serum creatinine >2.5 mg/dL). activity by reducing its binding target.
46 / CHAPTER 1 Pharmacokinetics—Fluconazole is well absorbedorally, and serum levels after ingestion of the oral prepa- KEY POINTSration are comparable to those with intravenous admin-istration. Penetration into tissues and body ﬂuids, About the Spectrum of Activity andincluding the cerebrospinal ﬂuid, is excellent. Itracona- Indications for Fluconazolezole is more variable in its oral absorption and requiresstomach acidity for adequate absorption. Capsuleabsorption is enhanced by food and reduced by agents 1. No activity against Aspergillus. Active againstthat reduce stomach acidity. Itraconazole penetrates most Candida albican, but natural resistance intissues, but does not cross the blood–brain barrier and C. glabrata and C. krusei is common. Activeenters ocular ﬂuids only minimally. Posaconazole oral against Cryptococcus neoformans.absorption is enhanced by food, particularly high-fat 2. With prolonged treatment, drug resistance canmeals or liquid nutritional supplements. Voriconazole is develop in Candida species.well absorbed orally, demonstrating 96% bioavailability, 3. Treatment of choice for oral candidiasis andand also can be given intravenously. Candida vulvovaginitis. All of the azoles are metabolized by the liver via the 4. Can be used for uncomplicated C. albicanscytochrome P450 system, and as a consequence, fungemia in the non-immunocompromiseddrug–drug interactions are common with these agents. patient.Rifampin, rifabutin, long-acting barbiturates, carba- 5. Can be used to complete therapy of cryptococ-mazepine, and cisapride usually lower azole levels. The cal meningitis in HIV patients after an initialazoles slow the metabolism of Coumadin, warfarin, course of amphotericin B.phenytoin, tacrolimus, cyclosporine, certain antihista- 6. Prophylaxis reduces Candida infections in neu-mines, benzodiazepines, calcium channel blockers, tropenic patients. The role of prophylaxis insulfonylureas, prednisolone, digoxin, statins, and anti- other settings remains controversial because ofHIV protease inhibitors. The doses of these agents the risk of selecting for resistant strains.usually need to be lowered in the presence of azoles.Drug–drug interactions have proven to be the mostproblematic with voriconazole. Voriconazole is metab-olized primarily by the P450 enzyme CYP2C19, and patient’s genetic background. As a consequence, serumthat enzyme has variable activity depending on the levels can vary by up to a factor of 4 in individuals with rapid as opposed to slow metabolism. In the United States, the co-administration of rifabutin and voriconazole is contraindicated because rifabutin levels KEY POINTS may increase by a factor of 3, while voriconazole levels drop below therapeutic levels. Rifampin, carba- mazepines, and long-acting barbiturates can also About Azole Toxicity markedly reduce voriconazole levels, and these drugs should probably be discontinued when voriconazole is 1. Ketoconazole interferes with testosterone and being administered. cortisone production, resulting in gynecomastia Spectrum of Activity and Treatment Recommenda- and loss of libido. Hepatitis can be severe, and tions—Fluconazole—Fluconazole has no activity the drug should be discontinued when symp- against Aspergillus species, and some strains of Candida, toms of hepatitis develop. Liver function tests including C. glabrata and C. krusei, demonstrate natural should be performed. resistance. Because of increased production of demethy- 2. Rare side effects of fluconazole, itraconazole, lase and increased drug efﬂux, any Candida species can posaconazole, and voriconazole include head- develop resistance. ache, gastrointestinal intolerance, asympto- Fluconazole is recommended for the treatment of matic elevation of serum transaminases. oropharyngeal and vulvovaginal candidiasis. Intra- 3. Intravenous infusion of voriconazole can be asso- venous ﬂuconazole has proved therapeutically equiva- ciated with transient loss of light perception. lent to amphotericin B in uncomplicated candidemia 4. Drug–drug interactions with other agents in the non-immunocompromised host. However, for metabolized by the cytochrome P450 system the immunocompromised (including neutropenia) are common, particularly with voriconazole and host, and for seriously ill patients with deep tissue ketoconazole. Candida infection, amphotericin B or caspofungin should be used. Fluconazole is also effective for
ANTI-INFECTIVE THERAPY / 47 fungi, ﬂuconazole prophylaxis is not recommended in KEY POINTS patients infected with HIV. Itraconazole—As compared with ﬂuconazole, itra- About the Spectrum of Activity and Indications conazole has demonstrated improved activity against for Itraconazole histoplasmosis, coccidiomycosis, blastomycosis, and sporotrichosis. Itraconazole can be used for acute and chronic vaginal candidiasis and HIV-associated oral 1. Improved activity against histoplasmosis, coc- and esophageal candidiasis, and for consolidation and cidiomycosis, blastomycosis, and sporotrichosis. maintenance therapy for cryptococcal meningitis in 2. Used in less severe cases of histoplasmosis and patients with AIDS. Itraconazole is the preferred agent coccidiomycosis. for the treatment of lymphocutaneous sporotrichosis 3. Used to prevent relapse of disseminated histo- and of non-meningeal, non-life-threatening histoplas- plasmosis in patients with AIDS. mosis, blastomycosis, and coccidiomycosis. For dis- 4. Absorption of the drug is erratic. seminated histoplasmosis and coccidiomycosis, amphotericin B remains the treatment of choice. Itra- conazole is recommended as primary prophylaxis and for the prevention of relapse of histoplasmosis in patients with AIDS.completing the treatment of cryptococcal meningitis Voriconazole and Posaconazole—As compared within patients with AIDS. After initial therapy with amphotericin B deoxycholate, voriconazole demon-amphotericin B, with or without flucytosine, for 2 strates increased activity against Aspergillus and hasweeks, fluconazole (400 mg daily) treatment for 2 proven to be superior for the treatment of invasivemonths, followed by daily fluconazole maintenance aspergillosis. Voriconazole is also approved for the treat-therapy (200 mg daily), is recommended. The role of ment of Fusarium and Scedosporium. Clinical trialsﬂuconazole in patients with non-AIDS-related cryp- exploring the efﬁcacy of voriconazole for invasive can-tococcal infection has not been deﬁned. didiasis are currently under way. The use of fluconazole for prevention of fungal The newest azole, posaconazole, has the broadestinfections has been explored in neutropenic allogeneic spectrum in the class. In addition to being effectivebone marrow transplant patients and was found to against Aspergillus, this agent has activity against manyreduce mortality and the incidence of invasive Can- of the Zygomycetes. Posaconazole is currently approved asdida infections, but no effect on the incidence of salvage therapy for mucormycosis.Aspergillus infections was observed. Fluconazole pro-phylaxis of leukemia patients also reduced the inci- CASPOFUNGIN/ANIDULAFUNGIN/MICAFUNGINdence of invasive Candida infections, but had no effect Chemical Structure and Mechanism of Action—Theon mortality. Fluconazole is frequently used in the sur- echinocandins are all derived from echinocandin B, agical intensive care unit in the hopes of preventingcandidemia in patients. To date, such prophylaxis hasnot been proved to signiﬁcantly reduce Candida infec-tions, and this practice increases the prevalence of KEY POINTSfluconazole-resistant fungi, including C. krusei andC. glabrata. Because of the risk of selecting for resistant About the Echinocandins 1. Block synthesis of a cell wall polysaccharide KEY POINTS vital to many pathogenic fungi. 2. Active against Aspergillus and Candida, includ- ing isolates resistant to other antifungal agents. About the Spectrum of Activity of Voriconazole Not active against Cryptococcus. and Posaconazole 3. Toxicities tend to be mild. 4. Recommended for the treatment of invasive 1. Voriconazole is preferred for Aspergillus and Aspergillus in patients who have failed on, or active against Candida albicans. cannot tolerate, amphotericin B and for oral and 2. Posaconazole has activity against Aspergillus esophageal candidiasis refractory to azoles and and Zygomyces (broadest-spectrum azole). amphotericin B.
48 / CHAPTER 1semisynthetic lipopeptide that blocks synthesis of Caspofungin can also be used to treat oral candidiasis -(1,3)-D-glucan. That polysaccharide is a critical com- that is refractory to azole or amphotericin B therapy.ponent of the cell wall in many pathogenic fungi. Toxicity—The echinocandins have proven to be very FLUCYTOSINEsafe, provoking only the occasional fever, rash, or ﬂush- Chemical Structure and Mechanism of Action—Flucyto-ing of the face during infusion (Table 1.17). Serum lev- sine, or 5-ﬂuorocytosine (5-FC), is a ﬂuorine analog ofels are increased by co-administration of cyclosporin. cytosine. After a multi-step conversion requiring deamina-Agents that may reduce serum levels including tion and phosphorylation, the resulting product, 5-ﬂuo-efavirenz, nelﬁnavir, Dilantin, Tegretol, rifampin, and rouracil (5-FU) acts as an inhibitor of thymidylate syn-dexamethasone. The echinocandins can reduce serum thetase, impairing DNA and RNA synthesis. In humans,levels of tacrolimus. 5-FC is not toxic because of a lack of the deaminase Pharmacokinetics—The echinocandins are not required for conversion to 5-FU.absorbed by the gastrointestinal tract and must be Toxicity—The major toxicity of ﬂucytosine is boneadministered intravenously (Table 1.18). They are marrow suppression leading to neutropenia, anemia, andmetabolized by the liver. thrombocytopenia (Table 1.17). This side effect is dose- Spectrum of Activity and Treatment Indications— related and usually occurs when serum levels exceed 125The echinocandins are active against Aspergillus and g/mL. Patients with diminished bone marrow reserveCandida, including isolates that are resistant to other such as those with AIDS and those receiving cancerantifungal agents. They are less effective against chemotherapy are more likely to suffer this complication.C. parapsilosis in vitro, and are not active against Commonly, 5-FC is administered in combination withCryptococcus. They are approved for the treatment of amphotericin B. As discussed earlier in this chapter,invasive aspergillosis in patients who fail on, or are amphotericin B impairs renal function, and reductions inunable to tolerate, amphotericin B or itraconazole. renal function reduce the clearance of 5-FC. In patientsTable 1.19. Spectrum of the Systemic Antifungals Agent Candida guilliermondii Candida lusitaniae Candida albicans Candida krusei Coccidiomyces Cryptococcus Zygomycetes Histoplasma Blastomyces Aspergillus Amphotericin B Deoxycholate Lipid preparation Flucytosine Fluconazole Itraconazole Ketoconazole Posaconazole Voriconazole Caspofungin Micafungin AnidulafunginDark gray usually susceptible; white not recommended.
ANTI-INFECTIVE THERAPY / 49 KEY POINTS KEY POINTS About Flucytosine About Antiviral Therapy 1. Impairs fungal DNA and RNA synthesis; fun- 1. Usually target viral nucleic acid synthesis. gistatic. 2. Development of resistance is common and is 2. Cleared by the kidneys; penetrates all tissues favored by and ﬂuids, including the cerebrospinal ﬂuid. a) high viral load, 3. High levels cause bone marrow suppression. b) high intrinsic viral mutation rate (RNA In patients with renal failure, doses should viruses more than DNA viruses), and be adjusted, and serum levels should be c) prolonged or intermittent antiviral therapy. monitored. 4. Never use as monotherapy. In cryptococcal meningitis, the combination of amphotericin B and ﬂucytosine sterilize the cerebrospinal ﬂuid step in viral replication, resistance may develop during faster than does amphotericin B alone. In animal treatment. The development of resistance is favored studies, combination therapy is beneﬁcial for by a high viral load, a high intrinsic viral mutation Candida infections, but efficacy has not be proven in humans. rate (more common in RNA than DNA viruses), and a high degree of selective pressure—that is, prolonged antiviral therapy or repeated courses of treatment. A second method for controlling viral infection is to modify the host immune response. Infusionswith renal dysfunction, monitoring of peak (2 hours after of antibody preparations and treatment with inter-oral administration) and trough levels (just before the next feron have proved efficacious in several viraldose) is recommended. Doses should be adjusted to main- infections.tain serum levels between 20 and 100 g/mL. Pharmacokinetics—Flucytosine is well absorbed Antivirals that Block DNA Transcriptionorally (Table 1.18). Because it is a small molecule, 5-FCpenetrates tissues well and crosses the blood–brain barrier. ACYCLOVIR, VALACYCLOVIR, FAMCICLOVIRTherapeutic levels can be achieved in the cerebrospinal Chemical Structure and Mechanisms of Action—ﬂuid, aqueous humor, joint ﬂuid, and respiratory secre- Acyclovir and valacyclovir are synthetic analogs oftions. The kidneys clear 5-FC. guanine in which a side chain has been substituted for Spectrum of Activity and Treatment Recommenda- a sugar moiety. Famciclovir is a acyclic guanosine ana-tions—Most strains of C. albicans and Cryptococcus log derived from penciclovir, and this prodrug isneoformans are sensitive to 5-FC. Native resistance quickly converted to penciclovir following oralvaries geographically. About 15% of C. albicans stains absorption. These antiviral agents are phosphorylatedand 3% to 5% of Cryptococcus neoformans demonstrate in virus-infected cells by viral thymidine kinase, form-resistance. The effect of 5-FC is usually fungistatic, and ing a monophosphate compound. Host cell kinasesit should never be used alone, because resistance rapidly then add two additional phosphates, allowing thedevelops with monotherapy. The combination of 5-FC triphosphate to add to replicating DNA. The acyclicand amphotericin B demonstrates additive or synergis- side chain of acyclovir prevents the addition oftic activity in cryptococcal infections. In cryptococcal subsequent nucleic acids to DNA causing prematuremeningitis, amphotericin B and 5-FC sterilize the cere- termination.brospinal ﬂuid faster than amphotericin B alone. In Penciclovir is not a DNA chain terminator; it actsvitro and animal testing also suggest that combination primarily as a viral DNA polymerase inhibitor. Acy-therapy for Candida may be of beneﬁt; however, efﬁ- clovir also selectively inhibits viral DNA polymerase.cacy has not been proven in patients. Because these agents require viral thymidine kinase for their initial phosphorylation step, the concentrations ofANTIVIRAL DRUGS (OTHER THAN the triphosphate compounds are 40 to 100 times higherANTIRETROVIRAL AGENTS) in infected than uninfected cells. Acyclovir and famci- clovir resistance are most commonly caused by a reduc-Most antiviral agents target viral nucleic acid tion in viral thymidine kinase. The loss or reduction insynthesis. Because these agents tend to act at a single viral thymidine kinase activity impairs acyclovir
50 / CHAPTER 1Table 1.20. Toxicities of Systemic Antiviral Agents Clinical symptom Antiviral agent Ganciclovir/valganciclovir Penciclovir/famciclovir Acyclovir/valacyclovir Rimantadine Oseltamavir Interferon- Zanamivir Foscarnet Cidofovir Ribavirin Allergic skin rash Pruritus Hypotension Fever and chills Nausea and vomiting Fatigue Diarrhea Headache Dizziness Seizures Other neurotoxicity Uveitis or retinitis Respiratory problems Phlebitis Alopecia Laboratory tests: Abnormal electrolytes Creatinine↑ Anemia Other cytopenias AST/ALT↑ Lactic acidosis Arrhythmias Drug–drug interactionsBlack = principle side effect; dark gray = less common side effect; light gray = rare side effect; white = not reported or veryrare; ↑ = rise; AST/ALT = aspartate aminotransferase/alanine transaminase.phosphorylation and also renders the virus resistant to occur in 1–4% receiving intravenous acyclovir and canganciclovir, because that agent also requires activation result in lethargy, obtundation, coma, hallucinations,by viral thymidine kinase. seizures, and autonomic instability. Most patients who Toxicity—Toxicity related to these drugs is generally suffer these complications have renal dysfunction result-minimal (Table 1.20). Rarely patients develop rash, ing in high acyclovir serum levels. Co-administration ofhematuria, headache and nausea. Neurotoxicity may zidovudine and acyclovir increases the risk of developing
ANTI-INFECTIVE THERAPY / 51Table 1.21. Systemic Antiviral Agents: Half-Life, Dosing, Renal Dosing, and Cost Antibiotic Half-life Dose Dose for reduced Costa (trade name) (h) creatinine clearance (mL/min) Acyclovir 2–2.5 200–800 mg PO 10–50: 800 mg PO q8h, $–$$$ (Zovirax) 3–5 daily 5–10 mg/kg IV q8h 5–12 mg/kg IV q12–24h <10: 800 mg PO q12h, 2.5–6 mg/kg IV q24h Valacyclovir 2.5–3.3 500 mg PO q12h to 10–50: 1 g q12–24h $$–$$$$$ (Valtrex) 1000 mg PO q8h <10: 500 mg q24h Famciclovir 2.3 125 mg PO q12h to 10–50: q12–24h $$$$– (Famvir) 500 mg PO q8h <10: 125–250 mg q48h $$$$$ Ganciclovir 2.5–3.6 5 mg/kg IV q12h 50–80: Half the dose, $ (Cytovene) induction, same intervals 5 mg/kg q24h 10–50: 2.5 mg/kg q24h, maintenance or 1.2 mg/kg q24h maintenance <10: 1.2 mg/kg 3 weekly, or 0.6 mg/kg 3 weekly maintenance Valganciclovir 4 900 mg PO q12h 10–50: Half the dose $$$$$ (Valcyte) 3 weeks, then <10: 450 mg q48h 900 mg q24h 3 weeks, then twice weekly Cidofovir 17–65 5 mg/kg IV twice weekly 50–80: Usual dose $ (Vistide) <50: Contraindicated Foscarnet 3 40–60 mg/kg IV q8h 50–80: 40–50 mg/kg $$$–$$$$ (Foscavir) induction, q8h induction, 90–120 mg/kg q24h 60–70 mg/kg q24h maintenance maintenance 10–50: 20–30 mg/kg q8h induction, 50–70 mg/kg q24h maintenance <10: Contraindicated Ribavirin 0.5–2 <75 kg: 400 mg AM, and <50: Not recommended $$$$– (Copegus, Rebetol) 600 mg PO PM $$$$$ >75 kg: 600 mg PO q12h Interferon 2B PEG-Intron: 1.5 g/kg SC No changes required $$$$$ (PEG-Intron, Pegasys) weekly Pegasys: 180 mg SC weekly Oseltamavir 6–10 Treatment: 75 mg PO 10–50: 75 mg q24h $$–$$$$ (Tamiﬂu) q12h Prophylaxis: 75 mg PO <10: Not recommended q24h Zanamivir 3 5 mg inhalation, 50–80: Usual dose $ (Relenza) 2 inhalations q12h 5 days <50: No data (Continued)
52 / CHAPTER 1Table 1.21. (Continued) Antibiotic Half-life Dose Dose for reduced Costa (trade name) (h) creatinine clearance (mL/min) Amantadine 15–20 <65 years: 100 mg q12h 50–80: 100–150 q24h $ (Symmetrel, >65 years: 100 mg 10–50: 100 mg 2–3 weekly Symadine) PO q24h <10: 100–200 mg weekly Rimantadine 24–30 <65 years: 100 mg <10: 100 mg q24h $ (Flumadine, PO q12h Rimantid) >65 years: 100–200 mg PO q24ha Intravenous preparations (daily cost dollars): $ = 20–70; $$ = 71–110; $$$ = 111–150; $$$$ = 150–200; $$$$$ ≥ 200; oralpreparations (10-day course cost dollars): $ = 10–50; $$ = 51–100; $$$ = 101–140; $$$$ = 141–180; $$$$$ ≥ 180. KEY POINTS lethargy. Intravenous administration can also cause crys- talluria and crystalline nephropathy, particularly if the About Acyclovir, Valacyclovir, and Famciclovir patient is dehydrated. Cyclosporin increases the risk of nephrotoxicity. Pharmacokinetics—The oral absorption of acyclovir 1. All require viral thymidine kinase phosphoryla- is limited, only 15% to 20% of the drug being tion for activity. bioavailable (Table 1.21). Absorption tends to be even 2. Acyclovir binds to the replicating viral DNA, poorer in transplant patients, necessitating higher oral causing premature chain termination; acyclovir dosing. The prodrug preparation valacyclovir is rapidly and famciclovir both inhibit viral DNA poly- and completely converted to acyclovir by hepatic and merase. intestinal valacyclovir hydrolase. Oral valacyclovir 3. Resistance is most commonly mediated by a achieves acyclovir serum levels that are 3 to 5 times reduction in viral thymidine kinase. higher than those achieved by oral acyclovir. Similarly, 4. Toxicity is minimal. Intravenous administration famciclovir is well absorbed orally, and in the liver and of acyclovir can cause lethargy, obtundation, intestine, its purine is quickly deacetylated and oxidized hallucinations, and seizures. to form penciclovir. 5. Valacyclovir is rapidly converted to acyclovir; Acyclovir and penciclovir are widely distributed in tis- resulting acyclovir levels are higher than sues and ﬂuids. Therapeutic levels can be achieved in cere- those achieved with oral preparations of brospinal ﬂuid, saliva, vaginal secretions, and the aqueous acyclovir. Famciclovir is rapidly converted to humor. Both drugs are excreted unchanged primarily in penciclovir. the urine. Probenecid reduces renal clearance and increases 6. Excellent activity against herpes simplex 1 and 2. the half life. Oral preparations recommended for treatment Antiviral Activity and Therapeutic Indications— and prophylaxis of genital herpes and ocular Acyclovir and famciclovir have excellent activity against herpes. Intravenous acyclovir recommended for herpes simplex viruses 1 and 2. Topical administration of herpes simplex encephalitis. these drugs is of minimal efﬁcacy against herpes simplex 7. Moderate activity against varicella (intravenous labialis, and topical preparations are rarely used. Oral acy- acyclovir recommended for the immunocom- clovir and famciclovir are recommended for treatment of promised host), and varicella pneumonia or genital herpes and are used to prevent recurrent herpes encephalitis in the normal host. High doses of genitalis. Acyclovir is also recommended for the treatment oral valacyclovir and famciclovir can be used to and prevention of recurrent ocular herpes simplex. treat less severe disease. Intravenous acyclovir has reduced the mortality from 8. Famciclovir can also be used to treat hepatitis B herpes simplex encephalitis and is the treatment of choice virus. for that disorder. Acyclovir and famciclovir also have sig- niﬁcant activity against varicella; however, higher drug
ANTI-INFECTIVE THERAPY / 53concentrations are required to kill that virus. Intravenousacyclovir is recommended for the treatment of varicella KEY POINTSand herpes zoster in the immunocompromised host, andfor treatment of varicella pneumonia or encephalitis in the About Ganciclovirpreviously healthy adult. Acyclovir demonstrates someactivity against Epstein–Barr virus, but is generally not rec- 1. Guanine analog that primarily inhibits viral DNAommended for therapy. This agent also demonstrates polymerase.modest protection against cytomegalovirus (CMV) whenused for prophylaxis in allogeneic bone marrow, renal, and 2. Like acyclovir and penciclovir, requires viral thymidine kinase for activation. Acyclovir-liver transplant recipients; however, ganciclovir has proved resistant strains are often resistant to ganciclovir.to be more efﬁcacious. Famciclovir can reduce levels ofhepatitis B viral DNA and serum transaminase in patients 3. Bone marrow suppression is a common toxicity,with chronic hepatitis B. Its effects are additive when com- particularly in AIDS patients.The drug should be discontinued if the neutrophil count drops tobined with interferon. Famciclovir has also been used to less than 500 cells/mm3.treat recurrent hepatitis B following liver transplantation. 4. Central nervous system complaints—includingGANCICLOVIR AND VALGANCICLOVIR confusion, psychosis, coma, and seizures—may occur.Chemical Structure and Mechanisms of Action—Likeacyclovir, ganciclovir is a guanine analog. Ganciclovir 5. Most active guanine analog againsthas an additional hydroxymethyl group on the acyclic cytomegalovirus (CMV). Also active against herpes simplex 1 and 2, varicella, and Epstein–side chain. Viral thymidine kinase converts this analog Barr virus.to the monophosphate form, after which host cell kinasephosphorylation produces the active triphosphate form. 6. Recommended for CMV retinitis, pneumonia,Ganciclovir triphosphate competitively inhibits viral and colitis. Useful for prophylaxis of immuno- compromised transplant patients. FollowingDNA polymerase incorporation of guanosine triphos- treatment of active infection in AIDS patientsphate into elongating DNA, but does not act as a chain with low CD4 counts, oral valganciclovir is giventerminator. to prevent relapse. In infected cells, intracellular concentrations of ganci-clovir triphosphate reach levels that are 10 times that ofacyclovir triphosphate, and once in the cell, ganciclovirtriphosphate persists, having a intracellular half life of count drops below 500 cells/mm3. Central nervous sys-16 to 24 hours. The resulting higher intracellular concen- tem (CNS) side effects (including headache, confusion,trations may account for the greater activity of ganciclovir psychosis, coma, and seizures) are also common.against CMV. Ganciclovir is also active against herpes Pharmacokinetics—Valganciclovir is a prodrug thatsimplex, varicella, and Epstein–Barr virus. Because ganci- is well absorbed orally and quickly converts to ganci-clovir requires viral thymidine kinase activity for conver- clovir (Table 1.21). With oral administration, excellentsion to the active triphosphate form, acyclovir-resistant serum levels that are nearly comparable to intravenousviral strains with reduced thymidine kinase activity are also ganciclovir can be achieved. Ganciclovir readilyless sensitive to ganciclovir. Mutations that alter the struc- penetrates all tissues and ﬂuids including the brain andture of the viral DNA polymerase also confer ganciclovir cerebrospinal fluid. The drug is primarily excretedresistance, and these mutants often demonstrate reduced unmodiﬁed in the urine.sensitivity to foscarnet and cidofovir. Spectrum of Activity and Treatment Indications— Toxicity—Signiﬁcant concentrations of ganciclovir Of the guanine analogs, ganciclovir has the highesttriphosphate accumulate in uninfected cells (Table activity against CMV. Ganciclovir is the treatment of1.20). Bone marrow progenitor cells are particularly choice for CMV infections including retinitis, pneumo-sensitive to this agent. The triphosphate form can nia, and colitis. Ganciclovir is also used for prophylaxisincorporate into cellular DNA and block host cell of CMV in transplant patients. In patients with AIDSDNA replication. Neutropenia and thrombocytopenia who have persistently low CD4 lymphocyte counts,are commonly observed in patients with AIDS who are ganciclovir maintenance therapy is required to preventreceiving ganciclovir, and these patients require close relapse of CMV infection after the treatment of activemonitoring for WBC and platelet counts during ther- infection has been completed.apy. The risk is lower, but significant, in transplantpatients. Co-administration of zidovudine increases the CIDOFOVIRrisk of bone marrow suppression. Discontinuation of Chemical Structure, Mechanisms of Action, and Phar-treatment is recommended if the absolute neutrophil macokinetics—Cidofovir (Tables 1.20, 1.21) is an analog
54 / CHAPTER 1of deoxycytidine monophosphate that inhibits viral DNAsynthesis. This agent does not require viral kinase for activ- KEY POINTSity, being converted by cellular enzymes to its activediphosphate form. It acts as a competitive inhibitor of viral About FoscarnetDNA polymerase and also adds to DNA, substituting fordeoxycytidine triphosphate (dCTP), causing premature 1. Blocks binding of deoxynucleotidyl triphos-chain termination. Viral thymidine kinase mutantations phates to viral DNA polymerase.do not impair cidofovir activity. Resistance is conferred through viral DNA poly- 2. Nephrotoxicity is common, usually developing during the second week of therapy. Can bemerase mutations. Such mutations can result in cross- reduced by saline hydration. Usually reversible.resistance to ganciclovir and, less commonly, to foscar-net. Cidofovir is cleared by the kidneys. 3. Also causes abnormalities in serum calcium, Toxicity—Cidofovir is highly nephrotoxic, causing magnesium, and phosphate.proteinuria in half of treated patients, and azotemia and 4. Active against cytomegalovirus (CMV), herpesmetabolic acidosis in a signiﬁcant number. Vigorous simplex, varicella, Epstein-Barr virus, and her-saline hydration and co-administration of probenecid pesvirus 8.reduces nephrotoxicity. The drug should be discontin- 5. Approved for the treatment of CMV retinitisued if 3+ proteinuria or higher develops, or if serum cre- and acyclovir-resistant mucocutaneous her-atinine increases by more than 0.4 mg/dL. Neutropenia pes simplex.is also commonly encountered. Spectrum of Activity and Treatment Indications—Cidofovir has activity against many DNA viruses: CMV;herpes simplex; herpesvirus 6 and 8; varicella; pox viruses, viral infections is likely to be limited. Topical therapy mayincluding smallpox; papilloma viruses; polyoma viruses; prove efﬁcacious in acyclovir-resistant herpes simplexand adenoviruses. This agent is approved only for the infections in patients with AIDS, and it is being studiedtreatment of CMV retinitis in patients with AIDS. Given for the treatment of anogenital warts.its highly toxic proﬁle, parenteral use of this drug in other FOSCARNET Chemical Structure and Mechanism of Action— Foscarnet is an inorganic pyrophosphate analog, KEY POINTS trisodium phosphonoformate, which reversibly blocks the pyrophosphate binding site of viral DNA polymerase. Foscarnet binding inhibits the polymerase from binding About Cidofovir deoxynucleotidyl triphosphates. Mutations to the viral DNA polymerase are primarily responsible for viral resis- 1. An analog of deoxycytidine monophosphate, it tance; however, resistance among clinical isolates is rare. causes premature chain termination of viral Toxicity. Nephrotoxicity is the most common seri- DNA and also inhibits viral DNA polymerase. ous side effect of foscarnet, resulting in azotemia, 2. Does not require viral thymidine kinase for con- proteinuria, and occasionally acute tubular necrosis version to its active form. Acyclovir-resistant (Table 1.20). Renal dysfunction usually develops dur- strains are usually not resistant to cidofovir. ing the second week of therapy and in most cases 3. Highly nephrotoxic;causes proteinuria,azotemia, reverses when the drug is discontinued. Dehydration and metabolic acidosis in nearly half of patients. increases the incidence of nephrotoxicity, and saline Saline hydration and probenecid reduce nephro- loading is of benefit in reducing this complication. toxicity. Neutropenia also is common. Metabolic abnormalities are frequent. Hypocalcemia 4. Broad spectrum of antiviral activity including is the most common, being the result of chelation by cytomegalovirus (CMV), herpes simplex, her- foscarnet. Reductions in ionized calcium can cause pesvirus 6 and 8, varicella, pox viruses, papil- CNS disturbances, tetany, paresthesias, and seizures. loma virus, polyoma viruses, and adenoviruses. Other metabolic abnormalities include hypophos- 5. Approved for CMV retinitis in patients with phatemia, hypomagnesemia, hypokalemia, hypercal- AIDS. Other indications are currently being cemia, and hyperphosphatemia. To minimize these explored. However, the usefulness of cidofovir is metabolic derangements, intravenous infusion should likely to be limited because of renal and bone not exceed 1mg/kg per minute. Electrolytes, magne- marrow toxicity. sium, phosphate, and calcium should be closely monitored. Other common side effects include fever,
ANTI-INFECTIVE THERAPY / 55headache, nausea, vomiting, and abnormal liver func-tion tests. KEY POINTS Pharmacokinetics—Foscarnet is poorly absorbedorally and is administered intravenously. This drug pen- About Ribavirinetrates all tissues and ﬂuids, achieving excellent levels inthe cerebrospinal ﬂuid and vitreous humor. Foscarnet is 1. Guanosine analog that interferes with viral mes-excreted unmodiﬁed, primarily by the kidneys. senger RNA formation and reduces guanosine Spectrum of Activity and Treatment Indications. triphosphate synthesis, lowering nucleic acidFoscarnet is active against CMV, herpes simplex, pools in the cell.varicella, Epstein–Barr virus, and herpesvirus 8. It is 2. Systemic drug causes red blood cell hemolysis.approved for the treatment of CMV retinitis and for Intravenous administration not approved in theacyclovir-resistant mucocutaneous herpes simplex. United States. Aerosolized form causes conjunc- tivitis and bronchospasm.Other Antiviral Agents 3. Teratogenic and embryotoxic. Pregnant healthRIBAVIRIN care workers should not administer.Chemical Structure and Mechanism of Action— 4. Active against DNA and RNA viruses including respiratory syncytial virus (RSV), inﬂuenza andRibavirin is a guanosine analog that contains the parainﬂuenza virus, herpes viruses, adenovirus,d-ribose side chain. It inhibits DNA and RNA viruses pox viruses, Bunyavirus, and arenaviruses.alike. The mechanisms of inhibition are complex andnot completely understood. Ribavirin is phosphorylated 5. Approved for aerosolized treatment of RSV bronchiolitis and pneumonia.to the triphosphate form by host cell enzymes, and thetriphosphate form interferes with viral messenger RNA 6. Approved for oral administration in combina-formation. The monophosphate form interferes with tion with interferon for chronic hepatitis C.guanosine triphosphate synthesis, lowering nucleic acidpools in the cell. Toxicity—Systemic ribavirin results in dose-relatedred blood cell hemolysis; at high doses, it suppresses the aerosol treatment of RSV bronchiolitis and pneumo-bone marrow (Table 1.20). The resulting anemia nia in hospitalized patients. Oral ribavirin in combi-reverses when the drug is discontinued. Intravenous nation with interferon is approved for the treatmentadministration is not approved in the United States, but of chronic hepatitis C.is available for patients with Lhasa fever and some otherforms of hemorrhagic fever. Aerosolized ribavirin is INTERFERONSassociated with conjunctivitis and with bronchospasm Chemical Structure and Mechanism of Action—Thethat can result in deterioration of pulmonary function. interferons (IFNs) are proteins of 16 to 27,000 Da mol-A major concern for health care workers exposed to ecular weight, synthesized by eukaryotic cells in responseaerosolized ribavirin are teratogenic and embryotoxic to viral infections. These cytokines in turn stimulate hosteffects noted in some animal studies. Pregnant health antiviral responses. Interferon receptors regulate approxi-care workers should not administer this drug. mately 100 genes, and in response to INF binding, cells Pharmacokinetics—Approximately one third of rapidly produce dozens of proteins. A wide variety oforally administered ribavirin is absorbed. The drug pen- RNA viruses are susceptible to the antiviral actions ofetrates all tissues and body ﬂuids. Ribavirin triphos- IFNs; most DNA viruses are only minimally affected.phate becomes highly concentrated in erythrocytes Toxicity—Side effects tend to mild when doses of(40 times plasma levels) and persists for prolonged peri- less than 5 million units are administered (Table 1.20).ods with red blood cells. The drug is cleared both by the Doses of 1 to 2 million units given subcutaneously orkidneys and by the liver. Aerosolized ribavirin produces intramuscularly are associated with an inﬂuenza-likehigh drug levels that have a half life of up to 2.5 h in syndrome that is particularly severe during the ﬁrst weekrespiratory secretions. A special aerosol generator is of therapy. This febrile response can be reduced by pre-required for proper administration. medication with antipyretics such as aspirin, ibuprofen, Spectrum of Activity and Treatment Recommenda- and acetaminophen. Local irritation at injection sites istions.—Ribavirin is active against a broad spectrum of also frequently reported. Higher doses of INF result inDNA and RNA viruses including respiratory syncytial bone marrow suppression, causing granulocytopeniavirus (RSV), inﬂuenza and parainﬂuenza virus, her- and thrombocytopenia. Neurotoxicity resulting inpes, adenovirus, pox viruses, Bunyavirus, and are- confusion, somnolence, and behavior disturbances isnaviruses. It is approved in the United States for the also common when high doses are administered.
56 / CHAPTER 1 Toxicity—Amantadine causes moderate CNS side KEY POINTS effects, especially in the elderly (Table 1.20). Insomnia, inability to concentrate, and dizziness are most com- About Interferon for Treatment monly reported. Amantadine also increases the risk of of Viral Infections seizures in patients with a past history of epilepsy. Rimantadine causes CNS side effects less frequently, and this agent is now preferred over amantadine. 1. Binds to host cell interferon receptors, upregu- Treatment Recommendations—To be effective, lating many genes responsible for the produc- treatment must be instituted within 48 hours of the tion of proteins with antiviral activity. onset of symptoms (Table 1.21). Efficacy has been 2. RNA viruses are more susceptible to the antivi- proven in healthy adults, but trials have not been per- ral actions of IFNs. formed in high-risk patients. 3. The most common side effect is an inﬂuenza- like syndrome. At doses above 5 million units, NEURAMIDASE INHIBITORS bone marrow suppression and neurotoxicity Mechanism of Action—The neuramidase inhibitors may develop. Hepatoxicity and retinopathy are have activity against both inﬂuenza A and B. commonly associated with high doses. Toxicity—Zanamivir is given by inhaler and com- 4. Approved for chronic hepatitis C, chronic monly causes bronchospasm, limiting its usefulness. hepatitis B, and Kaposi sarcoma. Intralesional Treatment—To be effective, neuramidase inhibitors injection approved for condyloma acuminatum. must be given within 48 hours of the onset of symptoms. Amantadine, rimantadine, or oseltamavir can be given for a longer duration as prophylaxis in patients at risk of serious complications from inﬂuenza during anHepatoxicity and retinopathy are other common side epidemic. Inﬂuenza vaccine is preferred for prophylaxis.effects with high dose therapy. Pharmacokinetics—Intramuscularly and subcuta- FURTHER READINGneously, INF-a is well absorbed; other interferons havemore variable absorption (Table 1.21). Assays for bio- Antibiotic Handbookslogic effect demonstrate activity that persists for 4 days Bartlett JG, Auwaerter PG, and Pham PA. The ABX Guide: Diagnosisafter a single dose. Pegylated forms result in slower and Treatment of Infectious Diseases. Montvale, NJ: Thompsonrelease and more prolonged biologic activity, allowing PDR; 2005.for once-weekly administration; these forms are Gilbert DN, Moellering RC Jr, Eliopoulos GM, and Sande MA. Thepreferred in most instances. Sanford Guide to Antimicrobial Therapy. 36th ed. Hyde Park, Vt: Spectrum of Activity and Treatment Recommenda- Antimicrobial Therapy; 2006.tions—The effectiveness of INFs has been limited bythe frequent side effects associated with effective doses. Electronic SourcesTreatment approvals have been issued for INFs in ePocrates and ePocrates ID [software]. San Mateo, Calif: Epocrates,chronic hepatitis C, chronic hepatitis B, Kaposi sarcoma Inc. [Web address: www.epocrates.com; cited:]and other malignancies, and condyloma acuminatum. The Johns Hopkins University, Division of Infectious Diseases. ABX Guide [Web resource]. Baltimore, Md: The Johns Hopkins Uni- versity. [Web address: www.hopkins-abxguide.org; cited:]Anti-inﬂuenza Viral AgentsAMANTADINE AND RIMANTADINE OtherMechanism of Action—Amantadine and rimantadine The choice of antibacterial drugs. Med Lett Drugs Ther. 2001;43:69–78.are effective only against inﬂuenza A. They bind to Bruton L, Lazo J, and Parker K. Goodman & Gilman’s The Pharmaco-and inhibit the M2 protein. This viral protein is logical Basis of Therapeutics. 11th ed. New York, NY:expressed on the surface of infected cells, and it is McGraw–Hill Medical Publishers; 2006.thought to play an important role in viral particle Mandell GL, Bennett JE, and Dolin R. Mandell, Douglas, and Ben-assembly. nett’s Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, Pa: Elsevier/Churchill Livingstone; 2005.
58 / CHAPTER 2the purposes of this chapter, sepsis is presumed to be a walls—is also recognized by a family of molecules on theresult of bacterial agents and their products. surfaces of target cells. This recognition leads to the synthesis of molecules that trigger inﬂammation andDEFINITIONS coagulation pathways.Sepsis represents a continuum that progresses from local-ized infection to severe sepsis (Figure 2.1). “Sepsis” is best Cell Wall Factorsdeﬁned as the systemic inﬂammatory response syndrome In gram-negative bacteria, the cytoplasmic bilayer is(SIRS) caused by microbial products. This deﬁnition covered with a layer of peptidoglycan. Overlying theacknowledges that SIRS may be produced by entities peptidoglycan layer is an outer membrane, into whichother than infection and that, in the absence of viable endotoxin is inserted. Endotoxin is the most carefullyorganisms, microbial products are capable of producing studied microbial substance implicated in sepsisthis clinical picture. “Severe sepsis” is deﬁned as sepsis syndrome and shock. There is compelling evidencewith organ dysfunction, and it represents progression of that endotoxin plays a key role in the pathogenesis ofSIRS with more severe pathophysiologic disturbances. gram-negative sepsis. Its structural organization is“Septic shock” is hypotension due to sepsis that has common across all gram-negative bacteria. From thebecome unresponsive to initial attempts at volume outside going inward, it consists of an “O” side chainexpansion. “Infection,” often colloquially called “sepsis,” that is joined to a core, which is in turn connected toindicates the presence of infection and should not be con- the “business” end of the molecule, the lipid Asidered synonymous with sepsis syndrome. Bacteremia is portion.often called sepsis, and although some bacteremias result Lipid A is anchored into the outer membrane. Thein sepsis syndrome, not all sepsis syndromes are caused by triggering of the inﬂammatory and coagulation systems isbacteremia. In fact, in earlier clinical trials of biologic believed to begin with the interaction of LPS with cellularagents in sepsis syndrome, using the best possible receptors on macrophages and mononuclear leukocytes.deﬁnitions and available laboratory studies, fewer than The structure of lipid A is remarkably well conserved in40% of patients have had proven infection. most common gram-negative bacteria, irrespective of the species from which it is obtained. Indeed, the clinicalPATHOGENESIS features of sepsis caused by Escherichia coli are similar toSIRS results from the activation of cellular pathways that those caused by Klebsiella or Enterobacter species.lead to a triggering of innate immune responses and coag- The infusion of LPS or lipid A into animals results inulation mechanisms. The pathways are linked to ancient a sepsis-like picture. Endotoxin can be found in themechanisms that defend the host by responding to tissue blood of patients with gram-negative sepsis. In someinjury or the presence of microbial products. This innate cases, such as meningococcemia, there is a good correla-immune response eventually leads to a classic adaptive tion between the plasma level of endotoxin and the out-immune response characterized by the production of come; even in more “general” types of gram-negativeantibodies, activated T cells and memory of antigens. infection, the presence of endotoxemia correlates with Much is now known about the microbial triggers of more severe physiologic variables.this system, with most of the information having been In addition to LPS, fungal cells walls, gram-positiveobtained using a portion of the gram-negative cell wall, cell walls and possibly bacterial ﬂagellins are also capablethe lipopolysaccharide molecule (LPS) or endotoxin. It of interacting with macrophages to trigger the sequenceis clear, however, that gram-positive cell wall material— of events leading to sepsis and shock. Endotoxin is notspeciﬁcally peptidoglycans and lipoteichoic acid, toxins present in gram-positive bacteria. Instead, the cell wallproduced by gram-positive bacteria, and fungal cell contains a thick layer of peptidoglycan on its surface. In capsular strains the peptidoglycan lies directly beneath the capsule. Embedded in the peptidoglycan are molecules of lipoteichoic acid. Several in vitro studies have demon- strated that these structural components of gram-positive cell walls are able to mimic some of the properties of endotoxin—for example, their ability to induce proin- ﬂammatory cytokines from mononuclear cells.Infection SIRS Sepsis Severe Septic Sepsis Shock Secreted FactorsFigure 2–1. Order of progression from infection to In addition to factors that are integral parts of the cellseptic shock. wall, secreted factors from gram-positive bacteria are
SEPSIS SYNDROME / 59believed to cause septic shock. The prototypical factor is Host Cell Receptors for Bacterial Productstoxic shock syndrome toxin 1 (TSST-1), produced bysome strains of Staphylococcus aureus. A detailed discussion of the physiologic host responses Toxic shock syndrome was ﬁrst described in men- to bacteria is beyond the scope of this chapter. Goodstruation-associated staphylococcal infection of young evidence suggests that, in gram-negative infections,women. Fever and profound shock were often followed monocyte–macrophage or dendritic cells are the ﬁrstby conjunctival and palmar hyperemia and desquama- cells to respond to endotoxin. Endotoxin ﬁrst binds totion. This condition proved to be associated with the LPS-binding protein, an acute-phase protein producedproduction of an exotoxin, TSST-1. by the liver. The LPS–protein complex acts as the ligand Another secreted factor responsible for shock was for CD14 (a cell-surface receptor on mononuclear cells)discovered in strains of the gram-positive bacteria and to toll-like receptor (TLR) 2 or 4 on these cells.Streptococcus pyogenes. It is called streptococcal pyro- There are a number of TLRs that recognize differentgenic exotoxin A (SPEA). Clinically, the action of substances regardless of microbial origin. For example,SPEA has been identiﬁed in necrotizing fasciitis due TLR2 recognizes peptidoglycans, mannans, lipoteichoicto Strep. pyogenes associated with shock. Infection is acids, and some LPS molecules; TLR4 recognizes LPS;hypothesized to lead to local or systemic release of and TLR5 recognizes bacterial ﬂagellin. TLR receptorstoxins, massive lymphocyte activation, and release of and co-receptors bind the foreign stimulant and inter-cytokines, resulting in cellular injury and organ fail- nalize it. Internalization results in signal transductionure. This mechanism bypasses the macrophage, and and cell activation, leading to cytokine release.the cytokine cascade is triggered at the level of the Tcells. This bypassing of the macrophage has given rise Cytokine and Other Inﬂammatoryto the term “superantigen” to describe toxins that, Mediator Cascadesunlike conventional antigens that require processing The activation of monocytes leads to the production ofby macrophages and dendritic cells are able to directly the proinﬂammatory cytokines (that is, the cytokinesactivate lymphocytes. that stimulate inflammation), particularly tumor necrosis factor (TNF- ) and interleukin 1 (IL-1). Infection also activates other host pathways, including the complement and coagulation pathways and the KEY POINTS production of reactive oxygen intermediates. Many studies have been conducted in animals in which About the Bacterial Products That cytokines have been measured in response to both puri- Cause Sepsis Syndrome ﬁed bacterial components and, perhaps more informa- tively, live bacterial infection. Intravenous injection of live E. coli into mice, rabbits, or baboons results in a 1. In gram-negative bacteria, lipopolysaccharide consistent picture in which proinﬂammatory cytokines (LPS), also called endotoxin, is linked to the such as IL-1, IL-6, IL-8, and TNF- , are released in a outer membrane. well-ordered sequence, followed by interferon gamma a) Endotoxin alone can produce the syndrome. and then counterregulatory cytokines such as IL-10. b) Endotoxin (LPS) is found in the bloodstream This picture is similar to that seen when endotoxin is of patients with gram-negative bacteremia. injected into humans. c) Endotoxin (LPS) blood levels correlate with the clinical severity of sepsis syndrome. How Infection Leads to Septic Shock 2. Gram-positive bacteria produce peptidogly- Figure 2.2 shows a simple diagram of the pathways lead- cans, and lipoteichoic acid can mimic endo- toxins. ing to septic shock. It must be realized that these events represent a continuum, and they progress at speeds that 3. Gram-positive bacteria also secrete exotoxins. have not been characterized. However, the general belief a) Staphylococcus aureus can secrete toxic is that the larger the inoculum of the challenge mole- shock syndrome toxin 1 (TSST-1). cule, LPS or gram-positive toxins, the more likely the b) Streptococcus pyogenes secretes streptococcal process is to progress rapidly. Additionally the various pyrogenic exotoxin A (SPEA). cell-wall products are likely to differ in their intrinsic c) Called “superantigens,” these exotoxins potency to stimulate the innate immune system. For bypass macrophages and directly stimulate example, clinical observation suggests that endotoxin is T cells. a more powerful stimulant than are the cells walls of enterococci or coagulase-negative staphylococci, because
60 / CHAPTER 2 Bacterial, fungal, viral infection Endotoxin, Cell walls Superantigens (Exotoxins) Macrophages, monocytes T CellsCytokine release—TNF- , Platelet and coagulation Complement activation IL-1, IL-6, IL-8, IL-10 activation Endothelial injury, coagulation, DIC, shock, end organ damage Irreversible shock–Multi organ failure–Death Figure 2–2. Pathophysiology of sepsis syndrome.humans demonstrate a remarkable tolerance for bac- CLINICAL MANIFESTATIONSteremia attributable to those organisms. CASE 2.1 KEY POINTS A 66-year-old white woman underwent elective tho- racoabdominal aneurysm repair. Three days after About the Roles of Host Cells surgery, she became confused and developed a new in Sepsis Syndrome fever. She had no cough, no dysuria, and no abdomi- nal pain. A surgical drain was noted to be leaking 1. Monocyte–macrophages or dendritic cells are increasing amounts of serous ﬂuid. She was receiving the ﬁrst cells to respond to endotoxin (LPS). vancomycin for operative prophylaxis. 2. Endotoxin binds to LPS–protein in serum, and On physical exam, her temperature was 39 C, her this complex binds to CD14 receptors and to pulse was 143 per minute, and her blood pressure was toll-like receptor 4 (TLR4) on mononuclear cells. 110/70 mm Hg. She was intubated and on a respirator. 3. TLR2 binds peptidoglycans, lipoteichoic acids She appeared toxic and somewhat lethargic. No skin found in gram-positive bacteria, and mannans lesions were noted, and her respiratory, cardiac, and found on fungi. It also binds to some forms of abdominal exams were unremarkable. Her extremities LPS. TLR-5 bind bacterial ﬂagellin. were warm to the touch. Chest X-ray revealed no 4. Receptor binding stimulates monocyte– macro- inﬁltrates. phages to release Laboratory workup showed that the patient’s a) proinﬂammatory cytokines tumor necrosis peripheral white blood cell (WBC) count had dropped to factor and interleukin-1, stimulating inﬂam- 1400/mm3 from 22,600/mm3 the day before, with 24% mation. polymorphonuclear leukocytes, 37% bands, and 9% b) toxic oxygen byproducts. metamyelocytes. Her hematocrit was 30%; blood urea c) products that activate the complement and nitrogen, 41 mg/dL; serum creatinine, 1.0 mg/dL; and coagulation cascades. HCO3, 26 mEq/L. Blood cultures and culture of the surgi- cal drain subsequently grew Escherichia coli.Computed
SEPSIS SYNDROME / 61tomography scan of the abdomen failed to reveal anabscess. She was initially treated with intravenous KEY POINTScefepime and subsequently switched to ceftriaxone.Except for a brief bout of hypotension requiring intra- About the Clinical Manifestationsvenous saline and dopamine, she fully recovered and of Sepsis Syndromewas subsequently discharged from the hospital. 1. Fever: a) Fever is the usual presentation. The higher the fever, the more likely the patient is to be bacteremic.Fever b) Hypothermia or normal temperature inAs noted in case 2.1, fever is usually the ﬁrst and most association with bacteremia is a bad prog-common manifestation of sepsis. In general, the higher nostic sign.the temperature, the more likely a patient is to be bac- 2. Hemodynamic changes:teremic. However, it should be emphasized that a) Tachycardia in association with fever is thehypothermia and normal body temperature are seen in rule; pulse is slower in typhoid fever andpatients who are bacteremic. In fact, there is good rea- brucellosis.son to believe that hypothermia is a poor prognostic b) Hypotension is the most important determi-indicator in bacteremic patients, indicating an inability nant of outcome. Failure to reverse earlyto mount an adequate inﬂammatory response. warm pre-shock leads to irreversible organ damage and death.Hemodynamic Changes 3. Acid–base balance a) Initially, respiratory alkalosis develops inTachycardia is a concomitant ﬁnding with fever and is response to anaerobic metabolism and lacticto be expected. Case 2.1 had marked sinus tachycardia acid build-up. Recognizing this pre-shockassociated with her bacteremia. Bradycardia, on the syndrome is critical.other hand, is unusual, and has been reported in b) Failure to treat leads to metabolic acidosispatients with specific bacterial infections, such as and an increased likelihood of death.typhoid fever and brucellosis. Of the easily measurable 4. Respiratory changeshemodynamic changes, hypotension is the most impor- a) Hyperventilation occurs early.tant in determining outcome. Failure to reversehypotension in its early stages results in serious end- b) Hypoxia and ARDS are common. Chest X-rayorgan damage that may not be reversed by antibiotics or reveals pulmonary edema.other therapy. The stage at which hypotension isreversible is called pre-shock. The pre-shock stage isoften characterized by warm skin, diminished menta-tion (often worse in the elderly), and oliguria. Persistent it signals the beginning of a fatal downward spiral. Casehypotension leads to the well-recognized septic shock 2.1 was recognized and treated before the developmentﬁndings of cool skin, acute renal failure, and, on occa- of acidosis, which explains the patient’s rapid recovery.sion, hepatic injury. Respiratory ChangesAcid–Base Disturbances Tachypnea is a common feature of sepsis, generatedReduced tissue perfusion requires a change from aerobic by cytokine stimulation of the central nervous system,to anaerobic metabolism and causes lactic acid accumu- elevated body temperature, and the accumulation oflation. Lactic acid and elevated cytokine levels stimulate lactic acid. In addition to hyperventilation, severethe respiratory center, resulting in hyperventilation, depression of oxygenation is often seen. The adultwhich initially produces a respiratory alkalosis. This is respiratory distress syndrome (ARDS) commonlythe ﬁrst pronounced change that is seen in impending develops in septic shock and can be experimentallyshock. It is diagnostic, and it is usually seen at a time induced by endotoxin. Endotoxin is thought to acti-when the hemodynamic changes are reversible with vate neutrophils that become trapped in the small ves-ﬂuid resuscitation. Recognition of this early stage is thus sels of the lungs and cause vessel-wall damage andvital to making improvements in the management of a leakage of ﬂuid into the alveoli.patient with sepsis syndrome. Metabolic acidosis can ARDS is diagnosed by chest X-ray changes thatdevelop just before or can accompany hypotension, and mimic cardiac pulmonary edema, and it is accompanied
62 / CHAPTER 2by severe hypoxemia. However, patients with sepsis mayalso demonstrate pneumonia on chest X-ray, and infec- KEY POINTStion of the lungs can be accompanied by bacteremia andsepsis syndrome (see Chapter 4). About the Diagnosis of Sepsis SyndromeDIAGNOSIS 1. Early diagnosis is difﬁcult and is based on clini- cal ﬁndings.Diagnosis of sepsis syndrome is perhaps the greatestchallenge encountered in designing clinical trials for new 2. Fever, tachycardia, and hypotension need to be accompanied by documented bacteremia.therapeutic agents. If fever, tachycardia, and tachypneawith or without leukocytosis are used to deﬁne SIRS, 3. Tests to quickly demonstrate bacteremia, tothen this deﬁnition includes other causes in addition to accurately assess the extent of inﬂammation,infection. Therefore evidence of actual infection must be and to assess organ ischemia are not currently available.sought. The most prevalent sites of infection are the lungs, 4. Thrombocytopenia and evidence of ﬁbrinogenbloodstream, abdomen, and wounds. Even with a posi- consumption and clot lysis combined withtive bacterial culture from any of these sites, sepsis in hypotension, increased cardiac output, and reduced peripheral vascular resistance suggestpatients ﬁtting the broad deﬁnitions of SIRS remains an the diagnosis.uncertainty. In fact, most patients with pneumoniawould ﬁt this deﬁnition of sepsis syndrome, althoughthey rarely require intensive care. The strictest criteriashould include the presence of a positive blood culture,preferably two, and should exclude most cases of useful warning that sepsis had developed, and it preci-coagulase-negative staphylococci that are common skin pitated the administration of broad spectrum antibioticcontaminants. Exceptions to a positive blood culture coverage.would have to be made in patients presenting clear clin- These common clinical and laboratory ﬁndings areical evidence of an intra-abdominal infection such as indicative of sepsis:peritonitis. Adjunctive information should also includethe presence of hypotension that is not a result of hypo- 1. Temperature: <36 C or >38 Cvolemia or a recent cardiac event. 2. Pulse rate: >90/min Critical diagnostic tools that are not currently avail- 3. Respiratory rate: >20 per minuteable include a means to rapidly diagnose the presence of 4. PaCO2: <32, with pH >7.45 (early sepsis)bacteria in the blood and a method to rapidly quantify 5. WBC count: <4000/mm3 or >12,000/mm3 with athe inﬂammatory response. (Infection produces more band count >10%inﬂammation than does a noninfectious cause.) Suchtests would guide a decision to initiate or not to initiate 6. Chills, lethargy, hemorrhagic skin lesionsantibiotics and activated protein C (see “Drotrecogin ” These laboratory studies are recommended inunder “Treatment”). A method for detecting early organ patients with suspected sepsis syndrome:damage would also be helpful for determining the sever-ity of SIRS. Currently, reliance must be be placed on 1. Two blood cultures, urine culture, and sputum cul-clinical assessment of illness severity and supportive bac- ture if the patient has chest X-ray abnormalitiesteriologic studies that usually do not become available 2. Complete blood count with differential and plateletsfor 24–48 hours. 3. Coagulation studies to include international nor- The presence of other abnormalities such as throm- malized ratio, ﬁbrinogen, and D-dimers or ﬁbrinbocytopenia, evidence of ﬁbrinogen consumption, and split productsclot lysis are helpful, and when accompanied by 4. Blood gases and metabolic panelshypotension, increased cardiac output and changes inperipheral vascular resistance may serve to deﬁne infec-tion as the cause of SIRS. However, these ﬁndings are TREATMENTmore likely to be seen in the more severe cases, where Antibiotic Therapythe diagnosis of infection is already clinically apparent. Case 2.1 had a marked drop in peripheral WBC, The outcome of patients with sepsis, in particular thosewith a marked shift to the left and a high percentage of with bacteremia, is governed by host and microbialimmature granulocyte forms indicating marked factors alike. In some studies, certain organisms, includ-consumption of granulocytes. That ﬁnding served as a ing Pseudomonas aeruginosa and Candida species have
SEPSIS SYNDROME / 63Table 2.1. Empiric Antibiotic Therapy for Sepsis Syndrome Site of infection Pathogens to be covered Antibiotics Lung Pseudomonas aeruginosa Cefepime, or (hospital acquired) Enterobacter ticarcillin–clavulanate Piperacillin–tazobactam, plus aminoglycoside Abdomen or pelvis Gram-negative rods Ticarcillin–clavulanate, or Anaerobes piperacillin–tazobactam, plus aminoglycoside Imipenem or meropenem Urinary tract Escherichia coli Ciproﬂoxacin Klebsiella Ceftriaxone Proteus Skin Staphylococcus aureus Oxacillin, or Streptococcus pyogenes vancomycin Mixed aerobic/anaerobic Ticarcillin–clavulanate (necrotizing fasciitis) Piperacillin–tazobactam Imipenem or meropenem Bacteremia of unknown source Methicillin-resistant Cefepime, plus (hospital acquired) Staph. aureus (MRSA) vancomycin Gram negative rods Bacteremia of unknown source Staph. aureus Vancomycin, plus (community acquired) Strep. pneumoniae ceftriaxone or cefepime Esch. coli Klebsiella Proteusbeen suggested to carry a higher mortality rate. Polymi- the infection and to cover the most likely pathogenscrobial bacteremia also carries an increased mortality from that site (Table 2.1).risk. Therefore, if the clinical situation is epidemiologi- It must be recognized that coverage for every possiblecally consistent with the isolation of more risky pathogen is not possible, and certain pathogens in certainpathogens, consideration must be given to covering locations are unlikely to be responsible for life-threateningthese possibilities empirically. sepsis. Such organisms include enterococci at most sites The other microbial factor of signiﬁcance is the sus- and S. aureus in the respiratory tract. These recommenda-ceptibility of the pathogen to empiric therapy. Patients tions are made with the assumption that 90% of organ-with gram-negative bacteremia treated empirically isms are sensitive to the drugs chosen, except for hospital-with antibiotics to which their organism is resistant acquired pathogens. Certain hospitals may have speciﬁchave significantly higher mortality rates. Therefore, resistance problems with any given pathogen. In theseempiric therapy should be embarked upon with a cases, empiric therapy must be adjusted to reﬂect antibi-knowledge of local susceptibility patterns, and in situ- otic sensitivities of the local bacterial ﬂora. The regimensations in which a bacterium was previously isolated suggested in Table 2.1 will cover most other pathogensfrom a suspicious site, empiric therapy should cover its that are isolated at these sites in signiﬁcant numbers. Insusceptibility pattern. 24–48 hours after blood culture results are available, the These foregoing considerations aside, other factors antibiotic regimen must be adjusted, with narrower spec-may possibly help in choosing empiric therapy for sep- trum antibiotics utilized whenever possible to reduce thesis. In patients presenting with sepsis and a petechial likelihood of selecting for highly resistant pathogens.skin rash, consideration must be given to meningococ-cemia, gonococcemia, S. aureus bacteremia or localized Patient ManagementS. aureus infection, and streptococcal bacteremia orlocalized S. pyogenes infection. The preferred approach is Management of patients with sepsis syndrome requiresto direct therapy to the most probable site of origin of prompt administration of antibiotics and volume
64 / CHAPTER 2expansion, initially with normal saline. The duration 3. Blood lactate and coagulation parameters initially,of hypotension before the administration of effective and perhaps every 4–6 hours until a clear senseantibiotics has been found to be extremely important develops of how the patient is progressingin the survival of hypotensive patients. Each hour of Failure of the patient to respond to fluids anddelay up to 6 hours resulted in an increase in mortality antibiotics—as indicated by a persistent fall in bloodof 7.9%. pressure, accumulation of lactate, increasing hypox- If there is a drainable site of infection in the emia, and laboratory signs suggesting a coagulopathy—abdomen or pelvis, or if those locations are the possible dictate that the patient be moved to an intensive caresources of infection, immediate surgical consultation unit for closer monitoring and more aggressive hemo-must be sought. (See Chapter 8, “Gastrointestinal and dynamic support. There are no proven superior therapiesHepatobiliary Infections.”) Similarly the presence of at this time. Judicious use of vasopressors is generallygas in soft tissues or clinical evidence of a necrotizing recommended, beginning with dopamine and progress-infection mandates surgical consultation and possibly ing to norepinephrine. Aggressive ﬂuid resuscitationintervention. (See Chapter 10, “Skin and Soft-Tissue should be continued with speciﬁc attention to centralInfections.”) Any intravascular catheter in place must venous pressures and pulmonary vascular congestion.be removed and cultured. (See Chapter 7, “Cardiovas- Further management needs to be deferred to the inten-cular Infections.”). sive care specialists. The following measurements are suggested in patientswho are initially stable and kept on a conventional ward:1. Hourly measurement of vital signs and urine output Adjunctive Therapies2. Two-hourly measurement of arterial blood pH, Many different substances have been used to reverse the PaCO2, and PaO2 persistent hypotension and associated end-organ dam- age associated with sepsis syndrome. Most of these adjunctive measures have failed to improve mortality in large studies. Given current knowledge of the pathogen- KEY POINTS esis of sepsis, additional trials are likely to be undertaken in the future. These are some of potential therapies that have not proved beneﬁcial to date: About the Treatment of Sepsis Syndrome 1. Anti-inﬂammatory agents such as ibuprofen and even narcotic antagonists have not proven to be of 1. Empiric antibiotic therapy must take into account value in large scale studies. a) the presumed primary anatomic site of the infection leading to bacteremia. 2. Monoclonal antibody against the core of the endo- toxin molecule has not been conclusively shown to b) local hospital antibiotic sensitivities. be beneﬁcial. c) sensitivities for bacteria previously grown 3. Antibody against TNF- and the TNF- receptor from possible sites of bacteremia. have failed. 2. Empiric therapy must be readjusted based on blood culture results. 4. Studies utilizing IL-1 receptor antagonists have been inconclusive. 3. Volume expansion with normal saline must be initiated emergently. 5. Platelet activating factor antagonists have failed. 4. Surgical consultation is required for possible intra-abdominal sepsis and for potential cases Corticosteroids of necrotizing fasciitis. 5. Potentially infected intravascular catheters The use of corticosteroids in septic shock has been must be removed. under debate for decades. It is known that some of these 6. Monitoring of patients on conventional wards patients have or develop adrenal insufﬁciency. Recent should include studies have re-examined this question with the startling a) hourly vital signs. revelation that, as compared with high doses, low phys- iologic doses of corticosteroids for 7 days are associated b) 2-hourly arterial blood gases. with improved survival. However, debate continues c) 4- to 6-hourly serum lactate measurements. regarding whether only patients with adrenal insufﬁ- 7. Deterioration of these parameters warrants ciency should receive these agents or whether all transfer to an intensive care unit. patients should be so treated. Further studies will be required to clarify the efficacy of low-dose steroids;
SEPSIS SYNDROME / 65however, pending these studies, treatment with is recent surgery, the risk of bleeding complications200–300 mg of hydrocortisone or its equivalent daily being prohibitively high in the postoperative patientfor 7 days should be strongly considered. population.Drotrecogin CONCLUSIONInvestigations of sepsis have shown that protein C levels The physician ﬁrst needs to make an immediate decisionare low and that septic patients are unable to activate about severity of the illness, and with clinical experience,this substance. Protein C plays a key role in inhibiting most physicians become skilled at recognizing the sickestcoagulation, and it may be an important inhibitor of patients. Among the severely ill, patients with sepsis syn-monocyte activation. Animal studies have shown that drome have the highest mortality and morbidity. Earlyinfusion of activated protein C reduces mortality in recognition of sepsis and efforts to remove the precipitat-lethal E. coli infections. Clinical trials in humans have ing cause and to deliver aggressive ﬂuid and vasopressorsubsequently shown a modest reduction of mortality in therapy, optimal supportive care for organ dysfunction,septic shock when patients are treated with activated and empiric antimicrobial therapy for the most likelyprotein C. This agent, now called drotrecogin , has microbial pathogens remain the standard of care.now been approved by the U.S. Food and Drug It is important that the physician reassess empiricAdministration as an adjunct to standard therapy for the antibiotic coverage in 48 hours when culture resultstreatment of severe sepsis. Drotrecogin reduced mor- have returned. The organisms grown on blood culturetality to 24.7% from 30.8% in placebo-treated patients can help to identify the site of primary infection. Theyover 28 days, a statistically significant reduction. also often allow the spectrum of antibiotic coverage toBecause of the complexity of patient inclusion criteria, be narrowed, reducing the likelihood of patient colo-very high costs, and potential for bleeding complica- nization with highly resistant bacterial ﬂora. (See Chap-tions, this agent is reserved for use by intensive care and ter 1, “Anti-infective Therapy.”) Activated protein C isinfectious disease specialists. Its major contraindication of modest beneﬁt, but not all patients are candidates for this agent. However, agents of this type that will be more effective are likely to be developed in the future, as more is learned about the mechanisms involved in the KEY POINTS progression of sepsis. About Adjunctive Therapies FURTHER READING for Sepsis Syndrome Balk RA. Sepsis and septic shock. Deﬁnitions, epidemiology, and clinical manifestations. Crit Care Clin. 2000;16:179–192. 1. Multiple clinical trials have failed to document Bernard GR, Vincent JL, Laterre PF, et al. Efﬁcacy and safety of efﬁcacy for recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699–709. a) anti-inﬂammatory agents. Kreger BE, Craven DE, McCabe WR. Gram-negative bacteremia. IV. b) monoclonal antibody against endotoxin. Reevaluation of clinical features and treatment in 612 patients. c) anti–tumor necrosis factor antibodies. Am J Med. 1980;68:344–355. d) interleukin-1 antagonists. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical e) platelet activating factor antagonists. determinant of survival in human septic shock. Crit Care Med. 2. Corticosteroids is low doses may be beneﬁcial. 2006;34:1589–1596. 3. Activated protein C (drotrecogin ) is of limited Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta- efﬁcacy (6% reduction in mortality) and analysis: the effect of steroids on survival and shock during sepsis a) is extremely expensive; depends on the dose. Ann Intern Med. 2004;141:47–56. Pittet D, Li N, Woolson RF, Wentzel RP. Microbiological factors b) should only be given by intensive care or inﬂuencing the outcome of nosocomial bloodstream infections: infectious disease specialists; and a 6-year validated, population-based model. Clin Infect Dis. c) is contraindicated in postoperative patients 1997;24:1068–1078. because of bleeding complications. Russell JA. Management of sepsis. N Engl J Med. 2006;355: 1699–1713.
THE FEBRILE PATIENT / 67 hepatic and renal failure), and acetaminophen should be KEY POINTS avoided in patients with serious underlying liver disease. Coronary artery vasoconstriction has been associated About Fever with NSAIDs, and therefore those drugs probably should not be used in patients with ischemic heart disease. To avoid repeated shifting of the thermal set 1. Body temperature is regulated by the hypothal- point and recurrent shivering and chills, antipyretic amus, and prostaglandin E2 acts on this region to stimulate fever. agents must be administered on a regular schedule until the primary cause of fever has been treated. 2. Fever most commonly occurs in the evening as a consequence of the diurnal variation of body temperature. 3. Fever may be protective and should be reduced only in patients with ischemic heart disease or ■ FEVER OF UNDETERMINED pulmonary disease, in elderly patients, and in ORIGIN children who have a history of febrile seizures. 4. Acetylsalicylic acid, nonsteroidal anti-inflam- matory drugs, and acetaminophen (agents that GUIDING QUESTIONS reduce prostaglandin E2 production), are the preferred method for reducing fever and need 1. What are the criteria used to deﬁne FUO? to be given on a regular schedule. 2. Which diseases are most commonly associated with FUO? 3. Which diseases are most commonly associated withunable to compensate for the increased oxygen demands FUO in the elderly?associated with fever. Elderly patients with limited men- 4. Which basic diagnostic tests should be ordered intal capacity may develop confusion and lethargy in cases of FUO?response to fever, complicating their care. Children cansuffer from seizures in association with high fever— 5. What is Sutton’s law, and how is this law appliedalthough, to date, there is no proof that reducing fever to FUO?prevents febrile seizures. 6. Should empiric antibiotics be started in cases of FUO?TREATMENT OF FEVER 7. What is the prognosis in patients with FUO?The primary treatment for fever is to treat the underly-ing cause. The role of lowering body temperature whiletrying to determine the primary cause of fever remainscontroversial. Based on current understanding of thermal regula- POTENTIAL SEVERITYtion, direct cooling of the body using ice, cold water, or acooling blanket should be considered only in conjunctionwith medicines that reset the thermal set point. Other- Fever of undetermined origin (FUO) is a chronic disor-wise, the central nervous system will respond to such der that requires a thoughtful diagnostic approach.measures by inducing chills and shivering, increasing thepatient’s discomfort. Use of antipyretics is probably war-ranted in patients with heart disease, pulmonary disease,and in elderly patients with mental dysfunction in associ-ation with fever. DEFINITION OF FUO The pharmacologic agents used to reset the thermalset point all inhibit prostaglandin synthetase activity and At the time that the patient ﬁrst visits the physician withreduce prostaglandin E2 production. Acetylsalicylic acid complaints of fever, the cause is in many cases not appar-(ASA), nonsteroidal anti-inﬂammatory drugs (NSAIDs), ent. Some physicians label these complaints as FUO. How-and acetaminophen are all effective. In children, ASA ever, the name “fever of undetermined origin” carries withshould probably be avoided because of the increased risk it speciﬁc criteria and should not be loosely applied. As ﬁrstof Reyes syndrome (a deadly syndrome consisting of fatal deﬁned in 1961, FUO requires that the patient have
68 / CHAPTER 3 Table 3.1. Major Causes of Fever of Unknown Origin KEY POINTS “Big 3” About the Definition of Fever 1. Infection of Unknown Origin 2. Neoplasm 3. Autoimmune disease 1. Fever must persist for more than 3 weeks in order to exclude self-limiting viral illnesses. “Little 6” 2. Temperature must be more than 38.3 C (101 F) 1. Granulomatous disease to exclude normal variations in core body tem- 2. Regional enteritis perature set point. 3. No diagnosis reached after 3 days of testing. 3. Familial Mediterranean fever 4. Drug fever 5. Pulmonary emboli 6. Factitious fever1. an illness that has lasted least 3 weeks,2. fever of more than 38.3 C on several occasions, and3. no diagnosis after routine work up for 3 days in hos- pital or after 3 or more outpatient visits. A duration of 3 weeks or longer was chosen to elimi- CASE 3.1nate self-limiting viral illnesses that are generally difﬁcultto diagnose and that resolve within that time period. A 19–year-old white male, university sophomore, pre-A temperature of more than 38 C was chosen to eliminate sented with a 3-week history of fevers to 40 C, fatigue,those individuals at the far right of the normal tempera- and anorexia.He was evaluated in the school inﬁrmaryture distribution curve who normally may have a slightly and was given intravenous ﬂuids for dehydration. Hehigher core temperature set point and an exaggerated diur-nal temperature variation. Recognizing that, in the present was treated empirically with penicillin and clar-era of managed care, most patients with FUO are now ithromycin. Despite this treatment, his fevers persisted.diagnosed and managed as outpatients, the third criterion Epidemiology indicated no recent travel. A reviewhas been modiﬁed to include outpatient diagnostic testing of systems was negative, other than 1 to 2 loose bowelas well as that conducted in hospital. movements daily for the week before admission. Before launching a complex and expensive series of Vital signs included a temperature of 39.2 C, pulsediagnostic tests, the physician must carefully document 88 per minute,respirations 20 per minute,blood pressurethat the patient fulfills the criteria for FUO. Most 122/60 mm Hg.The patient appeared mildly ill. His phys-important is the documentation of true fever. The ical exam was completely normal, including absence ofpatient should be instructed to measure both 6 A.M. and palpable lymph nodes, no skin rashes, no cardiac mur-6 P.M. temperature to rule out an exaggerated circadian murs,a benign abdominal exam without organomegaly,rhythm. Secondly, an electronic thermometer should and a normal joint and extremity exam.always be used to exclude the possibility of factitious Laboratory workup showed a white blood cellfever (discussed in the next subsection). The exact pat- (WBC) count of 11,600/mm3,with 93% polymorphonu-tern of fever generally is not helpful in identifying the clear leukocytes. Hematocrit was 35%; platelets,fever’s cause. 228,000/mm3; blood urea nitrogen, 6 mg/dL; serum albumin, 3.0 g/dL; total protein, 6.2 g/dL; alkaline phos-CAUSES OF FUO phatase (ALP), 327 IU/L; alanine transaminase (ALT),Many diseases can initially present with the primary man- 107 IU/L; and erythrocyte sedimentation rate (ESR),105ifestation of prolonged fever (Table 3.1). The possible mm/h. Blood cultures were twice negative, and a chestcauses can be classiﬁed into three major categories (“the big X-ray (CXR) was within normal limits.three”): infections, neoplasms, and autoimmune disorders. Because of the persistent fever and anorexia, theThe miscellaneous causes are numerous, the most common patient underwent an abdominal computed tomogra-being six diseases (“the little six”): granulomatous diseases, phy (CT) scan that demonstrated an hepatic abscessregional enteritis, familial Mediterranean fever (FMF), 9 cm in diameter in the right lower lobe of the liver.drug fever, pulmonary emboli, and factitious fever. Echinococcal serum titer was negative. Cutaneous
THE FEBRILE PATIENT / 69aspiration demonstrated thick pus,and culture grew Staphy- pathogens such as the HACEK organisms (see Chapter 7lococcus aureus, methicillin-sensitive. on bacterial endocarditis), and drawing large volumes ofComment blood for culture have improved the sensitivity of blood cultures and reduced the number of undiagnosed casesOther than a mildly elevated ALP level, no clinical clues of SBE. Transesophageal cardiac echo has also improvedindicative of liver abscess were seen. On further review of identification of vegetations. As a result of thosepast medical history, the patient reported having intermit- advances, SBE has become a less common cause of FUOtent furunculosis.His skin was likely the initial portal of entry, in recent reports. In almost every case, patients withresulting in transient bacteremia and seeding of the liver. SBE have an audible murmur, emphasizing the impor- tance of a careful physical exam during the initial evalu- ation of the patient with FUO. The physician must also keep in mind that, if the patient has received antibiotics, the utility of blood cul-Infection tures is markedly reduced. Administration of antibiotics temporarily sterilizes the bloodstream. Antibiotics mustIn patients under the age of 65 years, infection remains be discontinued for 7 to 10 days before blood culturesthe most common cause of FUO (Table 3.2). Common become positive.infectious causes of FUO include abscesses, particularly Biliary system infections also can present as FUO.abdominal abscesses that may persist for prolonged Such patients often have no right upper quadrant painperiods before being diagnosed. Improvements in imag- and no right upper quadrant tenderness. Subacuteing techniques have improved on the ability to locate pyelonephritis can also present with a prolonged fever inand drain occult pyogenic collections. Osteomyelitis— the absence of dysuria, frequency, or ﬂank pain.particularly of the vertebral bodies, mandible, and air In cases of FUO, miliary tuberculosis (TB) mustsinuses—can also present as FUO. Bone scan is partic- always be considered. This potentially lethal disease isularly helpful in identifying such infections. most common in elderly and immunocompromised In earlier series, subacute bacterial endocarditis patients, particularly patients with HIV and patients on(SBE) was a major cause of FUO. However, improved high-dose glucocorticoids or a TNF inhibitor. Boneculture techniques, including prolonged incubation of marrow culture is particularly helpful in making thisblood cultures to identify more fastidious slow-growing diagnosis. A CXR may demonstrate micronodular (“millet seed”) interstitial changes; however, this radio- logic ﬁnding may be absent in elderly individuals. IfTable 3.2. Infectious Causes of Fever appropriate antituberculosis therapy is not initiated promptly, these patients usually deteriorate over 2 toof Unknown Origin 3 weeks and die. Leptospirosis can cause persistent fever and is difﬁcult 1. Abscesses to diagnose. A combination of appropriate epidemiology 2. Osteomyelitis (vertebrae, mandible, sinuses) (animal or contaminated soil or water exposure), con- 3. Subacute bacterial endocarditis (murmur usually pre- junctival suffusion, aseptic meningitis, liver enzyme sent, beware of previous antibiotics) abnormalities, and renal dysfunction should alert the clinician to this possibility. Other spirochetal diseases 4. Biliary system infections (may have no right upper reported to cause persistent fever include Lyme disease quadrant tenderness) and relapsing fever. Animal exposure, particularly the 5. Urinary tract infections (in absence of related symp- skinning of wild boar, should raise the possibility of bru- toms) cellosis. Brucellosis can also be contracted by eating 6. Tuberculosis (especially miliary disease) unpasteurized cheese. Rickettsial infections can also cause FUO. Epidemiol- 7. Spirochetal infection (leptospirosis, Borrelia) ogy plays a critical role in alerting the clinician to this 8. Brucellosis (animal exposure, unpasteurized cheese) group of pathogens. A history of camping, hunting, or 9. Rickettsial infection other outdoor activities in areas endemic for these infec- tions should raise the possibility. Rickettsia are tick-borne; 10. Chlamydia however, a history of tick bite is not always obtained. 11. Epstein–Barr virus, cytomegalovirus Chlamydia is another intracellular pathogen that on 12. Fungal infection (Cryptococcus, histoplasmosis) occasion can cause prolonged fever. Chlamydia psittaci in particular can result in a mononucleosis-like syndrome. 13. Parasites (malaria, toxoplasmosis, trypanosomiasis) This organism is usually contracted from birds, including
70 / CHAPTER 3 Hodgkin lymphomas intermittently produce pyro- KEY POINTS gens: one week the patient may be afebrile, and the fol- lowing week may bring hectic fevers. This fever pattern About Infectious Causes of Fever has been termed Pel–Ebstein fever, which when present, of Unknown Origin raises the possibility of Hodgkin lymphoma. Patients with non-Hodgkin lymphoma may also present with fever. In some cases, the fever can be high and mimic sepsis. 1. Infection is the most common cause of FUO in Patients with leukemia may also present with fever. patients under 65 years of age. Older patients in the aleukemic or the preleukemic phase 2. Epidemiology (animal exposure, insect bites, of their disease may have little or no evidence of leukemia outdoor camping, travel, exposure to infected on peripheral smear. In earlier series, hypernephroma was humans) is helpful. noted to cause FUO; however, examination of a large 3. Physical exam may provide useful clues, partic- series of patients with hypernephroma has demonstrated ularly inspection of skin, nail beds, and fundi, that this solid tumor is rarely associated with fever. and cardiac auscultation. The solid tumor most frequently reported as a cause of 4. Abdominal abscess, miliary tuberculosis, and FUO is primary hepatoma, but tumors that metastasize to disseminated fungal infections can be fatal. liver rarely cause fever. Atrial myxoma is a rare disorder 5. Prior antibiotic administration interferes with that is associated with fever, and it can mimic subacute diagnosis. bacterial endocarditis. Small pieces of the atrial tumor can break off and embolize to the periphery, causing small infarcts similar to those observed in bacterial endocarditis.pigeons, members of the parrot family (parakeets, macaws,and cockatoos), ﬁnches (canaries, goldﬁnches), and poul-try. Epstein–Barr virus and cytomegalovirus can both KEY POINTScause a mononucleosis syndrome resulting in sore throat,lymphadenopathy, splenomegaly, and prolonged fever. About Neoplastic Causes of Fever In addition to bacteria and viruses, fungi can occa- of Unknown Originsionally result in FUO, cryptococcosis and histoplasmosisbeing the two most common fungal diseases reported. 1. Lymphoma is the most common neoplasiaParasites can similarly cause prolonged fever. Malaria causing FUO.(non-falciparum forms), toxoplasmosis, and trypanoso-miasis are the most commonly reported parasitic diseases 2. Pel–Ebstein fever strongly suggests Hodgkin lymphoma.associated with FUO. 3. Preleukemia can present as FUO in the elderly.Neoplasm 4. Primary hepatoma can be associated with FUO; however, metastatic liver disease usually doesNeoplastic disorders represent the second major cate- not cause fever.gory of diseases associated with FUO (Table 3.3). In 5. Renal cell carcinoma occasionally causes FUO.elderly patients, neoplasia is the most frequent cause, 6. Atrial myxoma can mimic subacute bacterialand in this category lymphomas are the most commonly endocarditis.reported cause of fever.Table 3.3. Neoplastic Causes of Feverof Unknown Origin CASE 3.2 1. Lymphoma (especially Hodgkin, Pel–Ebstein fever) A 27–year-old Asian man presented with a chief 2. Leukemia (aleukemic or preleukemic phase) complaint of fevers of 2 weeks’ duration. Two weeks 3. Hypernephroma (high sedimentation rate) earlier, he had begun to experience fever associated 4. Hepatoma (generally not metastatic liver disease) with weakness, malaise, shoulder and neck weakness, and muscle tenderness. He also noted a sore throat. He 5. Atrial myxoma was admitted to a hospital in Puerto Rico where a CXR
THE FEBRILE PATIENT / 71demonstrated diffuse pulmonary inﬁltrates and a spu- parasites were thrice negative. Hepatitis B surfacetum Gram stain showed gram-positive cocci. His WBC antibody was positive (Ab ),core was Ab ,and surfacecount was 16,000/mm3. He was treated with intra- antigen was negative. He had a 1:185, antinuclearvenous mezlocillin and gentamicin and later switched antibodies (ANAs) and rheumatoid factor were nega-to ampicillin. He failed to improve, remaining febrile, tive, and the rapid plasma reagin was also negative.and he came to the university hospital. Eight separate blood cultures were negative, and a Epidemiology indicated no pets, no allergies, no monospot test was negative. Repeat transaminaseconsumption of unpasteurized milk or raw meat, no values registered ALT 94 IU/L, AST 64 IU/L, ALP 403 IU/L,swimming in fresh water, no exposure to TB, no history and GGT 180 IU/L.of gonococcus or syphilis. The patient continued to have fevers. A liver biopsy Social history recorded occasional alcohol use, sin- demonstrated nonspeciﬁc inﬂammation. Weight lossgle status, and employment as a cook. Other than the continued, and the patient’s ESR and WBC remainedtrip to Puerto Rico, travel was unremarkable. No pets. elevated. After 8 days in the hospital, he developed aNo exposure to TB or other infectious diseases. swollen left wrist and swollen right elbow. He was Past medical history indicated that, at age 9, he treated with high-dose oral salicyclates. Withinhad an acute febrile episode associated with a rash, 24 hours of initiation of therapy, he defervesced. Oversevere joint swelling, and high fever. The illness spon- the next 2 weeks, his symptoms completely resolved.taneously subsided. Based on past medical history, clinical presentation, The patient’s physical exam showed a temperature and response to salicyclates, he was discharged with aof 38.3 C and a clear chest. Liver edge was palpated diagnosis of Still’s disease.2 cm below the right costal margin, slightly tender. Hisleft upper quadrant was also tender, Skin showeda macular rash over the chest where he had appliedrubbing ointment. Laboratory workup showed a peripheral WBC count Autoimmune Diseaseof 20,400/mm3, (with 94% polymorphonuclear;euko- Autoimmune disease is the third major category of dis-cytes,4% lymphocytes,2% macrophages.Platelet count eases that cause FUO (Table 3.4). In early series ofwas 354,000/mm3; hemoglobin,12.9 g/dL; PaO2,69 mm FUO cases, systemic lupus erythematosus (SLE) was aHg; PaCO2, 33 mm Hg; HCO3, 24 mEq/L. A urinalysis was frequent cause. However, with improvements in anti-negative.Total bilirubin was 2.8 mg/dL; ALT, 108 IU/L; nuclear and anti-DNA markers, these sensitive testsaspartate aminotransferase (AST) 98 IU/L; and -glu- readily identify cases of SLE. The diagnosis is now usu-tamyl transpeptidase (GGT),42 IU/L.A CXR showed inﬁl- ally made within 3 weeks.trate in the left lower lobe of the lungs. Still’s disease (adult-onset juvenile rheumatoid Ceftriaxone and erythromycin were started; how- arthritis) is one of the most frequent autoimmuneever, this patient’s fevers persisted in the range 38.3 C diseases resulting in FUO in younger patients. Key clin-to 40.6 C. ical features of this disease include an evanescent macu- A subsequent laboratory analysis included an lar rash, arthralgias, and a sore throat. Patients withESR above 100 mm/h, a peripheral WBC count of35,000/mm3, and a hemoglobin of 9.1 g/dL. After 4 days of persistent fever, the patient was Table 3.4. Autoimmune Diseases That Cause Feverswitched to a tetracycline antibiotic, followed by of Unknown Origin3 days of naproxen. Additional tests at that timeincluded a PPD skin test (4 mm), and an acid-fast bacilli 1. Systemic lupus erythematosusstain of sputum (negative). Abdominal ultrasound and 2. Still’s diseaseCT scans were negative with the exception of consolida-tion seen in the left and right lung bases. A bron- 3. Hypersensitivity angiitischoscopy was negative for Pneumocystis and 4. Polymyalgia rheumatica, combined with temporalLegionella; transbronchial biopsy was consistent with arteritisfocal pneumonitis. A lumbar puncture showed glucose 5. Polyarteritis nodosa89 mg/100 mL, total protein 11 mg/mL, and WBC count 6. Mixed connective tissue disease0 in the cerebrospinal ﬂuid. Thick and thin malariasmears were negative; stool samples for ova and 7. Subacute thyroiditis
72 / CHAPTER 3 Table 3.5. Drugs That Cause Fever KEY POINTS of Unknown Origin About Autoimmune Causes of Fever Antihistamines Isoniazid of Unknown Origin Barbiturates Nitrofurantoin Chlorambucil Penicillins 1. Still’s disease is associated with high fevers, evanescent skin rash, leukocytosis, high serum Dilantin Procaine amide ferritin, and elevated erythrocyte sedimentation Hydralazine Quinidine rate (ESR). A diagnosis by exclusion. Ibuprofen Salicyclates 2. Polymyalgia rheumatica and temporal arteritis are found in elderly patients and cause proxi- Iodides Thiouracil mal muscle weakness, visual symptoms, and a Aldomet Mercaptopurine high ESR. 3. Subacute thyroiditis should be considered if the thyroid is tender. ically demonstrate mild abnormalities in ALP, and liver 4. Kikuchi’s disease often presents with fever and biopsy reveals granulomas. lymphadenopathy. The second possibility is regional enteritis. This dis- ease can present with prolonged fever in the absence of gastrointestinal complaints. For this reason, contrast studies of the gastrointestinal tract are generally recom- mended to exclude this diagnosis.Still’s disease often have high fevers associated with a The third member of the “little 6” is familialhigh peripheral WBC counts, and this combination Mediterranean fever. As the name implies, this is afrequently causes the physician to begin antibiotic ther- genetic disorder associated with recurrent serositis pri-apy for a presumed bacterial infection. However, the marily of the abdominal cavity, but it can also result infever fails to subside after initiation of antibiotics. No pleuritis and pericarditis. A family history is critical inspeciﬁc test is available for Still’s disease. Serum ferritin raising this possibility.levels are generally markedly elevated, as is the ESR. The fourth disorder in this group is drug fever, In elderly patients, polymyalgia rheumatica is the one of the most frequently encountered causes ofmost common autoimmune disorder to cause FUO. FUO. Table 3.5 lists the drugs that most commonly causeThis disease results in proximal muscle weakness and a fever. The anti-seizure medication Dilantin is probably thehigh ESR. Temporal headaches and visual complaints drug that most frequently causes allergic reactions, includ-are present, as is temporal arteritis, a vasculitis com- ing fever. Quinidine, procaine amide, sulfonamides, andmonly associated with polymyalgia rheumatica. Other autoimmune diseases reported to causeFUO include polyarteritis nodosa, hypersensitivityangiitis, and mixed connective tissue disease. Suba- KEY POINTScute thyroiditis may present with prolonged fever. Onexamination, the thyroid is often tender and serum About Other Causes of Feverantithyroid antibodies are elevated. Recently, of Unknown OriginKikuchi’s disease, also called histiocytic necrotizinglymphadenitis, has been reported to cause prolongedfever. This self-limiting autoimmune disorder occurs 1. Regional enteritis can present with fever in the absence of gastrointestinal symptoms.in young Asian females and is associated with general-ized lymphadenopathy. Diagnosis is made by lymph 2. Pulmonary emboli can present with fever in thenode biopsy. absence of respiratory symptoms. 3. Discontinue all medications in the patient with FUO.Other Causes of FUO 4. Consider factitious fever in the female healthIn addition to the “big 3” categories, clinicians must care worker with a medical textbook at the bed-also consider the “little 6.” side and recurrent polymicrobial bacteremia. The ﬁrst is granulomatous diseases of unclear causa- 5. No diagnosis is made in an increasing percent-tion. This disease group presents with fever and malaise age of modern cases.and generally involves the liver. Liver function tests typ-
THE FEBRILE PATIENT / 73 any clear cause for fever, a history of health care training KEY POINTS should raise the clinician’s suspicion, particularly if the patient takes great interest in her illness and has a med- About the History in Fever ical textbook at the bedside. The diagnostic test of of Unknown Origin choice is often a search of the patient’s room seeking a syringe used for self injection. Finally, in a recent series, a high proportion of 1. A review of symptoms should be repeated fre- patients (30%) had no explanation for their FUO. In quently. many of these cases, fever spontaneously resolved over 2. Past medical history of infectious diseases and 3 to 6 months without harmful consequences. family history should be carefully reviewed. 3. Epidemiology history should include animal exposure, outdoor camping, insect bites, and HISTORY IN FUO travel to developing countries or the Southwest History can play a critical role in narrowing the United States and the Ohio River valley. differential diagnosis and in deciding on the most 4. All medications must be reviewed. appropriate diagnostic tests. A review of all symptoms associated with the illness needs to be periodically updated. Symptoms often are transient and are recalled by the patient only after repeated question-penicillins are other major offenders. When a patient pre- ing. A patient’s past medical history often providessents with FUO, all medications should be discontinued useful clues. History of tuberculosis, tuberculosisor switched to exclude this possibility. exposure, or a positive PPD should be included. Fam- Fifth of the “little 6” diseases is pulmonary emboli. ily history must also be thoroughly reviewed toProlonged bed rest increases the risk of thrombus exclude genetic disorders such as cyclic neutropeniaformation in the calves. When emboli are small, they and familial Mediterranean fever. Social history needsmay not result in respiratory complaints and may sim- to include animal exposure (pets, and other domesticply present as fever. In all patients at risk for throm- or wild animals), home environment, and occupa-bophlebitis who present with FUO, pulmonary emboli tional exposure. Travel history should explore travel toneed to be excluded. areas endemic for malaria and other parasites, The ﬁnal disorder in this list is factitious fever. In typhoid, coccidiomycosis, histoplasmosis, and tick-earlier series, patients often manipulated the mercury borne illnesses. A list of all medications, includingthermometer to fool the physician; the advent of the over-the-counter and natural organic remedies, mustelectronic thermometer has made this maneuver impos- be compiled to exclude the possibility of drug fever.sible. Today, patients usually inject themselves withsaliva or stool, causing polymicrobial bacteremia and PHYSICAL EXAM IN FUOfever. This disorder occurs almost exclusively in women.A medical background is also the rule. In the absence of In addition to a careful history, careful repeat physical examination is frequently helpful. Particular attention should be paid to the skin exam, looking for embolic or vasculitic lesions or evidence of physical manipula- KEY POINTS tion. Particular attention should be paid to the nail beds, where small emboli can become trapped in the distal capillaries of the ﬁngers and toes, resulting in About Physical Exam in Fever small splinter-shaped infarcts. Joint motion and the of Unknown Origin presence of effusions should be looked for. Careful eye exam should be repeated looking for conjunctival 1. Thoroughly examine skin for embolic lesions. petechiae, conjunctivitis, punctate corneal lesions, uveitis, optic nerve changes, retinal or choroidal 2. Palpate all lymph nodes. abnormalities. Thorough palpation of all lymph nodes 3. Perform a complete joint examination. needs to be repeatedly performed, documenting the 4. Listen carefully for cardiac murmurs. consistency, size, and tenderness. Cardiac exam 5. Abdominal exam should assess liver and spleen should be repeated daily, listening for cardiac mur- size and should palpate for masses and areas of murs and pericardial rubs. The abdomen also should tenderness. be palpated daily to detect new masses, areas of local- ized tenderness, and hepato- or splenomegaly.
74 / CHAPTER 3Table 3.6. Preliminary Tests Recommended for “Willy, why do you rob banks?” Willy replied, “That’sFever of Unknown Origin where the money is.” Clinicians need to focus on diag- nostic tests that are likely to have a high yield. They Complete history need to “go where the money is.” Careful physical exam Classes of Diagnostic Tests Complete blood count with differential SKIN TESTS Blood smears with Giemsa and Wright stain An intermediate-strength PPD should be performed in Liver function tests all patients with FUO who do not have a previously Antinuclear antibodies and rheumatoid factor documented positive PPD. The use of skin tests to Erythrocyte sedimentation rate detect histoplasmosis and coccidiomycosis is not gener- ally recommended. Urinalysis Blood culture CULTURES Urine culture Blood cultures should be part of the initial workup of all patients with signiﬁcant prolonged fever. Yield for sub- PPD skin test acute bacterial endocarditis is usually maximized by Chest and abdominal computed tomography scan drawing blood for three cultures (see Chapter 7). In general no more than six blood cultures should be drawn. They may be repeated periodically or if a signif- icant change occurs in the fever pattern. Because of theLABORATORY STUDIES IN FUO possibility of fastidious slow-growing bacteria, all bloodAll patients with FUO should receive a series of basic cultures should be held for 3 weeks.diagnostic tests (Table 3.6). However, because each Multiple urine samples should be obtained and cul-case is different, a series of yes-or-no branch points are tured for tuberculosis in addition to more conventionalnot possible for guiding the subsequent diagnostic bacteria. In patients with respiratory complaints or CXRapproach to FUO. abnormalities, sputum should be cultured, and in patients In recent years, rather than insufﬁcient studies being undergoing bone marrow biopsy, culture is an importantthe norm, clinicians have erred on the side of excessive component of the marrow analysis. All biopsy specimensand uninformative testing. Each patient’s diagnostic need to be cultured. Aerobic, anaerobic, mycobacterial,workup must be tailored to personal history and physi- and fungal cultures should be ordered on virtually all sam-cal ﬁndings. A cookbook approach subjects the patient ples. Viral cultures or quantitative polymerase chain reac-to undue costly testing and stress. “Tincture of time” tion (PCR) may also be considered in speciﬁc cases inand repeated history and physical exam often allow the which cytomegalovirus or Epstein–Barr virus is suspected.physician to apply Sutton’s law. Willy Sutton was a famous bank robber, who, when SMEARSfinally captured, was asked by newspaper reporters, Peripheral blood smears with Giemsa and Wright stains are critical for making the diagnosis of malaria, try- panosomiasis, or relapsing fever. In addition to a periph- eral WBC count, Wright stain with differential cell count is often helpful in determining the nature of the KEY POINTS inﬂammatory response associated with fever, and it should be performed in all patients with FUO. Stool About Diagnostic Workup in Fever smears for ova and parasites are usually less helpful, being of Unknown Origin that gastrointestinal parasites seldom present as FUO. OTHER PERIPHERAL BLOOD TESTS 1. Physicians usually err by overtesting. Antibody titers should be considered when speciﬁc 2. A cookbook approach should be avoided. pathogens are part of the differential diagnosis. To prove 3. Sutton’s law (“Go where the money is”) should active infection, rising antibody titers are required. A be applied. Tests should be directed toward single titer simply demonstrates a past history of exposure; specific complaints and abnormalities found a rising titer indicates recent infection. Therefore, two on preliminary testing. samples separated by 3 to 4 weeks need to be drawn. Anti- body titers are particularly useful in cytomegalovirus,
THE FEBRILE PATIENT / 75Epstein–Barr virus, Toxoplasma, Rickettsia, Chlamydia, and for detecting cardiac vegetations, and it is also helpful inBrucella infections. If liver functions are abnormal, hepati- detecting myocardial abscess and atrial myxoma.tis serology should also be ordered (see Chapter 8). An Ultrasound of the lower abdomen may be helpful inHIV antibody test should be performed in all patients cases in which pelvic lesions are suspected. Abdominalwith potential risk factors (see Chapter 17). CT is not as sensitive in that region because of reﬂection Tests that should be considered to diagnose connective artifacts generated by the pelvic bones. When other teststissue disease in most cases of FUO are antibody titers to are unrevealing, upper gastrointestinal barium studyhuman tissue, including ANAs, anti-DNA antibodies, with small bowel follow-through should be ordered torheumatoid factor, and immune complexes. An ESR exclude regional enteritis. Barium enema should be con-assay should be performed in all cases of FUO. A very sidered in older patients; however, yield from this pro-high ESR is seen in the polymyalgia rheumatica– cedure is likely to be low in FUO. Radiographs of alltemporal arteritis combination and in Still’s disease. A joints should be ordered in any patient with persistentnormal ESR virtually excludes these diagnoses, as well as joint complaints to document anatomic defects.subacute bacterial endocarditis. Invasive Procedures—If all noninvasive tests prove to be negative, liver biopsy is recommended to exclude theIMAGING STUDIES possibility of granulomatous hepatitis. LaparoscopicTests That Should Be Ordered in All Patients with guided biopsy improves the yield by allowing biopsies toFUO—As part of the preliminary workup, a chest be taken in areas where abnormalities in the externalCT scan should be ordered. Results to look for are capsule are seen.mediastinal enlargement (suggestive of lymphoma), Bone marrow aspiration and biopsy is also recom-micronodular interstitial changes (“millet seed” pattern, mended as a routine invasive test if all noninvasivesuggestive of miliary tuberculosis), or nodular lesions or studies are negative. Leukemia in its early stages may beinﬁltrates (can be seen in many infectious diseases, con- detected, as may stage IV lymphoma. It is critical thatnective tissue diseases, and neoplasms). Abdominal CT the bone marrow be appropriately cultured (see the ear-scan should also be performed to identify abdominal lier subsection titled “Cultures”), because disseminatedabscesses, mesenteric nodes, and tumors. Imaging of the tuberculosis, histoplasmosis, coccidiomycosis, andchest and abdomen by CT have an approximately 10% other fungal and mycobacterial infections often seedyield in patients with FUO who lack speciﬁc localizing the bone marrow.symptoms. Use of other invasive procedures will depend on the Tests That Should Be Ordered Depending on the diagnostic ﬁndings, history, and physical ﬁndings toPatient’s Symptoms and Signs—In patients who are sus- that point. In elderly patients with a high ESR and per-pected of having a chronic infection, radionuclide scans sistent fever, temporal artery biopsy is generally recom-may be helpful in localizing the site. Gallium scan may mended. It should be kept in mind that, because skipbe useful in patients with chronic infection because this lesions are common in temporal arteritis, a long sampleagent accumulates in areas of inﬂammation; however, of the temporal artery should be obtained and multipleindium white blood cell scan tends to be more speciﬁc. arterial sections examined.The indium white blood cell scan also has a higher pos- In early series of FUO, diagnostic laparotomy wasitive yield than abdominal CT scan does for identifying frequently recommended. With the advent of newoccult intra-abdominal infection. abdominal imaging techniques, this invasive procedure Another tracer molecule that accumulates in areas of is now seldom performed; however, it may be consid-inﬂammation and in malignant tumors is 18F ﬂuo- ered in selected cases.rodeoxyglucose. Unlike other scans, which require that In addition to a complete series of cultures, all biopsythe patient be scanned during a period of 24 to 36 hours, specimens should undergo Brown–Brenn, Ziehl–Neelsen,positron emission tomography with 18F ﬂuorodeoxyglu- methenamine silver, periodic acid Schiff, and Dieterle sil-cose is completed within a few hours. In preliminary ver staining in addition to routine hematoxylin and eosin.studies, this test has proved more sensitive and speciﬁc Frozen sections should be obtained for immunoﬂuores-than gallium scan. For the assessment of osteomyelitis or cence staining, and the remaining tissue block should betumor metastasis to bone (with the exception of prostate saved for additional future studies.cancer and multiple myeloma), technetium scan is the It should be emphasized that, when symptoms,most sensitive and speciﬁc technique. signs, or a speciﬁc diagnostic abnormality is found, all Air sinus ﬁlms or sinus CT scan can be performed to other scheduled diagnostic tests should be delayed, andexclude occult sinus infection and tooth abscess. In Sutton’s law applied. For example, if an abnormal ﬂuidpatients with a heart murmur and persistent fever, car- collection is found on abdominal CT, then all otherdiac echo should be considered. Transesophageal echo is diagnostic procedures can be halted while a needle aspi-the test of choice; it has a greater than 90% sensitivity ration of the potential abscess performed. If the result
76 / CHAPTER 3proves to be positive, additional investigations are treatment and surgical drainage. In the absence of a spe-unnecessary. The “money” has been found. ciﬁc diagnosis, clinicians have difﬁculty justifying a pro- Ordering tests for completeness’ sake is unnecessary. longed course of antibiotics, and therefore antibioticsWhen in doubt about performing additional tests, the are often discontinued after 1 to 2 weeks, allowing thewisest course of action is to wait. Over time, the infection to relapse.patient’s fever may spontaneously resolve, or new mani- When a connective tissue disorder appears to be thefestations may develop, helping to identify the cause. most likely explanation for FUO, empiric use of sys- temic glucocorticoids is often considered. These agentsTREATMENT OF FUO are very effective in treating temporal arteritis and polymyalgia rheumatica, they may be helpful in Still’sIn the past, many clinicians discouraged the use of disease, and they are used to treat speciﬁc complicationsantipyretics in FUO, because these agents mask the pat- in lupus erythematosus. However, because these agentstern of fever. However, as noted earlier in this chapter, markedly reduce inﬂammation and impair host defense,with rare exceptions, the pattern of fever has not proved administration of glucocorticoids can markedly exacer-to be helpful in determining the cause of FUO. bate bacterial, mycobacterial, fungal, and parasitic infec- Fever is commonly associated with chills, sweating, tions. Therefore, before considering an empiric trial offatigue, and loss of appetite. Therefore, once true fever glucocorticoids such as prednisone, dexamethasone, orhas been documented, antipyretics can be administered methylprednisone, infection must be convincingly ruledin most cases of FUO to relieve some of the patient’s out. The physician must also keep in mind the manysymptoms while the diagnostic workup is pursued. To potential side effects of prolonged glucocorticoid useavoid repeated shifting of the thermal set point and (Cushingoid face, osteoporosis, aseptic necrosis of therecurrent shivering and chills, ASA, NSAIDs, or aceta- hip, diabetes mellitus, and opportunistic infections)minophen must be administered at the proper time before committing the patient with FUO to a pro-intervals to maintain therapeutic levels. Otherwise, longed course of systemic steroid treatment.these antipyretics will exacerbate rather than reduce thesymptoms of fever. PROGNOSIS As was discussed in Chapter 1, physicians often over-prescribe antibiotics. In cases of FUO, the temptation Delay in diagnosis worsens the outcome in cases ofto institute an empiric trial of antibiotics is great. This intra-abdominal abscess, miliary tuberculosis, dissemi-temptation should be avoided. Antibiotics are con- nated fungal infections, and pulmonary emboli. How-traindicated until a speciﬁc diagnosis is made. Use of an ever, if these diseases are carefully excluded, lack of aempiric antibiotic trial often delays diagnosis and is diagnosis after an extensive workup is associated a withrarely curative. Because infections susceptible to con- 5-year mortality of only 3%. The prognosis is somewhatventional antibiotics represent a small percentage of the worse in elderly patients because of their increased riskdiseases that cause FUO, antibiotic treatment will have of malignancy. Therefore, once the clinician has com-no effect in most cases. In cases of occult bacterial infec- pleted the FUO diagnostic battery described in thistion, empiric antibiotics may mask the manifestations of chapter and serious life-threatening diseases have beenthe infection and delay appropriate treatment. Most excluded, additional diagnostic study is not warranted. Ifinfections that cause FUO require prolonged antibiotic fever persists for an additional 4 to 6 months, a complete series of diagnostic studies may then be repeated. KEY POINTS About the Treatment of Fever ■ FUO IN THE of Unknown Origin HIV-INFECTED PATIENT Primary HIV infection can present with prolonged 1. Once the pattern of fever has been docu- fever, and in patients with the appropriate risk proﬁle mented, NSAIDS, acetylsalicyclic acid, or aceta- (see Chapter 17), a diagnosis of HIV needs to be con- minophen can be used to lower fever. sidered. Serum markers are negative in the early stages 2. Empiric antibiotics are contraindicated. of HIV infection; quantitative PCR for HIV is therefore 3. Glucocorticoids should be used only when the diagnostic test of choice. infection has been excluded. In the later stages of HIV infection, fever is a common manifestation of opportunistic infection. In order of
THE FEBRILE PATIENT / 77 nosocomial pathogens such as Pseudomonas, Klebsiella, KEY POINTS and Escherichia coli are associated with wound infection. Appropriate antibiotic therapy is generally guided by About Fever of Unknown Origin culture and Gram stain. Empiric antibiotic therapy in HIV-Infected Patients should include gram-positive and gram-negative cover- age. In patients who have suffered bowel perforation, the development of intra-abdominal abscess is a com- 1. Can be a manifestation of primary HIV infection. mon cause of fever, and an abdominal CT scan should 2. Often the first symptom of an opportunistic be ordered to exclude this possibility. infection. Because most ICU patients are intubated, bacteria 3. Mycobacteria are the most common infectious colonizing the nasopharynx can more readily gain entry cause. to the bronchi and pulmonary parenchyma, causing 4. Cytomegalovirus is also common, as are Crypto- bronchitis and pneumonia. As is outlined in more detail coccus and Toxoplasma. in Chapter 4, sputum Gram stain is critical for differen- 5. Non-Hodgkin lymphoma is the most common tiating colonization from true infection. The presence of noninfectious cause. a single organism on Gram stain, combined with more than 10 neutrophils per high-power ﬁeld, strongly sug- gests infection. Sputum culture identiﬁes the offending organism and sensitivities to antibiotics. Other parame-frequency, the most common causes of FUO in patients ters that are helpful in differentiating colonization fromwith AIDS are mycobacterial infections (Mycobacterium true infection are CXR and arterial blood gases. Thetuberculosis, M. avium intracellulare, other atypical presence of a new inﬁltrate supports the diagnosis ofmycobacteria), other bacterial infections, cytomegalovirus, pneumonia, as does a reduction in arterial PaO2.Pneumocystis, toxoplasmosis, and Cryptococcus, and histo- Patients in the ICU usually have 1 or 2 intravenousplasmosis. In HIV patients coming from endemic areas, catheters in place, plus an arterial line. These lines arevisceral leishmaniasis also needs to be considered. Non- always at risk of becoming infected, and line sepsis is ainfectious causes include non-Hodgkin lymphoma and common cause of fever in the ICU setting. At the onsetdrug fever. Additional tests warranted in the HIV patient of new fever, all intravenous and arterial lines should beinclude mycobacterial blood culture, cryptococcal serum examined for erythema, warmth, and exudate. Particu-antigen, and cytomegalovirus quantitative PCR. Dis- larly in the patient who has developed shock, all linesseminated histoplasmosis may be difﬁcult to detect and, should be replaced, and appropriate empiric antibioticin our experience, is most readily diagnosed by bone coverage instituted.marrow culture. S. aureus, S. epidermidis, and gram-negative rods are the primary causes of line sepsis. Initial antibiotic coverage should include vancomycin and a 3rd-generation cephalosporin. Empiric antibiotic coverage must be indi- vidualized to take into account the prevailing bacterial■ FEVER IN SURGICAL INTENSIVE ﬂora in each ICU and the history of antibiotic use in the CARE AND MEDICAL patient. Patients who have been in the hospital for pro- longed periods and who have received multiple antibiotics INTENSIVE CARE PATIENTS are at risk of candidemia, particularly if two or moreOne of the most common problems encountered by the peripheral site cultures have grown this organism. Theseinfectious disease consultant is the evaluation of fever in patients should be empirically covered with ﬂuconazole orpatients residing in the surgical or medical intensive care an echinocandin (caspofungin, anidulafungin, or mica-unit (ICU). These patients are usually severely ill and fungin) pending blood culture results.have multiple potential causes for fever. Another major infectious cause of fever in the ICU In the postoperative patient, wound infection must patient is prolonged bladder catheterization. The blad-be excluded. All surgical wounds need to be carefully der catheter bypasses the urethra, and despite the use ofexamined looking for purulent discharge, erythema, closed urinary collecting systems, nearly all patientsedema, and tenderness. In the immediate postoperative with bladder catheters develop urinary tract infectionsperiod (24 to 48 hours) Streptococcus pyogenes can result within 30 days (see Chapter 9). Urinalysis and urineseptic shock and severe bacteremia with only minimal culture therefore need to be part of the fever workup inpurulence at the operative site. A Gram stain of serous all patients with urinary catheters.exudate usually demonstrates gram-positive cocci in In patients with nasogastric tubes or those who havechains. In the later postoperative period, S. aureus and been intubated through the nasal passage, the ostia
78 / CHAPTER 3 identiﬁed by CT scan. Generally, they do not require KEY POINTS drainage, but they take time to fully resorb. Fever in the ICU patient requires a systematic diag- About Fever in the Intensive nostic approach and the judicious use of antibiotics. Too Care Unit Patient often, patients are covered unnecessarily for prolonged periods using broad-spectrum antibiotics. This condi- tion leads to the selection of highly resistant bacterial 1. Fever is extremely common in intensive care pathogens, and it also predisposes the patient to can- unit patients. didemia and Clostridium difﬁcile colitis. 2. A systematic approach to diagnosis is critical. Empiric antibiotic coverage needs to be streamlined 3. Key sites of infection include these: once culture data are available. Close communication a) Lungs (critical to differentiate colonization between the ICU staff and the infectious disease con- from infection) sultant is critical to achieve the best care for the febrile b) Intravenous and intra-arterial lines ICU patient. c) Urinary tract (at high risk secondary to pro- longed bladder catheterization) FURTHER READING d) Wounds (particularly in the early postopera- Blockmans D, Knockaert D, Maes A, et al. Clinical value of tive period) [(18)F]ﬂuoro-deoxyglucose positron emission tomography for e) Sinuses (in patients with nasotracheal tubes) patients with fever of unknown origin. Clin Infect Dis. 2001;32:191–196. 4. Noninfectious causes include pulmonary Bujak JS, Aptekar RG, Decker JL, Wolff SM. Juvenile rheumatoid emboli, drug fever, and old hemorrhage. arthritis presenting in the adult as fever of unknown origin. 5. Empiric antibiotics need to be streamlined Medicine (Baltimore). 1973;52:431–444. based on culture results. de Kleijn EM, Vandenbroucke JP, van der Meer JW. Fever of 6. Prolonged broad-spectrum antibiotic coverage unknown origin (FUO). I A. prospective multicenter study of predisposes to colonization with highly resis- 167 patients with FUO, using ﬁxed epidemiologic entry crite- tant bacteria, fungemia, Clostridium difficile ria. The Netherlands FUO Study Group. Medicine (Baltimore). colitis, and drug allergies. 1997;76:392–400. Ghose MK, Shensa S, Lerner PI. Arteritis of the aged (giant cell arteritis) and fever of unexplained origin. Am J Med. 1976;60:429–436. Larson EB, Featherstone HJ, Petersdorf RG. Fever of undetermined origin: diagnosis and follow-up of 105 cases, 1970–1980. Med-draining the air sinuses can become occluded. This con- icine (Baltimore). 1982;61:269–292.dition can lead to sinusitis and fever. Fever work up in Marik PE. Fever in the ICU. Chest. 2000;117:855–869.these patients therefore needs to include sinus ﬁlms. If Mayo J, Collazos J, Martinez E. Fever of unknown origin in the set-sinusitis is discovered, the tube must be removed from ting of HIV infection: guidelines for a rational approach. AIDSthe nasal passage, and appropriate antibiotic coverage Patient Care STDS. 1998;12:373–378.instituted (see Chapter 5). Mueller PS, Terrell CL, Gertz MA. Fever of unknown origin caused Noninfectious causes of fever also need to be con- by multiple myeloma: a report of 9 cases. Arch Intern Med.sidered. As noted earlier in this chapter, pulmonary 2002;162:1305–1309.emboli may present with fever. Patients in the ICU are Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore). 1961;40:1–30.usually receiving a large number of medications, and Vanderschueren S, Knockaert D, Adriaenssens T, et al. From pro-they are therefore at higher risk of developing drug longed febrile illness to fever of unknown origin: the challengefever. All medications should be reviewed, and when continues. Arch Intern Med. 2003;163:1033–1041.possible, medications should be discontinued or Zenone T. Fever of unknown origin in adults: evaluation of 144 cases inchanged. a non-university hospital. Scand J Infect Dis. 2006;38:632–638. Another cause of persistent low-grade fever isundrained collections of blood. These collections can be
80 / CHAPTER 4Table 4.1. Common Causes of Acute Pneumonia mechanisms that prevent pathogens from gaining entry [Figure 4.1(A)]: Organism Cases (%)a 1. The nasal passages contain turbinates and hairs that Streptococcus pneumoniae 16–60 trap foreign particles. 2. The epiglottis covers the trachea and prevents secre- Haemophilus inﬂuenzae 3–38 tions or food from entering the trachea. Other gram-negative bacilli 7–18 3. The tracheobronchial tree contains cells that secrete Legionella spp. 2–30 mucin. Mucin contains a number of antibacterial Chlamydia pneumoniae 6–12 compounds including immunoglobulin A antibod- ies, defensins, lysozymes, and lactoferrin. Mucin Mycoplasma 1–20 also is sticky, and it traps bacteria or other foreign Staphylococcus aureus 2–5 particles that manage to pass the epiglottis. Inﬂuenza A and B — 4. Cilia lining the inner walls of the trachea and bronchi Parainﬂuenza — beat rapidly, acting as a conveyer belt to move mucin out of the tracheobronchial tree to the larynx. Respiratory syncytial virus — 5. When signiﬁcant volumes of ﬂuid or large particles Anaerobes (usually mixed) — gain access to the trachea, the cough reﬂex is acti-a From published series of bacterial pneumonia. vated, and the unwanted contents are quickly forced out of the tracheobronchial tree. 6. If pathogens are able to bypass all of the above pro-pneumoniae also account for a signiﬁcant percentage of tective mechanisms and gain entry into the alveoli,acute pneumonias. Staphylococcus aureus is an unusual they encounter a space that, under normal circum-community-acquired pathogen, but it can cause ventilator stances, is dry and relatively inhospitable. The pres-associated pneumonia. Gram-negative bacteria other than ence of an invading pathogen induces the entry ofH. inﬂuenzae are also an uncommon cause of community- neutrophils and alveolar macrophages that ingestacquired pneumonia except in patients with underlying and kill infecting organisms. Immunoglobulins andlung disease or alcoholism. Gram-negative pneumonia complement are found in this space. Surfactantsmost commonly develops in hospitals or nursing homes. also have a protective function.Legionella species vary in importance, depending on the 7. The lymphatic channels adjacent to the alveoli serveseason and geographic area. Anaerobes such as anaerobic to drain this space and transport ﬂuid, macrophages,streptococci and bacteroids can cause acute pneumonia and lymphocytes to the mediastinal lymph nodes.following aspiration of mouth contents. Common viralpathogens include inﬂuenza, parainﬂuenza, and respira- Bacterial pathogens usually gain entry into the lung bytory syncytial virus. aspiration of mouth ﬂora or by inhalation of small aerosolized droplets (<3 µm in diameter) that can bePathogenesis and Pathology transported by airﬂow to the alveoli. Once the pathogen takes hold, a series of inﬂammatory responses is triggered.Under normal conditions, the tracheobronchial tree is These responses have been most carefully studied insterile. The respiratory tract has a series of protective pneumonia attributable to S. pneumoniae.A BFigure 4–1. A. Host defense in the respiratory tract. B. Factors that interfere with host defense of the respiratory tract.
PULMONARY INFECTIONS / 81 Next, polymorphonuclear leukocytes (PMNs) and KEY POINTS some red blood cells begin to accumulate in the alveolar space. Eventually, they ﬁll the region and form a zone of About the Protective Mechanisms of the Lung consolidation. Macrophages then enter the lesions and assist the PMNs in clearing the infection. Histopathology reveals 1. Normally the tracheobronchial tree is sterile. zones of varying age. The most distal regions represent 2. The nasal turbinates trap foreign particles, and the most recent areas of infection. There, edema ﬂuid, the epiglottis covers the trachea. PMNs, and red blood cells predominant. On lower 3. Mucin has antibacterial activity, and cilia trans- power microscopy, this region has an appearance similar port mucin out of the lung. to the architecture of the liver—an effect termed “red 4. Coughing expels foreign material that enters hepatization.” Older central regions have more densely the tracheobronchial tree. packed PMNs and macrophages. This region has a 5. Alveoli can deliver polymorphonuclear leuko- grayer color and forms the zone of “gray hepatization.” cytes (PMNs), macrophages, immunoglobulins, Pulmonary pathogens demonstrate marked differ- and complement to destroy invading pathogens. ences in their invasiveness and ability to destroy lung 6. Lymphatics drain macrophages and PMNs to parenchyma. S. pneumoniae causes minimal tissue the mediastinal lymph nodes. necrosis and is associated with little or no scar forma- tion. Full recovery of pulmonary function is the rule. S. aureus releases a number of proteases that perma- nently destroy tissue. Gram-negative rods and anaerobic First, an outpouring of edema ﬂuid into the alveoli bacteria also cause permanent tissue destruction.occurs, serving as an excellent culture media for furtherbacterial growth. As ﬂuid accumulates, it spills over to Predisposing Factorsadjacent alveoli through the pores of Kohn and the ter-minal bronchioles, resulting in a centrifugal spread of Most bacterial pneumonias are preceded by a viral upperinfection. Coughing and the physical motion of respira- respiratory infection [Figure 4.1(B)]. Inﬂuenza virus istion further enhance spread. well known to predispose to S. pneumoniae and S. aureus pneumonia. Viral infections of the upper respiratory tract can damage the bronchial epithelium and cilia. KEY POINTS Virus-mediated cell damage also results in the pro- duction of serous ﬂuid that can pool in the pulmonary alveoli, serving as an excellent culture media for bacte- About the Pathogenesis of Pneumonia ria. The low viscosity of this fluid, combined with depressed ciliary motility, enables the viral exudate to 1. Pathogens are aspirated or inhaled as small carry nasopharyngeal bacteria past the epiglottis into the aerosolized droplets. lungs. Smoking also damages the bronchial epithelial 2. Bacterial invasion of the alveoli induces cells and impairs mucociliary function. As a conse- a) edema fluid that spreads to other alveoli quence, smokers have an increased risk of developing through the pores of Kohn, and pneumonia. Congenital defects in ciliary function (such b) infiltration by polymorphonuclear leuko- as Kartagener’s syndrome) and diseases resulting in cytes and red blood cells, followed by highly viscous mucous (such as cystic ﬁbrosis) predis- macrophages. pose patients to recurrent pneumonia. 3. Infection spreads centrifugally: An active cough and normal epiglottal function usu- ally prevent nasopharyngeal contents from gaining access a) Newer regions in the periphery appear red to the tracheobronchial tree. However, drugs such as (“red hepatization”). alcohol, sedatives, and anesthetics can depress the level of b) Older regions are central and appear gray consciousness and impair these functions, predisposing (“gray hepatization”). the patient to pneumonia. Elderly individuals, particu- 4. Streptococcal pneumonia does not cause per- larly after a cerebrovascular accident, often develop manent tissue destruction. impairments in swallowing that predispose them to aspi- 5. Staphylococcus aureus, gram-negative rods, and ration. In addition, elderly people demonstrate reduced anaerobes cause permanent damage. humoral and cell-mediated immunity, rendering them more susceptible to viral and bacterial pneumonia.
82 / CHAPTER 4 Physical exam showed these positive findings: KEY POINTS temperature, 39 C; throat, erythematous; nasal dis- charge, clear; muscles, diffusely tender. A chest x-ray About Factors that Predispose to Pneumonia (CXR) was within normal limits. Three days into the clinical course of her illness, 1. Viral infections damage cilia and produce the patient noted some improvement in her cough, serous exudate that can transport nasopharyn- muscle aches, and joint pains; however, on the 4th geal bacteria into the alveoli. day, she developed a high fever (40 C) preceded by a 2. Smoking damages bronchial epithelial cells and teeth-chattering chill. That day, her cough became impairs ciliary function. productive of rusty-colored opaque sputum, and she 3. Alcohol and other drugs depress coughing and began feeling short of breath. epiglottal function. A repeat physical exam showed a temperature of 4. Elderly patients have reduced humoral and cell- 40.6 C and a respiration rate of 36 per minute. In mediated immunity, and may have impaired general, this was a very ill-appearing, anxious swallowing because of stroke. woman, gasping for air. Lungs were mildly dull to 5. Patients on immunosuppressive agents and percussion, with E-to-A changes, and rales and patients with AIDS have depressed humoral rhonchi localized to the left lower lobe. and cell-mediated immunity. A peripheral white blood cell (WBC) count mea- 6. Patients with chronic diseases are at increased sured 16,000/mm3, with 68% PMNs, 20% immature risk for pneumonia. forms (bands and metamyelocytes), 8% lymphocytes, 7. Cold weather dries the mucous membranes and increases person-to-person spread of infection. Patients with impairments in immunoglobulin pro-duction, T- and B-cell function, and neutrophil andmacrophage function are also at greater risk for develop-ing pneumonia. Organ-transplant patients on immuno-suppressive agents and AIDS patients have a greaterlikelihood of developing pneumonia. Chronic diseases,including multiple myeloma, diabetes, chronic renal fail-ure, and sickle cell disease have been associated with an Aincreased risk of pneumonia. Cold weather is thought to contribute to the devel-opment of pneumonia. Cold, dry weather can alter theviscosity of mucous and impair bacterial clearance. Coldweather also encourages people to remain indoors, a sit-uation that enhances person-to-person spread of respi-ratory infections.Symptoms and Signs CASE 4.1A 55-year-old woman was ﬁrst seen in the emergency Broom in December complaining of a nonproductive Figure 4–2. Pneumococcal pneumonia: A. Chestcough, nasal stufﬁness, and fever. She also noted diffuse radiograph demonstrates classical lobar inﬁltrate (Cour-severe muscle aches and joint pains and a generalized tesy of Dr. Pat Abbitt, University of Florida); and B. sputumheadache. In her epidemiologic history, she noted that Gram stain shows Streptococcus pneumoniae. Note thatshe had recently seen her grandchildren, who all had the cocci come to a slight point, explaining the termhigh fevers and were complaining of muscle aches. “lancet-shaped.” See color image on color plate 1
PULMONARY INFECTIONS / 83and 4% monocytes. Sputum Gram stain showed manygram-positive lancet-shaped diplococci, many PMNs KEY POINTS(>10/high-power ﬁeld), and no squamous epithelialcells. A CXR revealed a dense left lower lobe and lobar About the Classiﬁcation of Pneumoniainﬁltrate (Figure 4.2). Pneumonias are classiﬁed by 1. pace of illness: In case 4.1, the patient’s initial symptoms suggested a a) Acute—symptoms develop over 24 to 48 hours.viral illness involving the upper respiratory tract (rhinitisand nonproductive cough); central nervous system (CNS) b) Chronic—symptoms progress over 3 weeksor air sinuses, or both (headache); and musculoskeletal or longer.system (myalgias and arthralgias). Such symptoms are gen- 2. speciﬁc constellations of symptoms:erally attributed to an inﬂuenza-like illness. A number of a) Typical—rapid onset, more severe symp-viruses can explain these symptoms, including inﬂuenza, toms, productive cough, dense consolidationparainﬂuenza, adenovirus, respiratory syncytial virus on chest X-ray (CXR).(more common in children, but also found in elderly indi- b) Atypical—somewhat slower onset,less severeviduals and transplant patients), rhinoviruses (usually less symptoms, nonproductive cough, patchysevere), and enteroviruses. interstitial pattern on CXR. Subsequently, within a 24-hour period, this patient 3. environment in which the pneumonia wasexperienced the abrupt onset of a new constellation of acquired:symptoms. The onset of the new illness can be classiﬁed a) Community-acquired—patient not recentlyas acute. An illness is termed “acute” when symptoms (>14 days) in a hospital or chronic care facility.and signs develop over 24 to 48 hours. Symptoms that b) Nosocomial—patient in a hospital at thedevelop over 3 days to 1 week are generally classiﬁed as time the infection developed.subacute, and symptoms that progress more slowly (over3 weeks to several months) are classiﬁed as chronic. In generating a potential list of causative agents, theinfectious disease specialist frequently uses the pace of the 1. Cough. Frequency of the cough, production ofillness to narrow the possibilities. Pneumonias are gener- sputum, and color of the sputum should be docu-ally classiﬁed into two groups: acute and chronic. Most mented. A nonproductive cough or a coughbacterial and viral pneumonias develop quickly; fungal productive of scanty sputum suggests an atypicaland mycobacterial pulmonary infections tend to develop pneumonia; a cough productive of rusty-coloredat a slower pace. Acute pneumonia can be further classi- sputum raises the possibility of S. pneumoniae.ﬁed as “typical” or “atypical.” Typical pneumonia is char- Thick, “red current jelly” sputum has been reportedacterized by the more rapid onset of symptoms, more in cases of Klebsiella pneumoniae; green-colored spu-severe symptomatology, a productive cough, and dense tum is more frequently encountered in patients withconsolidation on CXR, as observed in case 4.1. Atypical H. inﬂuenzae and Pseudomonas aeruginosa pneumo-pneumonia tends to be slower in onset (often subacute), nia (typically a nosocomial pathogen, or found insymptoms tend to be less severe, cough is productive of patients cystic fibrosis). Frank hemoptysis isminimal sputum, and CXR usually reveals a patchy or observed in cavitary tuberculosis, lung abscess, andinterstitial pattern. Finally, pulmonary infections are sep- lung carcinoma. It should be emphasized that con-arated into community-acquired or nosocomial. “Com- siderable overlap occurs in the sputum characteris-munity–acquired” is deﬁned as an infection developing in tics of the various forms of pneumonia, and thesea patient who has not recently (>14 days) been hospital- observations cannot be considered speciﬁc.ized or resided in a chronic care facility. 2. Chest discomfort. Pleuritic chest pain (pain associ- Although considerable overlap in symptoms, signs, ated with deep inspiration) is classically described inand CXR ﬁndings are observed in cases of acute commu- patients with S. pneumoniae. Pain is usually sharpnity-acquired pneumonia, certain key clinical characteris- and stabbing. Because the pulmonary parenchymatics are helpful in guiding the determination of the most has no pain-sensing nerves, the presence of chestlikely causes (Table 4.2). Generation of a logical differen- pain indicates inﬂammation of the parietal pleura.tial list of potential pathogens guides the choice of diag- When the diaphragm becomes inﬂamed, the painnostic tests and narrows the possible treatment regimens. can mimic cholecystitis or appendicitis, and on occa- Important symptoms that need to be reviewed sion this sort of pain has precipitated exploratoryinclude these: laparotomy. Anaerobes, S. pyogenes, and S. aureus are
84 / CHAPTER 4Table 4.2. Clinical Characteristics of Acute Community-Acquired Pneumonia Classiﬁed by Cause Causative agent Classical symptoms Typical radiographic ﬁndings Streptococcus Rusty-colored sputum, rigor, Lobar inﬁltrate, air bronchograms pneumoniae pleuritic chest pain Haemophilus More gradual onset; seen in Lobar or patchy inﬁltrates inﬂuenzae smokers with COPD Staphylococcus Follows inﬂuenza pneumonia, Bronchopneumonia, lung abscess, aureus rapidly progressive acute disease pneumothorax, and empyema Aspiration pneumonia Follows from loss of Dense consolidation (more in the right lower consciousness, poor gag lobe than in the left lower lobe, or in posterior reﬂex, abnormal swallowing; segment of upper lobes); later, lung abscess foul-smelling sputum and empyema Legionella Nonproductive cough, Lobar pneumonia, cavities in pneumophila gastrointestinal symptoms, immunocompromised patients confusion Atypical pneumonia Mild-to-moderate symptoms, Patchy lower lobe bronchopneumonia nonproductive cough, pulmonary exam often normalCOPD = chronic obstructive pulmonary disease. other pathogens that can also spread to the pleura cidiomycosis, and travel to the Ohio River valley and cause chest pain. Pleuritic pain is also character- raises the possibility of histoplasmosis. Because istic of pleurodynia, a pain syndrome caused by the many respiratory illnesses spread from person to enteroviruses coxsackievirus and echovirus. person, a history of exposure to family members or3. Rigor. Mild chills are encountered in most febrile ill- friends with illnesses should be ascertained. Occu- nesses. However, a teeth-chattering, bed-shaking chill pational and sexual history should also be elicited. indicative of a true rigor is usually associated with bacteremia. This symptom is very prominent, and patients often can report the exact time of their ﬁrst KEY POINTS rigor. A single rigor is the rule in pneumococcal infec- tion; multiple rigors are more typical of S. aureus, anaer- obes, Klebsiella species, and S. pyogenes. H. inﬂuenzae About the History in Pneumonia seldom causes rigors.4. Shortness of breath. A report of increased short- 1. Cough. Frequency, production of sputum, color ness of breath suggests poor alveolar oxygen and thickness of sputum. exchange, indicative of severe infection. Some 2. Chest pain. Pain on deep inspiration, usually patients experience shortness of breath as a result of sharp, suggests pleural involvement. Seen in pleuritic chest pain that limits the ability to breath Streptococcus pneumoniae, Staphylococcus deeply. To avoid pain, patients may breath quickly aureus, Streptococcus pyogenes, anaerobes, and and shallowly, and this breathing pattern may be coxsackievirus and echovirus. interpreted as shortness of breath. 3. Rigor. Bed-shaking chills, 1 rigor in S. pneumo-5. Epidemiology. A careful epidemiologic history is niae, more than 1 in S. aureus, Klebsiella spp., often helpful. A number of environmental factors S. pyogenes, and anaerobes. predispose to pneumonia. Animal exposure must be 4. Shortness of breath. A worrisome symptom, carefully reviewed, including contact with wild may be the result of pleuritic chest pain rather game, birds, bats, and rodents (see Chapter 13). than poor gas exchange. Exposure to outside air conditioning units or con- 5. Epidemiology. Travel history, animal exposure, struction sites should be identiﬁed (legionnaires’ exposure to people with respiratory illnesses, disease). Travel history may be helpful. For example, occupational and sexual history. travel to the Southwest raises concerns about coc-
PULMONARY INFECTIONS / 85 effusion. A “leathery” friction rub may be heard over the KEY POINTS site of consolidation, indicating pleural inﬂammation. About the Physical Exam in Pneumonia Laboratory Findings Physical examination is unreliable for making the diag- 1. A respiratory rate >30/min, a blood pressure nosis of pneumonia. If pneumonia is a potential diag- <90 mm Hg,a pulse >125/min,and a temperature nosis, CXR must to be performed to conﬁrm or exclude <35 C or >40 C are bad prognostic ﬁndings. the disease. The radiologic pattern can serve as a rough 2. Depressed mental status and stiff neck suggest guideline to possible causative agents; however, the use bacterial meningitis. of immunosuppressive agents (resulting in neutropenia, 3. Pulmonary auscultation often underestimates decreased cell-mediated immunity, and depressed the extent of pneumonia: macrophage function) can greatly alter the typical a) Bronchial breath sounds and egophony sug- radiologic appearance of speciﬁc pathogens. Patients gest consolidation. with AIDS also present with atypical CXR. b) Dullness to percussion indicates consolida- Five classical patterns have been described: tion or a pleural effusion. 1. Lobar pneumonia. “Lobular pneumonia” refers to c) Pleural effusion is accompanied by decreased a homogeneous radiologic density that involves a breath sounds and, in some cases, a friction distinct anatomic segment of the lung (Figure 4.2). rub. Infection originates in the alveoli. As it spreads, this form of infection respects the anatomic boundaries of the lung and does not cross the ﬁssures. Lobar pneumonia is most commonly seen with S. pneumoniae, H. inﬂuenzae, and Legionella. A thorough physical examination should be 2. Bronchopneumonia. The bronchopneumonia formperformed during the initial evaluation for possible of pulmonary infection originates in the smallpneumonia. Vital signs are helpful in determining the airways and spreads to adjacent areas (Figure 4.3).severity of illness. A respiratory rate of more than Inﬁltrates tend to be patchy, to involve multiple areas30 breaths per minute, a systolic blood pressure under of the lung, and to extend along bronchi. Inﬁltrates90 mm Hg, a pulse above 125 beats per minute, and a are not conﬁned by the pulmonary ﬁssures. Bron-temperature below 35 C (95 F) or above 40 C (104 F) chopneumonia is commonly observed with S. aureus,are all bad prognostic signs. Depressed mental status is gram-negative bacilli, Mycoplasma, Chlamydia, andalso associated with a poor prognosis. respiratory viruses. Ear, nose, and throat examination may reveal vesicu-lar or crusted lesions consistent with Herpes labialis, an 3. Interstitial pneumonia. Infections causing inﬂam-infection that may reactivate as a consequence of the mation of the lung interstitium result in a ﬁne dif-stress of the primary illness. Neck stiffness in association fuse granular inﬁltrate (Figure 17.2). Inﬂuenza andwith depressed mental status may indicate the develop- cytomegalovirus commonly present with this CXRment of bacterial meningitis, a potential complication pattern. In AIDS patients, Pneumocystis jiroveciiof pneumococcal pneumonia. infection results in interstitial inflammation Pulmonary auscultation often fails to detect the combined with increased alveolar fluid that canextent of infection, and when pneumonia is being con- mimic cardiogenic pulmonary edema. Miliarysidered, the physical exam should be followed by a tuberculosis commonly presents with micronodularCXR. Asymmetry of chest movements may be observed, interstitial inﬁltrates.movement being diminished on the side with the pneu- 4. Lung abscess. Anaerobic pulmonary infectionsmonia. When infection has progressed to consolidation, often cause extensive tissue necrosis, resulting in lossas in case 4.1, ﬁlling of the lung parenchyma with exu- of lung tissue and formation of cavities ﬁlled withdate alters sound conduction. Air ﬂow from the bronchi inﬂammatory exudate (Figure 4.4). S. aureus alsois conducted through this ﬂuid to the chest wall, result- causes tissue necrosis and can form cavitary lesions.ing in bronchial or tubular breath sounds. When the 5. Nodular lesions. Histoplasmosis, coccidiomycosis,patient is asked to say “E,” an “A” is heard on ausculta- and cryptococcosis can present as nodular lungtion (egophony). Percussion of the chest wall also lesions (multiple or single) on CXR. Hematogenousdemonstrates dullness in the areas of consolidation. pneumonia resulting from right-sided endocarditisDullness to percussion in association with decreased commonly presents with “cannonball” lesions thatbreath sounds suggests the presence of a pleural can mimic metastatic carcinoma.
86 / CHAPTER 4 alveolar function and lack of oxygen transfer to alveolar KEY POINTS capillaries. Deoxygenated blood passes from the right side of the heart to the left side, creating a physiologic About Chest X-Ray in Pneumonia right-to-left shunt. Other metabolic parameters also need to be assessed. 1. If pneumonia is being considered, a chest X-ray A blood urea nitrogen level above 30 mg/dL reﬂects (CXR) should always be performed. hypoperfusion of the kidneys or dehydration (or both) and is a negative prognostic ﬁnding. A serum sodium 2. Radiographic patterns may be atypical in reading below 130 mEq/L reﬂects increased antidiuretic patients receiving immunosuppressants and in patients with AIDS. hormone secretion in response to decreased intravascu- lar volume in addition to severe pulmonary disease. 3. Five typical CXR patterns have been described: Such a reading is another negative prognostic ﬁnding, as a) Lobar pattern. Streptococcus pneumoniae, is a serum glucose level exceeding 250 mg/dL. Two Haemophilus inﬂuenzae, and Legionella. blood cultures should be drawn before antibiotics are b) Bronchopneumonia pattern. Staphylococ- started. Positive blood cultures deﬁnitively identify the cus aureus, gram-negative organisms, Myco- cause of the disease. Blood cultures are positive in 1% to plasma, Chlamydophila, and viral. 16% of cases of community-acquired pneumonia. c) Interstitial pattern. Inﬂuenza and cytome- Sputum requires careful analysis and frequently pro- galovirus, Pneumocystis, miliary tuberculosis. vides helpful clues to the probable diagnosis. Sputum d) Lung abscess. Anaerobes, S. aureus. samples often become contaminated with bacteria and e) Nodular lesions. Fungal (histoplasmosis, cells from the nasopharynx, making interpretation of coccidiomycosis, cryptococcosis) and right- the cultures difficult. Ideally, acquisition of sputum sided endocarditis. should be supervised by a physician to ensure that the 4. Patterns on chest radiographs are only rough patient coughs deeply and brings up the sample from guides. Considerable overlap between the vari- the tracheobronchial tree and does not simply expecto- ous pathogens has been observed. rate saliva from the mouth. The adequacy of the sample should be determined by low-power microscopic analy- sis of the sputum Gram stain. The presence of more than 10 squamous epithelial cells per low-power ﬁeld The role of high-resolution chest CT scan is evolv- indicates signiﬁcant contamination from the nasophar-ing, and this test has proved helpful for more clearlydemonstrating interstitial inﬁltration, pulmonary cavi-ties, nodules, and pleural ﬂuid collections. Patients with an inﬁltrate, who are under age 65, KEY POINTShave a normal mental status, and normal or only mildlyderanged vital signs can be treated as outpatients About Blood Tests in Pneumonia(Figure 4.5). Sputum Gram stain and culture areoptional in these patients, as are any additional tests. In more severely ill patients who are being consid- 1. With the exception of patients under the age ofered for hospitalization, additional tests to assess the 50 years, without underlying disease, and withseverity of the illness need to be ordered. normal vital signs, multiple blood tests are used A complete and differential blood cell count should to assess the severity of disease.be obtained. Patients with bacterial pneumonia usually 2. A peripheral white blood cell count belowhave an elevated peripheral WBC count and a left shift. 6000/mm3 in Streptococcus pneumoniae is a badWhen pneumococcal pneumonia is accompanied by a prognostic ﬁnding.low peripheral WBC count (<6000), a fatal outcome is 3. Anemia (hematocrit <30%), blood urea nitrogenmore likely. The ﬁnding of anemia (hematocrit <30%), above 30 mg/dL, serum sodium belowusually indicative of chronic underlying disease, is also 130 mEq/L, and glucose above 250 mg/dL areassociated with a worse prognosis. associated with a worse prognosis. Blood oxygenation also needs to be assessed. The O2 4. Arterial blood O2 below 60 mm Hg and pHsaturation should be determined, and if it is at all below 7.35 worsen prognosis.depressed, an arterial blood gas should be obtained. 5. Two blood samples should be drawn beforeSystemic acidosis (pH <7.35) and an arterial partial antibiotics are stated; blood cultures are posi-pressure below 60 mm Hg are bad prognostic signs. A tive in up to 16% of patients.significant depression in oxygenation reflects loss of
PULMONARY INFECTIONS / 87ynx, and the sample should be discarded. The presenceof more than 25 PMNs per low-power ﬁeld and the KEY POINTSpresence of bronchial epithelial cells provide strongevidence that the sample originates from the tracheo- About Sputum Gram Stain and Culturebronchial tree. Despite originating from deep within the lungs, spu- 1. Ideally the sputum collection should be super-tum samples usually become contaminated with some vised by a physician.normal throat ﬂora as they pass through the nasophar- 2. Adequacy of the sample is assessed by low-ynx. Gram stain can be helpful in differentiating normal power microscopic analysis:ﬂora (mixed gram-positive and gram-negative rods andcocci) from the offending pathogen. When a single bac- a) More than 10 squamous epithelial cells indi-terial type predominates, that bacterium is likely to be cates extensive contamination with mouth ﬂora.the primary pathogen. For example, the presence of b) More than 25 polymorphonuclear leuko-more than 10 lancet-shaped gram-positive diplococci cytes (PMNs) or bronchial epithelial cellsper high-power field provides strong evidence that (or both) per low-power field indicate anS. pneumoniae is the cause of the pneumonia (approxi- adequate sample.mately 85% speciﬁcity and 65% sensitivity, Figure 4.2). 3. Sputum Gram stain should be performed in all In reviewing bacterial morphology, the observer seriously ill patients with pneumonia.must assess the adequacy of decolorization. In ideallystained regions, the nucleus and cytoplasm should be a) Decolorization should be assessed for ade- quacy.gram-negative, and a mixture of gram-positive b) Predominance of a single organism suggestsand gram-negative organisms should be seen. A gram- that the probable pathogen has been found.positive nucleus indicates underdecolorization, and the c) Predominance of PMNs suggests bacterialpresence of gram-negative bacteria only (including pneumonia.cocci) suggests overdecolorization. d) Predominance of mononuclear cells sug- Sputum Gram stain is also helpful for assessing the gests Mycoplasma, Chlamydophila, or a virus.inﬂammatory response. The presence of many PMNs 4. Sputum culturesuggests a bacterial cause for the disease; a predomi- a) Should never be ordered without an accom-nance of mononuclear cells is more consistent with panying Gram stain.Mycoplasma, Chlamydia, or a viral infection. b) Should not be the sole basis for antibiotic Sputum culture is less helpful than Gram stain, treatment.because normal flora contaminating the sample fre- c) Often represents colonization rather thanquently overgrow, preventing identification of the infection when positive in the intubatedtrue pathogen. To reduce overgrowth, samples should patient.be quickly inoculated onto culture media. Rapid d) Is insensitive, because mouth ﬂora can over-processing has been shown to increase the yield for grow the pathogen.S. pneumoniae. Sputum cultures are falsely negative e) Is helpful for determining the antibiotic sen-approximately half the time. Because of the potential sitivity of pathogens identiﬁed by Gram stain.problems with sampling error, and the inability toaccurately quantify bacteri by standard culture,sputum should never be cultured in the absence of anaccompanying Gram stain. pathogens. This method will be particularly helpful in Culture is most helpful in determining the antibiotic identifying organisms that are not normally part of thesensitivities of potential pathogens. The combination of mouth ﬂora and that are difﬁcult to culture: L. pneu-sputum Gram stain and antibiotic sensitivity testing mophila, Mycoplasma pneumoniae, Chlamydia pneumo-may allow the clinician to narrow the spectrum of niae, and P. jirovecii.antibiotic coverage, reducing the likelihood of selecting When Legionella pneumonia is a consideration (seefor highly resistant pathogens. In the intubated patient, speciﬁc discussion later in this chapter), urinary antigensputum culture alone should never be the basis for ini- for L. pneumophila serogroup 1 (the most commontiating antibiotic therapy. Sputum culture will almost pathogenic serogroup) should be performed. This test isalways be positive, a result that often simply represents moderately sensitive and highly speciﬁc. A positive test iscolonization and not true infection (see Chapter 1). therefore diagnostic; a negative test does not exclude the Additional methods for sputum analysis are being diagnosis, however. A urinary antigen test fordeveloped. Polymerase chain reaction (PCR) is being S. pneumoniae is also available and is recommended asused to amplify specific strands of DNA from potentially useful in adults (80% sensitivity for bacteremic
88 / CHAPTER 4patients, 97% speciﬁcity). This test is frequently positive Delays beyond this period have been associated within children colonized with S. pneumoniae, and is therefore increased mortality.not recommended for that patient population. In patients requiring hospitalization for acute More invasive procedures are usually not required in community-acquired pneumonia, cefotaxime or ceftri-community-acquired pneumonia, but may be consid- axone (covers S. pneumoniae, H. inﬂunezae, S. aureus,ered in the severely ill patient when an adequate sputum Klebsiella spp, some gram-negative organisms, andsample cannot be obtained. Invasive procedures such as aerobic mouth flora), combined with an advancedfiberoptic bronchoscopy with protected brushing or macrolide [azithromycin or clarithromycin (coverslavage are more commonly required in the immuno- Legionella, Mycoplasma, Chlamydia)] is recommendedcompromised patient (see Chapter 16). The sheath sur- for empiric therapy. If aspiration pneumonia isrounding the brush reduces, but does not eliminate, suspected, metronidazole can be added.contamination by mouth ﬂora. In ambulatory patients, either a macrolide in the Quantitative cultures are required to differentiate form of azithromycin or clarithromycin, or a respira-infection from contamination, with growth of more tory fluoroquinolone (gatifloxacin, moxifloxacin, orthan 103 to 104 organisms per milliliter indicating infec- levoﬂoxacin) possessing good gram-positive activity istion. Lavage of a lung segment with sterile ﬂuid samples considered efficacious. Concerns have been raiseda larger volume of lung and is particularly useful for about the development of resistance to fluoro-diagnosing P. jirovecii pneumonia in AIDS patients (see quinolones, and many experts recommend that thisChapter 17). Bronchoscopy has been shown to be use- class of antibiotics be reserved for older patients withful in diagnosing not only P. jirovecii, but also mycobac- underlying disease. These patients are not onlyterial infections and cytomegalovirus. exposed to the standard causes of community- The use of bronchial lavage to assist in the diagnosis acquired pneumonia, they also experience anof ventilator-associated pneumonia (VAP) is controver- increased incidence of gram-negative bacilli that willsial. Contamination of samples by organisms be covered by those agents.colonizing the endotracheal tube can result in The appropriate duration of treatment has not beenmisinterpretation of the quantitative cultures. As systematically studied. For S. pneumoniae, patients arecompared to samples derived from endotracheal suc- generally treated for 72 hours after they becometion, samples obtained by bronchoscopy offer no bene- afebrile. For infections with bacteria that cause necrosisﬁt in regard to morbidity, mortality, or reduction in of lung (S. aureus, Klebsiella, and anaerobes), therapyantibiotic use in VAP. should probably be continued for more than 2 weeks. Treatment for 2 weeks is generally recom-DECIDING ON HOSPITAL ADMISSION mended for Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella in the immunocompetentIN ACUTE PNEUMONIA patient. Patients on intravenous antibiotics can gener-The Pneumonia Patient Outcome Research Team devel- ally be switched to oral antibiotics when their clinicaloped useful criteria called the pneumonia severity index condition is improving, they are hemodynamically(PSI) for assessing pneumonia severity; however, that stable, their gastrointestinal tract is functioningindex proved to be complex and difﬁcult to use. A sim- normally, and they are capable of taking medications bypler index called the CURB-65 (confusion, urea nitro- mouth. In many cases, those criteria are met withingen, respiratory rate, blood pressure, age 65 years or 3 days. When possible, the oral antibiotic should be ofolder) has been shown to have sensitivity and speciﬁcity the same antibiotic class as the intravenous preparation.nearly equal to that of the PSI. Both indexes can be used If staying within the class is not possible, then the oralto guide decisions on admission to a hospital ward or agent should have a spectrum of activity similar to thatintensive care unit. As shown in Figure 4.5, patients of the intravenous agent.with a score of 0 or 1 can be treated as outpatients; those Response to treatment can be assessed by monitoringwith a score of 2 or more warrant hospitalization. A temperature, respiratory rate, PaO2 and oxygen saturation,patient with a score of 4 to 5 generally requires place- peripheral white blood cell count, and frequency of cough.ment in an intensive care unit. The changes seen on CXR often persist for several weeks despite clinical improvement. Although CXR is not help-Empiric Treatment ful for assessing improvement, conventional ﬁlms can be combined with pulmonary CT scan to assess the develop-The mainstay of treatment is administration of antibi- ment of complications such as pneumothorax, cavitation,otics (Table 4.3). Antibiotic treatment should not be empyema, and adult respiratory distress syndromedelayed because of difﬁculties with sputum collection. (ARDS), and to document continued progression of inﬁl-Therapy should be started within 4 hours of diagnosis. trates despite therapy.
PULMONARY INFECTIONS / 89Table 4.3. Empiric Treatment of Pneumonia, Infectious Diseases Society of America, 2003 Disease characteristics Drug Dose Comments Community-acquired pneumonia No comorbidity Clarithromycina 500 mg PO q12h Low serum levels, No previous antibiotics or Outpatient azithromycina 500 mg PO, followed high levels in macrophages, or by 250 mg PO q24h preferred for Haemophilus erythromycin 500 mg q6h inﬂuenzae or Gastrointestinal toxicity doxycycline 100 mg PO q12h is common Bacteriostatic agent No comorbidity Respiratory Previous antibiotics, or ﬂuoroquinolone: nursing home resident gatiﬂoxacin 400 mg PO q24h or levoﬂoxacin 500 mg PO q24h Levoﬂoxacin-resistant or Streptococcus pneumoniae reported in Canada moxiﬂoxacin 400 mg PO q24h Advanced macrolide, plus Doses as above -lactam antibiotic: If aspiration suspected, cefuroxime axetil 500 mg PO q12h amoxicillin or amoxicillin– or clavulanate recommended. cefpodoxime 400 mg PO q12h or cefprozil 500 mg PO q12h or amoxicillin–clavulanate 2 g PO q12h Comorbidity Advanced macrolide Doses as above (CHF, COPD, DM, Respiratory Doses as above cancer, renal disease) ﬂuoroquinolone Inpatient, medical ward Respiratory Doses as above No recent antibiotics ﬂuoroquinolone Clarithromycin Dose PO as above or azithromycin, 500 mg IV q24h plus ceftriaxone 1 g IV or IM q24h or cefotaxime 1 g IV q8h Inpatient, medical ward Advanced macrolide, Doses as above Regimen depends on the previous antibiotic Recent antibiotics plus -lactam antibiotic Doses as above (preferred) or respiratory ﬂuoroquinolone Inpatient, ICU IV -lactam antibiotic, Doses as above Pseudomonas not an plus issue advanced macrolide or respiratory ﬂuoroquinolone Continued
90 / CHAPTER 4Table 4.3. (Continued) Disease characteristics Drug Dose Comments Inpatient, ICU Piperacillin–tazobactam 4 g/0.5 g IV q6h Pseudomonas an issue or imipenem 0.5–1 g IV q6h or meropenem 1 g IV q8h or cefepime 1–2 g IV q8h Aspiration pneumonia Community Penicillin G 2 106 U IV q4h Covers usual mouth ﬂora Clindamycin 600 mg IV q8h Slightly more effective than penicillin for lung abscess In hospital Ceftriaxone 1 g IV q24h plus metronidazole 500 mg IV q8h Respiratory Doses as above ﬂuoroquinolone plus metronidazole 500 mg IV q8h Piperacillin–tazobactam 3 g/0.375 g IV q6h Regimen used by the author or ticarcillin–clavulanate 3.1 g IV q4–6h Requires a large ﬂuid loada Advanced macrolides.CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease; DM = diabetes mellitus; ICU = intensive care unit.Outcome can better predict the clinical course of pneumonia and can narrow antibiotic coverage.In the United States, 45,000 deaths are attributed topneumonia annually. In hospitalized patients, overall Streptococcus pneumoniaemortality ranges from 2% to 30%. Mortality frompneumonia and inﬂuenza is particularly high in indi- PATHOGENESISviduals over the age of 65 years, causing 150 to 250 Pathogenic strains of S. pneumoniae have a thick cap-deaths per 100,000 population annually. Mortality is sule that prevents PMN binding and that blocksalso higher in individuals with underlying diseases. Five phagocytosis. Certain capsular types (1, 3, 4, 7, 8, andcomorbid illnesses have been identiﬁed that result in 12 in adults, and 3, 6, 14, 18, 19, and 23 in children)statistically signiﬁcant increases in mortality: account for most pneumonia cases. Type 3 has the• Neoplastic disease • Cerebrovascular disease thickest polysaccharide capsule, and it is the most vir- ulent strain, being associated with the worst progno-• Liver disease • Renal disease sis. Immunoglobulins that specifically recognize the• Congestive heart failure capsule are able to link the bacterium to the PMN surface through Fc receptors, enabling PMNs andSPECIFIC CAUSES OF ACUTE macrophages (classified as phagocytes) to efficientlyCOMMUNITY-ACQUIRED PNEUMONIA ingest and kill the pneumococci. The complement product C3b enhances phagocytosis of the bacteria byGreat overlap occurs among the clinical manifestations the same mechanism. Immunoglobulins and C3b areof the pathogens associated with acute community- called “opsonins,” which are products that enhanceacquired pneumonia. However, constellations of symp- foreign particle ingestion by phagocytes.toms, signs, and laboratory ﬁndings serve to narrow the In addition to its polysaccharide capsule, S. pneumo-possibilities. By developing an ability to focus on a few niae possesses a number of other virulence factors thatpathogens or to identify a speciﬁc pathogen, clinicians enhance adherence to epithelial cells, resist phagocytosis,
PULMONARY INFECTIONS / 91 KEY POINTS KEY POINTS About Treatment and Outcome of Pneumonia About the Pathogenesis of Streptococcus pneumoniae 1. Treatment must be instituted within 4 hours of diagnosis. 1. The thick outer capsule blocks phagocytosis. 2. Delays are associated with increased mortality. Type 3 has the thickest capsule. 3. Appropriate triage should be guided by the 2. Immunoglobulins and complement are impor- CURB-65 classiﬁcation. tant opsonins that allow phagocytes to ingest 4. Empiric therapy depends on the patient and invading pneumococci. disease characteristics: 3. Strep. pneumoniae does not produce protease a) Outpatient with no comorbidity and no and seldom destroys lung parenchyma. previous antibiotics. Use a macrolide 4. It does not cross anatomic barriers such as lung (azithromycin or clarithromycin). If previous ﬁssures. antibiotics or elderly nursing home patient, 5. Disease manifestations are caused primarily add a -lactam antibiotic, or use a respira- by the host’s inflammatory response to the tory ﬂuoroquinolone. organism. b) Hospitalized patient. Use a 3rd-generation cephalosporin (ceftriaxone or cefotaxime) combined with a macrolide (azithromycin or clarithromycin). If Pseudomonas is a concern, use piperacillin–tazobactam, imipenem, or identiﬁed. Because opsonins are required for efﬁcient meropenem. phagocytosis of the encapsulated organism, patients with hypogammaglobulinemia and multiple myeloma c) Aspiration outpatient. Use penicillin or are at increased risk for developing this infection, as are clindamycin. patients with deﬁciencies in complement (C1, C2, C3, d) Aspiration inpatient. Use a 3rd-generation C4). Patients with HIV infection also have defects in cephalosporin or a respiratory ﬂuoro- antibody production, and they have a higher incidence quinolone plus metronidazole; or use ticar- of pneumococcal infection. Patients with splenic cillin–clavulanate or piperacillin–tazobactam. 5. Using chest radiographs to monitor improve- ment is not recommended. (They can take several weeks to clear.) They are useful for KEY POINTS documenting worsening of disease or devel- opment of complications. 6. Mortality ranges from 2% to 30%. Mortality About Streptococcus pneumoniae Prevalence higher with age more than 65 years, neoplas- and Predisposing Factors tic disease, liver disease, congestive heart failure, cerebrovascular accident, and renal 1. S. pneumoniae is the most common form of disease. community-acquired bacterial pneumonia. 2. The risk is higher in patients with deﬁciencies in opsonin production: a) Hypogammaglobulinemiaand activate complement. S. pneumoniae does not produce b) Complement deﬁciencysigniﬁcant quantities of proteases, and disease manifesta- c) HIV infectiontions are primarily the consequence of the host’s inﬂam- 3. Splenic dysfunction increases the risk of fatalmatory response. As a result, permanent tissue damage is pneumococcal bacteremia.rare, and spread of the disease across anatomic boundaries, 4. Risk is increased in patients with chronic diseases:such as lung ﬁssures, is uncommon. a) Cirrhosis b) AlcoholismPREVALENCE AND PREDISPOSING FACTORS c) Nephrotic syndromeS. pneumoniae remains the most common cause of d) Congestive heart failureacute community-acquired pneumonia; it represents e) Chronic obstructive pulmonary diseasetwo thirds of the cases in which a speciﬁc pathogen is
92 / CHAPTER 4 diplococci suggest the diagnosis [Figure 4.2(B)]. A KEY POINTS ﬁnding of pneumococci within the cytoplasm of a PMN strongly supports invasive infection. About Clinical Manifestations and Diagnosis Sputum Culture—S. pneumoniae is catalase nega- of Pneumococcal Pneumonia tive, bile soluble, and, like S. viridans, demonstrates alpha (green) hemolysis on blood agar plates. The propensity of normal mouth flora, in particular 1. Three classic features may be found: S. viridans, to overgrow frequently interferes with the a) Abrupt onset accompanied by a single rigor identification of S. pneumoniae. The optochin disk b) Rusty-colored sputum inhibits growth of S. pneumoniae, but not of S. viridans, c) Pleuritic chest pain and this test is used to differentiate the two organisms. 2. Sputum Gram stain is often helpful: more than Another problem with sputum culture arises from the 10 gram-positive lancet-shaped diplococci per fact that S. pneumoniae can be present as normal mouth high-power ﬁeld indicate pneumococcal pneu- ﬂora in up to 60% of healthy people. A positive sputum monia. culture in the absence of a positive Gram stain or a 3. Sputum culture is insensitive; specimens (alpha positive blood culture may therefore simply represent hemolytic, optochin sensitive) should be plated contamination of the sputum with saliva. quickly. Blood Cultures—Some reports have claimed that 4. Blood samples for culture should always be 25% of patients with pneumococcal pneumonia drawn; up to 25% may be positive. develop positive blood cultures; however, the denomi- nator required to calculate this percentage is uncertain. 5. A urine pneumococcal antigen test may prove Even in the absence of a positive sputum Gram stain, a helpful, but may be positive in patients who are simply colonized with Streptococcus pneumoniae. positive blood culture in combination with the appro- priate symptoms and CXR ﬁndings is interpreted as 6. A chest radiograph shows a classical lobar pat- true infection. A urine test for pneumococcal polysac- tern; small pleural effusions are common, true charide antigen is available and is positive in 80% of empyema rare. Abnormalities persist for 4 to 6 weeks after cure. adults with bacteremia. Chest X-Ray—The CXR usually reveals a single area of infiltration involving one or more segments of a single lobe. Involvement of the entire lobe is less com-dysfunction have a higher risk of overwhelming mon. This organism respects the conﬁning ﬁssures ofS. pneumoniae sepsis because the spleen plays a vital the lung and rarely extends beyond those boundaries,role in clearing this bacteria from the bloodstream, which explains the classical lobar radiologic patternparticularly in the absence of speciﬁc anti-pneumococ- [Figure 4.2(A)].cal capsule antibody. Other chronic diseases, including Air bronchograms are found in a few cases. Thiscirrhosis, nephrotic syndrome, congestive heart failure, radiologic finding is the consequence of the alveolichronic obstructive pulmonary disease, and alco- ﬁlling with inﬂammatory ﬂuid and outlining the air-holism, are also associated with greater risk of pneu- containing bronchi. When found, bronchograms aremococcal infection. associated with a higher incidence of bacteremia. Pleural ﬂuid may be detected in up to 40% of cases.UNIQUE CLINICAL CHARACTERISTICS In most instances, the volume of ﬂuid is too small toClassically, pneumococcal pneumonia has a very abrupt sample by thoracentesis, and if antibiotic treatment isonset that begins with a single severe rigor. Because prompt, only a small percentage go on to develop trueS. pneumoniae invasion of the lung leads to capillary empyema.leakage of blood into the alveolar space, sputum can The radiologic improvement of pneumococcal pneu-become rusty in color. Furthermore, pneumococcal monia is slow. Despite rapid defervescence and resolu-infection frequently infects the peripheral lung and tion of all symptoms, radiologic changes often persistspreads quickly to the pleura. As a result, pleuritic chest for 4 to 6 weeks. If the patient is improving clinically,pain is a common complaint. follow-up CXRs are therefore not recommended during this period.DIAGNOSISSputum Gram Stain—A careful analysis of the sputum TREATMENT AND OUTCOMEis best performed by a knowledgeable physician. Areas In the early antibiotic era, S. pneumoniae was highly sensi-with signiﬁcant numbers of PMNs per high-power ﬁeld tive to penicillin [minimum inhibitory concentrationand a predominance of gram-positive lancet-shaped (MIC)< 0.06 g/mL]. However, since the late 1990s,
PULMONARY INFECTIONS / 93isolates in the United States have become increasinglyresistant, with 40% demonstrating intermediate resistance KEY POINTS(MIC = 0.1–1 g/mL), and a small percentage demon-strating high-level resistance (MIC > 2 g/mL). In some About the Treatment, Outcome, and Preventionareas of Europe and South Africa, higher percentages of of Pneumococcal Pneumoniaresistant strains have been observed. In the Netherlandsand Germany, where strictly limited antibiotic use is thestandard of care, the prevalence of resistant strains is lower. 1. A signiﬁcant percentage of Streptococcus pneu- Currently, many intermediate strains remain sensi- moniae are resistant to penicillin:tive to the 3rd-generation cephalosporins ceftriaxone a) 25% to 35% are intermediately resistant (MICand cefotaxime (MIC < 1 g/mL); however, resistance = 0.12–1 g/mL).to these antibiotics is increasing. For intermediately b) a smaller percentage demonstrate high-levelresistant strains, amoxicillin is more active than is peni- resistance (MIC > 2 g/mL).cillin VK, and amoxicillin is therefore the preferred oral 2. Penicillin or ampicillin remain the treatment ofantibiotic. Because penicillin resistance results from a choice for penicillin-sensitive strains.decrease in the afﬁnity of penicillin-binding proteins, 3. High-dose parenteral penicillin, a 3rd-genera-intermediate (but not high–level) resistance can be over- tion cephalosporin or an oral amoxicillin usedcome by raising the concentration of penicillin. for intermediate-sensitivity strains, except for With the exception of the CNS, where the meningitis.blood–brain barrier limits antibiotic penetration, standard 4. A respiratory fluoroquinolone (gatifloxacin,doses of penicillin are effective in curing infections attrib- moxifloxacin, levofloxacin) is used for strainsutable to intermediately resistant pneumococci. Penicillin with high-level resistance. Avoid fluoro-resistance is usually associated with resistance to many quinolones in meningitis, and cover with van-other classes of antibiotics, including the tetracyclines, comycin.macrolides, and clindamycin. Imipenem is also inactive 5. Mortality is approximately 5%; prognosis isagainst highly resistant strains. The respiratory ﬂuoro- worse for infants and for patients older thanquinolones that possess good gram-positive activity (lev- 65 years of age, and for those whose treatmentoﬂoxacin, gatiﬂoxacin, moxiﬂoxacin) and vancomycin is delayed or who have capsular types 2 or 3,usually retain excellent activity against all resistant strains. multilobar pneumonia, bacteremia or meningi- tis, or jaundice, or who are pregnant, have anSeveral cases of pneumonia attributable to levoﬂoxacin- underlying disease, or alcohol intoxication.resistant S. pneumoniae have recently been reported; how-ever, the overall percentage of pneumococcal strains that 6. The 23-valent pneumococcal vaccine is safe andare resistant to ﬂuoroquinolones remains low. efﬁcacious. It should be given to patients who are over 65 years of age, who have a chronicTREATMENT RECOMMENDATIONS disease, and who are asplenic, immunocompro- mised, or alcoholic.For doses of the drugs discussed here, see Table 4.3. For penicillin-sensitive strains, penicillin G or amoxi-cillin remain the preferred treatment. Ceftriaxone is alsoeffective. If the patient fails to improve within 48 hours, 4. Involvement of more than one lobe of the lungthe possibility of a resistant strain must be considered,and coverage with a respiratory ﬂuoroquinolone is rec- 5. WBC count less than 6000/mm3ommended. For cases in which meningitis is suspected, a 6. Bacteremia, shock, or the development of meningitisﬂuoroquinolone should not be used because of poor pen- 7. Jaundiceetration of the cerebrospinal ﬂuid, and the patient should 8. Pregnancybe covered with vancomycin. In the penicillin-allergic 9. Presence of other underlying diseases (heart disease,patient, a respiratory ﬂuoroquinolone can be used. cirrhosis, diabetes) In the pre-antibiotic era, the mortality rate for 10. Alcohol intoxicationpneumococcal pneumonia was 20% to 40%. In theantibiotic era, the mortality rate was reduced to approx-imately 5%. Prognosis is adversely inﬂuenced by PREVENTION Despite the use of antibiotics, mortality during the ﬁrst1. Age (patients above 65 years of age and infants have 36 hours of hospitalization has not changed. To prevent worse outcomes) early mortality and to reduce the incidence of2. Delayed treatment S. pneumoniae infection—the penicillin-sensitive and3. Infection with capsular type 2 or 3 penicillin-resistant strains alike—vaccination is strongly
94 / CHAPTER 4recommended for all patients with chronic illnesses or extended-spectrum cephalosporins (cefpodoxime,those over the age of 65 years. ceﬁxime) are also active against this organism. Generation of speciﬁc antibodies directed againstthe bacterial cell wall confer, prevent, or reduce the Staphylococcus aureusseverity of disease. Polyvalent vaccine containing anti-gens to 23 capsular types is available and is effective Fortunately, community-acquired pneumonia attributable(approximately 60% reduction of bacteremia in to S. aureus is rare. The most common predisposing factorimmunocompetent adults). Efficacy decreases with is a preceding inﬂuenza infection. An increase in the inci-age and is not measurable in immunocompromised dence of S. aureus pneumonia is often a marker for thepatients. The vaccine has proved to be safe and inex- onset of an inﬂuenza epidemic. S. aureus pneumonia ispensive, and should be widely used. also more common in intravenous drug users and in AIDS patients, in association with P. jirovecii pneumonia.Haemophilus inﬂuenzae In a few communities, community-acquired methi- cillin-resistant S. aureus (cMRSA) pneumonia has beenGroup B and non-typable H. inﬂuenzae can both cause described in addition to methicillin-sensitive S. aureuscommunity-acquired pneumonia. Infection with non- (MSSA). The clinical manifestations of this infectiontypable H. inﬂuenzae is more common in elderly indi- are similar to other forms of bacterial pneumonia.viduals and in smokers with chronic obstructive However the illness is often severe, being associatedpulmonary disease. The onset of symptoms tends to be with high fever and a slow response to conventionalmore insidious than that seen with S. pneumoniae, but therapy. A CXR can demonstrate patchy inﬁltrates orthe clinical pictures are otherwise indistinguishable. A dense diffuse opacifications. S. aureus producesCXR can demonstrate lobar or patchy inﬁltrates, and multiple proteases that allow this bacterium to readilysputum Gram stain reveals small gram-negative cross the lung fissures and simultaneously involvepleomorphic coccobacillary organisms. multiple lung segments. This broader involvement Because of their small size and their color, which is explains the typical bronchopneumonia pattern onsimilar to background material, H. inﬂuenzae may be CXR [Figure 4.3(A)]. The rapid spread and aggressivemissed by an inexperienced diagnostician. For the patient destruction of tissue also explains the greater tendencyrequiring hospitalization, intravenous ceftriaxone or of S. aureus to form lung abscesses and induce a pneu-cefotaxime is recommended. For oral antibiotic treatment, mothorax. Spread of this infection to the pleural spaceamoxicillin–clavulanate is effective. However, a number of can result in empyema (seen in 10% of patients). Spu-other oral antibiotics, including trimethoprim– tum Gram stain reveals sheets of PMNs and an abun-sulfamethoxazole, the newer macrolides (azithromycin dance of gram-positive cocci in clusters and tetradsand clarithromycin), the ﬂuoroquinolones, and the [Figure 4.3(B)], and culture readily grows S. aureus. Blood cultures may also be positive. The treatment of choice for MSSA is high- dose intravenous nafcillin or oxacillin. For MRSA KEY POINTS About Haemophilus inﬂuenzae Pneumonia KEY POINTS 1. This small, gram-negative, pleomorphic coc- About Staphylococcus aureus Pneumonia cobacilli is aerobic. It may be mistaken for the background material on sputum Gram stain. 1. These large gram-positive aerobic cocci form 2. Non-typable strains are more common in eled- tetrads and clusters. erly people and in smokers with COPD. 2. The disease most commonly follows inﬂuenza, 3. Clinically, Haemophilus inﬂuenzae is similar to and is seen in patients with AIDS and in IV drug S. pneumoniae, with a somewhat slower onset. abusers. 4. Parenteral ceftriaxone or cefotaxime should be 3. Destructive bronchopneumonia is compli- used to treat hospitalized patients. Multiple cated by oral regimens–amoxicillin-clavulanate, newer macro-lides, ﬂuoroquinolones, and extended- a) lung abscesses, spectrum cephalosporins are useful in outpa- b) pneumothorax, and tients. c) empyema.
PULMONARY INFECTIONS / 95 BAFigure 4–3. Staphylococcus aureus pneumonia: A. Chest radiograph demonstrates a classic bronchopneumonia (Cour-tesy of Dr. Pat Abbitt, University of Florida), and B. sputum Gram stain shows gram-positive cocci in clusters and tetrads.See color image on color plate 1pneumonia, vancomycin is generally recommended. pneumonia. In the immunocompromised host, cavitaryThe dose of vancomycin should be adjusted to maintain lesions may be seen. Small pleural effusions are alsoa trough level of 15 to 20 g/mL to assure therapeutic commonly found.levels in the lung. Linezolid is an expensive alternative Diagnosis requires a high index of suspicion, becausethat has equivalent efﬁcacy. sputum Gram stain reveals only acute inﬂammatory cells. The microbiology laboratory must be alerted to the possi-Legionella pneumophila bility of Legionella species to assure that sputum samples are cultured on buffered-charcoal yeast-extract agar withLegionella species are gram-negative bacilli found added suppressive antibiotics. Legionella can also be iden-throughout the environment in standing water and soil. tiﬁed by direct ﬂuorescent antibody staining, although theInfection most commonly results from inhalation of sensitivity of this technique is low (30% to 50%). Ampli-water droplets contaminated with Legionella. Cooling ﬁcation of Legionella DNA from sputum samples by PCRtowers or shower heads are most often responsible for is available in certain reference laboratories, but not com-aerosolizing contaminated water. Less commonly, noso- mercially. For L. pneumophila serogroup 1, the most com-comial infection has resulted from the use of unsterilized mon cause of Legionella pneumonia in the United Statestap water in respiratory therapy devices. Outbreaks of (>80% of cases), a highly sensitive and speciﬁc urinaryLegionella pneumonia have also been associated with soil antigen test is commercially available. The antigen isexcavation. Immunocompromised patients, smokers, excreted early in the illness and persists for several weeks.and elderly people are more susceptible to this infection. For mild disease, an oral macrolide, ﬂuoroquinolone, Clinically, Legionella infection causes symptoms typ- or tetracycline may used. However, in more severe disease,ical of other acute community-acquired pneumonias, high doses of intravenous azithromycin or a ﬂuoro-including high fever, cough, myalgias, and shortness of quinolone (ciproﬂoxacin or levoﬂoxacin) are recom-breath. As compared with other bacterial pneumonias, mended. In transplant patients, a ﬂuoroquinolone iscough usually produces only small amounts of sputum. preferred because the macrolides interfere withGastrointestinal symptoms, confusion, and headache cyclosporin or tacrolimus metabolism. In the immuno-are more frequently encountered in patients with competent patient, therapy should be continued for 5 toLegionella. Laboratory ﬁndings are similar to other acute 10 days with azithromycin and for 10 to 14 days with apneumonias. The only distinctive finding may be ﬂuoroquinolone. In the immunocompromised patient,hyponatremia, which is noted in approximately one therapy needs to be prolonged for 14 to 21 days to preventthird of patients. A CXR frequently demonstrates lobar relapse. Mortality is high in legionnaires’ disease, being
96 / CHAPTER 4 individuals. The disease is seasonal, with the highest KEY POINTS incidence of Mycoplasma being seen in the late sum- mer and early fall. Sore throat is usually a prominent About Legionella Pneumonia symptom, and bullous myringitis is seen in 5% of cases. Presence of this abnormality is highly suggestive of Mycoplasma. Tracheobronchitis results in a hacking 1. These aerobic gram-negative bacteria do not take up Gram stain well. cough that is often worse at night and that persists for several weeks. Physical exam may reveal some moist 2. Found in soil and standing water. Aerosolized by rales, but classically, radiologic abnormalities are more cooling towers and shower heads. Also con- extensive than predicted by the exam. Findings on tracted after soil excavation. CXR consist of unilateral or bilateral patchy lower- 3. Elderly people, smokers, and immunocompro- lobe inﬁltrates in a bronchial distribution. The clini- mised patients are at increased risk. cal course is usually benign. Fever, malaise, and 4. Similar to other acute pneumonias. Somewhat headache usually resolve over 1 to 2 weeks, but cough unique characteristics include can persist for 3 to 4 weeks. Peripheral WBC is a) minimal sputum production, usually less than 10,000. And sputum Gram stain and b) confusion and headache, culture reveal only normal mouth ﬂora and a moder- c) gastrointestinal symptoms, and ate inﬂammatory response. d) hyponatremia. Diagnosis is made by history and clinical manifes- 5. Diagnostic techniques include tations. Epidemiologic history of contact with a per- son having similar symptoms is particularly helpful. a) culture on buffered-charcoal yeast-extract Currently, no deﬁnitive test is available. Sputum PCR agar, has been found to be sensitive and speciﬁc, but that b) direct ﬂuorescent antibody stain (low sensi- test is not commercially available. Cold agglutinin tivity), titers in excess of 1:64 support the diagnosis and c) polymerase chain reaction (still experimen- correlate with severity of pulmonary symptoms, but tal), and are not cost effective. Complement ﬁxation antibody d) urinary antigen to serotype I (causes 80% of titers begin to rise 7 to 10 days after the onset of infections), which is sensitive and specific, symptoms. and persists for several weeks. Because a reliable, rapid diagnostic test is not 6. Azithromycin or a fluoroquinolone are the currently available, therapy is usually empiric. A treatments of choice. In transplant patients, macrolide or tetracycline is the treatment of choice; fluoroquinolones are preferred. Mortality is alternatively, a ﬂuoroquinolone can be administered. high: 16% to 50%. Azithromycin is the preferred agent when Mycoplasma is suspected, and a standard 5-day course is effective in most cases. Chlamydia pneumoniae (Taiwan acute respiratory16% to 30% in community-acquired disease and up to agent) is another important cause of atypical pneumonia.50% in hospitalized patients. This pathogen is a common cause of community- acquired pneumonia, representing 5% to 15% of cases.Atypical Pneumonia The disease occurs sporadically and presents in a manner similar to Mycoplasma, with sore throat, hoarseness, andThe atypical forms of pneumonia tend to be subacute in headache in addition to a nonproductive cough. Radio-onset, with patients reporting up to 10 days of logic ﬁndings are also similar to those with Mycoplasma.symptoms before seeking medical attention. Atypical No rapid diagnostic test is widely available, and treat-pneumonia is associated with a nonproductive cough, ment is empiric. A tetracycline is considered the treat-and clinical manifestations tend to be less severe. It is ment of choice, but macrolides and ﬂuoroquinolones areimportant to keep in mind that significant overlap also effective.occurs in the clinical manifestations of this group of The ﬁnal major group of organisms that cause atyp-infections and the more typical forms of pneumonia ical pneumonia is the respiratory viruses: inﬂuenza Aassociated with purulent sputum production. and B, adenovirus, parainﬂuenza virus, and respiratory Mycoplasma pneumoniae is one of the most syncytial virus. The respiratory syncytial virus infectsfrequent causes of “walking pneumonia.” This infec- primarily young children, elderly people, and thetion is seen primarily in patients under age 40 years; immunocompromised host. These viruses can all pre-it is an uncommon cause of pneumonia in elderly sent with a nonproductive cough, malaise, and fever.
PULMONARY INFECTIONS / 97 KEY POINTS About Atypical Pneumonia 1. These diseases tend to be subacute in onset. 2. Cough is nonproductive. 3. Illness is often less severe than in other community-acquired pneumonias: “walking pneumonia.” 4. Findings in a chest radiograph are usually worse than the physical ﬁndings. 5. Three primary causes: a) Mycoplasma pneumoniae b) Chlamydophila pneumoniae c) Respiratory viruses: influenza, adenovirus, parainﬂuenza, and respiratory syncytial virus. 6. Rapid tests are available for inﬂuenza, but not Figure 4–4. Empyema following aspiration pneumo- for Mycoplasma or Chlamydia. nia. CT scan showing a large right pleural effusion as 7. Treatment with a macrolide or tetracycline is well as discrete rounded cavitary lesions in the lung recommended. If inﬂuenza is diagnosed, give amantadine, ranitidine, or a neuramidase parenchyma of both the left and right lower lobes. inhibitor within 48 hours of illness onset. (Courtesy of Dr. Pat Abbitt, University of Florida) passing out on at least two occasions. He developed aAuscultatory ﬁndings are minimal, and lower lobe inﬁl- persistent cough, productive of green sputum, 4 daystrates are generally observed on CXR. The clinical virol- before admission. At that time, he also began experi-ogy laboratory can culture each of these viruses from encing left-sided chest pain on deep inspiration (pleu-sputum or a nasopharyngeal swab. Rapid commercial ritic pain). Initially these pains were dull; however, overtests (10 to 20 minutes) are available for detection of the next few days, they became increasingly sharp.inﬂuenza (Quick View, Flu O1A, and Zstatﬂu). These Physical exam showed a temperature of 38 C andtests have a sensitivity of 57% to 77%, and all three can a respiratory rate of 42 per minute. This was adistinguish between types A and B. disheveled man, looking older than his stated age, If inﬂuenza A virus is diagnosed, early treatment of breathing shallowly and rapidly, in obvious pain.the virus with amantadine or rimantadine is recom- A check of the throat revealed a good gag reﬂex,mended. Neuramidase inhibitors are also available, and extensive dental caries, several loose teeth, severe gin-these agents have activity against both inﬂuenza A and givitis, and foul-smelling breath and sputum.B. The inﬂuenza vaccine is safe and efﬁcacious, and Decreased excursion of the right lung was noted, andshould be given annually in October through early the right lower lung ﬁeld was dull to percussion.November to patients over 65 years of age, individuals Bronchovesicular breath sounds were heard diffuselywith serious underlying diseases, nursing home resi- (inspiratory and expiratory breath sounds of equaldents, and health care workers (see Chapter 15). duration); moist, medium rales were heard in the right lower and left lower lung ﬁelds. Egophony and whis-Aspiration Pneumonia pered pectoriloquy were also heard in these areas. Laboratory workup showed a hematocrit of 50%; a WBC count of 21,400/mm3, with 79% PMNs, 7% bands, CASE 4.2 1% lymphocytes, and 13% monocytes. Blood gasses showed a pH of 7.46, PaO2 of 56 mm Hg, and a PaCO2 ofA 35–year-old white man arrived in the emergency 36 mm Hg. Sputum Gram stain revealed many PMNsroom complaining of left-sided chest pain during the and a mixture of gram-positive cocci, gram-positivepreceding 4 days. He had begun drinking large quan- rods, and gram-negative rods. A CXR demonstratedtities of alcohol 8 days earlier. He vaguely recalled dense right lower lobe inﬁltrate.
98 / CHAPTER 4 While on antibiotics, this patient continued to com- of PMNs are called empyemas. Necrosis of the pleural lin-plain of chest pain and developed decreased breath ing and lung parenchyma can result in formation of a ﬁs-sounds in the right lower lobe associated with dullness tula tracking from the bronchus to the pleural space.to percussion. A repeat CXR and CT scan demonstrated Development of a bronchopleural ﬁstula prolongs hospi-a large right pleural effusion [see Figure 4-4(A)], and talization and may eventually require surgical repair.thoracentesis revealed more than 100,000 PMNs/mm3,pleural ﬂuid pH of 7.0, and total protein 3.4 mg/mL. DIAGNOSISGram stain showed a mixture of gram-positive cocci Sputum is often foul-smelling as a result of the highand gram-positive and gram-negative rods. numbers of anaerobic bacteria. Sputum Gram stain reveals many PMNs and a mixture of gram-positive and gram-negative organisms. Sputum culture usually grows normal mouth ﬂora. When aspiration occurs in the hospitalized patient, the mouth often is colonizedAspiration pneumonia should be suspected in patients with more resistant gram-negative organisms pluswith a recent history of depressed consciousness and in S. aureus. In these patients, a predominance of gram-patients with a poor gag reﬂex or an abnormal swallow- negative rods or gram-positive cocci in clusters may being reﬂex. The elderly patient who has suffered a stroke seen on Gram stain, and gram-negative rods oris particularly susceptible to aspiration. In case 4.2, the S. aureus may be cultured from the sputum.patient’s heavy consumption of alcohol led to depres- A CXR reveals inﬁltrates in the dependent pulmonarysion in consciousness. segments. When aspiration occurs in the upright position, Three major syndromes are associated with aspiration: the lower lobes are usually involved, more commonly the right lower lobe than the left. This difference has an1. Chemical burn pneumonitis. Aspiration of the anatomic explanation. The right bronchus divides from acidic contents of the stomach can lead to a the trachea at a straighter angle than does the left main- chemical burn of the pulmonary parenchyma. stem bronchus, increasing the likelihood that aspirated Aspiration of large quantities of fluid can result material will ﬂow to the right lung. When aspiration in the immediate opacification of large volumes of lung. Acid damage causes pulmonary capillar- ies to leak fluid, release cytokines, and permit infiltration by PMNs. In some patients, noncar- KEY POINTS diogenic pulmonary edema or ARDS develops. Onset of symptoms occurs immediately after About Aspiration Pneumonia aspiration.2. Bronchial obstruction resulting from aspiration 1. Can occur in cases of loss of consciousness, poor of food particles. The inhalation of solid particles gag reﬂex, or difﬁculty swallowing. results in mechanical obstruction and interferes 2. Three forms of aspiration: with ventilation. The patient immediately becomes a) Aspiration of gastric contents leads to pul- tachypneic. monary burn and noncardiogenic pul- monary edema.3. Pneumonia resulting from a mixture of anaerobic b) Aspiration of an obstructing object causes and aerobic mouth ﬂora. This form of pneumonia atelectasis and immediate respiratory distress. develops several days after aspiration of mouth ﬂora. c) Aspiration of mouth ﬂora, when associated Patients with severe gingivitis have higher bacterial with poor dental hygiene and mixed mouth colony counts in the mouth, and they aspirate a aerobes and anaerobes, can lead to foul higher inoculum of organisms, increasing the likeli- smelling sputum and eventually lung hood of a symptomatic pneumonia. abscess and empyema. Hospital-acquired Case 4.2 had poor dental hygiene and severe gingivitis, aspiration causes gram-negative and Staphy-predisposing him to the latter form of pneumonia. Often, lococcus aureus pneumonia.the sputum is putrid-smelling as a result of the high num- 3. Treatment depends on the form of the disease:ber of anaerobes. Necrosis of tissue is common in this a) Penicillin or clindamycin for community-infection, resulting in the formation of lung abscesses. acquired infection.Infection often spreads to the pleura, resulting in pleuritic b) Third-generation cephalosporin and metron-chest pain as experienced in case 4.2. Pleural effusions idazole for hospital-acquired infection.ﬁlled with bacteria and PMNs can develop as observed in c) Bronchoscopy for obstructing foreign bodies.this case. Effusions containing bacteria and large numbers
PULMONARY INFECTIONS / 99occurs in the recumbent position, the superior segments of neous drainage of an empyema through the chest wallthe lower lobes or the posterior segments of the upper should strongly suggest the possibility of actinomyco-lobes usually become opaciﬁed. sis. “Sulfur granules” are often found in purulent exudate; they consist of clusters of branchingTREATMENT Actinomyces ﬁlaments.Clindamycin or penicillin are both effective antibiotic Gram stain reveals branching forms that are weaklycoverage for community-acquired aspiration pneumonia gram-positive. These forms can be differentiated frombecause they kill both aerobic and anaerobic mouth ﬂora Nocardia by modiﬁed stain for acid-fast bacilli (AFB),(Table 4.3). In cases in which lung abscess has developed, Actinomyces being acid-negative and Nocardia being acid-clindamycin has been shown to be slightly superior. positive. The organism should be cultured under anaero- In nosocomial aspiration, broader coverage with a bic conditions, and grows slowly, with colonies usually3rd-generation cephalosporin combined with metronida- requiring a minimum of 5 to 7 days to be identiﬁed.zole is generally recommended. Alternatively, a semisyn- Growth can take up to 4 weeks.thetic penicillin combined with a -lactamase inhibitor High-dose intravenous penicillin (18 to 24 106(ticarcillin–clavulanate or piperacillin–tazobactam) or a U daily) is recommended for 2 to 6 weeks, followed bycarbapenem (imipenem or meropenem) can be used. oral penicillin therapy for 6 to 12 months. Therapy If aspiration of a foreign body is suspected, bron- must be continued until all symptoms and signs ofchoscopy is required to remove the foreign material active infection have resolved. Other antibiotics thatfrom the tracheobronchial tree. have been successfully used to treat actinomycosis include erythromycin, tetracyclines, and clindamycin.Rarer Causes of Community-Acquired NOCARDIOSISPneumonia Nocardia is an aerobic gram-positive ﬁlamentous bac-ACTINOMYCOSIS terium that often has to be differentiated from Actino-Actinomyces species are microaerophilic or anaerobic myces. Nocardia is ubiquitous in the environment,gram-positive rods that can be part of the polymicrobial growing in soil, organic matter, and water. Pneumoniaﬂora associated with aspiration pneumonia, particularly occurs as a consequence of inhaling soil particles. Thein patients with poor oral hygiene. Disease is most com- number of species causing human disease is large andmonly caused by Actinomyces israelii. Actinomycosis pulmonary infection is oftenindolent and slowly progressive. Lung parenchymal KEY POINTSlesions are usually associated with pleural infection,resulting in a thickened pleura and empyema. Thisorganism can break through fascial planes. Sponta- About Nocardiosis 1. Nocardia are gram-positive branching bacteria, aerobic, slow growing, modiﬁed acid-fast. KEY POINTS 2. Ubiquitous organism found in the soil. 3. Inhalation of soil particles leads to pneumonia. About Actinomycosis 4. The organism infects a) immunocompromised patients (causing dis- 1. These branching gram-positive bacteria are seminated disease in AIDS), microaerophilic or anaerobic, slow growing, b) normal hosts, and modiﬁed acid-fast negative. c) patients with alveolar proteinosis. 2. Infection is associated with poor oral hygiene. 4. Pulmonary infection can lead to bacteremia 3. Slowly progressive infection, breaks through and brain abscess that can mimic metastatic fascial planes, causes pleural effusions and ﬁs- lung carcinoma. tula tracks, forms “sulfur granules.” 5. Alert clinical microbiology to use selective 4. Alert clinical microbiology to hold anaerobic media and to hold cultures. cultures. 6. Treatment must be prolonged. High-dose par- 5. Treatment must be prolonged: high-dose intra- enteral trimethoprim–sulfamethoxazole for at venous penicillin for 2 to 6 weeks, followed by least 6 weeks, followed by oral treatment for 6 to 12 months of oral penicillin. 6 to 12 months.
100 / CHAPTER 4includes N. abscessus, N. brevicatena/paucivorans com- infectious-related cause of death in the hospital, theplex, N. nova complex, N. transvalensis complex, mortality being roughly 1 of every 3 cases. DevelopmentN. farcinica, N. asteroides complex, N. brasiliensis, and of pneumonia in the hospital prolongs hospitalizationN. pseudobrasiliensis. by more than 1 week. Infection more commonly develops in patients who The condition that most dramatically increases theare immunocompromised; however, 30% of cases occur risk of nosocomial pneumonia is endotracheal intuba-in otherwise normal individuals. Patients with AIDS, tion. Endotracheal tubes bypass the normal protectiveorgan transplant, alcoholism, and diabetes are at mechanisms of the lung, and they increase the risk ofincreased risk of developing nocardiosis. In addition to pneumonia by a factor of between 6 and 21. It has beenpulmonary disease, these patients are at increased risk estimated that the risk of pneumonia while on a venti-for developing disseminated infection. Patients with lator is 1% to 3% daily. Other factors that increase thechronic pulmonary disorders, in particular patients with risk of pneumonia include age greater than 70 years;alveolar proteinosis, have an increased incidence of pul- CNS dysfunction, particularly coma, leading to anmonary Nocardia infection. increased likelihood of aspiration; other severe underly- Onset of pulmonary disease is highly variable. In ing diseases; malnutrition; and metabolic acidosis.some cases, onset is acute; in others, onset is gradual. Patients on sedatives and narcotics have depressedSymptoms are similar to other forms of pneumonia. A epiglottal function and are also at increased risk of aspi-CXR may reveal cavitary lesions, single or multiple nod- ration. Corticosteroids and other immunosuppressantsules, a reticular nodular pattern, interstitial pattern, or a reduce normal host defenses and allow bacteria to morediffuse parenchymal infiltrate. Nocardia pulmonary readily invade the lung parenchyma.infection often seeds the bloodstream and forms Aerobic gram-negative bacteria account for moreabscesses in the cerebral cortex. The combination of a than half the cases of nosocomial pneumonia.lung inﬁltrate with a CNS lesion or lesions is often mis-taken for lung carcinoma with CNS metastasis. Diagnosis is made by sputum examination or lung or KEY POINTScerebral cortex biopsy. Gram stain demonstrates weaklygram-positive branching ﬁlamentous forms that are acid-fast on modiﬁed AFB stain. On tissue biopsy, organisms About Nosocomial Pneumoniaare demonstrated on Brown–Brenn or methenamine sil-ver stain. The organism is slow growing and is frequently 1. Pneumonia is one of the most common noso-overgrown by mouth ﬂora on conventional plates. The comial infections.clinical laboratory should be alerted to the possibility of 2. Risk factors includeNocardia so that they can incubate bacteriologic plates a) endotracheal intubation (20 times the base-for a prolonged period and use selective media. line risk, 1% to 3% incidence daily), Most Nocardia are sensitive to sulfonamides and b) age greater than 70 years,trimethoprim. Trimethoprim–sulfamethoxazole is c) depressed mental status,generally accepted as the treatment of choice, with a d) underlying disease and malnutrition, anddaily dose of 2.5 to 10 mg/kg of the trimethoprim e) metabolic acidosis.component. High-dose therapy should be continued 3. Primary causes are gram-negative bacilli andfor at least 6 weeks, followed by lower doses for 6 to Staphylococcus aureus.12 months. Some Nocardia species are resistant to sul- 4. Colonization is difficult to differentiate fromfonamides, but they are sensitive to amikacin, infection. Bronchoscopy is not helpful. Factorsimipenem, 3rd-generation cephalosporins, minocy- that favor infection include:cline, dapsone, and linezolid. Whenever possible, cul- a) worsening fever and leukocytosis with leftture and antibiotic sensitivities should be used to shift;guide antibiotic therapy. b) sputum Gram stain with increased PMNs, predominance of one organism;NOSOCOMIAL (HOSPITAL-ACQUIRED) PNEUMONIA c) decreasing PaO2 indicative of pulmonaryPneumonia is the second most common form of noso- shunting; andcomial infection. It accounts for 13% to 19% of all d) expanding inﬁltrate on chest radiographs.nosocomial infections. Hospital-acquired pneumonia is 5. Broad-spectrum empiric therapy can be initi-defined as a pneumonia that develops 48 hours or ated after samples are obtained for culture, butlonger after hospitalization and that was not developing coverage should be adjusted based on cultureat the time of admission. Nosocomial pneumonia is a results and clinical response.very serious complication and represents the leading
PULMONARY INFECTIONS / 101Escherichia coli, Klebsiella, Serratia, Enterobacter, and When infection is likely or the patient is extremelyPseudomonas species represent the most common gram- ill, and when a new pulmonary infection cannot be con-negative rods. S. aureus is the most common gram-pos- vincingly ruled out, antibiotics should be quicklyitive pathogen, causing 13% to 40% of nosocomial started; or, if the patient is receiving antibiotics, the reg-pneumonias. The risk of S. aureus infection is higher in imen should be changed to cover for antibiotic-resistantpatients with wound infections or burns, and it is also bacteria. In the absence of speciﬁc ﬁndings indicative ofhigher in intubated patients with head trauma or infection, colonization is more likely, and the antibioticneurosurgical wounds. Anaerobes are often isolated in regimen should not be changed.nosocomial pneumonia, but they are thought to be the Indiscriminate modiﬁcations of antibiotic therapyprimary agent in only 5% of cases. S. pneumoniae is eventually select for highly resistant pathogens that are dif-seldom the cause of pneumonia in the patient who has ﬁcult—or in some cases impossible—to treat. Switches tobeen hospitalized for more than 4 days. broader-spectrum, more powerful antibiotics should be Diagnosis of true pneumonia is often difﬁcult in the undertaken cautiously, and should be initiated only whenintubated patient. In elderly patients with chronic bron- convincing evidence for a new infection is present. In thechitis and congestive heart failure or ARDS, deﬁnitively patient who is deteriorating clinically, broader-spectrumproving that the patient has or does not have an coverage can be temporarily instituted once blood, urine,infection is often impossible. Differentiating infection and sputum samples for culture and Gram stain have beenfrom colonization represents a critical branch point in obtained. The 3-day rule should then be applied (seethe appropriate management of antibiotics (see case Chapter 1), with the antibiotic regimen being modiﬁed1.0). Within 3 to 5 days of antibiotic initiation, the within 3 days, based on the culture results, so as to preventmouth flora and the flora colonizing the tracheo- colonization with even more highly resistant bacteria.bronchial tree change. A change in the organisms grow- These regimens (see Table 4.3) are recommended foring from sputum culture is therefore to be expected and nosocomial pneumonia:does not in itself indicate that the patient has a new 1. Third-generation cephalosporin (ceftriaxone, cefo-infection. The change simply documents colonized of taxime, ceftizoxime, or ceftazidime)the patient with resistant ﬂora. For example, in a highpercentage of patients receiving broad-spectrum antibi- 2. Cefepimeotics, Candida albicans begins to grow in sputum 3. Ticarcillin–clavulanate or piperacillin–tazobactamcultures because of the reduction in the competing bac- 4. Imipenem or meropenemterial mouth ﬂora. However, that organism does not An aminoglycoside (gentamicin, tobramycin, orinvade the lung and almost never causes airborne pneu- amikacin) may or may not be added. If P. aeruginosa ismonia. Antifungal coverage is therefore not required suspected, ciproﬂoxacin, piperacillin–tazobactam, ticar-unless the patient develops symptomatic thrush. cillin–clavulanate, cefepime, aztreonam, imipenem, or Evidence supporting the onset of a new infection meropenem should be used. Many experts recommendincludes administration of two agents from different classes to pre-• a new fever or a change in fever pattern; vent development of resistance. Aminoglycosides should• a rise in the peripheral WBC count, with a increase in never be used alone to treat Pseud. aeruginosa because the the percentage of PMNs and band forms (left shift); antibiotic levels achievable in the lung are low. Aerosolized• Gram stain demonstrating increased number of PMNs tobramycin (80 mg twice daily) has proven to be useful in association with a predominance of bacteria that are adjunctive therapy. If Staph. aureus is suspected, van- morphologically consistent with the culture results; comycin should be added pending culture and sensitivity results. Speciﬁc anaerobic coverage is usually not required• increased purulent sputum production from the in the absence of clear aspiration. endotracheal tube;• reduced arterial PaO2, indicating interference with alveolar–capillary oxygen exchange; and Empyema• enlarging inﬁltrate on CXR. CAUSATION Multiple studies have used bronchoscopy with pro- Infection of the pleural space is most commonly the con-tected brushings or bronchial lavage and quantitative sequence of spread of pneumonia to the parietal pleura.cultures and Gram stains. A randomized trial found More than half of empyema cases are associated withthat that samples obtained by bronchoscopy provide pneumonia. The most common pathogens in this settingno advantage over endotracheal suction, and therefore are S. pneumoniae, S. aureus, S. pyogenes, and anaerobicthat procedure is not recommended in ventilation- mouth ﬂora. Empyema is also a complication of traumaassociated pneumonia. and surgery, and when those are the inciting factors,
102 / CHAPTER 4 enclosed pleural infection. Fever is often accompanied by KEY POINTS chills and night sweats. Pleuritic chest pain is a common complaint, as is shortness of breath. Physical exam is help- About Empyema ful in detecting large effusions. As noted in case 4.2, the area in which ﬂuid is collecting is dull to percussion, and breath sounds are decreased. At the margin between ﬂuid 1. Suspect empyema if fever persists despite appropriate antibiotic treatment of pneumo- and aerated lung, egophony and bronchial breath sounds nia. are commonly heard, reﬂecting areas of pulmonary con- solidation or atelectasis. 2. The condition is most common with Streptococ- On CXR, ﬂuid collections as small as 25 mL can cus pneumoniae, Staphylodcoccus aureus, S. pyogenes, and mouth anaerobes. alter the appearance of the hemidiaphragm on poste- rior–anterior view, and on lateral views, 200 mL of ﬂuid 3. A chest radiograph with lateral decubitus is is generally required to blunt the posterior costophrenic sensitive; computed tomography scan is also angle. A lateral decubitus view with the pleural effusion helpful. side down can demonstrate layering of 5 to 10 mL of 4. If empyema is being considered, an ultra- free ﬂuid. Contrast-enhanced chest CT is particularly sound guided thoracentesis should be per- helpful in differentiating lung abscess from empyema, formed. and it demonstrates the full extent of the effusion and 5. When pH is less than 7.2, glucose is less than 40 the degree of pleural thickening. mg/dL, and lactate dehydrogenase exceeds Ultrasound is very useful in determining the 1000 IU/L, empyema is strongly suggested. dimensions of the effusion, and it is the most effective 6. Use tube drainage initially; if loculation contin- method for guiding thoracentesis. Septations are read- ues, urokinase can be given. May require surgi- ily visualized by this technique and indicate the devel- cal intervention. opment of a loculated collection that requires 7. Early diagnosis and drainage prevents lung and drainage. Ultrasound guidance of thoracentesis is pleura compromise. strongly recommended because of the associated 8. Mortality associated with empyema is high: 8% decreased incidence of complicating pneumothorax. to 15% in young patients, and 40% to 70% in The ﬂuid should be analyzed for cellular content, and elderly ones. Gram stain, fungal stain, AFB stain, and aerobic and anaerobic cultures should be obtained. If the ﬂuid is frankly purulent, the pleural space should be com- pletely drained. If the ﬂuid is not overtly purulent, theS. aureus and aerobic gram-negative bacilli predominate. ﬂuid should also be analyzed for pH, glucose, lactateIn the immunocompromised patient, fungi and gram- dehydrogenase, and total protein. A pleural ﬂuid pHnegative bacilli are most commonly encountered. below 7.2, a glucose level below 40 mg/dL, and a lac- tate dehydrogenase level above 1000 IU/L are consis-PATHOPHYSIOLOGY tent with empyema and justify pleural ﬂuid drainagePleural effusions occur in approximately half of all pneu- to prevent loculation, pleural scarring, and restrictivemonias; however, only 5% of pneumonias develop true lung disease.empyema. Because pleural ﬂuid is deﬁcient in theopsonins, immunoglobulin G, and complement, bacteria TREATMENTthat ﬁnd a way to this culture medium are only ineffec- Antibiotic therapy for the offending pathogen is of pri-tively phagocytosed by PMNs. As PMNs break down in mary importance, and antibiotic coverage depends onthe closed space, they release lysozyme, bacterial perme- the pathogen identified by sputum or pleural fluidability-increasing protein, and cationic proteins. These Gram stain and culture. When a signiﬁcant pleural ﬂuidproducts slow the growth of bacteria, lengthening dou- collection is apparent, a more prolonged course ofbling times by a factor of 20 to 70. The slow growth of the antibiotics (2 to 4 weeks) is generally required.bacteria renders them less sensitive to the cidal effects of Parapneumonic effusions that move freely and thatantibiotics. In the empyema cavity, pH is low, impairing are less than 1 cm in width on lateral decubitus ﬁlmWBC function and inactivating some antibiotics—in par- can be managed medically; thoracentesis is notticular, the aminoglycosides. required. If the collection is larger or does not ﬂow freely, thoracentesis should be performed. If biochem-CLINICAL MANIFESTATIONS ical evidence for empyema is present, drainage byPersistent fever despite appropriate antibiotic treatment chest tube is recommended. Repeated thoracentesis isfor pneumonia should always raise the possibility of an rarely successful in completely draining the pleural
PULMONARY INFECTIONS / 103fluid collection unless the fluid has a thin viscosity TUBERCULOSISand is present in small volumes. Drainage by closedchest tube is usually successful with smaller effusionsoccupying up to 20% of the hemithorax, but it is POTENTIAL SEVERITYoften ineffective when the volume of ﬂuid occupiesmore than 40% of the hemithorax. Interventionalradiology is required to precisely place French The miliary form of the tuberculosis can be fatal.catheters at sites of loculation and to break up areas of Clinicians must maintain a high index of suspicionadhesion under CT guidance. If tube drainage proves for tuberculosis in immigrants, indigent and elderlyineffective after 24 hours, intrathoracic urokinase patients, and patients with AIDS.(125,000 U diluted in 50 to 100 mL sterile normalsaline) should be instilled to break down intrapleuralﬁbrin and encourage free drainage of infected ﬂuid. Ifthoracentesis and urokinase are unsuccessful, opera-tive intervention is required. Empyema is a serious complication, with an associ- CASE 3.3ated 8% to 15% mortality in young, previously healthypatients and 40% to 70% mortality in patients who are A 73-year-old black man, a retired bartender, cameelderly or have signiﬁcant underlying disease. Patients to the emergency room complaining of increasingwith nosocomial pathogens and polymicrobial infection shortness of breath and worsening cough over the pre-also have a worse prognosis. Delay in diagnosis and ceding 3 weeks.About 5 months earlier,he had begun toappropriate drainage increases the need for surgical resec- notice night sweats that drenched his pajamas. Thattion of the pleura and manual re-expansion of the lung. symptom was followed by development of a nonpro- ductive cough. He began bringing up small quantities of yellow sputum 1 month before presentation at the emer-■ CHRONIC PNEUMONIAS gency room.At the time that he noticed the sputum pro- duction, he began experiencing increased shortness of breath, even after mild exertion (walking 2 blocks to theGUIDING QUESTIONS grocery store). During the past few months, he felt very 1. How is tuberculosis contracted, and how can this tired, and he has lost 10 pounds despite a “good” diet. Epidemiologic history indicated city residence and disease be prevented? visits with a number of old drinking buddies. The 2. What is primary tuberculosis? patient denied exposure to anyone with tuberculosis, and he had no family history of tuberculosis. 3. What is secondary tuberculosis? Past medical history revealed an abnormal CXR 20 4. Why are the apices of the lung the most common years earlier and treatment at New York City’s Bellevue location for tuberculosis? Hospital with isoniazid (INH) and para-aminosalicylic acid for 1 year. 5. What are the typical symptoms and ﬁndings in mili- Social history indicated that the patient had tary tuberculosis? recently retired after 35 years of tending bar. He lives 6. How is tuberculosis diagnosed? alone in a 1-bedroom apartment and supports him- self on Social Security. He is a former smoker (half a 7. Why should combination antituberculous therapy pack daily for 28 years) and drinks half a pint daily. always be prescribed in active tuberculosis? On physical exam, his temperature was 38 C and his respiratory rate was 18 per minute, presenting a 8. What does having a positive PPD mean, and how picture of a thin male breathing comfortably. Aside should an individual with a positive test be treated? from mild clubbing of his nail beds, the physical ﬁnd- 9. In which areas of the country is histoplasmosis most ings (including lung exam) were within normal limits. commonly encountered, and why? The laboratory workup showed a hematocrit of 39% and a WBC count of 6000/mm3, with 55% PMNs, 10. In which areas of the country is coccidiomycosis 30% lymphocytes, and 15% monocytes. most commonly encountered, and why? Sputum Gram stain revealed many PMNs, few gram-positive cocci, and rare gram-negative rods.
104 / CHAPTER 4 BAFigure 4–5. Cavitary pulmonary tuberculosis: A. Chest radiograph demonstrates bilateral upper lobe cavitary lesions,and B. sputum smear for acid-fast bacilli conﬁrms the presence of those organisms. See color image on color plate 1Bilateral upper lobe cavitary lesions were observed on lipogenesis and lipolysis. The resulting high lipid con-CXR [see Figure 4.5(A)]. Acid-fast stain of the sputum tent of this pathogen accounts for many of its uniquerevealed multiple acid-fast bacilli per high-power ﬁeld clinical characteristics, including its ability to resist[see Figure 4.5(B)]. killing by macrophages and PMNs and to survive for many years within the body. Rate of growth in M. tuberculosis is very slow, being about 1/20th the growth rate of most conventional bacteria. The slow rate of growth may also be explained by the waxy cell wall,Pathogenesis which limits access to nutrients. Mycobacteria survive and grow in macrophages,Mycobacterium tuberculosis is an aerobic, nonmotile and they therefore induce a profound chronic inﬂam-bacillus with a waxy lipid-rich outer wall containing matory response. On gaining entry to the lungs, thesehigh concentrations of mycolic acid. This waxy outer organisms are ingested by alveolar macrophages andwall fails to take up Gram stain. Visualization of transported to the hilar lymph nodes. Heremycobacteria requires heating to melt the outer wall, macrophages and dendritic cells present tubercularwhich allows for penetration and binding of the red dye antigens to T cells, inducing a cell-mediated immunefuchsin. The lipids in the cell wall bind this dye with response. Helper T cells (CD4 ) then activatehigh afﬁnity and resist acid–alcohol decolorization. This macrophages to kill the mycobacteria and control theacid-fast bacillus is small in size and appears beaded infection. Accumulation of one of the cell wall waxes,[Figure 4.5(B)]. Genomic analysis reveals that, as com- cord factor, stimulates the formation of granulomaspared with other bacteria, M. tuberculosis has a large that contain clusters of epithelioid cells, giant cells,number of genes encoding for enzymes that regulate and lymphocytes. Over time, the centers of the
PULMONARY INFECTIONS / 105granulomas become necrotic, forming cheesy debris tuberculosis often harbor a large organism burden.called caseous necrosis. Caseating granulomas are the Patients with large pulmonary cavities tend to intermit-hallmark lesion of tuberculosis. This pathologic ﬁnd- tently release large numbers of infectious particles.ing is only rarely found in other diseases. If intracellu- Repeated exposure and close contact are generallylar growth of M. tuberculosis continues, increasing required to contract this disease. Respiratory isolationnumbers of macrophages are activated to produce mul- and rapid treatment of infected individuals are the pri-tiple cytokines. Interleukin 1 stimulates the hypothal- mary ways to prevent spread of infection.amus to raise core body temperature, causing fever. Despite the availability of antituberculous agents,Tumor necrosis factor interferes with lipid metabolism tuberculosis remains a leading cause of death world-and causes severe weight loss. These cytokines are pri- wide. Crowded living conditions and the existence ofmarily responsible for the symptoms of fever, night immunologically naive populations continue to allowsweats, and weight loss described in case 4.3. rapid person- to-person spread, particularly in underde- veloped countries. After a surge in cases in the UnitedEpidemiology States during the mid-1980s because of the AIDS epi- demic, the case rate has steadily declined. In 2002, itHumans are the only reservoir for M. tuberculosis. Per- reached the lowest level ever recorded: 5.2 cases person-to-person spread of infection is almost exclusively 100,000. This steady decline among permanent U.S.caused by inhalation of droplet nuclei that have been residents contrasts with the steady increase in the per-aerosolized by coughs or sneezes. The likelihood of centage of tuberculosis cases among people immigratinginhaling infectious droplets is greatly increased in a to the United States. Immigrants now account for halfclosed, crowded environment. A single cough has been of all reported cases in the United States. Individualsestimated to form 3000 infectious droplets, with a immigrating from underdeveloped countries havesneeze producing even higher numbers. higher rates of infection. For example, the rate among The infectiousness of an individual patient can be Vietnamese immigrants is 120 per 100,000estimated by AFB smears. The higher the number oforganisms per microscopic ﬁeld, the greater the infec-tious potential. Patients with laryngeal tuberculosis areparticularly infectious and can release large numbers of KEY POINTSorganisms while speaking. Patients with AIDS and About the Epidemiology of Tuberculosis 1. Humans are the only reservoir of this disease. KEY POINTS 2. Person-to-person spread occurs via aerosolized infectious droplets from sneezes or coughs. About the Pathogenesis of Tuberculosis a) Laryngeal tuberculosis is highly infectious. b) Patients with HIV release large numbers of organisms. 1. Slow-growing aerobic rod, not seen on Gram c) Large cavitary lesions are also highly infec- stain. The lipid-rich outer wall binds the red dye tious. fuchsin, which is not removed by acid, making the bacterium acid-fast. 3. People with these characteristics are at increased risk: 2. The lipid wall also allows the bacterium to resist a) Immigrants from developing countries drying and many disinfectants. It further allows b) Alcoholics the bacterium to survive within macrophages c) Urban poor for years. d) Single men 3. Macrophages carry the mycobacterium to the e) Intravenous drug abusers lymph nodes, where a cell-mediated immune f ) Migrant farm workers response is generated. g) Prison inmates 4. Caseating granulomas are formed as a conse- h) People infected with HIV quence of the cell-mediated immune response i) Elderly people and the accumulation of lipid-rich bacteria. 4. A genetic predisposition is found in people who 5. Increased levels of interleukin 1 cause fever, and are black, Hispanic, Asia Pacific Islanders, and increased levels of tumor necrosis factor cause Native Americans (5 to 10 times the incidence weight loss. seen in caucasians)
106 / CHAPTER 4 Any of: • Confusion* • Urea 7 mmoI/I • Respiratory rate 30/min • Blood pressure (SBP 90 mm Hg or DBP 60 mm Hg) • Age 65 years CURB-65 0 or 1 2 3 or more score GROUP 1 GROUP 2 GROUP 3 Mortality low Mortality intermediate Mortality high (1.5%) (9.2%) (22%) (n = 324, died = 5) (n = 184, died = 17) (n = 210, died = 47) Treatment options Likely suitable for home Consider hospital Manage in hospital as treatment supervised treatment severe pneumonia Options may include: Assess for ICU (a) short stay inpatient admission especially if (b) hospital supervised CURB-65 score = 4 or 5 outpatient *defined as a Glasgow Coma Score of 8 or less, or new disorientation in person, place or time Figure 4–6. CURB-65 (confusion, urea, respirations, blood pressure, age 65) criteria for the management of community-acquired pneumonia (30-day mortalities in parenthesis). Adapted from Lim WS, van der Eerden MM, Laing R, et al. Deﬁning community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 2003;58:377–382.person–years, and among Haitian immigrants it is 133per 100,000. Immigrants from established market KEY POINTSeconomies such as those of Western Europe have ratessimilar to those in the United States. About Primary Tuberculosis Tuberculosis occurs more frequently in single men,alcoholics, intravenous drug abusers, the urban poor(particularly homeless people), migrant farm workers, 1. Represents the ﬁrst exposure to inhaled infec- tious particles.and prison inmates. Elderly people are more likely todevelop secondary tuberculosis because cell-mediated 2. Followed by a ﬂu-like illness.immunity wanes with age. 3. Spread is controlled over 4 to 8 weeks by the A genetic predisposition to the development of development of cell-mediated immunity.active tuberculosis is known. People with European 4. Ghon foci are calciﬁed lung lesions at the site ofheritage tend to be more resistant, probably as a con- the primary infection.sequence of the devastating effects of the tuberculosis 5. Bacteremia develops and seeds the kidneys,epidemic during the Industrial Revolution. At that epiphyses of the long bones, and vertebral bod-time, tuberculosis was responsible for one fourth of ies (areas with high oxygen content). The infec-the deaths in Europe, killing off a signiﬁcant percent- tion can later reactivate.age of the population that had a reduced immune
PULMONARY INFECTIONS / 107response to mycobacteria. As compared with whitepeople, people who are black or Hispanic, or who are KEY POINTSAsia Paciﬁc Islanders or Native Americans experiencea 5 to 10 times higher incidence of tuberculosis. About Miliary TuberculosisPatients with AIDS are particularly susceptible totuberculosis, and this population has spread the infec- 1. The disease develops in very young, very old,tion to others. Areas and demographic groups in and HIV-infected patients.which AIDS is more prevalent therefore have a higherincidence of tuberculosis. 2. It is also associated with alcoholism, malig- nancy, connective tissue diseases, renal failure, The patient in case 4.3 has a number of epidemio- and pregnancy.logic characteristics that increase his risk for tuberculo-sis. He is a single male, black, possibly alcoholic, and 3. In children, it presents with high fever, nightelderly. sweats, weight loss, hepatosplenomegaly, and lymphadenopathy. 4. Adults usually show moderate- to low-gradeClinical Manifestations fever, night sweats, malaise, anorexia, weakness, and weight loss.There are two forms of human tuberculosis infection:primary tuberculosis and secondary tuberculosis. 5. Look for choroid tubercles in the fundi (present in up to 50% of cases).PRIMARY TUBERCULOSIS 6. Provokes leukemoid reaction, anemia, hypona-Primary disease occurs when a patient inhales infectious tremia, abnormal liver function tests. May alsoM. tuberculosis droplets for the ﬁrst time. A ﬂu-like ill- produce adrenal insufﬁciency.ness usually follows; however, some people experience 7. Micronodular interstitial pattern on chest radi-no symptoms. Within 4 to 8 weeks of exposure, the ographs; may be negative in elderly and HIV-human host usually mounts a cell-mediated immune infected patients.response. Activated macrophages control the spread and 8. Blood samples, transbronchial biopsy, bonegrowth of the organism. Pulmonary lesions heal sponta- marrow samples, and liver biopsy may all yieldneously and form areas of ﬁbrosis or calciﬁcation called positive cultures.Ghon lesions or foci. A Ghon lesion in combination 9. Provide early treatment for all suspected cases,with hilar adenopathy is called a Ranke complex. using isoniazid, rifampin, ethambutol, and In addition to transporting organisms to the hilum pyrazinamide.and mediastinum, infected macrophages may gain accessto the thoracic duct, enter the bloodstream, and spreadthroughout the body. M. tuberculosis grows best inregions with high oxygen tension, including the kidneys, with HIV infection. Underlying medical conditionslong-bone epiphyses, and vertebral bodies. It most com- often associated with miliary tuberculosis includemonly infects the apices of the lung, the regions with the alcoholism, malignancy, connective tissue diseases,highest oxygen content and reduced lymphatic ﬂow. renal failure, and pregnancy. However, it must be Although the infection is brought under control, emphasized that absence of an underlying disease doesthe bacilli are not usually completely eradicated. not exclude the possibility of miliary tuberculosis.Organisms can survive for decades, being held in Children usually present to the physician with highcheck by the host immune response. But any fever, night sweats, weight loss, hepatosplenomegaly,condition that subsequently depresses cell-mediated and lymphadenopathy. However in adults, particularlyimmunity can free M. tuberculosis to grow and cause elderly people, the clinical manifestations may be subtle.symptomatic secondary tuberculosis. Patients usually have nonspeciﬁc complaints of fever, malaise, anorexia, weakness, and weight loss. NightMILIARY TUBERCULOSIS sweats are also common.In some individuals, initial exposure to M. tuberculo- Physical exam usually reveals a chronically illsis fails to induce cell-mediated immunity, or the patient with no specific findings. In some patients,immune response is not robust enough to control the lympha-denopathy may be detected. In all patients,infection. Under these conditions, the mycobacteria fundoscopic exam should be carefully performedcontinue to multiply and disseminate, causing miliary following pupillary dilation and may reveal choroidtuberculosis. Very young and very old patients are at tubercles in up to 50% of cases. The diagnosis is oftenhigher risk of developing disseminated disease, as are missed, and in up to 20% cases, it is made post-patients receiving immunosuppressants and those mortem.
108 / CHAPTER 4 The peripheral WBC count is usually normal; how- suggest more advanced disease are hemoptysis (indicat-ever, some patients develop extremely high WBC counts ing erosion of a tuberculous cavity into an arteriole) and(30,000 to 40,000/mm3), also termed a “leukemoid pleuritic chest pain (suggesting pleural involvement andreaction,” that can be mistaken for leukemia. Pancy- probable tuberculous pleural effusion).topenia can also develop. Liver function abnormalities Physical exam is often unrevealing, as observed inare common. Elevated alkaline phosphatase and moder- case 4.3. Despite the presence of extensive pulmonaryate increases in transaminase values are found in most disease, auscultation may be normal. Fine rales may bepatients. Serum sodium may be low as a consequence of heard in the apices after a short cough and quick inspi-adrenal insufficiency (a well-known complication of ration or after full expiration followed by a cough andmiliary tuberculosis) or inappropriate antidiuretic hor- rapid inspiration (post-tussive rales).mone secretion. Morning and evening serum cortisol The hallmark of secondary pulmonary disease is thelevels should be measured to exclude adrenal insufﬁ- presence of apical cavitary lesions on CXR. Lesionsciency. In approximately two thirds of patients, CXR usually develop in posterior segments of the upper lobesreveals small nodules (0.05 to 1 mm in diameter) that just below the clavicle. Less frequently, inﬁltrates areresemble millet seeds (the basis for the designation “mil- noted in the apex of the lower lobe (usually obscurediary”); however, a negative CXR in elderly patients and by the heart shadow). In addition to routine poste-in patients with HIV does not exclude this diagnosis. In rior–anterior and lateral chest ﬁlms, an apical lordotica few patients, ARDS may develop, causing complete view is often helpful in visualizing upper lobe apicalopaciﬁcation of the lungs. lesions. A chest CT scan can be helpful for assessing the The key to the diagnosis of miliary tuberculosis is a extent of disease and for deﬁning the size of the cavities.high index of suspicion. Sputum smears are positive in Unlike conventional lung abscesses, tuberculous cavitiesonly a few patients. Samples from enlarged lymphnodes, liver biopsy, and bone marrow should thereforebe sought for histopathology (seeking granulomas andacid-fast bacilli) and culture. Transbronchial biopsy canyield the diagnosis in many patients. Blood samples for KEY POINTSculture should be drawn; in AIDS patients, cultures arecommonly positive. If CNS symptoms are noted, a lum- About Secondary Tuberculosisbar puncture should also be performed, although theresulting smears are usually negative. A delay in treatment can have fatal consequences. 1. Reactivation occurs in 10% to 15% of patients, half within 2 years of primary disease.Therefore, if miliary tuberculosis is high on the differ-ential diagnosis, empiric antituberculous therapy should 2. Reactivation is most common in men 30 to 50be initiated as soon as samples for culture have been years of age.obtained. A 4-drug combination consisting of INH, 3. Apical infection is most common. The high oxy-rifampin, pyrazinamide, and ethambutol is the preferred gen content and reduced lymphatic ﬂow favorregimen. Patients usually defervesce within 7 to 14 days. M. tuberculosis survival in this region. 4. Symptoms progress slowly over several months:SECONDARY TUBERCULOSIS worsening cough with sputum production, low-Reactivation of tuberculosis after primary disease occurs grade fever, night sweats, fatigue, and weightin 10% to 15% of patients. In half of these cases the loss.infection reactivates within 2 years of exposure. In past 5. Hemoptysis or pleuritic pain indicate severedecades, reactivation occurred most commonly in disease.elderly patients, but in the United States today, most 6. Physical exam usually produces minimal ﬁnd-secondary cases are now reported in middle-aged adults ings; post-tussive rales may be seen.(30 to 50 years of age). Early in the course of reactiva- 7. Chest radiograph shows apical cavities (withouttion, patients are often asymptomatic, and evidence of ﬂuid); order apical lordotic. A computed tomog-reactivation is found only on CXR. However if the raphy scan is often helpful.infection is not detected, symptoms slowly develop and 8. Cavitary disease is highly infectious; cavitiesworsen over several months. The gradual nature of contain between 109 and 1010 organisms. Isolatesymptom onset often causes patients to delay seeing a all patients. In HIV infection, the chest radi-physician. The patient in case 4.3 has the typical symp- ograph often does not show cavities. All pneu-toms of secondary tuberculosis: a progressively worsen- monias in patients with AIDS are considered toing cough with sputum production, low-grade fever, involve tuberculosis until proven otherwise.night sweats, fatigue, and weight loss. Symptoms that
PULMONARY INFECTIONS / 109rarely have air ﬂuid levels. In patients with AIDS, inﬁl- auramine–rhodamine is more sensitive and allows spu-trates may be in any region of the lung and may not cav- tum to be examined at low magniﬁcation (20x or 40xitate. Any HIV-infected patient with a new pulmonary magnification) as compared with conventional AFBinﬁltrate should therefore be considered to have tuber- smears that must be examined at high magniﬁcationculosis until proven otherwise. In fact, in some (100x). Sputum smear has only a 60% sensitivity asinstances, HIV-infected patients with active respiratory compared with sputum culture. The PCR technique cantuberculosis may have a negative CXR. effectively detect as few as 10 organisms in a clinical Individuals with cavitary disease are potentially specimen. Two assays, one using mycobacteria RNA ashighly infectious. Cavities may contain between 109 and its initial template, and the other using mycobacterial1010 organisms. Patients should be placed in respiratory DNA, are commercially available. Sensitivity and speci-isolation while sputum AFB smears and cultures are ﬁcity are greater than 95% in smear-positive cases, andobtained. The number of organisms seen on smear speciﬁcity in smear-negative cases is high. False negativedirectly correlates with infectiousness—that is, the and false positive results are common in less experiencedhigher the number of organisms per microscopic ﬁeld, laboratories, and nucleic acid ampliﬁcation assays arethe higher the likelihood of disease spread. recommended only to complement traditional meth- ods. In patients on antituberculous therapy, PCR can-Diagnosis not differentiate killed from actively growing organisms. Culture remains the most accurate method for diag-The classic test for making the diagnosis of pulmonary nosing M. tuberculosis. In patients that fail to producetuberculosis is the Ziehl–Nielson acid-fast sputum sputum, aspiration of the gastric contents in the morn-smear. Morning sputum samples tend to have the high- ing before the patient arises from bed is useful forest yield. A single negative smear should not delude the obtaining samples for culture. In patients with sus-clinician into a false sense of security. Three sputum pected disseminated disease, blood samples in which allsmears are recommended, because in cavitary disease, cells are lysed to release intracellular mycobacteriathe release of infectious droplets is intermittent. Only should be collected. The bacterium grows at aboutafter three smears are negative should the patient be 1/20th the rate of more conventional bacteria, taking 3declared to be at low risk for spreading infection. Nega- to 6 weeks to grow on Lowenstein–Jensen medium. Liv-tive smears do not deﬁnitively exclude tuberculosis. ing mycobacteria can be more quickly detected in To be positive, the sputum smear must contain blood, sputum, pleural ﬂuid, or CSF using the Bactec104 organisms per milliter. A ﬂuorochrome stain using radiometric or ﬂuorometric culture system, which is designed to detect mycobacteria metabolism within 9 to 16 days. Drug susceptibilities can also be reliably tested using this method. KEY POINTS About the Diagnosis of Tuberculosis Treatment The principal strategies for treating mycobacteria differ 1. Ziehl–Nielson acid-fast stain can detect somewhat from more conventional bacteria. Because 104 organisms per milliter with 60% sensitivity. mycobacteria are intracellular and grow very slowly, and 2. Release of acid-fast bacilli from cavitary lesions because dormant tuberculous organisms found in is intermittent. To ensure low infectivity, three necrotic cavitary lesions are difﬁcult to kill, antitubercu- negative smears are needed. lous therapy must be prolonged—a period of months. 3. Culture remains the most sensitive and spe- Secondly, because the number of mycobacterial organ- ciﬁc test. isms in the host is usually high, the potential for selecting for resistant mycobacteria is high. To reduce this risk, a) Mycobacterium tuberculosis grows at 1/20th treatment with two or more antimycobacterial medica- the rate of conventional bacteria. tions is recommended. Generally, 1 in 106 organisms is b) Automated techniques can detect bacteria resistant to INH. Cavitary lesions often contain between within 9 to 16 days. 109 and 1010 organisms, assuring the survival and replica- c) Growth in conventional Lowenstein–Jensen tion of resistant organisms. Administration of two drugs medium takes 3 to 6 weeks. reduces the probability of selecting for a resistant organism 4. Polymerase chain reaction is available, but because only 1 in 1012 organisms (106 106) would be should be performed only by experienced labo- expected to be resistant to both antimicrobial agents. ratories. A third major consideration is advent of multidrug- resistant M. tuberculosis (MDR-TB). These mycobacteria
110 / CHAPTER 4Table 4.4. Toxicities of Antibtuberculousis Medications Clinical symptom Antibiotic Para-aminosalicylic acid Pyrazinamide Streptomycin Ethionamide Ethambutol Quinolones Cycloserine Rifampin Isoniazid Allergic skin rash Fever Photosensitivity Anaphylaxis Diarrhea (Clostridium difﬁcile) Gastrointestinal intolerance Behavior changes Neuropathy Hearing or balance problems Vision problems Seizures Musculoskeletal problems Orange urine and tears Laboratory tests: Hyperuricemia Creatinine↑ Cytopenias Eosinophilia AST/ALT↑ Bilirubin↑ Glucose↑ or ↓ Prolonged QT Drug interactionsBlack principal side effect; dark gray less common side effect; light gray rare side effect; white not reported or veryrare; ↑ rise; AST/ALT aspartate aminotransferase/alanine transaminase.are resistant to isoniazid and rifampin, and they must be Resistance is classiﬁed as either secondary or primary.treated with three or more other antimycobacterial Primary resistance is deﬁned as infection with a resistantagents. In the early 1990s in the United States, MDR- strain in a patient who has never received antituberculousTB was major concern; however, with improved infec- drugs. When a resistant strain is cultured from a patienttion control measures, the use of four drug regimens, and who were previously treated for drug-sensitive tuberculo-directly observed therapy, the incidence of MDR-TB has sis, the infection is said to be secondarily resistant. Sec-been reduced to less than 2%, and resistance to INH ondary resistance is a major problem among homelessalone is approximately 8%. people, illicit drug users, and patients with AIDS.
PULMONARY INFECTIONS / 111Table 4.5. Antituberculous Medications: Half-Life, Dosing, Renal Dosing, and Cost Antituberculous Half- Dose Dose for reduced Costa agent life creatinine clearance (trade name) (h) (mL/min) First line Isoniazid 0.5–4 300 mg PO or IM q24h No change required $ (Tubzid, Nydrazid) 2–5 No change required $ Rifampin early 600 mg PO q24h (Rifadin, Rimactane) 2 late No change required $ Pyrazinamide 10–16 15–30 mg/kg PO q24h, divided into 2–4 doses Ethambutol 3–4 15–25 mg/kg PO q24h 50–80: 15 mg/kg q24h $ (Myambutol) 10–50: 15 mg/kg q24–36h <10: 15 mg/kg q48h Streptomycin 2–5 1–2 g IM or IV q24h 50–80: 15 mg/kg q24–48h $ 10–50: 15 mg/kg q72–96h <10: 7.5 mg/kg q72–96h Second line Ciproﬂoxacin (Cipro) 4 750 mg PO q12h 10–50: q18h/<10: q24h $$$ Amikacin 2 7–10 mg/kg IM or IV q24h Renal dosing $$ (Amikin) (not to exceed 1 g), based on serum levels 5 /week Capreomycin 4–6 1 g IM q24h 10–50: 7.5 mg/kg q24–48h $$$$$ (Capastat) <10: 7.5 mg/kg 2 weekly Cycloserine 8–12 250–500 mg PO q12h 10–50: 250–500 mg q24h $$$$ (Seromycin) <10: 250 mg q24h Para-aminosalicylic 2 10–12 g PO q24h Obtain from the U.S. Centers acid for in 3–4 divided doses Disease Control and Prevention Ethionamide 4 0.5–1 g PO q24h <10: 5 mg/kg q48h $$– (Trecator) in 1–3 doses $$$a 10-Day course cost dollars: $ = 10–50; $$ = 51–100; $$$ = 101–140; $$$$ = 141–180; $$$$$ ≥180.Table 4.6. Typical Course of Direct Observed Therapy for Tuberculosis Timing Frequency Regimen Weeks 1–2 Once daily Isoniazid 300 mg Rifampin 600 mg Pyrazinamide 1.5 g (<50 kg), 2 g (51–74 kg), 2.5 g (>74 kg) Streptomycin 750 mg (<50 kg) or 1 g (>50 kg) Weeks 3–8 Twice weekly Isoniazid 15 mg/kg Rifampin 600 mg Pyrazinamide 3 g (<50 kg), 3.5 g (51–74 kg), 4.0 g (>74 kg) Streptomycin 1 g (<50 kg), 1.25g (51–74 kg), 1.5 g (>74 kg) Weeks 9–26 Twice weekly Isoniazid 15 mg/kg Rifampin 600 mg
112 / CHAPTER 4 Outside of the United States, the percentages of The recommended treatment for presumed drug-MDR-TB and INH-resistant strains vary widely. The sensitive pulmonary tuberculosis (pending sensitivityworldwide median frequency of primary INH resistance tests) is a four-drug regimen: INH, rifampin, pyrazi-is estimated to be 7.3%, with higher levels being namide, and ethambutol or streptomycin. This regimenobserved in Asia, Africa, and Latin America, and lower is recommended for 2 months, to be followed by INH,levels in Europe and Oceania. The worldwide incidence rifampin, and pyrazinamide for 4 months. If MDR-TBof primary MDR-TB is 1.4%; however, rates of MDR- is suspected, extensive susceptibility testing should beTB as high as 14% have been reported in countries performed, and expert advice sought to design aninwhich tuberculosis control programs have deteriorated appropriate regimen. Treatment should consist of at(Latvia, South Korea, and Russia, for example). Exten- least three drugs to which the organism is proven to besively drug resistant tuberculosis (XDR) has recently susceptible. Fluoroquinolones combined with amino-been reported in South Africa. XDR TB fails to respond glycosides are particularly useful for treating MDR-TB.to nearly all drugs. The mortality can exceed 90%. In patients who are deemed to be unreliable, directly The various antituberculous agents have been classi- observed therapy (DOT) should be instituted. Poorfied as first-line and second-line drugs. First-line adherence greatly increases the risk of secondary MDR-medications include INH, rifampin, pyrazinamide, TB, and with the institution of DOT in these patients,streptomycin, and ethambutol. These agents are more the emergence of resistance is minimized. DOT isefﬁcacious and less toxic than the second-line drugs. recommended for all patients with INH- or rifampin-With the exception of ethambutol, ﬁrst-line agents are resistant organisms. One commonly accepted DOT reg-also bactericidal. Whenever possible, first-line drugs imen is outlined in Table 4.6.should be employed for the treatment of M. tuberculo-sis. Tables 4.4 and 4.5 summarize the toxicities and rec- Preventionommended doses of each of these agents. Tuberculosis is spread strictly from person to person. Identifying and preventing individuals who have been exposed to tuberculosis from developing active disease is a major public health goal. The purified protein KEY POINTS derivative (PPD) test is a very helpful skin test that assesses exposure to tuberculosis. The test is produced About Antieuberculous Therapy by acid precipitation of tubercle bacilli proteins, and the 5-tuberculin unit dose has been standardized and 1. A four-drug regimen (pending sensitivity test- is administered as a 0.1-mL subcutaneous injection on ing) is recommended. the volar aspect of the forearm. Deeper injection is a) Of every 106 organisms, 1 is naturally resis- ineffective because tuberculous proteins can be tant to one drug. removed by blood flow, producing a false negative result. b) Cavitary lesions contain between 109 and The injection should produce a discrete raised 1010 organisms. blanched wheal. The test is read 48 to 72 hours after c) A minimum of two effective drugs are needed injection; however, the reaction usually persists for to prevent resistance (106 106 1012). 1 week. The diameter of induration is measured, and a d) Primary isoniazid (INH) resistance is com- diameter of more than 10 mm is deﬁned as positive. A mon; to reliably prevent resistance, treat with positive test indicates high risk for contracting tubercu- INH, rifampin, pyrazinamide, and ethambutol losis. Of people with a PPD reaction 10 mm in diame- (pending sensitivities). ter, 90% are infected with tuberculosis. If the reaction 2. INH-resistance is 8% in the United States, 7.3% measures more than 15 mm, 100% are infected. The worldwide. Higher in Asia, Africa, and Latin 15-mm diameter is deﬁned as a positive reaction in indi- America. viduals with no risk factors for tuberculosis. In individ- 3. Multidrug resistance is below 2% in the United uals who are immunocompromised (HIV-positive, States, but up to 14% in parts of Eastern Europe. organ transplant patients receiving more than 15 mg 4. Secondary resistance occurs in patients who prednisone daily) or who are recent household contacts don’t reliably take their medications. of a patient with active tuberculosis, more than 5 mm is 5. Directly observed therapy (DOT) is now recom- considered a positive reaction. mended for unreliable patients, and for patients A positive test simply indicates that, sometime in with INH- or rifampin-resistant strains. the past, the individual was exposed to active tuber- culosis; however, this ﬁnding does not indicate active
PULMONARY INFECTIONS / 113 In other individuals with a positive PPD, the risk of INH KEY POINTS hepatotoxicity must be balanced against the likelihood of preventing the development of active disease. About Tuberculosis Testing and Prophylaxis The U.S. Centers for Disease Control and Prevention currently recommends that all individuals with a positive PPD receive prophylaxis. However, in 1. The purified protein derivative (PPD) test is carefully standardized, and induration at 48 individuals 35 years of age or older, the risk of hepato- hours is considered positive at toxicity may outweigh the potential beneﬁt of INH prophylaxis. Hepatic enzymes should be monitored at a) more than 5 mm in people who are HIV- monthly intervals in HIV-positive patients, pregnant positive or immunocompromised, or who have had recent household exposure; women, patients with underlying liver disease, and in those receiving other potentially hepatotoxic drugs or b) more than 10 mm in people at overall risk for drinking alcohol daily. Prophylaxis should discontin- exposure; and ued if transaminase levels rise exceed 3 times the nor- c) more than 15 mm in people with no risk mal values in association with symptoms consistent factors. with hepatitis. 2. A positive result indicates exposure sometime in The recommended prophylactic regimen is INH the past; negative to positive conversion indi- 300 mg daily for 6 months. For HIV-infected patients, cates exposure during the period between tests. 12 months of INH prophylaxis is recommended. 3. Prophylaxis with isoniazid (300 mg daily for 6 months) if a) conversion within the last two years and Atypical Mycobacteria negative chest radiograph (CXR). Atypical mycobacteria are found throughout the b) positive PPD and negative CXR (recommen- environment in soil and water. These organisms have a dation of the Centers for Disease Control and low virulence, and they do not usually cause pulmonary Prevention). disease in otherwise healthy individuals. In patients with c) abnormal CXR, and three follow-up sputum underlying pulmonary disease, these organisms can be smears for acid-fast bacilli are negative. inhaled and cause pulmonary infection. 4. If prophylaxis recipient is older than 35 years, a M. avium complex is the most common of the consumer of alcohol or other hepatotoxic drugs, atypical mycobacteria to infect the lung. A cavitary pregnant, or HIV-positive, risk of INH hepatitis upper lobe lesion is the usual manifestation of this requires monthly monitoring of hepatic enzymes. disease. The cavities tend to be somewhat smaller and thinner walled than those with M. tuberculosis. Pul- monary infection with M. avium complex is seendisease. The conversion from negative to positive inan individual who is tested annually indicates expo- KEY POINTSsure to tuberculosis during the time interval betweentests. Tuberculin skin tests are useful in otherwisehealthy individuals, but cannot be relied upon to About Atypical Mycobacteriadetermine exposure in HIV patients with low CD4 Pulmonary Infectioncounts, in patients receiving immunosuppressants, orin patients with severe malnutrition. Individuals with a positive PPD should have a CXR, 1. Atypical mycobacteria are found in soil and water.and if pulmonary lesions are noted, three sputum samples 2. Infects males over the age of 50 years, who areshould be obtained for culture and smear. Prophylaxis also alcoholic,smokers with chronic lung disease.should be given only if all sputum samples prove negative Often presents as upper lobe cavitary disease.for tuberculosis. Because the risk of developing active dis- 3. Infects women over the age of 60 years withoutease is highest within 2 years of exposure, all individuals apparent underlying disease. Presents as rightwho have converted from a negative to a positive test middle lobe or lingular disease.within 2 years should receive INH prophylaxis. Preven- 4. M. avium is the most common pathogen;tive therapy is also warranted when a positive test is asso- M.kansasii,M.fortuitum,and M.abscessus are rarer.ciated with other speciﬁc risk factors (HIV infection, 5. Management is complex and requires a pul-known recent exposure to tuberculosis, abnormal CXR, monary or infectious disease specialist.intravenous drug abuse, and certain underlying diseases).
114 / CHAPTER 4primarily in male smokers in their early fifties whoabuse alcohol. Infection of the lungs is also seen in KEY POINTSwomen 60 year of age or older with no apparentunderlying disease, most commonly involving the About the Epidemiology and Pathogenesisright middle lobe or lingula. of Histoplasmosis M. kansasii, M. fortuitum, and M. abscessus can alsoinfect the lungs, causing chronic cavitary disease.Because these organisms are found throughout the 1. Found primarily in the Midwest and Southeastenvironment and may colonize as well as infect United States.patients with chronic lung diseases, elaborate criteria 2. Grows in moist soil in temperate zones, mainlyfor differentiating colonization from infection have Ohio and Mississippi River valleys.been established. Therapy for atypical mycobacterial 3. Found in caves and old buildings; bat guano is ainfection must be prolonged and is based on concentrated source.sensitivity testing. Often these organisms respond 4. Mycelial form in soil, as macro- and microconi-poorly to therapy, and resection of the infected lung dia. Microconidia readily aerosolized.segment may be required for cure. Management of 5. Inhaled microconidia ingested by macrophagesthese patients is complex and requires the supervision and neutrophils convert to yeast forms andof an experienced pulmonary or infectious disease upregulate many genes, including a gene forspecialist. calcium binding. 6. Yeast forms are transported to hilar nodes,Fungal Pneumonias where cell-mediated immunity is induced.The most common forms of fungal pneumonia in thenormal host are histoplasmosis and coccidiomycosis.In the immunocompromised host, Cryptococcus andAspergillus can also cause pneumonia (see Chapter 15). expression of this calcium-binding protein may explain the frequent ﬁnding of calciﬁcations in infected tissues.HISTOPLASMOSIS As is observed in tuberculosis, infected macrophagesEpidemiology. Histoplasma capsulatum is one of the transport the yeast forms to the hilar lymph nodesmore common causes of chronic pneumonia in the Mid- where Histoplasma antigens are presented to T cells.western and Southeastern United States. This organism Within several weeks, cell-mediated immunity develops,survives in moist soil in temperate climates and is most and CD4 T cells activate macrophages to producecommonly reported in the Ohio and Mississippi River fungicidal products.valleys. The development of histoplasmosis is generally Clinical Manifestations. In more than 90% ofassociated with construction or excavation of soil conta- patients, infection is controlled. In many patients, pri-minated with H. capsulatum. Infection is also reported in mary exposure is asymptomatic or results in a mildspelunkers, who contract the infection by disturbing inﬂuenza-like illness. Very young people, elderly peo-dried bat guano containing high concentrations of infec- ple, and patients with compromised immune systemstious particles. Exposure to infectious particles can also are more likely to develop active disease. Symptomsoccur after the renovation of old buildings previously usually develop within 14 days of exposure and mayinhabited by birds or bats. include high fever, headache, nonproductive cough, Pathogenesis. H. capsulatum is a fungus and exists in and dull nonpleuritic chest pain. This form of chesttwo forms: mycelia or yeast. In the moist soil of temperate pain is thought to be the result of mediastinal nodeclimates, the organism exists in the mycelial form as enlargement. In other patients, chest pain may bemacroconidia (8 to 15 µm in size) and microconidia (2 to sharper and may worsen upon lying down, reﬂecting5 µm in size). When infected soil is disturbed, microconi- the development of pericarditis (observed in approxi-dia ﬂoat in the air and can be inhaled into the lung. Once mately 6% of cases).in the lung, microconidia are ingested by alveolar On CXR, patchy inﬁltrates may be seen during acutemacrophages and neutrophils. In the intracellular disease that subsequently calcify producing a “buck-environment of these phagocytes, the mycelia transform shot” appearance. Healed histoplasmosis is also the mostto rounded, encapsulated yeast cells. During this transfor- common cause of calcified lesions in the liver andmation, multiple genes are upregulated, including a gene spleen. In acute disease, mediastinal lymphadenopathythat increases production of a calcium-binding protein may be prominent and may mimic lymphoma orimportant for acquiring calcium (an essential ion for yeast sarcoidosis. A history of exposure to a site where soil wassurvival) from the intracellular environment. The excavated is particularly important in trying to
PULMONARY INFECTIONS / 115 Progressive disseminate histoplasmosis occurs in KEY POINTS about 10% of symptomatic primary infections. Progres- sive dissemination also develops as a consequence of About the Clinical Manifestations reactivation of old disease. In the immunosuppressed of Histoplasmosis individual, reactivation is the most likely pathway for disseminated disease. Onset of symptoms is usually abrupt. Fever and malaise are followed by non- 1. In 90% of cases, a brief self-limiting ﬂu-like illness productive cough, weight loss, and diarrhea. Hepato- occurs or the person remains asymptomatic. splenomegaly usually develops, and lymphadenopathy 2. Disease can develop in elderly, very young, and may be detected. Anemia, thrombocytopenia, and immunocompromised individuals. leukopenia are observed in a high proportion of patients. 3. At 14 days post exposure,the individual may have Meningitis may develop, resulting in lymphocytosis and a) high fever, headache, nonproductive cough, low glucose in the cerebrospinal ﬂuid. A CXR may show and dull, nonpleuritic chest pain. a reticulonodular pattern or scattered nodular opacities; b) a CXR with patchy inﬁltrates that later con- however, the CXR is normal in nearly one third of cases. vert to “buckshot” calciﬁcations. Mortality is high if treatment is not initiated. c) mediastinal lymphadenopathy that may Diagnosis. H. capsulatum can be readily grown from mimic lymphoma or sarcoidosis. tissue samples and body ﬂuids using brain–heart infu- sion media containing antibiotics and cycloheximide d) progressive mediastinal ﬁbrosis (a rare com- (inhibits the growth of saprophytic fungi). Mycelial plication). growth can usually be detected within 7 days and con- 4. Cavitary disease is clinically similar, with men ﬁrmed using a DNA probe. The clinical microbiology older than 50 years who have chronic obstruc- tive pulmonary disease at higher risk. 5. Disseminated disease occurs in 10% of sympto- matic primary disease. KEY POINTS a) Likelihood of dissemination occurs in people who are very old, very young, or immunosup- pressed (because of AIDS or transplantation). About the Diagnosis of Histoplasmosis b) Meningitis with lymphocytosis and low glu- cose may develop. 1. Sputum culture is often positive. c) Reticulonodular pattern on CXR in most a) Requires selective media (brain–heart infu- cases, but CXR normal in one third. sion with antibiotics and cycloheximide). b) Not a routine method; clinical microbiology must be notiﬁed. c) Bronchoscopy improves yield (90% in HIVdifferentiate between these various possibilities. Occa- patients).sionally, mediastinal nodes can become massively 2. Bone marrow positive in 50% of cases.enlarged, reaching diameters of 8 to 10 cm. Severe 3. Lysis–centrifugation method positive in up tomediastinal ﬁbrosis is rare, but it can lead to impinge- 50% of blood samples.ment and obstruction of the superior vena cava, 4. Polysaccharide urine and serum antigen test isbronchi, and esophagus. the most sensitive, being positive for Chronic cavitary histoplasmosis develops in about a) 90% of disseminated disease,8% of patients. This complication is more common in b) 40% cavitary disease, andmen over the age of 50 years who have chronicobstructive pulmonary disease. The symptoms and c) 20% acute pulmonary diseaseCXR findings associated with chronic pulmonary 5. Method can also be used to test bronchoscopichistoplasmosis are indistinguishable from cavitary lavage ﬂuid.tuberculosis. In fact, in the past, patients in the 6. Histopathology shows noncaseating or caseat-Midwestern and Southeastern United States with ing granulomas. Silver stain best for identifyingchronic pulmonary histoplasmosis were frequently the yeast forms.Hematoxylin–eosin is not useful;misdiagnosed as having pulmonary tuberculosis and periodic acid Schiff may help with identiﬁcation.were mistakenly conﬁned to tuberculosis sanatoriums. 7. Urine antigen test positive in 90% of dissemi-Spontaneous resolution of cavitary disease occurs in nated histoplasmosis10% to 60% of cases.
116 / CHAPTER 4 can be administered intravenously until symptoms KEY POINTS subside. In patients with extensive mediastinal involve- ment, itraconazole 200 mg daily, can be given for 3 to About the Treatment of Histoplasmosis 6 months. If rapid resolution of symptoms is necessary, amphotericin B is preferred. Patients with severe mediastinal ﬁbrosis may also 1. Itraconazole the oral agent of choice. Recom- mended for require surgical intervention to correct vascular and a) acute pulmonary disease that fails to airway obstruction. In cavitary pulmonary disease, improve over 7 days. progression of lesions over 2 to 3 months or persistent b) extensive mediastinal involvement. cavities associated with declining respiratory function c) progressive cavitary disease. warrant treatment with itraconazole 200 mg twice 2. Amphotericin B is used for more severe disease. daily for a minimum of 6 months. Amphotericin B Recommended for may be required if lesions fail to improve on itracona- a) primary pulmonary disease when the zole therapy. In acute, life-threatening progressive dis- patient cannot take oral medications. seminated histoplasmosis, amphotericin B should be b) cavitary disease that fails to improve on itra- given in high doses: 0.7 to 1 mg/kg daily. Once the conazole. patient has defervesced, the dosage can be lowered to c) progressive disseminated disease. 0.4 to 0.5 mg/kg, or the patient can be switched to itraconazole 200 mg twice daily. COCCIDIOMYCOSISlab must be notiﬁed that H. capsulatum is the possible Epidemiology—Like H. capsulatum, Coccidioides immi-pathogen, because the necessary culture methods are not tis survives and grows in soil. The ideal conditions foremployed on routine samples. survival of C. immitis are dry, alkaline soil, hot summers, A single sputum culture has only a 10% to 15% yield; and winters with few freezes. These conditions exist incollection of multiple sputum cultures increases the central California’s San Joaquin Valley and in the south-yield. Bronchoscopy has proved useful for providing ern regions of Arizona, New Mexico, and Texas.good sputum samples yielding positive cultures in 90% C. immitis is also found in Mexico, Central America,of HIV patients with pulmonary histoplasmosis. Bonemarrow and blood cultures should also be obtained andare positive in up to 50% of cases. The lysis–centrifuga-tion blood culture technique (also used to culture KEY POINTSmycobacteria) is the most sensitive method. The mosteffective method for detecting progressive disseminatedhistoplasmosis is the urine and serum polysaccharide About the Epidemiology and Pathogenesisantigen test. Antigen is detected in up to 90% of patients of Coccidiomycosiswith disseminated disease. The antigen test is also posi-tive in 40% of patients with cavitary pulmonary diseases 1. Grows in soil; prefers dry, alkaline soil, hot sum-and 20% with acute pulmonary histoplasmosis. Pul- mers, and winters with few freezes.monary lavage ﬂuid can also be tested in this manner. A 2. Primarily found in central California, southernPCR method is available only on an experimental basis. Arizona, New Mexico, and Texas. Also found in Histopathologic examination of infected tissue also Mexico, Central America, and South America.allows for rapid diagnosis. Noncaseating or caseating 3. Contracted during the summer, often throughgranulomas may be seen. An excessive ﬁbrotic reaction dust storms, excavation, earthquakes.may be seen in some patients. Silver stains are mosteffective for identifying the typical yeast forms in tissue 4. Mycelial form of this dimorphic fungus is called arthroconidia.biopsies. Organisms are poorly visualized by hema-toxylin–eosin staining, but can often be seen on peri- 5. Inhaled arthroconidia transform to spherulesodic acid Schiff stain. (yeast forms) that release endospores. Treatment. Itraconazole is the most effective azole for 6. Endospores ingested by macrophages areoral treatment. In patients with acute pulmonary histo- transported to hilar lymph nodes, lymphatics,plasmosis who fail to improve over the ﬁrst week, and bloodstream.itraconazole 200 mg daily for 4 to 6 weeks is recom- 7. Cell-mediated immunity critical for control ofmended. If the patient is unable to tolerate azoles or can- infection.not take oral medications, amphotericin B 0.4 to 0.5 g/kg
PULMONARY INFECTIONS / 117and South America. Infections are most commonlyreported in the summer months when dry soil more KEY POINTSreadily forms dust particles. Epidemics have been asso-ciated with disruption of soil by archeological excava- About the Clinical Manifestationstion, earthquakes, and dust storms. In recent years, the of Coccidiomycosisincidence of coccidiomycosis has increased as a conse-quence of the increased numbers of people living inendemic areas. 1. Symptoms (nonproductive cough, fever, pleu- Pathogenesis. Also like H. capsulatum, C. immitis ritic chest pain, shortness of breath, headache,is a dimorphic fungus. It exists in soil as mycelia that and fatigue) occur in about one third ofcan form small arthroconidia (5- m barrel-shaped exposed individuals 7 to 21 days after inhala-structures). Arthroconidia can become airborne, tion.whereupon they are inhaled by humans and become 2. Skin manifestations are common: erythemalodged in the terminal bronchioles. In the warm moist nodosum, erythema multiforme, nonpruriticenvironment of the lung, the arthroconidia transform papular rash.into spherules. As the spherules mature, their outer 3. Eosinophilia may be noted on peripheral bloodwalls thin, and they release endospores that are smear.ingested by macrophages. As is observed in histoplas- 4. Abnormal CXR ﬁndings are frequent: unilateralmosis and tuberculosis, macrophages transport the inﬁltrates, pleural effusions, hilar adenopathy.infectious particles to the hilar lymph nodes, the lym- 5. In patients with AIDS whose CD4 counts fallphatic system, and the bloodstream, resulting in below 100/mm3, the disease can disseminate,dissemination. Cell-mediated immunity is critical for causing diffuse lung opaciﬁcation, meningitis,control of the infection. bone infection, and arthritis. Clinical Manifestations. Approximately two thirds 6. Chronic lung disease can lead to ﬁbrosis, nod-of patients exposed to arthroconidia experience mini- ules, or cavities.mal symptoms. When symptoms are noted, they 7. Isolated pulmonary nodules are not calciﬁed,usually develop 7 to 21 days after exposure. Nonpro- can be differentiated from neoplasm by biopsy.ductive cough and fever are the most frequent 8. Chronic pleural effusions most commonlysymptoms. Pleuritic chest pain, shortness of breath, develop in young, healthy, athletic males.headache, and fatigue are also commonly reported.Skin manifestations may include erythema nodosum(red, painful nodules on the anterior shins), erythema effusion can result from the rupture of a peripheralmultiforme (target-like lesions involving the entire cavitary lesion into the pleural space. This complica-body, including the palms and soles) or a nonpruritic tion is most commonly reported in young, otherwisepapular rash. Arthralgias may develop in association healthy, athletic males.with erythema nodosum. Eosinophilia is commonly Diagnosis. Travel to, or past residence in, anobserved on peripheral blood smear. endemic area should alert the clinician to the possibil- In about half of patients, a CXR is abnormal, most ity of coccidiomycosis. Examination of induced spu-commonly demonstrating unilateral inﬁltrates, pleural tum or sputum obtained by bronchoscopy may revealeffusions, and hilar adenopathy. In patients with spherules. The fungus is not seen on Gram stain, butdepressed cell-mediated immunity (primarily patients can be detected by silver stain. Biopsies of infected tis-with AIDS and CD4 counts below 100/mm3), the sue should be obtained; they usually reveal caseatinginfection can disseminate, causing diffuse opaciﬁcation or noncaseating granulomas and spherules. Theof the lungs and severe respiratory failure. Meningitis, organism grows readily as a white mold on routineskin lesions, bone infection and arthritis may also mycology media and on bacterial media under aerobicdevelop as a consequence of dissemination. conditions. In some patients pulmonary infection can persist, Multiple serologic tests are available. These testscausing progressive destruction of lung parenchyma are often required to make the diagnosis, because ofassociated with a productive cough, chest pain, weight unavailability of sputum and biopsy specimens.loss. A CXR may demonstrate areas of fibrosis, Immunoglobulin M (IgM) serum titers againstnodules, cavitary lesions, or a combination. An iso- C. immitis are usually positive within the ﬁrst week oflated nodule can persist in approximately 4% of pul- disease. Immunoglobulin G (IgG) levels are mostmonary cases and can be differentiated from neoplasm commonly tested by complement ﬁxation or immun-only by biopsy. These lesions seldom calcify as the odiffusion. Levels of IgG increase after IgM and oftenlesions of histoplasmosis do. A chronic pleural persist for years. A correlation has been observed
118 / CHAPTER 4 or progressive coccidioidal pneumonia with hypoxia. KEY POINTS Treatment needs to also be considered in patients with pulmonary disease who are at increased risk for dissem- About the Diagnosis of Coccidiomycosis ination, including people that are black, Philippino, pregnant, diabetic, and immunosuppressed (including patients with AIDS). 1. Spherules may be seen on induced sputum or after bronchoscopy. Amphotericin B remains the preferred initial ther- apy for life-threatening disseminated disease or severe 2. The organisms are readily cultured on routine pulmonary disease until the infection is under control. bacterial and mycology culture plates. High doses of amphotericin B (0.7 to 1 mg/kg daily) 3. Histopathology shows noncaseating and are recommended. In less severe disease, ﬂuconazole caseating granulomas; Gram stain is not useful, (400 to 800 mg daily) or itraconazole (200 mg twice silver stain is best. daily) are used. These agents are preferred because of 4. Multiple serology tests are available to measure their low toxicity and suitability for prolonged therapy. immunoglobulin G (IgG) and M (IgM) antibody Treatment should be continued until symptoms and titers. signs of infection have resolved. A minimum of 6 a) The IgM titer is elevated in acute disease. months’ therapy is recommended. In patients with b) The IgG level often persists for years. A rising meningeal involvement, triazole therapy should be con- titer exceeding 1:32 signals dissemination; a tinued indeﬁnitely. falling titer is indicative of a favorable prog- Surgical debridement of large purulent collections is nosis. recommended. Resection of rapidly expanding pulmonary cavities should be performed to prevent rupture into the pleural space. Surgical resection is also recommended to prevent bronchopleural ﬁstula formation and to correctbetween the IgG serum titer and severity of disease. A life-threatening pulmonary hemorrhage.rising titer that exceeds 1:32 may signal disseminateddisease; a falling titer indicates a favorable prognosis.Patients with no detectable lesions can have titers FURTHER READINGbelow 1:8 for many years after exposure. General Treatment. Most infections with this organismspontaneously resolve. Treatment is reserved for patients File TM. Community-acquired pneumonia. Lancet. 2003;362:with disseminated disease and patients with persistent 1991–2001. Hageman JC, Uyeki TM, Francis JS, et al. Severe community- acquired pneumonia due to Staphylococcus aureus, 2003-04 inﬂuenza season. Emerg Infect Dis. 2006;12:894–899. Heyland D, Dodek P, Muscedere J, Day A. A randomized trial of diag- KEY POINTS nostic techniques for ventilator-associated pneumonia. N Engl J Med. 2006;355:2619–2630. About the Treatment of Coccidiomycosis Jackson ML, Neuzil KM, Thompson WW, et al. The burden of com- munity-acquired pneumonia in seniors: results of a population- based study. Clin Infect Dis. 2004;39:1642–1650. 1. Treatment usually reserved for disseminated Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases disease. Society of America/American Thoracic Society consensus guide- 2. Amphotericin B given for severe disease. lines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27–S72. 3. Fluconazole or itraconazole given for less- severe disease. Lim WS, van der Eerden MM, Laing R, et al. Deﬁning community acquired pneumonia severity on presentation to hospital: an 4. Treatment continues for a minimum of 6 months. international derivation and validation study. Thorax. 5. Complement ﬁxation immunoglobulin G titers 2003;58:377–382. should decline to a stable low tier. Marrie TJ, Wu L. Factors inﬂuencing in-hospital mortality in commu- 6. For meningitis, triazole therapy should be con- nity-acquired pneumonia: a prospective study of patients not ini- tinued indeﬁnitely. tially admitted to the ICU. Chest. 2005;127:1260–1270. Mortensen EM, Restrepo M, Anzueto A, Pugh J. Effects of guideline- 7. Surgical resection can be used to expand lung concordant antimicrobial therapy on mortality among patients lesions. with community-acquired pneumonia. Am J Med. 2004; 117:726–731.
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