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  • 1. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 1 15 ANTIBIOTICS Nicolas V Christou, M.D. . Antibiotic Therapy in Surgical Patients Several important advances in antimicrobial therapy have been National Committee for Clinical Laboratory Standards made since the early 1980s. Among these advances are (1) im- (NCCLS)1 for in vitro susceptibility testing. Commercially avail- proved understanding of the microbiologic spectrum of so-called able paper disks containing specific amounts of antimicrobial optimal therapy, (2) better application of pharmacokinetic princi- agents are placed on Mueller-Hinton agar plates that contain a ples to drug administration, (3) the development of several new standard bacterial inoculum. A zone of inhibition of bacterial classes of antibiotics, and (4) greater insight into the interplay growth develops around each active antibiotic after overnight among host resistance factors, microorganisms, and chemotherapy. incubation. The size of the zone determines the organism’s sus- ceptibility or resistance; prior studies have correlated zone sizes with MICs obtained through dilution tests. Arbitrary zone-size General Principles of Antimicrobial Therapy break points for susceptibility have been established by clinical and laboratory investigators on the basis of such additional factors as EMPIRICAL THERAPY achievable serum levels, degree of protein binding, and toxicity. Even with the most rapid bacteriologic tests currently available, The broth dilution method exposes an inoculum of bacteria to it may not be possible to identify a pathogen in less than 24 hours, various concentrations of an antimicrobial agent during incuba- and antimicrobial sensitivities can rarely be obtained in less than tion. The MIC of an agent that inhibits growth can be deter- 48 to 72 hours. In seriously ill patients, treatment cannot be mined, and this value can be correlated with blood, urine, or delayed for 2 to 3 days until these data become available. If ther- other body fluid levels of the antimicrobial agent. Moreover, apy is to be successful, it must be started as soon as a life-threat- those tubes that show inhibition of growth can be subcultured to ening infection is diagnosed or, in some patients, as soon as such an antimicrobial-free medium, and the minimal bactericidal con- an infection is suspected. Which antimicrobial agents are to be centration (MBC) can be determined. Unfortunately, this test is used depends on the suspected site of infection and on the organ- not well standardized at present, and its reproducibility is poor isms that are commonly pathogenic at this site.Therapy is initiat- when it is subjected to intralaboratory and interlaboratory com- ed with an agent or combination of agents whose action is broad parisons.2 enough to cover all the suspected microbial pathogens.The appli- The agar dilution method works in much the same way as the cation of such broad-spectrum antibiotic therapy in the absence broth dilution method, except that the former employs agar of microbiologic confirmation is termed empirical therapy. plates that contain various dilutions of antimicrobial agents, and To make a rational decision regarding empirical therapy, the as many as 36 organisms can be efficiently inoculated on each surgeon must be familiar with the organisms that are likely to be plate by means of a replicator device. The MIC is determined by encountered when a particular infection (e.g., an intra-abdominal reading inhibition of colony growth on the agar surface. Agar abscess) is suspected. Selection of the agent or agents is based on dilution has the advantage of producing MIC data efficiently in a the history, the physical examination, where the infection was laboratory that performs large numbers of tests daily. likely to have been acquired, the host defense status, the overall In the serum bactericidal test (SBT), samples of the serum of clinical severity of the infection, and the response of the host. the treated patient are obtained and incubated with the infecting Definitive therapy is initiated after the host response to the infec- organism in doubling dilutions with broth to determine the high- tion and to the empirical treatment has been monitored and the est dilution that is bactericidal. (Not all antimicrobial agents results from the microbiology laboratory—specifically, identifica- exhibit bactericidal activity; some exhibit only bacteriostatic activ- tion of the isolated organisms and the minimal inhibitory con- ity [see Table 1].) The drawing of serum specimens can be timed to centrations (MICs) of various antimicrobial agents—have been coincide with anticipated peak and trough antimicrobial levels. In assessed. effect, this test indirectly assesses both the susceptibility of the organism and the serum concentration of the antimicrobial agent, LABORATORY TESTS as well as the interactions between serum and organism and Many laboratory tests, if used in the proper context, can guide serum and drug.The NCCLS has developed proposed guidelines selection of optimal antimicrobial therapy. for the SBT.3 A comprehensive review of the technical and clini- In vitro susceptibility tests are indicated when the susceptibili- cal considerations associated with the SBT has been published.4 ty of an organism is not completely predictable or when certain other specific problems arise, such as the necessity of determin- ing whether resistance has developed during the course of thera- Factors Influencing Application of Antimicrobial Therapy py. An organism is generally considered susceptible if the con- ROUTE OF ADMINISTRATION centration of antimicrobial agent necessary to inhibit its growth is lower than that usually attainable in body fluids, particularly Many antibiotics are absorbed sufficiently well via the oral blood, cerebrospinal fluid, or urine. route to provide effective blood levels in patients with normal GI The disk diffusion method has been standardized by the function.5 The enteral absorption of some antimicrobials is
  • 2. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 2 impeded by food and some medications (e.g., antacids). Many ume, glomerular filtration rule (GFR), and hepatic metabolic antibiotics cannot be given intramuscularly because of local pain activity often reduce the maternal serum levels of antimicrobials or necrosis at the injection site. Intravenous administration must by 10% to 50%, especially late in pregnancy and in the early be used in the treatment of major and life-threatening infections postpartum period. In some women, delayed gastric emptying such as suppurative diffuse peritonitis. In many cases, patients are may reduce the absorption of antibiotics that have been admin- clinically stable during intravenous treatment, and it is often pos- istered orally during pregnancy. sible to discharge them and to administer parenteral antibiotics Even though 25% to 40% of women receive antibiotics during on an outpatient basis. Supervision by special teams of physi- pregnancy, data regarding safety and efficacy in this setting are cians, nurses, and pharmacists is required6; antibiotics can be often scarce. Some general recommendations have been pro- administered either in the hospital outpatient department or at posed, but they are intended only as a guide [see Table 2]; in all home if competent family members are available. New antibi- cases, therapy must be individualized, and both the indications for otics with long half-lives can be used with improved intravenous antibiotics and the possible risks to mother and fetus must be con- catheters and delivery devices in simplified regimens; this leads sidered. Individual decisions are also required for lactating moth- to substantial economic benefits, enhanced patient comfort, and ers; although most antimicrobials appear safe for breast-fed in- good therapeutic results with few complications.7 fants, chloramphenicol and the tetracyclines should be avoided.9 HOST FACTORS Advanced Age Physiologic changes that occur with age can alter the phar- Hypersensitivity to Antibiotics macokinetics of antimicrobial agents. For example, decreased Because of widespread exposure to antimicrobial agents, many gastric acidity and intestinal motility can impair drug absorp- patients develop allergies to them.8 A careful history of hyper- tion; increased body fat and decreased serum albumin levels can sensitivity should thus be obtained [see Hypersensitivity Reac- alter drug distribution; and decreased hepatic blood flow and tions, below]. enzymatic action can delay drug metabolism. Although these factors have not consistently affected antibiotic levels in the Concurrent Illnesses elderly, the decrease in GFR that occurs with age can lead to the Patients with immunosuppressive illnesses are vulnerable to accumulation of drugs excreted by the kidney. The high thera- opportunistic pathogens. These patients may require broader peutic index of the penicillins and cephalosporins obviates antimicrobial coverage as well as intense therapy for ordinary major changes in dosage schedules in elderly patients who have pathogens. The same is true to a lesser extent for patients with a normal serum creatinine levels. However, in the case of amino- chronic debilitating illness. Patients with renal insufficiency or glycosides and vancomycin, decreased dosage schedules are liver disease may be unusually susceptible to direct drug toxicity. often required; ideally, drug levels should be measured and renal function should be monitored when these agents are given. The Pregnancy dosage of amantadine and rimantadine should also be reduced The administration of antimicrobial agents during pregnancy in elderly patients. and in the postpartum period poses several problems. Foremost is the question of safety, both for the mother and the fetus or neonate. Although most antibiotics cross the placenta and enter Antibiotic Selection for Infections in Surgical Patients maternal milk, the concentrations to which the fetus or neonate The term surgical infection is difficult to define, but for the is exposed vary widely. Because the immature liver may lack the purposes of this chapter, it means infections that are related to enzymes required to metabolize certain drugs, pharmacokinetics surgical procedures or that require, in addition to antibiotic ther- and toxicities in the fetus are often very different from those in apy, surgical debridement or control of the source of the infec- older children and adults.Teratogenicity is a major concern when tion. Such infections include infections of the soft tissues of the any drug is administered during pregnancy. Finally, it may be integument; muscles; bones; and body cavities (e.g., empyema, necessary to alter the dosage schedules of drugs that appear to be intra-abdominal infections, pyelonephritis, and infections of the safe to use during pregnancy; increases in maternal blood vol- retroperitoneum). A framework for antibiotic selection for intra-abdominal infections is presented [see Table 3]; this framework can be mod- Table 1 Bactericidal and Bacteriostatic Agents155 ified for the selection of antibiotic for other types of surgical infection. A therapeutic regimen for the treatment of intra- Bactericidal Agents Bacteriostatic Agents abdominal infection should include agents that are active against Staphylococcus aureus, enteric gram-negative bacilli, and anaer- Aminoglycosides* Chloramphenicol obes, including Bacteroides fragilis. The regimen that has been Aztreonam Clindamycin regarded as the gold standard consists of an aminoglycoside, to Bacitracin Erythromycin cover the enteric gram-negative organisms, and clindamycin or Cephalosporins Sulfonamides metronidazole, to cover the anaerobes; other approaches, how- Imipenem Tetracyclines ever, look promising. Penicillins Trimethoprim A well-designed, controlled, prospective, randomized trial that Polymyxins† Quinolones‡ compared imipenem therapy with acceptable aminoglycoside- Vancomycin based regimens supports the use of imipenem as monotherapy for intra-abdominal infections in which an enteric mixed flora is *Including streptomycin, neomycin, kanamycin, gentamicin, tobramycin, amikacin, and netilmicin. anticipated.10 When the analysis was restricted to the residual † Including polymyxin B and colistimethate. effect of treatment assignment, a significant improvement in out- ‡ Including norfloxacin and ciprofloxacin. come was found in the patients receiving imipenem (P = 0.043).
  • 3. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 3 Table 2 Antibiotics in Pregnancy155 Major Toxic Potential Pharmacology Drug Maternal Excreted in Maternal Fetal Serum Levels Mother’s Milk Considered safe Cephalosporins Allergies None known Decreased Trace Erythromycin base Allergies, GI intolerance None known Decreased Yes Penicillins Allergies None known Decreased Trace Spectinomycin ? None known ? ? Use with caution Aminoglycosides Ototoxicity, nephrotoxicity Ototoxicity Decreased Yes Clindamycin Allergies, colitis None known Unchanged Trace Ethambutol Optic neuritis Probably safe ? ? Isoniazid Allergies, hepatotoxicity Neuropathy, seizures Unchanged Yes Rifampin Hypersensitivity, hepatotoxicity Probably safe Unchanged Yes Sulfonamides Allergies, crystalluria Kernicterus (at term), hemolysis Unchanged Yes (contraindicated at term) (G6PD deficiency) Avoid if possible Metronidazole Hypersensitivity, alcohol intolerance, None known (teratogenic in animals) Probably unchanged Yes neuropathy Contraindicated Chloramphenicol Blood dyscrasias Gray syndrome Unchanged Yes Erythromycin estolate Hepatotoxicity None known Decreased Yes Nalidixic acid GI intolerance Increased intracranial pressure ? ? Nitrofurantoin Allergies, neuropathy, GI intolerance Hemolysis (G6PD deficiency) Decreased Trace Norfloxacin, ciprofloxacin, GI intolerance Arthropathies in immature animals ? ? ofloxacin, lomefloxacin Tetracyclines Hepatotoxicity, renal failure Tooth discoloration and dysplasia, Probably unchanged Yes impaired bone growth Trimethoprim Hypersensitivity Teratogenicity Unchanged Yes Meropenem was found to be as effective as imipenem for the addressed by guidelines published by members of the Surgical treatment of moderately severe intra-abdominal infections.11 Infection Society.15 The third-generation cephalosporins have Ertapenem has a pharmacokinetic profile and an antimicrobial been proposed as candidates for single-agent therapy for infection spectrum that support its use as a once-daily agent for the treat- in the abdominal cavity because their spectra of activity encom- ment of common mixed aerobic and anaerobic infections. A pass both the aerobic gram-negative bacilli and some of the prospective, randomized, controlled, double-blind trial com- anaerobic isolates that cause infection in this region. No pared ertapenem with piperacillin-tazobactam as therapy follow- cephalosporin, of any generation, has been shown to have a clear ing adequate surgical management of complicated intra-abdom- advantage over an aminoglycoside-clindamycin combination in inal infections.The modified intent-to-treat population consisted the treatment of intra-abdominal infections. of 633 patients, of whom 396 met all criteria for the evaluable Interpretation of overall results in intra-abdominal infections is population. Patients with a wide range of infections were en- difficult because of the numerous variables involved, including rolled. A prospective expert-panel review was conducted to the diversity of the possible infectious processes, the variable assess the adequacy of surgical source control in patients in quality of the surgical technique employed, the variety of the whom therapeutic failure was a component of evaluability. For patient characteristics observed, the possibility of one or more the modified intent-to-treat groups, 245 of 311 patients treated underlying diseases, and the differing doses of antibiotics used in with ertapenem (78.8%) were cured; 232 of 304 patients individual studies.16 Most third-generation cephalosporins do not (76.3%) treated with piperacillin-tazobactam were cured. Of 203 cover anaerobes well and should be used in conjunction with an microbiologically evaluable patients treated with ertapenem, 176 antianaerobic agent, such as clindamycin or metronidazole, for (86.7%) were cured; 157 of the 193 patients (81.3%) treated empirical therapy for serious intra-abdominal infections. In a with piperacillin-tazobactam were cured. In this study, ertapen- recent prospective, randomized, double-blind study, cefoxitin was em, 1 g once a day, was equivalent to piperacillin-tazobactam, found to be comparable to imipenem with regard to outcome 3.375 g every 6 hours, in the treatment of a range of intra- (defined as survival); failure to cure infections was attributed to abdominal infections. Ertapenem may be a useful option that resistant organisms at the primary site in the cefoxitin arm of the could eliminate the need for combination therapy, multidose trial.17 antibiotic regimens, or both for the empirical treatment of intra- abdominal infections.12 Appropriate surgical control of the source of the intra-abdom- Adverse Reactions to Antimicrobial Agents inal infection is of utmost importance in determining outcome; There are three general types of adverse reactions to antimi- antibiotics play a necessary but secondary role.13,14 The contro- crobial agents: hypersensitivity reactions (which are not dose versies regarding the pathogenicity of enterococci have been related), direct drug toxicity (which usually is dose related and
  • 4. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 4 Third Pass 06/24/03 Table 3 Antibiotic Selection for Infections in Surgical Patients Type of Infection Expected Pathogen First Choice I.V. Rx Second Choice I.V. Rx Switch to P.O. Choice Brain infection (abscess, subdural empyema, intracranial suppurative thrombophlebitis) Staphylococcus aureus, Traumatic brain injury Enterobacteriaceae, Cefepime, 2 g I.V. q. 8 hr Meropenem, 1 g I.V. q. 8 hr Not recommended Pseudomonas aeruginosa Nafcillin, 2 g I.V. q. 4 hr or Postneurosurgical S. aureus, S. epidermidis Cefepime, 2 g I.V. q. 8 hr Meropenem, 1 g I.V. q. 8 hr Linezolid, 600 mg p.o., q. 12 hr procedure or If methicillin resistant: Linezolide, 600 mg I.V. q. 12 hr Vascular graft infection Vancomycin, 1 g I.V. S. aureus, Enterobacteriaceae, plus Meropenem, 1 g I.V. q. 8 hr Moxifloxacin, 400 mg p.o. and Arteriovenous graft/shunt and remove graft remove graft enterococci Gentamicin, 240 mg I.V. and remove graft Cefepime, 2 g I.V. q. 12 hr Aortic graft or Ceftizoxime, 2 g I.V. q. 8 hr Levofloxacin, 500 mg p.o., q. 24 hr S. aureus, S. epidermidis, (treat with antibiotics Enterobacteriaceae Imipenem, 1 g I.V. q. 8 hr or or until graft is replaced) or Cefotaxime, 2 g I.V. q. 6 hr Moxifloxacin, 400 mg p.o., q. 24 hr Meropenem, 1 g I.V. q. 8 hr Intra-abdominal infection (peritonitis, abscess) Ceftizoxime, 2 g I.V. q. 8 hr Levofloxacin, 500 mg p.o., q. 24 hr Gastric perforation Candida, oral anaerobes, Cefazolin, 1 g I.V. q. 8 hr or or (peptic ulcer disease) S. aureus Cefotaxime, 2 g I.V. q. 6 hr Moxifloxacin, 400 mg p.o., q. 24 hr Cefepime, 2 g I.V. q. 12 hr or Ceftizoxime, 2 g I.V. q. 8 hr Levofloxacin, 500 mg p.o., q. 24 hr Gastric perforation S. aureus, S. epidermidis, Imipenem, 1 g I.V. q. 8 hr or or (malignancy) Enterobacteriaceae, Candida or Cefotaxime, 2 g I.V. q. 6 hr Moxifloxacin, 400 mg p.o., q. 24 hr Meropenem, 1 g I.V. q. 8 hr Levofloxacin, 500 mg p.o., q. 24 hr Cholecystitis with Escherichia coli, Klebsiella, Piperacillin-tazobactam, 4.5 g I.V. Cefotaxime, 2 g I.V. q. 6 hr or gangrene/perforation enterococci q. 8 hr Moxifloxacin, 400 mg p.o., q. 24 hr Emphysematous Piperacillin-tazobactam, 4.5 g I.V. Clostridium perfringens q. 8 hr Ertapenem, 1 g I.V. q. 24 hr Clindamycin, 300 mg p.o., q. 8 hr cholecystitis Imipenem, 1 g I.V. q. 8 hr Levofloxacin, 500 mg p.o., q. 24 hr Ascending cholangitis E. coli, Klebsiella, enterococci or Cefoperazone, 2 g I.V. q. 12 hr or Meropenem, 1 g I.V. q. 8 hr Moxifloxacin, 400 mg p.o., q. 24 hr Clindamycin, 300 mg p.o., q. 8 hr Imipenem, 1 g I.V. q. 8 hr Piperacillin-tazobactam, plus or 4.5 g I.V. q. 8 hr Infected hemorrhagic/ Enterobacteriaceae, Levofloxacin, 500 mg p.o., q. 24 hr necrotizing pancreatitis Bacteroides fragilis Meropenem, 1 g I.V. q. 8 hr or or or Ampicillin-sulbactam, 3 g I.V. q. 6 hr Moxifloxacin, 400 mg p.o., q. 24 hr Ertapenem, 1 g I.V. q. 24 hr Metronidazole, 1 g I.V. q. 24 hr Imipenem, 1 g I.V. q. 8 hr Metronidazole, 500 mg p.o., q. 12 hr plus or plus Liver abscess (bacterial) Enterobacteriaceae, Levofloxacin, 500 mg I.V. B. fragilis Meropenem, 1 g I.V. q. 8 hr Levofloxacin, 500 mg p.o., q. 24 hr q. 24 hr or or or Ertapenem, 1 g I.V. q. 24 hr Moxifloxacin, 400 mg p.o., q. 24 hr Moxifloxacin, 400 mg I.V. q. 24 hr Liver abscess Tinidazole, 2 g/day p.o. in Entamoeba histolytica Metronidazole, 750 mg p.o., q. 8 hr Not applicable (amebiasis) three divided doses (continued )
  • 5. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 5 Table 3 (continued ) Type of Infection Expected Pathogen First Choice I.V. Rx Second Choice I.V. Rx Switch to P.O. Choice Intra-abdominal Infection (peritonitis, abscess) (continued) Distal small bowel, appendix, colon, rectum Piperacillin-tazobactam, 4.5 g I.V. Cefoxitin, 2 g I.V. q. 6 hr Ciprofloxacin, 250–750 mg p.o., q. perforation in nonhospi- Enterobacteriaceae, enterococ- q. 8 hr or 12 hr talized patient (mild to ci, B. fragilis or plus Ampicillin-sulbactam, 3 g I.V. moderate infection) Ertapenem, 1 g I.V. q. 24 hr q. 6 hr Metronidazole, 500 mg p.o., q. 12 hr Distal small bowel, Tobramycin, 5 mg/ kg load- appendix, colon, rec- ing dose, then 3 mg/kg Imipenem, 1 g I.V. q. 8 hr I.V. q. 8 hr tum perforation in hos- Enterobacteriaceae, entero- cocci, B. fragilis, P. aerugi- or plus Moxifloxacin, 400 mg p.o., q. 24 hr pitalized patient (severe infection requiring ICU nosa, Acinetobacter Meropenem, 1 g I.V. q. 8 hr Clindamycin, 900 mg I.V. support) q. 8 hr Ciprofloxacin, 250–750 mg p.o., q. Spontaneous bacterial 12 hr Enterobacteriaceae Ciprofloxacin, 400 mg I.V. q. 12 hr Cefepime, 2 g I.V. q. 12 hr peritonitis plus Metronidazole, 500 mg p.o., q. 12 hr Pelvic inflammatory disease (tubo-ovarian abscess, salpingitis, endometritis, infected abortion) Ciprofloxacin, 250–750 mg p.o., q. Enterobacteriaceae, B. fragilis, 12 hr Mild to moderate infec- Neisseria gonorrhoeae, Moxifloxacin, 400 mg p.o., q. 24 hr None tion (outpatients) plus Chlamydia trachomatis Doxycycline, 100 mg p.o., q. 12 hr Levofloxacin, 500 mg p.o., q. Enterobacteriaceae, B. fragilis, Doxycycline, 200 mg I.V. q. 12 hr 24 hr Severe infection (hospi- N. gonorrhoeae, C. tracho- plus plus Moxifloxacin, 400 mg p.o., q. 24 hr talized patient) matis Clindamycin, 600 mg I.V. q. 8 hr Metronidazole, 1 g I.V. q. 24 hr manifests in a single organ or, occasionally, in several organs), and probably secondary to injury to the red cell membrane. Flucyto- microbial superinfection. sine causes bone marrow suppression (leukopenia or pancytope- nia) when its excretion is reduced by renal failure. Linezolid can HYPERSENSITIVITY REACTIONS also produce myelosuppression; although experience is limited, A history of allergies should be taken before antimicrobial ther- bone marrow function usually recovers when the drug is discon- apy is initiated in any patient. More information is available tinued. Neutropenia can occur during therapy with penicillins, regarding allergies to the penicillins than allergies to other agents, cephalosporins, or vancomycin. It may be severe, but it is self-lim- but skin eruptions, drug fever, and even anaphylaxis may be pro- ited; recovery occurs 1 to 7 days after the antibiotic is withdrawn. duced by many antibiotics. Allergic reactions occur in 1% to 10% Penicillins inhibit platelet aggregation by adenosine diphosphate, of patients who receive penicillin. Fatal anaphylactic reactions are which may account for the bleeding that occurs in some patients much less frequent. receiving these antibiotics in high doses. Various cephalosporins may produce coagulopathies by prolonging the prothrombin DIRECT DRUG TOXICITY time; the methylthiotetrazole side chain present in cephalosporins Although antimicrobials can produce damage to virtually all such as cefotetan appears to be responsible. human organ systems, the potential for toxicity varies widely from Antibiotics may produce a wide range of toxic effects on the drug to drug.18 The principal antibiotics that are directly toxic to central and peripheral nervous systems. Ototoxicity, either the kidney are aminoglycosides, polymyxins, and amphotericin B; vestibular or auditory, can be produced by any of the aminogly- azotemia and renal tubular damage may be caused by any of cosides; neuromuscular blockade is much less common. these drugs. Patients with preexisting renal insufficiency are at Minocycline has occasionally been reported to produce signifi- increased risk for toxic reactions to various antibiotics, including cant vestibular reactions. Vancomycin can cause auditory neuro- nephrotoxicity, coagulopathies and other hematologic toxicities, toxicity. Intravenous administration of large doses of penicillin seizures, and ototoxicity and other neurotoxicities. and other β-lactams may produce seizures, especially when Penicillins, cephalosporins, tetracyclines, and rifampin can administered in very high doses or when given to azotemic cause hemolytic anemia, thrombocytopenia, and leukopenia that patients or to patients with underlying epilepsy. involve an immune mechanism, but these reactions are uncom- Metronidazole can sometimes cause ataxia, encephalopathy, mon. Macrolides and trimethoprim-sulfamethoxazole have been seizures, or peripheral neuropathies. Ofloxacin has been reported associated with agranulocytosis. Trimethoprim can produce ane- to cause seizures; mania has been attributed to clarithromycin. mia, leukopenia, and thrombocytopenia from folate deficiency; Optic neuritis, usually manifested by decreased visual acuity and the effect is reversible with folinic acid. Amphotericin B com- decreased perception of the color green, may occur as a side effect monly produces a reversible normocytic normochromic anemia, of ethambutol.
  • 6. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 6 Table 4 Antimicrobial Drugs of Choice for Various Infections in Adults18 Causative Organism Drug of Choice Alternative Drugs Staphylococcus aureus Methicillin-sensitive Linezolid; quinupristin-dalfopristin Methicillin-resistant1 Vancomycin,2 with or without rifampin or Trimethoprim-sulfamethoxazole (TMP-SMX),2 with or without gentamicin rifampin2; a fluoroquinolone3; a tetracycline4 Penicillinase-resistant penicillin5 A cephalosporin,6 clindamycin, vancomycin,7 meropenem or imipenem,8 ticarcillin–clavulanic acid, ampicillin-sulbactam, amoxicillin–clavulanic acid, piperacillin-tazobactam, a fluoroquinolone3 Coagulase-negative Vancomycin,7 with or without rifampin2 or Linezolid, quinupristin-dalfopristin, a cephalosporin, a penicilli- staphylococci9 gentamicin nase-resistant penicillin, meropenem or imipenem,8 a fluoro- quinolone3 Anaerobic streptococcus Penicillin G 10 Clindamycin, a cephalosporin,6 vancomycin7 Gram-Positive Cocci (Peptostreptococcus) Streptococcus bovis Penicillin G 10,11 A cephalosporin,6 vancomycin7 Groups A, G, and C streptococci Penicillin G10,12 or penicillin V A cephalosporin,6 vancomycin,7 an erythromycin,13 clindamycin, clarithromycin, azithromycin Group B streptococcus Penicillin G10,12 or ampicillin A cephalosporin,6 vancomycin,7 an erythromycin S. pneumoniae (pneumococcus) Penicillin sensitive Penicillin G10,12 or penicillin V, amoxicillin An erythromycin,12,13 a cephalosporin,6 meropenem or imipenem,8 vancomycin,7,12 azithromycin, clarithromycin, a fluoroquinolone; a tetracycline4 Non–penicillin sensitive Vancomycin; ceftriaxone or cefotaxime6; — levofloxacin, moxifloxacin, or gatifloxacin3; linezolid; quinupristin-dal- fopristin; imipenem or meropenem Viridans streptococcus Penicillin G,10,11 with or without A cephalosporin,6 vancomycin7 gentamicin Enterococcus Endocarditis or other serious Penicillin or ampicillin, plus gentamicin14 or Vancomycin,7 with gentamicin or streptomycin; linezolid; infection streptomycin quinupristin-dalfopristin Uncomplicated urinary tract Ampicillin or amoxicillin A fluoroquinolone,3 nitrofurantoin,15 fosfomycin infection Bacillus cereus, B. subtilis Vancomycin Meropenem or imipenem,8 clindamycin Gram-Positive Bacilli Bacillus anthracis Penicillin G Ciprofloxacin,3 a tetracycline,4 an erythromycin2 Clostridium difficile Metronidazole16 Vancomycin16 C. perfringens Penicillin G; clindamycin Metronidazole, meropenem or imipenem,8 chloramphenicol7 C. tetani Metronidazole Penicillin G, a tetracycline4 Corynebacterium diphtheriae An erythromycin Penicillin G Corynebacterium, JK group Vancomycin Penicillin G, with gentamicin; an erythromycin Listeria monocytogenes Ampicillin, with or without gentamicin TMP-SMX Propionibacterium Penicillin G Clindamycin, an erythromycin Moraxella (formerly Branhamella) Cefuroxime,6 a fluoroquinolone3 TMP-SMX, amoxicillin–clavulanic acid, an erythromycin, a tetra- Gram-Negative Cocci catarrhalis cycline, third-generation cephalosporins, clarithromycin, azithromycin Neisseria gonorrhoeae17 Ceftriaxone or cefixime,6 ciprofloxacin, Cefotaxime,10 penicillin or ampicillin ofloxacin, or gatifloxacin3 N. meningitidis Meningitis, bacteremia Penicillin G A third-generation cephalosporin,6 TMP-SMX, a fluoroquinolone,3 chloramphenicol7 Carrier state Rifampin Minocycline, ciprofloxacin Bacteroides GI tract strains (B. fragilis) Metronidazole or clindamycin Cefoxitin, cefotetan, ceftizoxime, or cefmetazole; chloramphen- Enteric Gram-Negative Bacilli icol18; imipenem or meropenem8; ticarcillin–clavulanic acid; ampi- cillin-sulbactam, piperacillin-tazobactam Respiratory tract strains Penicillin G or clindamycin Metronidazole, cefoxitin,6 cefotetan, ceftizoxime, cefmetazole, chloramphenicol7 Campylobacter fetus Imipenem or meropenem8 Gentamicin C. jejuni Azithromycin or an erythromycin A fluoroquinolone,3 a tetracycline,4 gentamicin7 Citrobacter Imipenem or meropenem8 A fluoroquinolone,3 amikacin; TMP-SMX; a tetracycline4; a third- generation cephalosporin6 Enterobacter Imipenem or meropenem8 A third-generation cephalosporin6; for serious infections, use with a fluoroquinolone3 or gentamicin; gentamicin, tobramycin, amikacin, a fluoroquinolone,3 a carboxypenicillin or acylaminopenicillin,19 aztreonam20 Escherichia coli Ampicillin, a cephalosporin,6 a fluoro- Gentamicin,21 tobramycin, amikacin, imipenem or meropenem,8 quinolone,3 TMP-SMX22 aztreonam20 Note: all superscript numbers refer to footnotes that follow table.
  • 7. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 7 Table 4 (continued) Causative Organism Drug of Choice Alternative Drugs Helicobacter pylori Tetracycline with metronidazole and bis- Amoxicillin with metronidazole and bismuth subsalicylate; tetracy- muth subsalicylate or omeprazole with cline with clarithromycin and bismuth subsalicylate; clarithromycin amoxicillin and clarithromycin with omeprazole; amoxicillin with clarithromycin Klebsiella A cephalosporin6 Imipenem or meropenem,9 gentamicin,23 tobramycin, amikacin, TMP-SMX,21 a carboxypenicillin or acylaminopenicillin,21 amoxi- Enteric Gram-Negative Bacilli (continued) cillin–clavulanic acid, ampicillin-sulbactam, ticarcillin–clavulanic acid, piperacillin-tazobactam, aztreonam,20 a fluoroquinolone3 Proteus mirabilis Ampicillin A cephalosporin, gentamicin or tobramycin, chloramphenicol,7 a car- boxypenicillin or acylaminopenicillin,19 imipenem or meropenem,8 TMP-SMX, aztreonam,20 a fluoroquinolone3 non-mirabilis, including P. vul- A third-generation cephalosporin6 Gentamicin, tobramycin, amikacin, a carboxypenicillin or acyl- garis, Morganella morganii, aminopenicillin,19 imipenem or meropenem,8 aztreonem,20 ampi- and Providencia rettgeri cillin-sulbactam, ticarcillin–clavulanic acid, piperacillin-tazobactam, amoxicillin–clavulanic acid, a fluoroquinolone3 Providencia stuartii A third-generation cephalosporin6 An aminoglycoside, TMP-SMX,21 imipenem or meropenem,8 aztreonam,20 a carboxypenicillin or acylaminopenicillin,19 a fluoroquinolone3 Salmonella typhi Ceftriaxone or a fluoroquinolone3 Chloramphenicol or ampicillin,22 TMP-SMX Other Salmonella species Ceftriaxone or cefotaxime or a Ampicillin or amoxicillin, TMP-SMX, chloramphenicol7 fluoroquinolone3 Serratia Imipenem or meropenem A third-generation cephalosporin,6 gentamicin or amikacin, a car- boxypenicillin or acylaminopenicillin,19 chloramphenicol,7 aztreo- nam, a fluoroquinolone3 Shigella A fluoroquinolone3 TMP-SMX, ampicillin, ceftriaxone, azithromycin Acinetobacter (Herellea) Imipenem or meropenem8 Tobramycin, gentamicin, amikacin, doxycycline, minocycline, a car- boxypenicillin or acylaminopenicillin,19 TMP-SMX, a fluoro- quinolone,3 ceftazidime Aeromonas hydrophilia TMP-SMX 2 A fluoroquinolone,3 gentamicin, tobramycin, imipenem or meropenem8 Bartonella henselae Azithromycin Ciprofloxacin,3 TMP-SMX, gentamicin; rifampin, erythromycin (cat-scratch disease) Bartonella henselae Erythromycin Doxycycline, azithromycin (bacillary angiomatosis) Bordetella pertussis Erythromycin TMP-SMX; azithromycin or clarithromycin (whooping cough) Brucella A tetracycline, with rifampin A tetracycline with gentamicin or streptomycin; chloramphenicol,7 with or without streptomycin; TMP-SMX 2 with or without gentami- cin; ciprofloxacin3 with rifampin Eikenella corrodens Ampicillin An erythromycin, a tetracycline,4 amoxicillin–clavulanic acid, ampi- cillin-sulbactam, ceftriaxone Francisella tularensis (tularemia) Streptomycin Gentamicin, a tetracycline,4 chloramphenicol,7 ciprofloxacin3 Other Gram-Negative Bacilli Fusobacterium Penicillin Clindamycin, metronidazole, chloramphenicol7; cefoxitin Gardnerella (formerly Haemo- Metronidazole2 (oral) Intravaginal metronidazole, intravaginal or oral clindamycin philus) vaginalis Haemophilus influenzae TMP-SMX Ampicillin or amoxicillin; a tetracycline4; amoxicillin–clavulanic acid, Bronchitis, otitis media cefuroxime axetil, ceftizoxime, clarithromycin, azithromycin, a fluoroquinolone3 Meningitis, epiglottitis, life- Cefotaxime or ceftriaxone Chloramphenicol,24 meropenem9 threatening infections Legionella species Azithromycin or a fluoroquinolone3 Erythromycin, rifampin,25 TMP-SMX,2 doxycycline4 Pasteurella multocida Penicillin G A tetracycline,4 a cephalosporin,6 amoxicillin–clavulanic acid, ampi- cillin-sulbactam Calymmatobacterium granuloma- TMP-SMX A tetracycline4; ciprofloxacin with or without rifampin tis (granuloma inguinale) H. ducreyi (chancroid) Ceftriaxone or azithromycin A fluoroquinolone3 Pseudomonas aeruginosa Urinary tract infections Ciprofloxacin3 Levofloxacin; gentamicin or tobramycin; amikacin; ceftazidime,6 with or without gentamicin or tobramycin; imipenem or meropenem8; aztre- onam,20 a carboxypenicillin or acylaminopenicillin19 Other infections Gentamicin or tobramycin, with or without Amikacin, with or without a carboxypenicillin or acylaminopenicillin19; a carboxypenicillin or acylamino- ciprofloxacin7 penicillin19; ceftazidime or cefipime; imi- penem or meropenem8; aztreonam,20 alone or with gentamicin or tobramycin P. cepacia TMP-SMX Chloramphenicol,7 ceftazidime,2 imipenem2,8 or meropenem8 Streptobacillus moniliformis Penicillin G A tetracycline,4 streptomycin (rat-bite fever) Note: all superscript numbers refer to footnotes that follow table.
  • 8. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 8 Table 4 (continued) Causative Organism Drug of Choice Alternative Drugs Vibrio cholerae A tetracycline4 TMP-SMX, a fluoroquinolone3 Other Gram-Negative V. vulnificus A tetracycline4 Cefotaxime Bacilli (continued) Agents of Vincent stomatitis Penicillin G A tetracycline,4 an erythromycin (trench mouth) Stenotrophomonas (formerly TMP-SMX Minocycline, ceftazidime,6 a fluoroquinolone3 Xanthomonas) maltophilia Yersinia enterocolitica TMP-SMX 2 A fluoroquinolone, gentamicin,2 tobramycin,2 amikacin, cefotaxime2,6 or ceftizoxime2,6 Y. pestis (plague) Streptomycin with or without a A tetracycline,4 chloramphenicol,7 gentamicin,2 TMP-SMX tetracycline Mycobacterium avium complex Clarithromycin or azithromycin plus Rifampin, amikacin one or more of the following: ethambutol, rifabutin, ciprofloxacin M. fortuitum Amikacin2 with clarithromycin Rifampin,2 cefoxitin, a sulfonamide, doxycycline, ethambutol, Acid-Fast Bacilli linezolid M. kansasii Isoniazid with rifampin, with or without Cycloserine, ethionamide, clarithromycin ethambutol or streptomycin M. leprae Dapsone 7 with rifampin, with or without Minocycline,4 ofloxacin or sparfloxacin,3 clarithromycin clofazimine M. marinum (balnei)26 Minocycline TMP-SMX, rifampin, clarithromycin, doxycycline M. tuberculosis27 Isoniazid with rifampin, and pyrazinamide Ciprofloxacin or ofloxacin; third-line agent with or without ethambutol or strepto- mycin mycetes Actino- Actinomyces israelii Penicillin G A tetracycline4; an erythromycin; clindamycin Nocardia TMP-SMX Minocycline, sulfisoxazole, imipenem or meropenem,8 amikacin,2 cycloserine, linezolid Chlamydia psittaci (psittacosis) A tetracycline4 Chloramphenicol7 C. trachomatis Inclusion conjunctivitis An erythromycin (oral or I.V.) A sulfonamide (topical plus oral) Lymphogranuloma venereum A tetracycline4 An erythromycin Chlamydia Pneumonia An erythromycin A sulfonamide Trachoma Azithromycin A tetracycline4 (topical plus oral), a sulfonamide (topical plus oral) Urethritis or pelvic inflammatory Doxycycline or azithromycin Erythromycin, ofloxacin, amoxicillin disease C. pneumoniae An erythromycin or clarithromycin or A tetracycline azithromycin; a fluoroquinolone Mycoplasma pneumoniae An erythromycin, clarithromycin or — plasma Myco- azithromycin; a fluoroquinolone,3 doxycycline4 Ureaplasma urealyticum An erythromycin A tetracycline,4 clarithromycin, or azithromycin; ofloxacin3 Various rickettsial organisms Doxycycline4 Chloramphenicol,7 a fluoroquinolone,3 rifampin Rickettsia Rocky Mountain spotted fever, epidemic and endemic (murine) typhus, rickettsial pox, Q fever, scrub typhus Borrelia burgdorferi (Lyme Doxycycline or amoxicillin or Penicillin, an erythromycin, clarithromycin, azithromycin, Spirochetes disease) ceftriaxone cefuroxime B. recurrentis (relapsing fever) A tetracycline4 Penicillin G Leptospira Penicillin G A tetracycline,4 an erythromycin Treponema pallidum Penicillin G A tetracycline,4 an erythromycin, ceftriaxone 1. Some strains of S. aureus and most strains of coagulase-negative staphylococci pected penicillin allergy but not in patients with serious hypersensitivity (especially imme- are resistant to penicillinase-resistant penicillins; these strains are also resistant to ceph- diate anaphylactic or accelerated urticarial reactions). Patients allergic to penicillin may alosporins. be hypersensitive to cephalosporins. Only third-generation cephalosporins are effective 2. Not approved for this indication by the FDA. in bacterial meningitis. 3. None of these drugs is recommended for children. In 1999, the FDA limited tro- 7. In view of the occurrence of adverse reactions, this drug should be used only for seri- vafloxacin to inpatient use for limb- or life-threatening infections. ous infections and when less toxic drugs are ineffective. 4. Doxycycline is the safest tetracycline for treatment of extrarenal infections in renal in- 8. Imipenem and meropenem are β-lactam antibiotics that should be used with caution sufficiency. Tetracyclines should be avoided in pregnant women and in children younger in patients who are allergic to penicillins and cephalosporins. than 8 yr. 9. In vitro sensitivity testing with cephalosporins or penicillins may be misleading be- 5. For severe infections, I.V. nafcillin or oxacillin should be used. For mild infections, oral cause of heteroresistance and because these antibiotics may be bacteriostatic only. For cloxacillin, dicloxacillin, or oxacillin may be employed. Between 1% and 2% of S. aureus serious infections, vancomycin is preferred (see text). strains are resistant to penicillinase-resistant penicillins (and usually to cephalosporins) 10. Crystalline penicillin G is administered parenterally for serious infections. For less se- but are susceptible to vancomycin. High doses of penicillin G, ampicillin, amoxicillin, car- vere infections caused by pneumococci, group A streptococci, gonococci, or T. palli- benicillin, or ticarcillin do not overcome the clinical resistance of penicillinase-producing dum, procaine penicillin is administered I.M. once or twice daily. For mild infections staphylococci to these drugs. caused by streptococci and pneumococci, oral penicillin V is preferable to oral penicillin G. 6. Cephalosporins are sometimes used as alternatives to penicillin in patients with sus- Benzathine penicillin G is given I.M. (once monthly for the prophylaxis of rheumatic fever,
  • 9. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 9 Table 4 (continued) a single injection for the treatment of group A streptococcal pharyngitis) when patients’ 18. In CNS infection, metronidazole or chloramphenicol should be used. compliance for oral medication is questionable and for treatment of syphilis, in one to 19. The carboxypenicillins are carbenicillin and ticarcillin; the acylaminopenicillins are three doses at weekly intervals, depending on the stage of the disease. mezlocillin, azlocillin, and piperacillin. When one of these drugs is used for a severe infec- 11. The combination of penicillin G with streptomycin for the first 2 wk of treatment of tion, an aminoglycoside is often recommended as well. endocarditis caused by viridans streptococci is preferred by some. 20. Aztreonam is a β-lactam antibiotic; cross-sensitivity has not occurred, but use with 12. In patients with major allergy to penicillin, erythromycin is the alternative for respira- caution in patients allergic to penicillins, cephalosporins, or imipenem. tory tract infections; chloramphenicol is the preferred alternative for meningitis. Occa- 21. Principally in treatment of uncomplicated urinary tract infections. sional strains of pneumococci have high-level resistance to penicillin and to most other 22. Ampicillin or amoxicillin may be effective in milder cases. antibiotics except vancomycin. 23. In severely ill patients, an aminoglycoside is combined with a cephalosporin. 13. Some strains of pneumococci and group A streptococci are erythromycin resistant. 24. Some encapsulated H. influenzae (type b) strains and some unencapsulated strains 14. Various aminoglycosides have been used in synergistic combination with penicillin are resistant to ampicillin, and rare strains are resistant to chloramphenicol. Chloram- or vancomycin. Because of the appearance of enterococcal strains resistant to the syn- phenicol plus ampicillin (or chloramphenicol alone) should be used for initial treatment of ergistic action with streptomycin (but not gentamicin), gentamicin is preferred for use in meningitis or epiglottitis in children until the organism is identified and its susceptibility is the combination. determined. For adults with meningitis of unknown etiology and an indeterminate Gram 15. Contraindicated in pregnancy or in the presence of renal insufficiency. stain and in whom H. influenzae is suspected, chloramphenicol is added to ampicillin (or 16. Antibiotics may be administered orally for antibiotic-associated pseudomembra- penicillin G) for the first 24 hr until the results of culture are available. Ampicillin is pre- nous enterocolitis. Vancomycin and metronidazole are equally effective but metronida- ferred when the infecting strain of H. influenzae is susceptible. zole is much less expensive. 25. Not an FDA-approved use. Evidence for possible efficacy comes only from in vitro susceptibility testing and from treatment of infections in experimental animals. In both 17. Large doses of penicillin G or ampicillin (or amoxicillin) may be required because cases, L. pneumophila is highly susceptible to rifampin. some strains are resistant to these drugs. Penicillinase-producing gonococci, which are more resistant to penicillin, have appeared in the United States; spectinomycin is the 26. Most infections are self-limited without therapy. treatment of choice for infections with such strains. 27. Various combination treatments are available. Public Health Considerations Trovafloxacin was restricted for use in seriously ill patients because of hepatotoxicity, but other fluoroquinolones have not ANTIMICROBIAL RESISTANCE been implicated. The tetracyclines can occasionally cause fatty liver; hepatotoxicity is most likely to occur in patients receiving The extensive use of antimicrobial agents, especially in ICUs24 2 g or more daily by the intravenous route. Patients receiving and other health care facilities, strongly favors the selection of high-dose β-lactam antibiotics may develop hepatitis or cholesta- resistant microbial species, particularly bacterial strains harboring sis, presumably as a result of hypersensitivity reactions. Nitrofu- plasmids that confer transmissible resistance.25,26 Although rantoin may cause chronic active hepatitis in some patients. antibiotics have played a major role in the treatment of such infec- Erythromycins and sulfonamides have been associated with acute tions, the pathogens have responded to the antibiotic challenge, hepatitis, and a case of fatal hepatic necrosis has been attributed developing resistance to all available antimicrobial agents to a to fluconazole. greater or lesser degree. Specific mechanisms of resistance are GI reactions to antibiotics result either from direct irritation by evident in the reduced permeability of cell wall membranes, the drug, the occurrence of which is usually dose related, or from changes in the target sites of antimicrobial agents, enzymatic inac- bacterial overgrowth.19 Irritative GI side effects are usually pro- tivation of antibiotics, and the development of pathways bypass- duced when antibiotics are administered orally rather than par- ing antimicrobial targets.27 enterally. The predominant site of irritation varies from drug to The widespread use of antibiotics for animals compounds the drug; for example, erythromycin more commonly produces gas- problem; about 50% of the 25,000 tons of antibiotics that are sold tric irritation with epigastric distress and nausea, whereas tetra- annually in the United States are used in agriculture and aquicul- cyclines may produce diarrhea as well as upper GI symptoms. ture.28 Infections from highly resistant strains of Enterococcus, Some qualitative and quantitative changes in the intestinal flora Pneumococcus, Staphylococcus aureus, Gonococcus, Salmonella, occur after antibiotic administration; they may contribute to flat- Serratia, Klebsiella, Acinetobacter, Enterobacter, and Mycobacterium ulence and other lower GI symptoms, which are quite common have become important problems. Infections from resistant strains when broad-spectrum antibiotics are administered orally. can spread rapidly, first within an institution, then throughout a Selective overgrowth of Clostridium difficile can result in antibiot- community, and eventually even globally.29 Although antibiotic ic-induced pseudomembranous enterocolitis.20 resistance is a worldwide problem, control depends on local mea- Antibiotics may cause various other toxicities. Erythromycin and sures, beginning with the judicious prescription of antibiotics by other macrolides can cause prolongation of the QT interval and individual practitioners30 and with formulary restrictions that rein- polymorphic ventricular tachycardia; in rare instances, this toxicity force prudence.31 Patients harboring resistant strains should be occurs in the absence of predisposing factors, but it is more likely to identified rapidly, treated appropriately, and isolated as needed to occur in patients with significant heart disease and in patients tak- prevent the spread of infection. ing terfenadine, astemizole, or cisapride. Several fluoroquinolones, The incidence of suprainfection with cephalosporin therapy is such as moxifloxacin, gatifloxacin, and sparfloxacin, can have simi- actually quite low (< 5%); however, the organisms encountered lar effects on cardiac conduction.21,22 All fluoroquinolones can are often more virulent and difficult to eradicate than the original cause tendinitis. Trimethoprim-sulfamethoxazole can cause hyper- infecting pathogen.32 Commonly seen suprainfecting pathogens kalemia, particularly in azotemic patients. Sulfonamides, fluoro- include Enterobacter species, Pseudomonas aeruginosa, S. aureus, quinolones, and tetracyclines can produce photosensitivity.23 Acinetobacter species, enterococci, and Candida species. Because these organisms are generally multiresistant, therapy with antibi- MICROBIAL SUPERINFECTION otic combinations, including aminoglycosides, is usually neces- Antimicrobial therapy reduces susceptible organisms from the sary. There appear to be no significant differences among the normal flora of the skin, oral and genitourinary mucosae, and GI cephalosporins with respect to the incidence of suprainfection or tract and exerts selective pressures that favor survival of drug- the types of suprainfecting pathogens found. resistant organisms. Such resistant organisms can occasionally The most worrisome resistance is that of vancomycin-resistant establish a superinfection, either at the site of the original infec- enterococci (VRE). Risk factors for bloodstream infection with tion or at remote sites. VRE are an increasing APACHE II (Acute Physiology and
  • 10. © 2003 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 10 Table 5 Antimicrobial Drug Dosages for Treatment of Bacterial Infections in Adults with Normal Renal Function155 Modest Infections* Class of Agent Specific Agent Trade Names Oral Intramuscular Daily Dose Interval Daily Dose Interval Pentids, Crystifor, Pfizerpen, 0.8–3.2 8 hr Penicillin G 6 hr 1.2 million units etc. million units 1.2–2.4 million Penicillin G benzathine — — See fn. 1 Bicillin units Penicillinase-susceptible penicillins 0.6–4.8 million Penicillin G procaine — — 6–24 hr Crysticillin, Duracillin, etc. units 0.8–3.2 Penicillin V Pen-Vee K, V-Cillin K, etc. million units 6 hr — — (0.5–2.0 g) Amoxicillin Amoxil, Larotid, etc. 750–1,500 mg 8 hr — — Ampicillin Omnipen, Polycillin, etc. 1–4 g 6 hr 1–2 g 6 hr Penicillinase-susceptible Azlocillin Azlin — — — — penicillins with activity Geocillin — — Carbenicillin indanyl sodium — — against gram-negative bacilli Mezlocillin Mezlin — — — — Piperacillin Pipracil — — See fn. 3 See fn. 3 Ticarcillin Ticar — — See fn. 4 See fn.4 Cloxacillin Tegopen 1–3 g 6 hr — — Penicillinase-resistant Dicloxacillin Dynapen, Pathocil 1–2 g 6 hr — — penicillins Nafcillin Nafcil, Unipen 2–4 g5 6 hr 2–3 g 4–6 hr Oxacillin Bactocill, Prostaphlin 2–4 g 6 hr 1–2 g 6 hr Amoxicillin-clavulanate Augmentin 750 mg–1.5 g 8 hr — — (amoxicillin) Penicillins with Unasyn — — 1 g (ampicillin) 6 hr Ampicillin-sulbactam β-lactamase inhibitors Piperacillin-tazobactam Zosyn — — — — Ticarcillin-clavulanate Timentin — — — — Cefaclor Ceclor 750 mg–1.5 g 8 hr — — Cefadroxil Duricef, Ultracef 500 mg–2g 12–24 hr — — Cefamandole Mandol — — 2–4 g 6 hr Cefazolin Ancef, Kefzol — — 750 mg–1.5 g 8 hr Cefdinir Omnicef 600 mg 24 hr — — Cefditoren pivoxil Spectracef 200–400 mg 12 hr — — Cefepime Maxipime — — — — Cefixime Suprax 400 mg 24 hr — — Cefmetazole Zefazone — — — — Cefonicid Monocid — — See fn. 7,8 See fn. 7,8 Cefoperazone Cefobid — — See fn. 7,8 See fn. 7,8 Ceforanide Precef — — See fn. 7,8 See fn. 7,8 Cephalosporins Cefotaxime Claforan — — See fn. 7,8 See fn. 7,8 Cefotetan Cefotan — — See fn. 7,8 See fn. 7,8 Cefoxitin Mefoxin — — 2–4 g 6 hr Cefpodoxime Vantin 200–800 mg 12 hr — — Cefprozil Cefzil 500 mg–1 g 12–24 hr — — Ceftazidime Fortaz, Tazidime — — See fn. 7,8 See fn. 7,8 Ceftibutin Cedax 400 mg — — — Ceftizoxime Cefizox — — See fn. 7,8 See fn. 7,8 Ceftriaxone Rocephin — 24 hr See fn. 7,8 See fn. 7,8 Cefuroxime Zinacef, Ceftin (p.o.) 250–500 mg 12 hr See fn. 7,8 See fn. 7,8 Cephalexin Keflex 1–4 g 6 hr — — Cephapirin Cefadyl — — 2–3 g 6 hr Cephradine Anspor, Velosef 1–4 g 6 hr 2g 6 hr Loracarbef Lorabid 400–800 mg 12 hr — — Imipenem-cilastatin Primaxin — — — — Carbapenems Meropenem Merrem — — — — Ertapenem Ivanz — — — — Note: all superscript numbers refer to footnotes following table. (continued ) *Infections of the upper respiratory tract, soft tissues, etc.
  • 11. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 11 Table 5 (continued ) Uncomplicated Major and Systemic Infections† Urinary Tract Infections Oral Intramuscular Intravenous Daily Dose Interval Daily Dose Interval Daily Dose Interval — — — — 4–24 million units 2–4 hr — — — — — — — — — — — — — — — — — — 750–1,500 mg 8 hr — — — — 2–4 g 6 hr — — 4-12 g 2–4 hr — — — — 12–18 g 4 hr 4–8 tablets2 6 hr — — — — — — — — 12–18 g 4 hr — — See fn. 3 See fn. 3 12–18 g 4 hr — — — — 16–24 g 3–6 hr — — — — — — — — — — — — — — — — 4–12 g 4–6 hr — — — — 4–12 g 4–6 hr 750 mg 8 hr — — — — (amoxicillin) — — 1–2 g (ampicillin) 6 hr 1–2 g (ampicillin) 6 hr — — — — 12 g (piperacillin) 6 hr — — — — 12–18 g (ticarcillin) 4–6 hr 750 mg–1.5 g 8 hr — — — — 500 mg–2 g 12–24 hr — — — — — — — — 4–12 g 2–4 hr See fn. 6 See fn. 6 2–3 g 6–8 hr 2–6 g 6–8 hr — — — — — — — — — — 2–6 g 8–12 hr 400 mg 24 hr — — — — — — — — 2–4 g 12 hr — — — — 4–8 g 6–12 hr — — — — 0.5–2.0 g 12–24 hr — — — — 2–12 g 6–8 hr — — — — 1–2 g 12 hr — — — — 2–12 g 4–6 hr — — — — 2–6 g 12 hr — — — — 4–12 g 4 hr 200 mg 12 hr — — — — — — — — — — — — — — 2–6 g 8–12 hr 400 mg 24 hr — — — — — — — — 2–6 g 8–12 hr — — — — 1–4 g 12–24 hr — — — — 3–6 g 6 hr 1–4 g 6 hr — — — — — — — — 4–12 g 2–4 hr 2g 6 hr — — 3–8 g 4–6 hr 400 mg 12 hr — — — — — — — — 1–4 g 6–8 hr — — — — 3g 8 hr — 12 hr — — 1g 24 hr †Osteomyelitis, peritonitis, bacteremia, meningitis, endocarditis, etc. (continued )
  • 12. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 12 Table 5 (continued ) Modest Infections* Class of Agent Specific Agent Trade Names Oral Intramuscular Daily Dose Interval Daily Dose Interval Monobactams Aztreonam Azactam — — 1–2 g 8–12 hr Amikacin Amikin — — — — Gentamicin Garamycin — — 3–5 mg/kg11 8 hr Kanamycin Kantrex — — — — Aminoglycosides Neomycin — See fn. 15 See fn. 15 — — Netilmicin Netromycin — — 4–6 mg/kg11,12 8 hr Streptomycin — — — 1–2 g 12 hr Tobramycin Nebcin — — 3–5 mg/kg11 8 hr Demeclocycline Declomycin 600 mg 6 hr — — Doxycycline Vibramycin, etc. 100–200 mg17 12 hr — — Minocycline Minocin 200 mg19 12 hr — — Tetracyclines Oxytetracycline Terramycin 1–2 g 6 hr See fn. 21 See fn. 21 Tetracycline Achromycin, Panmycin, 1–2 g 6 hr See fn. 21 See fn. 21 Sumycin, Tetracyn, etc. Azithromycin Zithromax 500 mg day 1 24 hr — — 250 mg days 2–5 Clarithromycin Biaxin 500 mg–1 g 12 hr — — Macrolides Dirithromycin Dynabac 500 mg 24 hr — — Erythromycin E-Mycin, Erythrocin, Ilotycin 1–2 g 6 hr See fn. 21 See fn. 21 Erythromycin estolate23 Ilosone 1–2 g 6 hr — — Sulfadiazine — 2–4 g24 6 hr — — Sulfisoxazole Gantrisin 2–6 g24 6 hr — — Sulfonamides Trimethoprim-sulfamethoxazole Bactrim, Septra 4 tablets25 12 hr — — Clindamycin Cleocin 600 mg–1.8 g 6 hr 600 mg–1.2 g 6–8 hr Chloramphenicol Chloromycetin 1.5–3.0 g 6 hr See fn. 26 See fn. 26 Miscellaneous Metronidazole Flagyl 250 mg 8 hr — — antibacterial agents Spectinomycin Trobicin — — 2 g28 Single injection Trimethoprim Proloprim, Trimpex 200 mg 12 hr — — Vancomycin Vancocin 2 g29 6 hr — — Fosfomycin Monurol — — — — Methenamine mandelate Mandelamine — — — — Urinary tract Methenamine hippurate Hiprex — — — — disinfectants Nalidixic acid NegGram — — — — Nitrofurantoin Furadantin, Macrodantin — — — — Amphotericin B Fungizone — — — — Fluconazole31 Diflucan 100–200 mg32 24 hr — — Flucytosine Ancobon 50–150 mg/kg33 6 hr — — Itraconazole Sporanox 100–400 mg 12 or 24 hr — — Antifungal drugs Ketoconazole Nizorol 200 mg33 24 hr — — Miconazole Monistat — — — — Nystatin Mycostatin 1.5–3.0 million 8 hr — — units35 Alatrofloxacin36 Trovan I.V. — — — — Ciprofloxacin Cipro 500 mg 12 hr — — Levofloxacin Levaquin 500 mg 24 hr — — Lomefloxacin Maxaquin 400 mg 24 hr — — Norfloxacin Noroxin — — — — Fluoroquinolones36 Ofloxacin Floxin 400–800 mg 12 hr — — Sparfloxacin Zagam 400 mg first day, 24 hr — — then 200 mg Trovafloxacin36 Trovan See fn. 36 See fn. 36 — — Gatifloxacin Tequin 400 mg 24 hr — — Moxifloxacin Avelox 400 mg — — — (continued )
  • 13. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 13 Table 5 (continued ) Uncomplicated Major and Systemic Infections† Urinary Tract Infections Oral Intramuscular Intravenous Daily Dose Interval Daily Dose Interval Daily Dose Interval — — — — 3–8 g 6–8 hr — — 15 mg/kg9 8–12 hr 15 mg/kg10 8 hr — — 3–5 mg/kg 8 hr 3–5 mg/kg12 8 hr — — 15 mg/kg13 8–12 hr 15 mg/kg14 8 hr — — — — — — — — 4–6 mg/kg 8 hr 4–6 mg/kg16 8 hr — — 1–2 g 12 hr — — — — 3–5 mg/kg 8 hr 3–5 mg/kg16 8 hr 600 mg 6 hr — — — — 100–200 mg17 12 hr — — 100–200 mg18 12 hr 200 mg19 12 hr — — 200 mg20 12 hr 1–2 g 6 hr — — — — 1–2 g 6 hr See fn. 21 See fn. 21 750 mg–1.0 g22 6–12 hr — — — — — — — — — — — — — — — — — — — — See fn. 21 See fn. 21 2–4 g 6 hr — — — — — — 2–4 g24 6 hr — — — — 2–6 g24 6 hr — — 100 mg/kg24 4–6 hr 8–12 mg/kg25 4 tablets25 12 hr — — 6 hr25 (trimethoprim) — — 1.2–2.4 g 6–8 hr 1.8–3.0 g 6–8 hr 1.5–2.0 g27 6 hr See fn. 26 See fn. 26 2–4 g 6 hr — — — — 30 mg/kg 6 hr — — — — — — 200 mg 12 hr — — — — — — — — 1–2 g 6–12 hr 3g 1 dose — — — — 4g 6 hr — — — — 2g 12 hr — — — — 2–4g 6 hr — — — — 200–400 g 6 hr — — Not recommended — — — — — 0.25–1.0 mg/kg30 24 hr — — — — 200 mg31 24 hr — — — — — — — — — — — — — — See fn. 32 See fn. 32 See fn. 32 See fn. 32 — — — — 600 mg–3.6 g34 8 hr — — — — — — — — — — 200 mg 24 hr 200–500 mg 12 hr — — 400 mg 12 hr 500 mg 24hr — — 500 mg 24 hr 400 mg 24 hr — — — — 800 mg 12 hr — — — — 400 mg 12 hr — — 800 mg 12 hr — — — — — — — — — — — — 400 mg 24 hr — — 400 mg 24 hr 400 mg 24 hr — — — — (continued )
  • 14. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 14 Table 5 (continued ) Modest Infections* Class of Agent Specific Agent Trade Names Oral Intramuscular Daily Dose Interval Daily Dose Interval Streptogramins Quinupristin-dalfopristin Synercid — — — — Oxazolidinones Linezolid Zyvox 400 mg 12 hr — — Note: all superscript numbers refer to footnotes following table. *Infections of the upper respiratory tract, soft tissues, etc. † Osteomyelitis, peritonitis, bacteremia, meningitis, endocarditis, etc. 1. Benzathine penicillin G is used primarily in three circumstances. (1) Treatment of strepto- dose should be administered during a period of at least 60 min q. 8 hr. coccal pharyngitis in cases in which patient compliance is questionable (a single dose of 1.2 15. There are no clinical indications for the parenteral administration of neomycin in view of its million units I.M.). (2) Prophylaxis of rheumatic fever recurrences (1.2–2.4 million units I.M. marked toxicity and the availability of safer alternative drugs. The drug is given p.o. or by naso- once monthly). (3) Treatment of syphilis: for primary, secondary, or early (< 1 yr) latent syphilis, gastric tube (4–6 g daily in 4 divided doses) to reduce the number of ammonia-forming bacteria a single dose of 2.4 million units I.M.; for late syphilis (late latent, cardiovascular, neurosyphilis, in the intestine in the short-term treatment of acute hepatic coma. It is also given in a total etc.), 2.4 million units I.M. weekly for three doses has been recommended, but many authorities now treat neurosyphilis with high-dose I.V. penicillin. daily dose of 2–3 g in long-term therapy for chronic hepatic encephalopathy or episodic hepatic coma. Nephrotoxicity and ototoxicity have followed prolonged high-dose therapy in 2. Each tablet of carbenicillin indanyl sodium is equivalent to 382 mg of carbenicillin (usual hepatic coma, particularly in patients with some renal impairment. Neomycin is also used dosage is one to two tablets p.o., q.i.d.). along with vigorous mechanical cleansing of the large bowel as preoperative prophylaxis for 3. Piperacillin is most often used in the treatment of serious infections caused by susceptible bowel surgery. In this situation, it is administered for 1–3 days preoperatively (40 mg/ kg p.o. Pseudomonas, Klebsiella, Enterobacter, and non-mirabilis Proteus strains; the agent is given daily in 6 divided doses). in maximal dosage (12–18 g I.V. daily). It is commonly used in synergistic combination with tobramycin or gentamicin for treatment of Pseudomonas infections. Occasionally, it is given in 16. Dosage must be reduced in the presence of renal insufficiency. The I.V. dose should be smaller dosages (1.0–1.5 g I.M. or I.V. q. 6 hr) to treat an uncomplicated urinary tract infection administered during a period of 30–60 min q. 8 hr. caused by the same organisms. 17. Usually administered as 100 mg p.o. q. 12 hr on the first day of treatment, followed by 50 4. Ticarcillin, piperacillin, mezlocillin, and azlocillin are usually used in the treatment of serious mg q. 12 hr. For more difficult infections, the dosage may be continued at 100 mg q. 12 hr. infections caused by susceptible Pseudomonas, Enterobacter, and non-mirabilis Proteus 18. Usually administered as 100 mg I.V. q. 12 hr on the first day of treatment. Thereafter, it may strains and are given in maximal dosage (12–24 g I.V. daily). One of these agents is commonly be given as 50–100 mg I.V. q. 12 hr. Each I.V. dose should be given during a period of 1–4 hr. used in synergistic combination with tobramycin or gentamicin for treatment of Pseudomonas 19. Usually administered initially as 200 mg p.o., followed by 100 mg q. 12 hr. infections. Occasionally, they are given in smaller dosages (1 g I.M. or I.V. q. 6 hr) to treat an uncomplicated urinary tract infection caused by the same organisms. 20. Usually given initially as 200 mg I.V., followed by 100 mg q. 12 hr. Maximum dose in any 5. Nafcillin is not reliably absorbed by the oral route. 24-hr period is 400 mg. 6. Cefazolin may be used in the treatment of acute uncomplicated urinary tract infections 21. I.M. administration is generally unsatisfactory because of poor absorption and local caused by susceptible gram-negative bacilli (E. coli, P. mirabilis, and Klebsiella). It is administered irritation. I.M. in a dosage of 2 g daily (given as aliquots q. 8 hr). 22. In special circumstances, it may be given in higher doses but not in excess of 500 mg q. 6 hr. 7. Although the second- and third-generation cephalosporins can be used for milder infections 23. Cholestatic hepatitis may develop as a hypersensitivity response to erythromycin estolate at the lower end of their recommended dosage range, these potent but expensive agents but not to the other erythromycin preparations. For this reason, erythromycin base or erythro- should generally be reserved for treatment of serious infections or for the treatment of resistant mycin stearate is preferable. organisms when the alternative is a more toxic antimicrobial drug. 24. A loading dose of one half the daily dose is given initially. In severe infections, the dosage of 8. The I.M. route is acceptable for milder illnesses, but the I.V. route is recommended for seri- sulfonamide is adjusted to provide a blood level of 10–15 mg/dl. Sulfonamides must be used ous infections, including bacteremias and meningitis. The range for the I.M. dosage is the with caution in patients with renal insufficiency. Sulfisoxazole is the preferred sulfonamide. same as that for the I.V. dosage. 25. Each tablet contains 80 mg trimethoprim and 400 mg sulfamethoxazole. Double-strength 9. Dosage must be reduced in the presence of renal insufficiency. The daily parenteral dose tablets are also available (usual dosage is 1 tablet q. 12 hr). Pediatric suspensions contain 40 should not exceed 15 mg/kg, and the total daily amount administered should not exceed 1.5 g, mg trimethoprim and 200 mg sulfamethoxazole/5 ml. Trimethoprim-sulfamethoxazole has regardless of the patient’s weight. also been used in the treatment of typhoid fever in the same dosage as recommended for uri- 10. The I.V. dose should be infused during a period of 30–60 min q. 8 hr. nary tract infections. It has been used in a dosage of 4–8 standard tablets daily in the treat- 11. For urinary tract infections caused by resistant organisms. ment of brucellosis. For pneumonia caused by Pneumocystis carinii, the oral dosage is 20 mg/kg trimethoprim and 100 mg/kg sulfamethoxazole/24 hr (equally divided doses q. 6 hr). 12. Dosage must be reduced in the presence of renal insufficiency. The I.V. dose should be The I.V. dosage of trimethoprim-sulfamethoxazole ranges from 8 mg/kg trimethoprim and 40 administered for a period of 30–60 min q. 8 hr. In patients with meningitis caused by sus- mg/kg sulfamethoxazole/24 hr to 20 mg/kg trimethoprim and 100 mg/kg sulfamethoxazole/24 ceptible gram-negative bacilli, intrathecal gentamicin (5 mg for adults, 1–2 mg for infants) is hr. The lower dosage range is used in the treatment of urinary tract infections that require often administered once daily along with parenteral gentamicin until CSF cultures are negative. parenteral antimicrobial therapy and in the treatment of shigellosis; the larger dosage is 13. Dosage must be reduced in the presence of renal insufficiency. The daily parenteral dose employed in the treatment of P. carinii pneumonia. should not exceed 15 mg/kg (daily dose should not exceed 1.5 g, regardless of the patient’s 26. Chloramphenicol sodium succinate, the parenteral preparation, should only be used I.V. weight); the total quantity administered in a therapeutic course should not exceed 15 g. It is ineffective when administered I.M. 14. The I.V. route should be employed only when I.M. administration is not possible. The I.V. 27. Chloramphenicol should not be used in the treatment of a urinary tract infection that could (continued ) Chronic Health Evaluation II) score, treatment with vancomycin, bial use and resistance has been documented for nosocomial and a diagnosis of hematologic malignancy. Thus, severe illness, infections34 and community-acquired infections in studies associ- underlying disease, and the use of vancomycin are major risk fac- ating resistance patterns with rates of drug use on a regional or tors for infection of the bloodstream with VRE.33 Fueling the national basis.35 excessive use of broad-spectrum antimicrobial drugs is the lack of Resistance to antimicrobial drugs is a global problem. reliable tests that would permit physicians to discern when Multidrug-resistant pathogens travel not only locally but global- antimicrobial drugs are not needed. When antimicrobial therapy ly. Because of increased international travel and increased foreign is needed, improved diagnostic tests would permit better target- trade in fresh-food products, the threat of global spread of antibi- ing and thereby reduce the widespread administration of broad- otic resistance is greater than ever. There is no national or global spectrum drugs. Selective pressure exerted by widespread antimi- surveillance system for the monitoring of antibiotic resistance in crobial use is the driving force in the development of antibiotic animals or humans. New classes of antimicrobials are being resistance. The association between increased rates of antimicro- developed to deal with drug resistance.
  • 15. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 15 Table 5 (continued ) Uncomplicated Major and Systemic Infections† Urinary Tract Infections Oral Intramuscular Intravenous Daily Dose Interval Daily Dose Interval Daily Dose Interval — — — — 7.5 mg/kg 8 hr — — — — 600 mg (I.V. or p.o.) 12 hr † Osteomyelitis, peritonitis, bacteremia, meningitis, endocarditis, etc. be managed with another, safer, effective antimicrobial. used in combination with amphotericin B to treat systemic 28. The only approved indication for the use of spectino- fungal infections. mycin is in the treatment of anogenital and urethral gon- 33. Ketoconazole is indicated in the treatment of patients orrhea in a penicillin-allergic patient or when the infecting with susceptible fungal infections that have failed to organism is highly penicillin resistant. In geographic areas respond to amphotericin B or in the treatment of patients where antibiotic-resistant gonococci are prevalent, treatment unable to tolerate the toxic effects of amphotericin B. In with 4 g of spectinomycin (2 g in each gluteal region) may either role, it is generally preferred to therapy with micona- be indicated. zole when the patients can take oral medications. It is also 29. Vancomycin is not absorbed through the GI tract. Its the drug of choice in the long-term treatment of chronic use orally is for treatment of staphylococcal enterocolitis mucocutaneous candidiasis. It has been useful in the or antibiotic-associated enterocolitis. treatment of histoplasmosis, coccidioidomycosis, chro- momycosis, and paracoccidioidomycosis. In view of its 30. The dry powder is reconstituted by addition of Sterile poor penetration of the CSF, it should not be used in the Water for Injection, USP, without a bacteriostatic agent. treatment of coccidioidal or cryptococcal meningitis. The solution is then added to a bottle of 5% Dextrose Ketoconazole requires gastric acidity for dissolution and Injection, USP. The pH of the dextrose solution should first absorption. Antacids and cimetidine, if needed, should be be checked to verify that it is above 4.2. If it is not, a buffer given at least 2 hr after a dose of ketoconazole. The most solution (as described in package insert) should be frequent side effects have been nausea and vomiting. added. Amphotericin B solutions should be administered promptly after preparation and should be protected from Several cases of liver injury of varying severity, possibly light during administration. It is given once a day over 6 hr. the result of idiosyncratic reactions, have occurred during (Later in the course of administration, double the daily ketoconazole therapy. Liver function tests, therefore, dose is sometimes given on an alternate-day schedule.) should be evaluated before and periodically during treat- Dosage is 1 mg on the first day and then increased in 5 ment, especially in patients who are on prolonged thera- mg increments each day until maintenance dosage is py or who have preexisting hepatic disease. Ketocona- reached. The daily dose is determined by the susceptibil- zole, in daily dosages of 200–1,800 mg p.o., is used in ity of the organism and the occurrence of toxic side major and systemic fungal infections for which the mycot- effects. In some instances (e.g., cryptococcal meningitis), ic agent is susceptible and amphotericin B cannot be combination therapy with flucytosine p.o. may allow employed. employment of smaller daily doses (0.3–0.4 mg/kg) of 34. Miconazole is available for parenteral therapy for sys- amphotericin B. In fungal meningitis, intrathecal adminis- temic mycoses. Experience is relatively limited, and it tration may be necessary (0.1 mg initially, increased grad- should probably be reserved for patients who cannot tol- ually to 0.5 mg q. 48–72 hr), depending on the evaluation erate or who do not respond to amphotericin B and flucy- of the patient’s condition. tosine. Miconazole is metabolized by extrarenal mecha- 31. Fluconazole is very useful for the treatment of oropha- nisms, and patients with fungal bladder infections require ryngeal, esophageal, and disseminated infections caused supplementary bladder irrigation with the drug. Side by Candida and for control of cryptococcus, especially effects of miconazole include phlebitis, fever, rash, nausea chronic suppression of cryptococcal meningitis in patients and vomiting, anemia, thrombocytopenia, and transient with AIDS. To initiate therapy, a loading dose of twice the hyperlipidemia caused by the diluent used. usual daily dose should be used. A daily dose of 400 mg 35. Not absorbed from the GI tract. Use only in treatment can be used for cryptococcal meningitis, depending on of intestinal tract colonization by Candida species and not the patient’s response to therapy. The dose should be for any systemic mycotic infection. Nystatin suspension reduced in patients who have renal insufficiency. (400,000–600,000 units q.i.d.) is used as a mouthwash in 32. Used in the treatment of urinary tract infections and treatment of oral thrush. The suspension can also be swal- visceral infections caused by Candida. Also used in cryp- lowed for use in the treatment of candidal esophagitis. tococcal infections in which amphotericin B is not tolerat- 36. None of these drugs is recommended for children. In ed. Resistance to flucytosine may develop during treat- 1999, the FDA limited trovafloxacin to inpatient use for ment of candidal and cryptococcal infections. Sometimes limb- or life-threatening infections. Discussion The antimicrobial agents of choice for various infections (e.g., The action of the penicillins depends on the presence of a bacter- community-acquired pneumonia7-9) in adults are well established ial cell wall containing peptidoglycans that are accessible to the agent. [see Table 4], as are their dosages in patients with normal renal In actively growing bacteria, interference with biosynthesis of the function [see Table 5]. Excellent reviews and practice guidelines peptidoglycan structure—specifically, of the cross-linkages between have been published.18,19 the peptide chains—prevents the bacterium from developing its nor- mal structural firmness, and this lack of firmness leads to lysis. Penicillins NATURAL PENICILLINS Although the original penicillins are still useful against specific bac- teria, there are some infections in which both they and the penicilli- Aqueous Crystalline Penicillin G nase-resistant semisynthetic penicillins are ineffective because of the Aqueous crystalline penicillin G is used when a high serum emergence of penicillinase-producing staphylococci and methicillin- concentration of the agent is required.36 Its half-life is normally 30 resistant staphylococci.The penicillins can be classified by structure, minutes but may be as long as 10 hours in patients with anuria. β-lactamase susceptibility, and spectrum of action [see Figure 1]. Approximately 50% of penicillin G is bound to plasma proteins.
  • 16. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 16 Generic Name Side-Chain Substituent (R) Penicillin Structure Penicillin G CH2 C C Oxacillin N C O O S CH3 CH3 R C HN CH CH C CH3 O Nafcillin C N CH C O OH OC2H5 β -Lactamase (Penicillinase) CH Ampicillin NH2 CH Carbenicillin COOH Figure 1 Various semisynthetic penicillins have been produced by modifying the structure of the side chain (R) attached to the penicillin nucleus (right). In this way, penicillins have been developed that lack some of the draw- backs of penicillin G, such as poor gastrointestinal absorption, limited spectrum of antibacterial activity, and inactivation by penicillinase-producing microorganisms; for example, oxacillin and nafcillin are resistant to inac- tivation by penicillinase. This bacterial enzyme (also termed β-lactamase) cleaves the β-lactam ring of penicillin to form an inactive product; the site of action of penicillinase is shown at right. Penicillin G sodium contains approximately 2 mEq of sodium per mild infections of the throat, the respiratory tract, or soft tissue in one million units. Therefore, the potassium salt of penicillin G doses of 125 to 500 mg given four to six times daily. should be used except in patients with renal insufficiency, who PENICILLINASE-RESISTANT PENICILLINS may not be able to tolerate the 1.7 mEq of potassium contained in each one million units. This agent is destroyed by gastric acid Methicillin when given orally. Methicillin is the least protein-bound of this group (39%); naf- Penicillin G Benzathine cillin (90%), oxacillin (94%), cloxacillin (95%), and dicloxacillin Penicillin G benzathine, 1.2 to 2.4 million units I.M., is used in (98%) all have higher rates of protein binding. Methicillin was the the definitive management of certain infections, such as strepto- first of the semisynthetic penicillinase-resistant penicillins.37 It coccal sore throat, and as prophylaxis for several conditions, such must be administered parenterally and is usually given every 4 to as rheumatic fever, in which reinfection by β-hemolytic strepto- 6 hours in a total daily dose of 100 to 300 mg/kg body weight. cocci is a constant threat. Oxacillin and Nafcillin Penicillin G Procaine Oxacillin seems to be as effective as methicillin against staphy- Penicillin G procaine is used intramuscularly when a long-act- lococcal infections, and it causes interstitial nephritis less often. ing preparation is preferred and high blood levels are not For parenteral use, oxacillin or nafcillin can be given in dosages of required. It is indicated for the treatment of pneumococcal pneu- 100 to 300 mg/kg/day for children and up to 4 to 12 g/day for monia, uncomplicated cases of which are adequately treated by adults. administration of one or two daily doses of 300,000 units, and for treatment of acute genitourinary gonorrhea, for which a dose of Cloxacillin and Dicloxacillin 4.8 million units is divided and injected at two sites and 1 g of If penicillinase-producing organisms are identified or suspect- probenecid is given orally before the injection. ed and oral therapy is desired, cloxacillin or dicloxacillin, 1 to 2 g/day, can be given. Penicillin V AMINOPENICILLINS Phenoxymethyl penicillin, or penicillin V, is resistant to gastric acid and therefore reaches higher serum concentrations, when given orally, than penicillin G does at similar doses. Penicillin V Ampicillin should not be substituted for parenterally administered penicillin Ampicillin is active against a variety of bacteria, including many G when such therapy is needed, but it can be given orally to treat strains of Escherichia coli, Proteus mirabilis, Salmonella, Shigella,
  • 17. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 17 Listeria, and Haemophilus influenzae. Most strains of Klebsiella enterococci, most Enterobacteriaceae, Pseudomonas, β-lactamase– and all strains of P aeruginosa are resistant. . negative staphylococci, Neisseria, and Haemophilus.46-48 β- Because it is stable in gastric juices, ampicillin is suitable for Lactamase–producing staphylococci and H. influenzae are resis- oral as well as parenteral use.When it is given orally, peak serum tant. The major advantage the ureidopenicillins have over other levels are reached in about 2 hours, but they seldom exceed 0.3 penicillins in clinical use is their increased activity against P aeru- . µg/ml. When it is given intramuscularly, peak serum levels are ginosa and Klebsiella. achieved in 1 hour, and they are both higher and more prolonged The recommended dosages of the ureidopenicillins are 6 to 16 than the peak levels achieved after oral administration. About g/day for mild to moderate infections and 18 to 24 g/day for 10% of ampicillin is bound to plasma proteins.The recommend- severe to life-threatening infections. Small doses may be given ed daily dose is 1 to 4 g; parenteral administration of up to 12 intramuscularly, but large doses must be given intravenously.The g/day is recommended for major systemic infections. dosing interval is usually 4 to 6 hours. Amoxicillin Cephalosporins Amoxicillin is closely related to ampicillin, both in chemical structure and in spectrum of antibacterial activity.38 Amoxicillin, Cephalosporium acremonium was discovered in 1948. This fun- however, is more completely absorbed than ampicillin: approxi- gus was found to produce cephalosporin C, from which mately 70% of a dose of amoxicillin is absorbed, compared with cephalothin, the first cephalosporin to be introduced, was in turn approximately 50% of a dose of ampicillin. Consequently, the derived. The basic cephalosporin structure consists of a dihy- blood levels attainable with a given dose of amoxicillin are usual- drothiazine ring fused to a β-lactam ring. ly about twice those attainable with a comparable dose of ampi- Substitutions at the acyl side chain have led to differences in cillin. Amoxicillin is at least as effective as ampicillin in the treat- antibacterial spectrum and β-lactamase stability. The side chains ment of respiratory disorders that are caused by susceptible bac- substituted at this position interfere with proper stereotactic teria, including otitis media, sinusitis, and bronchitis. binding of the molecule to the β-lactamase active site, thus pre- venting degradation of the cephalosporin. Some of the side CARBOXYPENICILLINS effects involving platelet aggregation that have been observed with the use of moxalactam can be traced to substitutions at this Carbenicillin position. Carbenicillin has an antibacterial range similar to that of ampi- For convenience, cephalosporins are divided into four genera- cillin, with the added benefit of activity against certain strains of tions or groups according to the nature and extent of their P aeruginosa,39 indole-positive Proteus species, and Enterobacter . antibacterial spectra. More specifically, the division into genera- species.40 Because carbenicillin is inactivated by penicillinase, tions is based on the number of gram-negative bacterial species penicillinase-producing S. aureus is resistant to it. Klebsiella against which each cephalosporin demonstrates clinical activity. species are resistant to carbenicillin, as are many Serratia organ- It must be remembered, however, that although the members of isms. Carbenicillin is bactericidal and is recoverable from blood, each generation are sufficiently similar to be grouped together, urine, lymph, CSF, and most body tissues. About 50% of the they also are different from one another in a number of ways [see drug is bound to serum proteins.41 Table 6]. Ticarcillin FIRST-GENERATION CEPHALOSPORINS The antibacterial spectrum of ticarcillin is similar to that of First-generation cephalosporins have good activity against aer- carbenicillin; however, it is two to four times more active against obic gram-positive cocci such as S. aureus, group B streptococci, P aeruginosa. It is frequently preferred to carbenicillin in the treat- . and Streptococcus pneumoniae. In addition, they are effective ment of serious gram-negative infections because of its greater against three aerobic gram-negative bacilli—E. coli, K. pneumoni- potency and the lower incidence of adverse effects.42 The prima- ae, and P mirabilis—although even among these three, resistance . ry use of ticarcillin is in the treatment of proven or suspected is common, occurring in as many as 30% of cases. First-genera- Pseudomonas infections. The recommended dosage is 16 to 24 tion cephalosporins are also active against most anaerobic cocci g/day. and bacilli (other than B. fragilis). They have little or no activity against Enterobacter, Serratia, Acinetobacter, Pseudomonas, methi- UREIDOPENICILLINS cillin-resistant S. aureus, S. epidermidis, and enterococci. They are also inactive against B. fragilis, Citrobacter, Listeria monocytogenes, Mezlocillin, Azlocillin, and Piperacillin Proteus (except for P mirabilis), and Providencia. . Mezlocillin, azlocillin, and piperacillin are semisynthetic peni- First-generation cephalosporins are used for infections caused cillins derived from the ampicillin molecule with side-chain adap- by gram-positive cocci, such as skin infections and osteomyelitis, tations. The ureidopenicillins are generally bactericidal and act although penicillins are the agents of choice for all streptococcal primarily by inhibiting cell wall synthesis in dividing bacteria. In infections and for infections proven by culture to be caused by comparison with the carboxypenicillins carbenicillin and ticar- susceptible staphylococci.The best use for first-generation cepha- cillin, the ureidopenicillins exhibit less pronounced plasma pro- losporins is in surgical prophylaxis. For this application, cefazolin tein binding, a shorter serum half-life, and a greater volume of sodium is the preferred agent. distribution.43-45 They are minimally metabolized (10%) and are SECOND-GENERATION CEPHALOSPORINS primarily excreted in an active form by glomerular filtration and tubular secretion. Unlike carbenicillin and ticarcillin, the urei- Second-generation cephalosporins possess the same spectrum dopenicillins achieve high concentrations in bile because of of activity as the first-generation cephalosporins, with the addi- increased biliary excretion. tion of broader coverage of gram-negative organisms, including In vitro, the ureidopenicillins are active against streptococci, H. influenzae, E. aerogenes, and some Neisseria species. Fewer than
  • 18. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 18 Table 6 Properties of Cephalosporins155 Specific Agent Trade Names Comment* Oral First Generation Cefadroxil Duricef, Ultracef Longer half-life Cephalexin Keflex Most experience with this agent Cephradine Anspor, Velosef Properties are similar to those of cephalexin Parenteral Cefazolin Ancef, Kefzol Longer half-life; well tolerated when given I.M. Cephapirin Cefadyl Properties are similar to those of other first-generation cephalosporins Cephradine Anspor, Velosef Properties are similar to those of other first-generation cephalosporins Oral Cefaclor Ceclor Moderately active against Haemophilus influenzae Cefprozil Cefzil Active against H. influenzae Second Generation Cefuroxime axetil Ceftin Active against H. influenzae Loracarbef Lorabid A carbacephem with properties and spectrum similar to those of cefuroxime Parenteral Cefamandole Mandol Active against H. influenzae; may cause bleeding Cefmetazole Zefazone Spectrum and half-life similar to cefoxitin; may cause bleeding Cefonicid Monocid Spectrum similar to that of cefamandole Ceforanide Precef Spectrum similar to that of cefamandole Cefotetan Cefotan Spectrum similar to that of cefoxitin; longer half-life than cefoxitin; may cause bleeding Cefoxitin Mefoxin Active against Bacteroides fragilis, Serratia, Neisseria gonorrhoeae Cefuroxime Zinacef, Kefurox Active against H. influenzae; only second-generation drug approved for meningitis (selected pathogens) Oral Cefixime Suprax More active against gram-negative bacilli, gonococci, Moraxella catarrhalis, and H. influenzae than other oral cephalosporins but much less active against Staphylococcus aureus; not active against Pseudomonas Cefpodoxime Vantin Similar to cefixime but more active against S. aureus Third Generation Ceftibuten Cedax Similar to cefixime but has poor activity against pneumococci and staphylococci Parenteral Cefepime Maxipime Active against most gram-positive cocci (except enterococci and methicillin-resistant staphylococci), Neisseria, Haemophilus, enteric gram-negative bacilli, and Pseudomonas Cefoperazone Cefobid Increased activity against Pseudomonas aeruginosa but less against Enterobacteriaceae; may cause bleeding Cefotaxime Claforan More active against gram-positive cocci Ceftazidime Fortaz, Tazidime, Tazicef Most active against Pseudomonas Ceftizoxime Cefizox Properties are similar to those of cefotaxime Ceftriaxone Rocephin Longer half-life; less active against Pseudomonas, B. fragilis Note: detailed information about the various cephalosporins is covered in the text. *Agents are being compared with other members of the same generation of cephalosporins. 5% of E. coli and Proteus strains are resistant to second-generation Loracarbef is an oral agent of the carbacephem class that is cephalosporins. The activity of second-generation agents against active in vitro against the common pathogens associated with skin S. pyogenes and S. pneumoniae is equal to that of the first-genera- infections, otitis media, sinusitis, bronchopulmonary infections, tion agents, but their activity against staphylococci is variable: the and urinary tract infections.54 MIC ranges from 0.20 to 25 µg/ml. Of the second-generation THIRD-GENERATION CEPHALOSPORINS agents, the most active against staphylococci is cefamandole, which has an MIC of 0.6 µg/ml for S. aureus. Cefotetan and In the third-generation cephalosporins, activity against gram- cefoxitin have significant activity against B. fragilis. Cefoxitin is positive cocci is replaced by broader gram-negative coverage.This less active against H. influenzae and E. aerogenes than other sec- development is illustrated by susceptibility testing done on S. ond-generation cephalosporins, but it is more active against aureus: the MIC of first-generation cephalosporins is 1 µg/ml, that Serratia species. Cefoxitin by itself is effective in patients with of second-generation cephalosporins is 2 µg/ml, and that of third- community-acquired peritonitis who are unlikely to be infected generation cephalosporins is 3 µg/ml. Third-generation cephalo- with Enterobacter or P aeruginosa.49 Cefuroxime and cefamandole . sporins are more active against the enteric gram-negative bacilli have been used with some success in empirical therapy for com- covered by first- and second-generation cephalosporins. Their munity-acquired pneumonia.50 Cefotetan, a cephamycin intro- spectrum of activity includes Serratia and Citrobacter. They are duced in 1986, has a spectrum of activity very similar to that of also highly active against H. influenzae and N. gonorrhoeae and cefoxitin.51 It is as active as cefoxitin against B. fragilis but is less moderately active against P aeruginosa and some anaerobes. At . active against other strains in the B. fragilis group. Unlike cefox- first, the third-generation cephalosporins seemed capable of pro- itin, cefotetan is active against H. influenzae. Cefotetan has proved viding the same spectrum of activity as the aminoglycosides but effective and safe in a variety of clinical situations, including gyne- without their inherent toxicity; however, they have failed to gain cologic infections and surgical prophylaxis.52 wide popularity in the treatment of high-risk patients or patients Cefprozil is an oral agent whose spectrum of activity includes with extensive infections.The reasons for this failure include their gram-positive and gram-negative pathogens. It has achieved good incomplete spectra of activity against the range of organisms like- results in patients with pharyngitis or tonsillitis.53 ly to be encountered in polymicrobial infections, their unexpect-
  • 19. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 19 ed agent-specific toxicity, their suboptimal pharmacokinetic cacy between antibiotics.64 Many studies that find no difference properties, and their high propensity for inducing resistance. between two regimens are in fact subject to this type of error. Cefixime, an orally absorbed iminomethoxyaminothiazolyl FOURTH-GENERATION CEPHALOSPORINS cephalosporin, inhibits 90% of S. pneumoniae, H. influenzae, and H. parainfluenzae strains, whether they produce β-lactamase or Cefepime is an extended-spectrum parenteral cephalosporin not, at concentrations of less than 0.25 mg/L. It inhibits 90% of that provides coverage against both gram-positive and gram-neg- Moraxella catarrhalis strains at concentrations of less than 1 mg/L. ative organisms, including S. aureus and P aeruginosa. Cefepime, . Ceftibuten is an orally active third-generation cephalosporin which is a zwitterion, has a net neutral charge that allows it to that possesses increased potency against members of the penetrate the outer membrane of gram-negative bacteria faster Enterobacteriaceae.55 Generally, it is about 16 times more active than third-generation cephalosporins. It is more stable against β- than cefuroxime, cefaclor, cephalexin, or amoxicillin-clavulanate; lactamases because of the lower affinity of the enzymes for its activity is comparable to that of cefixime. Ceftibuten is inef- cefepime when compared with third-generation cephalosporins. fective against staphylococci and only partially effective against S. In comparison with third-generation cephalosporins, cefepime pneumoniae. H. influenzae and Neisseria species, however, are high- appears to be less likely to induce resistance, because of a lower ly susceptible to this agent. rate of hydrolysis by β-lactamases, a low affinity for these enzymes, and more rapid permeation into the cell. It has been Pharmacokinetics used to treat patients with pneumonia, with results comparable After I.V. administration, third-generation cephalosporins con- to those obtained with ceftazidime.65 Because of its antibacterial form to an open, two-compartment model, characterized by an coverage and proven tissue penetration in acute pancreatitis, initial rapid distribution phase followed by a slower terminal cefepime should be studied in patients with severe acute pancre- elimination phase. The relatively long elimination half-lives of atitis.66 However, it offers poor coverage against Bacteroides and many of the newer β-lactam antibiotics make less frequent dos- must be combined with metronidazole or clindamycin.The com- ing possible. Most third-generation cephalosporins are primarily bination of cefepime and metronidazole was found to be equiva- eliminated renally, with two exceptions: cefoperazone and ceftri- lent to imipenem in a prospective, randomized study of intra- axone. Cefoperazone is primarily eliminated unchanged in the abdominal infections.67 bile, and only about 25% of an administered dose is recovered in the urine after 24 hours.56 Peak biliary concentrations of cefo- ADVERSE EFFECTS perazone approach or exceed 2,000 µg/ml after a 2 g I.V. dose.57 Cephalosporins are associated with a number of adverse side Fifty percent of an administered dose of ceftriaxone is eliminat- effects.The adverse reactions associated with their use are similar ed in the bile; the rest is eliminated renally. Ceftriaxone elimina- to those associated with use of other β-lactam compounds, such tion is decreased to a small extent in end-stage renal disease; as local pain and irritation, hypersensitivity reactions, positive however, because the drug is normally given every 12 to 24 Coombs reaction, leukopenia, thrombocytopenia, transient hours, there is little accumulation and therefore no need to adjust abnormalities in liver function enzyme levels, and GI distur- the dose. In general, third-generation cephalosporins penetrate bances.68,69 These reactions are usually mild and reversible, except most tissue and fluid compartments in amounts that, though in those rare patients who manifest life-threatening hypersensitiv- variable, usually exceed the MIC for most susceptible pathogens. ity reactions. Cephalosporins may be administered to most Sputum concentrations in the range of 0.3 to 6.0 µg/ml are patients who are allergic to penicillin, because only 5% to 15% of attained with all the agents, and higher concentrations are found penicillin-allergic patients react adversely to cephalosporins.70 An in purulent sputum. Ascitic fluid concentrations ranging from 2.4 excellent review of cephalosporin allergy and its treatment has µg/ml with ceftizoxime to greater than 60 µg/ml with cefopera- been published.71 zone are seen in patients with peritonitis.58 Concentrations in excess of the MIC for susceptible aerobic and anaerobic organisms (except for B. fragilis) are achieved in Aminoglycosides female genital tissue with all these agents.59 These compounds Aminoglycosides are composed of two or more amino sugars also appear to penetrate the prostate, the testes, the ureters, and bound by glycosidic linkage to a central hexose (aminocyclitol) renal tissue in significant amounts.60 nucleus. Their highly polar, polycationic structure contributes to With each of these agents, therapeutic concentrations can be their poor GI absorption and their meager ability to penetrate the obtained in the gallbladder wall; these concentrations may be as blood-brain barrier. They bind irreversibly to the 30S bacterial high as 60 µg/g with cefoperazone. Bone-penetration studies ribosome and interfere with protein synthesis. Aminoglycosides reveal penetration with each of these agents.61 also disturb calcium homeostasis and induce cell death as a result of efflux of potassium, sodium, and other essential bacterial con- Clinical Utility stituents. Unlike most other antimicrobial agents that inhibit pro- Many studies have compared third-generation cephalosporins tein synthesis, aminoglycosides are bactericidal. in an effort to establish a superior drug or drug combination for All aminoglycosides share certain pharmacokinetic properties. life-threatening infections; most have found no statistically signif- Because they are poorly absorbed when given orally, adequate icant differences. It is important to remember that even if there is serum concentrations can be obtained only through parenteral a difference in efficacy between two or more antibiotics, that dif- administration. Protein binding is negligible,72 and the volume of ference may not be apparent if the study group is not large distribution approximates the volume of the extracellular space.73 enough. For example, if one agent fails in 10% of patients and In adults with normal renal function, the aminoglycosides have a another in only 5%, a study group of 250 to 500 patients would half-life of about 2 hours, but there is considerable variation be required to show a statistical difference.62,63 Most comparative between individual patients.74 In patients with deteriorating renal antibiotic trials, however, have reported on fewer than 60 patients function, the half-life of an aminoglycosides increases, often and thus have not been able to pinpoint small differences in effi- exceeding 24 hours in patients with end-stage renal disease.75
  • 20. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 20 NETILMICIN AND SISOMICIN The prolonged half-lives of aminoglycosides are substantially shortened during hemodialysis76; these agents are much less effi- Netilmicin, a semisynthetic derivative of sisomicin, is not ciently removed by peritoneal dialysis.77 The aminoglycosides do metabolized by most of the aminoglycoside-modifying enzymes not penetrate the blood-brain barrier well, even in patients with and therefore is active against some strains of Enterobacteriaceae meningeal inflammation.78,79 Drug levels in pulmonary secretions that are resistant to gentamicin and tobramycin; however, it is less are typically 20% to 40% of serum levels. Low concentrations of active against P aeruginosa. Animal studies suggest that netilmicin . aminoglycosides in purulent fluids are probably related to local may be less nephrotoxic than other aminoglycosides,82,85 and inactivation caused by DNA released from leukocytes80 and by human studies suggest that it is somewhat less likely to exert toxic the low regional pH. effects on cranial nerve VIII.82 Sisomicin is more active than gen- The aminoglycosides are rapidly excreted, primarily by tamicin against Enterobacteriaceae and P aeruginosa, but the . glomerular filtration. Urine concentrations may be 100 times the nephrotoxicity it has exhibited in animal studies exceeds that of serum level in patients with normal renal function. The amino- other aminoglycosides.86 glycosides accumulate in the renal cortex; sensitive assay tech- ADVERSE EFFECTS niques can detect them in urine and serum for up to 10 days after cessation of therapy. Unlike β-lactam antibiotics, aminoglycosides, have a narrow range between therapeutic and toxic levels and are thus more STREPTOMYCIN likely to cause side effects. Their ototoxicity is potentially more Widespread resistance among Enterobacteriaceae has limited significant than their nephrotoxicity because it is often irre- the usefulness of streptomycin. At present, streptomycin is almost versible. Cochlear toxicity has been reported in 8% to 10% of always employed in combination with other antimicrobial agents. patients and has been clinically evident in as many as 4% of With penicillin or vancomycin, streptomycin is used to treat patients treated with aminoglycosides for various infections.87 infective endocarditis caused by viridans streptococci or suscepti- Vestibular toxicity, as manifested by electronystagmographic ble enterococcal streptococci. It may also be given in conjunction changes, has been found in 5% to 10% of patients and has been with other antituberculous drugs to treat mycobacterial diseases clinically significant in 1% to 5%.82 Vestibular toxicity is more fre- and in conjunction with tetracycline to treat brucellosis. quently associated with streptomycin, gentamicin, and Streptomycin is used alone in the treatment of tularemia and tobramycin, whereas auditory toxicity is more typical of plague. kanamycin and amikacin. Ototoxicity and vestibular toxicity are difficult to monitor, particularly in hospitalized patients for whom KANAMYCIN formal audiometry and caloric testing may be cumbersome or Because of widespread resistance among Enterobacteriaceae uncomfortable. Because aminoglycoside-associated auditory tox- and P aeruginosa, kanamycin is rarely used today. It is occasional- . icity generally affects the higher frequencies, early bedside detec- ly used as a second-line agent in combination with other antibi- tion is difficult. Toxic effects on cranial nerve VIII seem to be otics in the treatment of tuberculosis. related to advanced age, previous aminoglycoside treatment, and excessive serum levels. GENTAMICIN AMINOGLYCOSIDE PHARMACOKINETICS Gentamicin is used for serious hospital-acquired infections caused by Enterobacteriaceae and most strains of P aeruginosa in . Peak aminoglycoside concentrations higher than 5 µg/ml are institutions in which there is minimal background resistance to associated with improved survival in patients with gram-negative this agent (other Pseudomonas species are predictably resistant to infections.88,89 With gram-negative pulmonary infections, peak aminoglycosides). Gentamicin is given with penicillin to treat concentrations of 8 to 10 µg/ml are necessary because of poor enterococcal endocarditis and with vancomycin plus rifampin to penetration of aminoglycosides into the lungs.90,91 It has been treat prosthetic valve endocarditis caused by S. epidermidis. shown that a loading dose of gentamicin or tobramycin of 2 mg/kg of lean body weight cannot guarantee adequate peak con- TOBRAMYCIN centrations in acutely ill patients. The most likely explanation for Tobramycin closely resembles gentamicin with respect to the usually low peak serum concentrations of aminoglycosides in antimicrobial spectrum and pharmacokinetics. Tobramycin is acutely ill patients is an expanded volume of distribution.92-96 more active against some strains of A. calcoaceticus but less active Dosage adjustments based on blood levels should be made as against S. marcescens. Although tobramycin has slightly greater soon as possible after the beginning of therapy and after the intrinsic activity against P aeruginosa, most gentamicin-resistant . steady state has been reached. strains of this organism are also resistant to tobramycin. The dif- ference in nephrotoxicity between gentamicin and tobramycin is Once-Daily Dosing of Aminoglycosides clinically insignificant.81-83 Efforts to improve the toxic-to-therapeutic ratio of aminogly- cosides include once-daily dosing schedules and reevaluations of AMIKACIN the recommended therapeutic ranges. In conventional adminis- Amikacin is a semisynthetic derivative of kanamycin. Its major tration of aminoglycosides to patients with normal renal function, advantage is its resistance to aminoglycoside-modifying enzymes, divided doses are administered at 8- to 12-hour intervals. In an the production of which is the principal mechanism of bacterial effort to improve efficacy and decrease toxicity and cost, once- resistance to aminoglycosides. Amikacin may therefore be used daily regimens have been compared with conventional regimens. against gentamicin-resistant organisms, and it is clearly the In most protocols, the total doses were equivalent in the single aminoglycoside of choice where gentamicin resistance is preva- and divided-dose regimens.Two meta-analyses of such trials have lent. Fortunately, no substantial increase in amikacin resistance concluded that once-daily dosing is as effective as divided dosing has been noted, even in medical centers where it has been used and has a lower risk of toxicity in patients with normal renal func- extensively.84 tion.97,98 Although most trials evaluated immunocompetent
  • 21. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 21 adults, similar trends were noted for children and for patients Erythromycin is the agent of choice for the treatment of M. with febrile neutropenia. In elderly patients, however, the high pneumoniae and Legionella infections. It is also effective against peak serum concentrations that occur with once-daily dosing infections caused by group A β-hemolytic streptococci or S. pneu- may increase the risk of nephrotoxicity,99 probably because of moniae. Accordingly, it is the agent of choice for the treatment of diminished renal clearance.There are several excellent reviews of community-acquired pneumonia in nonimmunosuppressed the subject in the literature.100,101 patients who do not require hospitalization and who are allergic to penicillin.103 In addition, erythromycin may be used to treat gonorrhea and syphilis in patients who are unable to tolerate peni- Tetracyclines cillin G or tetracycline. The incidence of serious erythromycin- The tetracyclines act against microorganisms by inhibiting related adverse effects is low. protein synthesis; their site of action is the bacterial ribosome. CLARITHROMYCIN AND AZITHROMYCIN Resistance to the tetracyclines appears slowly and in a stepwise fashion and is mediated by plasmids. Plasmids impart resistance Clarithromycin and azithromycin are new semisynthetic by coding for proteins that interfere with active transport of tetra- macrolides that are structurally related to erythromycin. They cycline through the cytoplasmic membrane. Microorganisms inhibit protein synthesis in susceptible organisms by binding to that acquire resistance to one tetracycline are usually resistant to the 50S ribosomal subunit. Clarithromycin and azithromycin are the other tetracyclines as well. well absorbed and widely distributed, with excellent cellular and At appropriate dosages, peak serum concentrations 1 hour tissue penetration. Both agents have a broader spectrum of ac- after intravenous administration of tetracycline, doxycycline, or tivity than erythromycin does; in addition, they have fewer GI minocycline are typically 10 to 20 µg/ml. The newer semisyn- side effects (a major obstacle to compliance with erythromycin thetic tetracyclines—doxycycline, methacycline, and minocy- therapy). cline—have considerably longer serum half-lives than the older Clarithromycin is several times more active against gram-pos- agents. itive organisms in vitro than erythromycin, whereas azithromycin Tetracyclines are metabolized by the liver and concentrated in is two to four times less potent than erythromycin. Azithromycin the bile. Biliary concentrations of these agents are, on average, has excellent in vitro activity against H. influenzae; clar- five to 10 times higher than concurrent plasma concentrations. ithromycin, although less active against H. influenzae according to The tetracyclines penetrate body tissues well and are capable of standard in vitro testing, is metabolized into an active compound entering the CSF even in the absence of inflammation of the with twice the in vitro activity of the parent drug. Azithromycin meninges. They readily cross the placental barrier, and relatively and clarithromycin also are active against some unexpected high concentrations are found in human milk. pathogens (e.g., Borrelia burgdorferi, Toxoplasma gondii, M. avium Tetracyclines are useful in the treatment of sexually transmit- complex, and M. leprae). At present, clarithromycin appears to be ted diseases. Tetracyclines are also effective for the treatment of the more active of the two against atypical mycobacteria, giving other chlamydial infections, such as lymphogranuloma venereum, new hope to surgeons faced with what has become a difficult psittacosis, inclusion conjunctivitis, and trachoma. A tetracycline group of infections to treat. may also be used in the treatment of gonococcal infections in Superior pharmacodynamic properties distinguish these new patients who are unable to tolerate penicillin G. Other sexually macrolides from the prototypical macrolide, erythromycin. transmitted diseases that may be treated with tetracyclines are Azithromycin has a large volume of distribution, and although chancroid and granuloma inguinale. serum concentrations remain low, it concentrates readily within A tetracycline or erythromycin is the agent of choice for the tissues, demonstrating a tissue half-life of approximately 3 days; treatment of Mycoplasma pneumoniae infection. Tetracyclines are a 5-day course of therapy will provide therapeutic tissue concen- also effective against rickettsial infections, tularemia, and cholera; trations for at least 10 days. These properties allow novel dosing in patients unable to tolerate penicillin, they may be used to treat schemes. For instance, azithromycin can be given once daily for actinomycosis. Doxycycline is useful as prophylaxis against trav- 5 days to treat respiratory tract and soft tissue infections, and eler’s diarrhea caused by toxicogenic strains of E. coli. Unfortu- administration of a single 1 g dose of azithromycin can effective- nately, the widespread use of tetracyclines as additives to livestock ly treat Chlamydia trachomatis genital infections; these more con- feed has resulted in increasing bacterial resistance to these agents. venient dosing schedules improve patient compliance. DIRITHROMYCIN Macrolides Dirithromycin is an oral macrolide antibiotic with an antibac- terial spectrum similar to that of erythromycin; it can be admin- ERYTHROMYCIN istered once daily but has no other advantages over erythromycin. Erythromycin is a macrolide that contains a many-membered The drugs produce similar GI side effects, and dirithromycin is lactone ring to which one or more deoxy sugars are attached. substantially more expensive. Erythromycin and other macrolide antibiotics inhibit protein synthesis through reversible binding to the 50S ribosomal sub- units of susceptible microorganisms. Clindamycin Erythromycin is well absorbed from the GI tract.The presence Clindamycin is a 7-deoxy-7-chloro derivative of lincomycin of food in the stomach reduces absorption of the drug, except that consists of an amino acid attached to a sulfur-containing when it is in the estolate form.102 Erythromycin is excreted pri- octose. Clindamycin binds exclusively to the 50S subunit of bac- marily in the bile; only 2% to 5% of a given dose is excreted in terial ribosomes and suppresses the synthesis of protein. the urine. Concentrations in the bile may be more than 10 times Clindamycin, erythromycin, and chloramphenicol all act at the those in plasma. Erythromycin diffuses readily into most tissues, same site, and the binding of one of these antibiotics to the ribo- except for the brain and the CSF. some may inhibit the binding of the others. Plasmid-mediated
  • 22. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 22 resistance to clindamycin has been reported in B. fragilis; this may have indicated that vancomycin is not bactericidal for enterococ- be caused by methylation of bacterial RNA found in the 50S ribo- ci.110 Vancomycin is indicated for other serious infections caused somal subunit.104 Peak serum concentrations 1 hour after intra- by organisms with multiple antibiotic resistance, such as CSF venous administration of a 600 mg dose are approximately 10 to shunt infections and prosthetic valve infection caused by S. epi- 12 µg/ml. Clindamycin is metabolized by the liver and excreted in dermidis or Corynebacterium diphtheriae.111 It is the agent of choice an inactive form in the urine. It readily penetrates most body tis- for infections caused by penicillin-resistant group JK corynebac- sues but not the CSF.105 teria112 and is uniformly active against rare, multiply resistant Clindamycin is active against B. fragilis and other anaerobic strains of S. pneumoniae.113 Given orally, vancomycin is also the microorganisms and is useful in the treatment of patients with agent of choice for C. difficile–associated enterocolitis,114 although intra-abdominal, pelvic, and pulmonary infections. It is associat- less expensive agents, such as bacitracin115 and metronidazole,116 ed with a modest number of adverse effects. may be as effective. Anaphylactoid reactions to vancomycin have been reported since the earliest clinical trials. Such reactions can occur with the Chloramphenicol first dose; signs and symptoms range from mild pruritus to dra- Chloramphenicol is unique among antibiotics in that it con- matic hypotension and cardiovascular arrest. The rapid intra- tains a nitrobenzene moiety and is a derivative of dichloroacetic venous infusion of vancomycin can cause a peculiar reaction con- acid. Like clindamycin, it inhibits bacterial protein synthesis by sisting of pruritus; an erythematous or maculopapular rash involv- binding reversibly to the 50S ribosomal subunit, thus keeping the ing the face, neck, and upper torso; and possible hypotension. amino acid–containing end of aminoacyl–transfer RNA (tRNA) from binding to the ribosome. Chloramphenicol is rapidly and completely absorbed from the GI tract, and absorption is not Metronidazole impaired by concomitant ingestion of food or administration of Metronidazole acts by disrupting bacterial DNA and inhibit- antacids. It is inactivated in the liver by glucuronyl transferase. ing nucleic acid synthesis117; it is bactericidal against almost all Chloramphenicol and its metabolites are excreted rapidly in the anaerobic gram-negative bacilli, including B. fragilis, and against urine. About 80% to 90% of a dose is excreted in this way, about most Clostridium species. Although true anaerobic streptococci 5% to 10% of which is in the biologically active form. The drug are generally susceptible to it, microaerophilic streptococci as well penetrates well into all tissues, including the brain; it also pene- as Actinomyces and Propionibacterium species are often resistant. trates well into the CSF and the aqueous humor. Metronidazole is excellent for anaerobic infections of the Because of the risk of serious or fatal bone marrow toxicity, abdomen and pelvis. For serious anaerobic infections, the drug is chloramphenicol should be used only against those infections for administered intravenously; a loading dose of 15 mg/kg is given, which the benefits of its use outweigh the risks of its potential tox- followed by 7.5 mg/kg every 6 hours until the patient is well icity. It still plays a major role in the treatment of typhoid fever, enough to take an oral dosage of 7.5 mg/kg every 6 hours. The although plasmid-mediated resistance of S. typhi to chloram- dosage need not be reduced in azotemic patients, but it should be phenicol has been reported. Chloramphenicol is effective therapy reduced in patients with hepatic insufficiency. Because of its bac- for bacterial meningitis and brain abscesses caused by susceptible tericidal action and excellent tissue penetration, intravenous microorganisms; in conjunction with penicillin, it is effective em- metronidazole may be the treatment of choice for B. fragilis endo- pirical therapy for brain abscesses. carditis and central nervous system infections, both of which are uncommon.When metronidazole is administered orally, it is well absorbed and is widely distributed in body tissues, including Vancomycin those of the CNS. Vancomycin is a narrow-spectrum antibiotic derived from Side effects of metronidazole include dry mouth (associated Nocardia orientalis.Vancomycin exerts its bactericidal effect by with a metallic taste) and nausea. Concurrent use of alcohol may inhibiting the biosynthesis of the major structural cell wall poly- cause a reaction similar to that produced when alcohol is ingest- mer, peptidoglycan.106 Vancomycin is about 55% protein bound. ed after taking disulfiram. Neurologic symptoms, including Its activity is not significantly affected by pH values between 6.5 peripheral neuropathy and encephalopathic reactions, and neu- and 8.0. It is poorly absorbed from the GI tract. Because patients tropenia are uncommon. Pancreatitis has been reported,118 but invariably experience pain after intramuscular injections, par- alternative drugs are available. enteral administration is limited to the intravenous route. Vancomycin is primarily excreted by the kidneys; about 80% to 90% of the dose is eliminated in a 24-hour period. Its half-life is Carbapenems approximately 6 hours in patients with normal renal function. In Imipenem and meropenem were the first carbapenems avail- anuric patients, the half-life may be prolonged to approximately able for clinical use in the United States; the third, ertapenem, 7 days.107 Vancomycin is not removed by hemodialysis or peri- was released in 2002. Like other β-lactam antibiotics, they are toneal dialysis. bactericidal and act by inhibiting bacterial cell wall synthesis.119 Vancomycin is mainly effective against gram-positive organ- Three properties account for the extraordinarily broad antibacte- isms. No cross-resistance has been demonstrated between van- rial spectrum of the carbapenems: there is no permeability barri- comycin and other antibiotics, and resistance is uncommon. er excluding the drugs from bacteria; they have high affinity for Vancomycin, given alone, is the agent of choice in the treatment penicillin-binding protein 2, which is a crucial component of cell of methicillin-resistant S. aureus infections.108,109 Some strains of wall structure; and they are extremely resistant to hydrolysis by methicillin-resistant S. aureus, however, are resistant to vanco- β-lactamases. mycin. If vancomycin therapy is ineffective against severe infec- Carbapenems are extraordinarily active against gram-negative tions caused by such strains, the addition of either an aminogly- bacteria. Whereas imipenem tends to be more active against coside or rifampin, or both, should be considered. Several reports gram-positive cocci, meropenem appears to be more active
  • 23. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 23 against gram-negative bacilli. Virtually all Enterobacteriaceae are em; they have been observed in 0.9% of patients who have susceptible. Haemophilus and Neisseria species are also susceptible received the drug; risk factors for seizure include excessive dosages to carbapenems but at concentrations somewhat higher than of the drugs, preexisting CNS lesions, epilepsy, and renal insuffi- those of third-generation cephalosporins. Acinetobacter, which is ciency. Meropenem is less likely to provoke seizures.119 Transient resistant to most other β-lactam antibiotics, is susceptible to elevations of liver enzymes and leukopenia can occur in patients imipenem and meropenem, as are Serratia, Salmonella, Citrobacter, who are given carbapenems. Antibiotic-associated pseudomem- Yersinia, and Brucella species. Gram-negative anaerobes, includ- branous colitis has occurred. ing B. fragilis, are susceptible. P aeruginosa is also susceptible, but . Because the structure of the carbapenems resembles that of some resistant strains have emerged during therapy; as a result, the penicillins and cephalosporins, there is potential for cross- imipenem or meropenem should probably be combined with a reactivity in patients allergic to other β-lactam antibiotics. second antipseudomonal drug when they are used to treat serious Clinical experience in this situation is limited, but it appears pru- pseudomonal infections. Certain nosocomial pathogens, such as dent to avoid carbapenems in patients with anaphylactic sensitiv- Stenotrophomonas maltophilia and P cepacia, are resistant, as are . ity to β-lactam drugs and to use them with caution in patients Flavobacterium species. with milder allergies to penicillins or cephalosporins.122 Imipenem is extensively degraded in the renal tubule, which Carbapenems have been used successfully in patients with results in low urinary levels of the drug. This drawback can be pneumonia, intra-abdominal infections, urinary tract infections, prevented by using cilastatin, an inhibitor of the brush-border endocarditis, bacteremia, osteomyelitis, cellulitis, and febrile neu- enzyme dehydropeptidase-1. Cilastatin also appears to prevent tropenia. The broad spectrum and apparent low toxicity of car- the tubular damage that is occasionally observed in animals given bapenems is impressive, but they should be used selectively and imipenem alone in high doses. For clinical use, imipenem and with restraint. cilastatin are administered simultaneously in equal doses. Meropenem is pharmacologically similar to imipenem except that it is not susceptible to degradation by dehydropeptidase; as Monobactams a result, it can be administered without cilastatin. About 70% of The monobactams are monocyclic β-lactam antibiotics that both meropenem and imipenem is excreted in the urine; the lack the thiazolidine ring found in penicillins and the dihydro- dosage should be reduced in azotemic patients. Like imipenem, thiazine ring found in cephalosporins. Although there are several meropenem is active against most clinically active gram-positive monobactams under investigation, only aztreonam has been and gram-negative bacteria, including anaerobes; however, nei- approved for clinical use in the United States. It has been evalu- ther drug is active against methicillin-resistant staphylococci or E. ated in open and comparative studies against a number of agents faecium. Resistant strains of P aeruginosa have emerged during . currently used to treat infections.123,124 It inhibits only aerobic therapy with each drug. gram-negative species. It can be administered two or three times The clinical efficacy and toxicity of meropenem are similar to daily. It is a poor hapten and has been successfully administered those of imipenem, except that meropenem appears more likely to small numbers of patients with proven allergy to penicillins to be effective in meningitis and less likely to cause seizures. and cephalosporins.125 Because the newest carbapenem, ertapenem, has a longer half- Aztreonam has been shown to be effective against bacteremia life than the other members of the group, it can be administered caused by E. coli, K. pneumoniae, P mirabilis, S. marcescens, P aeru- . . in a single daily intravenous dose.120 Like the other carbapenems, ginosa, Enterobacter species, Proteus species, and Providencia ertapenem is excreted in the urine, and the dosage should be species.126,127 It has also been used, alone or in combination with reduced in azotemic patients. The antibacterial spectrum of clindamycin, to treat gram-negative aspiration pneumonia, with ertapenem is similar to that of meropenem, except that results comparable or superior to those obtained with an amino- Pseudomonas and Acinetobacter strains are less susceptible, and E. glycoside-clindamycin combination.128,129 faecalis is resistant.121 Ertapenem appears effective against com- Aztreonam has been advocated as directed therapy to obviate munity-acquired pneumonias, intra-abdominal infections, com- more toxic drugs. It seems possible that aztreonam could replace plicated skin and soft tissue infections, and complicated urinary aminoglycosides in many situations in which they are combined tract infections, but experience is limited. with other agents. The carbapenems have broader antibacterial spectrums than any other β-lactam antibiotics. They are active against most gram-positive bacteria—both aerobes and anaerobes. Exceptions β-Lactamase Inhibitors include some enterococci; many E. faecalis strains are sensitive to A novel approach to antibacterial chemotherapy is the use of β- imipenem and meropenem but not ertapenem, and most E. fae- lactamase inhibitors with β-lactam agents. Clavulanate has been cium strains are resistant to all three drugs. Some diphtheroids are combined with both amoxicillin and ticarcillin. Because neither resistant. Although most S. aureus strains are very sensitive, the clavulanate nor sulbactam inhibits the β-lactamases that function susceptibility of methicillin-resistant S. aureus and coagulase-neg- primarily as cephalosporinases in Enterobacter, Serratia, and P . ative staphylococci is highly variable. Methicillin-resistant S. aeruginosa infections, the addition of clavulanate or sulbactam aureus and Listeria exhibit carbapenem tolerance. Finally, some does not enhance ticarcillin’s activity against Pseudomonas. The strains of C. difficile are resistant. principal use of amoxicillin-clavulanate has been in the treatment Ertapenem has a spectrum of activity similar to that of of upper respiratory tract infections caused by β-lactamase–pro- meropenem, except that Pseudomonas and Acinetobacter strains ducing H. influenzae or M. catarrhalis. Ticarcillin-clavulanate has are much less susceptible, and E. faecalis is resistant. been used to treat pneumonia caused by P aeruginosa and mixed . The safety of carbapenems seems comparable to that of other β-lactamase–producing flora as well as intra-abdominal infections β-lactam antibiotics. Nausea and vomiting, local pain at injection and gynecologic infections in which the infecting organisms often sites, and hypersensitivity are the most common reactions. possess β-lactamases. In febrile neutropenic patients, its efficacy Seizures, although unusual, are a potential concern with imipen- is comparable to that of other agents, but superinfections may be
  • 24. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 24 a problem.130,131 Because some strains of K. pneumoniae are not other streptococci; ciprofloxacin and ofloxacin are moderately adequately inhibited by ticarcillin-clavulanate, addition of an active; and levofloxacin, sparfloxacin, gatifloxacin, moxifloxacin, aminoglycoside would be appropriate in neutropenic patients. and trovafloxacin are highly effective, even against non–penicillin- Sulbactam has also been combined with ampicillin. sensitive pneumococci. Even fastidious intracellular pathogens can Clavulanate, sulbactam, and tazobactam have all been com- be inhibited by the quinolones; Chlamydia, Mycoplasma, Listeria, bined with piperacillin in an attempt to enhance the agent’s activi- Legionella, and M. tuberculosis are in this category. Only trova- ty against β-lactamase–producing bacteria.132,133 Tazobactam en- floxacin is highly active against anaerobes. Levofloxacin, gati- hances the spectrum of action and potency of piperacillin to a floxacin, moxifloxacin, and sparfloxacin demonstrate some activi- greater extent than sulbactam does. Although piperacillin-clavu- ty against anaerobes, but the other quinolones do not. C. difficile is lanate is more potent than piperacillin-tazobactam, the two combi- resistant to quinolones. nations are effective against virtually the same spectrum of resistant The fluoroquinolones are rapidly absorbed from the GI tract. β-lactamase–producing gram-negative organisms. Piperacillin- Penetration into body fluids and tissues is generally excellent; tazobactam is more potent than ticarcillin-clavulanate and is effec- therapeutic concentrations are readily achieved in blister fluid, tive against a wider range of gram-negative enteric organisms. bile, urine, saliva and sputum, bone, and muscle. Excellent con- Combinations of piperacillin with tazobactam or clavulanate have centrations of these drugs are achieved in the prostate, and stool a broader spectrum of activity than combinations of piperacillin levels are extraordinarily high. The fluoroquinolones appear to with sulbactam against bacteria that produce characterized plas- penetrate the CSF in the presence of meningeal inflammation,138 mid-mediated enzymes of clinical significance. In particular, but experience in treating meningitis is scant. piperacillin-tazobactam and piperacillin-clavulanate inhibit TEM- Although serum protein binding is modest, the fluoro- 1, TEM-2, and SHV-1 β-lactamases, but piperacillin-sulbactam quinolones have long serum half-lives, which range from 3 to 4 does not. In mice infected with β-lactamase–producing E. coli, K. hours for ciprofloxacin to 12 hours for moxifloxacin. Most fluo- pneumoniae, P mirabilis, and S. aureus, both tazobactam and clavu- . roquinolones are eliminated by glomerular filtration and tubular lanate have provided greater enhancement of the therapeutic effi- secretion, and their dosages should be reduced in the presence of cacy of piperacillin than sulbactam has. Reviews of the TEM-type moderately severe renal failure. Trovafloxacin and moxifloxacin, β-lactamases134 and the piperacillin-tazobactam combinations135 however, are excreted chiefly by the liver. have been published. The fluoroquinolones appear to be very well tolerated, with mild GI side effects (nausea, vomiting, or anorexia), CNS side effects (light-headedness, dizziness, somnolence, or insomnia), or Quinolones rash occurring in fewer than 10% of treated patients. Lome- The addition of a fluorine group and a piperazine substituent floxacin and sparfloxacin can cause phototoxicity. Less common to the first quinolones has greatly improved the antibacterial side effects include allergic intestinal nephritis, pseudomembra- spectrum of this class of drugs; the addition of a methyl group on nous colitis, and neutropenia. Sparfloxacin and moxifloxacin may the piperazine ring appears to further enhance the bioavailability cause QT interval prolongation and should not be used by of these compounds. patients who have conditions or are using drugs known to prolong The fluoroquinolones are bactericidal compounds that act by the QT interval or predispose to arrhythmias.139 Tendinitis has inhibiting DNA gyrase, the bacterial enzyme responsible for been reported; in severe cases, it has resulted in rupture of the ten- maintaining the supertwisted helical structure of DNA; DNA dons of the shoulder and hand and the Achilles tendon. topoisomerase IV is a secondary target.136 The fluoroquinolones Crystalluria has been reported after the use of very large doses. rapidly kill bacteria, probably by impairing DNA synthesis and Because fluoroquinolones have caused arthropathy in young ani- possibly by mechanisms involving the cleaving of bacterial chro- mals, these drugs should be avoided in children and in women mosomal DNA. Bacterial resistance to the fluoroquinolones who are pregnant or nursing. Ciprofloxacin is safe in long-term depends on a change in their DNA gyrase. Bacterial strains that use; there is less long-term experience with the other fluoro- are resistant to one fluoroquinolone tend to be cross-resistant to quinolones. related compounds; such resistance is usually mediated by chro- The fluoroquinolones have been useful clinically in a variety of mosomes, but plasmid-mediated resistance raises the possibility infections, including urinary tract, genital, prostatic, GI, respira- of transferable resistance. tory tract, soft tissue, and bone infections. Because of its excellent The fluoroquinolones are broad-spectrum antimicrobials. Most activity against anaerobes, trovafloxacin was considered useful in enteric gram-negative bacilli, including E. coli, Proteus, Klebsiella, intra-abdominal and pelvic infections, but concerns about serious and Enterobacter, are highly susceptible; common GI pathogens, hepatotoxicity have restricted its use to infections deemed life- or such as Salmonella, Shigella, and Campylobacter species, are also limb-threatening and for patients in whom the benefit of very sensitive. Other gram-negative organisms that are killed by trovafloxacin outweighs its potential risks. If it must be used, liver low concentrations of the fluoroquinolones are N. gonorrhoeae and function must be monitored carefully. N. meningitidis, H. influenzae, P multocida, M. catarrhalis, and Y. . The fluoroquinolones, administered in various regimens rang- enterocolitica. Acinetobacter and Serratia are somewhat less suscep- ing from a single dose to 5 days of therapy, are effective in pre- tible. P aeruginosa is susceptible to ciprofloxacin and trovafloxacin; . venting and treating traveler’s diarrhea and shigellosis. They have ofloxacin and levofloxacin are moderately active, but the other been highly effective in the treatment of typhoid fever. However, quinolones are not effective. P cepacia and S. maltophilia are . prolongation of the carrier state limits their role in nontyphoidal quinolone-resistant. Ciprofloxacin is the drug of choice for Bacillus Salmonella enteritis, and the development of resistance limits their anthracis; oflaxacin and levofloxacin are also active in vitro.137 role in Campylobacter enteritis.The fluoroquinolones may be use- Among gram-positive cocci, methicillin-sensitive strains of S. ful in the empirical treatment of severe community-acquired gas- aureus and coagulase-negative staphylococci are usually suscepti- troenteritis, particularly if treatment is started early. ble to quinolones, but methicillin-resistant S. aureus and entero- Because of their extraordinarily broad antimicrobial activity, cocci are not. Lomefloxacin is not active against pneumococci and their favorable pharmacokinetics, and their low toxicity,140 the
  • 25. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 25 fluoroquinolones are extremely valuable new drugs. Like all multocida, and Nocardia species. C. difficile, C. perfringens, and antimicrobials, however, fluoroquinolones should be used judi- Bacteroides species are susceptible, but enteric gram-negative bacil- ciously, especially in view of new concerns about resistance141,142 li and Pseudomonas species are not.150 and toxicity and practical considerations about expense. Intravenous and oral preparations of linezolid are available; the oral form is absorbed rapidly and completely with 100% bioavail- ADVERSE EFFECTS ability that is not affected by meals. Linezolid is widely distrib- Adverse reactions to the quinolones are estimated to occur in uted in well-perfused tissues. Nonrenal mechanisms account for 4% to 8% of cases.143 Most such reactions are not severe: cessa- 65% of the drug’s clearance. Patients with mild to moderate renal tion of therapy has been necessary in only about 1% to 2% of or hepatic insufficiency do not appear to require reduced doses; patients, and in all cases, the reactions have been reversible. The linezolid is removed by hemodialysis. most common adverse effects are gastrointestinal—namely, nau- Linezolid is well tolerated. Adverse effects have been reported sea, vomiting, and diarrhea. The next most common are CNS in about 2.8% of all patients150; nausea, vomiting, and headaches effects, which include dizziness, headache, insomnia, hallucina- are the most common side effects, but reversible marrow sup- tions, agitation, and seizures. (The last three have been attributed pression, including thrombocytopenia, leukopenia, and anemia, to coadministration of enoxacin and theophylline.) Other effects can also occur. Because linezolid is a reversible inhibitor of include skin rash, pruritus, photosensitivity (with ofloxacin and monoamine oxidase, patients taking linezolid may experience an pefloxacin), and mild alterations in hematologic and biochemical exaggerated hypertensive response to sympathomimetic agents. laboratory values. In addition to avoiding decongestants, patients taking linezolid should avoid foods or beverages with a high tyramine content; aged cheeses, air-dried meats, tap beer, red wine, soy sauce, and Streptogramins sauerkraut are examples. Monoamine oxidase inhibitors and Quinupristin and dalfopristin are two structurally distinct other antidepressants should not be administered during linezol- streptogramins that bind to separate sites on the bacterial 50S id therapy. ribosomal subunit; they thus act synergistically to inhibit protein Linezolid has been used successfully in the therapy of mul- synthesis. The drugs are marketed together in a 30:70 ratio as tidrug-resistant gram-positive bacterial infections.146,147,151 The Synercid.144 drug is approved for vancomycin-resistant enterococcal infec- Although quinupristin-dalfopristin is active against a variety of tions and for pneumonias and skin and soft tissue infections.The bacteria, its major use is in the treatment of serious infections usual dosage is 600 mg every 12 hours (p.o. or I.V.); uncompli- caused by vancomycin-resistant strains of E. faecium. The drugs cated skin and soft tissue infections may be treated with 400 mg may also be useful in occasional vancomycin-intolerant patients every 12 hours. with severe infections caused by methicillin-resistant S. aureus or Linezolid is a very promising new antimicrobial agent, but coagulase-negative staphylococci. Resistance to quinupristin-dal- clinical experience is still limited. Although resistance is uncom- fopristin is emerging.145 mon, it can develop during therapy. As a result, it may be wise to Quinupristin-dalfopristin is administered intravenously; reserve this unique antibiotic for serious infections in hospitalized because of a high incidence of phlebitis, a central line should be patients; in particular, linezolid should be useful for infections used. Other adverse effects include arthralgias and myalgias, caused by methicillin-resistant S. aureus or coagulase-negative which may be severe, and elevated bilirubin levels.The antibiotic staphylococci that do not respond to vancomycin, for penicillin- may elevate levels of drugs that are metabolized by the hepatic resistant pneumococcal infections that do not respond to other enzyme CYP3A4; nifedipine and cyclosporine are examples. agents, and for vancomycin-resistant enterococcal infection. An The usual dose of quinupristin-dalfopristin is 7.5 mg/kg given excellent general review of the use of linezolid in serious gram- intravenously over 1 hour every 8 hours.The drug is metabolized positive infections has been published.152 by the liver, so no dose reduction is required in azotemic patients. Quinupristin-dalfopristin is extremely expensive. Fosfomycin Fosfomycin is a broad-spectrum antibiotic that inhibits cell Oxazolidinones wall synthesis in infections caused by E. coli, S. saprophyticus, and In 2000, linezolid became the first member of the oxazolidi- many other common urinary tract pathogens.153 Although it has none class to be approved for clinical use in the United States.146 been used parenterally in Europe for many years, the drug is Linezolid is a synthetic antibiotic that inhibits protein synthesis approved in the United States only for the single-dose treatment by binding to a site on the bacterial 23S ribosomal RNA of the of uncomplicated urinary tract infections in women. A 3 g dose 50S subunit, thus preventing function of the initiation complex is generally effective and well tolerated; diarrhea is the most com- that is required for ribosomal function.147 Because no other mon side effect. Because of its activity against vancomycin-resis- antibiotic acts in this way, bacteria that have developed resistance tant enterococci (VRE), fosfomycin may be a useful alternative to to other ribosomally active antimicrobials do not display cross- linezolid and quinupristin-dalfopristin in the treatment of VRE resistance to linezolid. infections in certain clinical situations (e.g., uncomplicated uri- Linezolid is active against nearly all aerobic gram-positive cocci nary tract infections). In addition, the use of fosfomycin could at concentrations of 4 mg/ml or less,148 including penicillin-resis- limit the use of newer agents, thus reducing the chance of devel- tant pneumococci, methicillin-resistant staphylococci, and van- opment of further resistance in the enterococci.154 comycin-resistant enterococci; however, resistant strains have been isolated.149 The drug is bacteriostatic against staphylococci and enterococci, but it is bactericidal against most streptococcal Concerns for the Future strains. Linezolid is also active against L. monocytogenes, M. catar- Despite a century of often-successful prevention and control rhalis, H. influenzae, N. gonorrhoeae, Bordetella pertussis, Pasteurella efforts, infectious diseases remain an important global problem in
  • 26. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 15 ANTIBIOTICS — 26 public health, causing over 13 million deaths each year. Changes active against a standard set of drug targets. Although many effec- in society, technology, and the microorganisms themselves are tive compounds have been discovered, insufficient chemical vari- contributing to the emergence of new diseases, the reemergence ability has been generated to prevent a serious escalation in clin- of diseases once controlled, and the development of antimicrobial ical resistance. Recent advances in genomics have provided an resistance. Two areas of special concern in the 21st century are opportunity to expand the range of potential drug targets and food-borne disease and antimicrobial resistance. The effective have facilitated a fundamental shift from direct antimicrobial control of infectious diseases in the new millennium will require screening programs toward rational target-based strategies. The effective public health infrastructures that will rapidly recognize application of genome-based technologies such as expression and respond to outbreaks and will prevent emerging problems. profiling and proteomics will lead to further changes in the drug Over the past 40 years, the search for new antibiotics has been discovery paradigm by combining the strengths and advantages largely restricted to well-known classes of compounds that are of both screening strategies in a single program. References 1. Jones RN: NCCLS regulatory guidelines. Anti- 17. Christou NV, Turgeon P, Wassef R, et al: coccus pneumoniae in Europe. J Antimicrob Chemo- microbic Newsletter 1:5, 1984 Management of intra-abdominal infections: the ther 28(suppl C):31, 1991 2. 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