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.