Reese: Practical Approach to Infectious Diseases, 4th ed., Copyright 1996 Richard E. Reese and Robert F. Betts

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1 [Pre [Ne Reese: Practical Approach to Infectious Diseases, 4th ed., Copyright 1996 Richard E. Reese and Robert F. Betts Antibiotic Checklist I. Question 1. Is an antibiotic indicated on the basis of clinical findings? A. Obvious bacterial infections require antibiotic therapy. 1. Localized infection. Patients with pneumonia, urinary tract infection, wound infection, or cellulitis require therapy. 2. Urgent "probable" infections deserve therapy, as discussed in sec. B.3. B. Probable bacterial infection. The patient with fever and systemic symptoms but no focal findings is more problematic. The severity of symptoms, patient's age, and underlying illnesses must be considered before one chooses an antibiotic for such patients. Travel history, exposure to community infections (e.g., influenza) and, in hospitalized patients, the presence of an implantable device used for prolonged venous access or prolonged antibiotic therapy affect the decision about antibiotic treatment. 1. Nonspecific nature of symptoms, signs, and laboratory test results. Many of the clinical manifestations that suggest bacterial infection (fever; leukocytosis; chills; rapid onset of symptoms; acute, tender adenopathy; myalgias; and localizing symptoms such as pharyngitis, dysuria, and cough) are not diagnostic and may be due to noninfectious causes or nonbacterial agents. Fever may be due to drugs, tumor, or connective tissue diseases as well as infection. Shaking chills may be the first sign. By contrast, some patients, especially elderly patients, may have bacteremia with little or no fever. The peripheral WBC count can be normal even in patients with bacteremia. 2. Viral infections. Viruses may produce symptoms and signs similar to those of bacterial infection. In early viral infections, leukocytosis with a predominance of polymorphonuclear leukocytes may be seen, causing further confusion. Antibiotics are ineffective against viruses and may be associated with adverse side effects. In addition to false expectations, the risks inherent in antibiotic exposure (i.e., potential allergies, side effects, superinfection, and added cost) P1060 are real. Unnecessary treatment of viral infections is a major source of excess antibiotic use. a. Upper respiratory tract infections, including pharyngitis, are commonly caused by viruses.

2 Characteristically, exudates are not present in most viral infections. Only by throat culture or properly performed positive rapid streptococcal screening can one reliably differentiate between the bacterial causes that require treatment. b. Influenza is a viral syndrome in which antibiotics play no role unless there is bacterial superinfection. Because influenza occurs in epidemics, the presence of this virus in the community should affect one's thinking about empiric antibiotic therapy. In an influenza epidemic, patients presenting with fever, myalgias, sore throat, and cough most probably will have infection with influenza virus. Antibiotics are not indicated unless there is secondary bacterial pneumonia, bronchitis, or sinusitis (see Chap. 8). Furthermore, some viruses--for example, influenza and respiratory syncytial virus--can cause nosocomial infections. Viral infection must be considered in fever workups in hospitalized patients (children and adults) during community epidemics. 3. Urgency of the situation. A very important factor in the decision to use antibiotics is the urgency of the problem. a. Nonurgent situation. The otherwise healthy patient with mild illness and no focal findings does not require treatment until a diagnosis has been reached. Furthermore, unnecessary antibiotic therapy may confuse the clinical picture. Even a single dose of parenteral antibiotic may suppress follow-up cultures for several days, especially urine and blood cultures. b. Urgent situation. In contrast, a patient with presumed infection who is severely ill, with or without focal findings, needs immediate therapy. Because cultures may require hours to become positive, the patient should be treated presumptively. A careful history, physical examination, and laboratory assessment provide the information for a rational choice of antibiotics that should be active against the organisms most likely to be involved. Once cultures have revealed the offending pathogen, the therapeutic regimen can be altered to be more specific. In fact, initiation of antibiotic therapy is carried out most commonly on the basis of clinical judgment. The laboratory results help one refine and adjust therapy. The following are examples of patients who require presumptive therapy. (1) Patients with signs or symptoms of a focal infection such as pneumonia, urinary tract infection (UTI), or biliary tract infections. These patients should be treated even if they are only moderately ill but especially if they are severely ill. In elderly patients, even those mildly ill with focal symptoms, therapy must be initiated early.

3 (2) Septic patients. Any patient with sepsis from an obvious or unclear source (see Chap. 2). P1061 (3) Febrile leukopenic patients. In these high-risk patients, empiric antibiotics are used for unexplained fever even if the patient is not septic in appearance (see Chap. 2). (4) Possible acute endocarditis. The patient with valvular heart disease or the narcotic addict who presents with fever and chills may have endocarditis with a virulent organism that quickly could lead to destructive changes in the heart valve if empiric therapy is not initiated (see Chap. 10). (5) Bacterial meningitis (known or suspected). See Chap. 5. (6) Acute necrotizing cellulitis is a rapidly progressive infection and deserves empiric antibiotic therapy and often surgical debridement. See Chap. 4. II. Question 2. Before antibiotics are initiated, have appropriate clinical specimens been obtained, examined, and cultured? This is extremely important. Even in the most urgent situations, blood and appropriate cultures (e.g., sputum and urine) must be obtained prior to initiation of antibiotics. A. A Gram stain of any exudate or bodily fluid may help one to recognize the major organism or organisms (Table 28A-2) (Table Not Available) and thus help guide selection of specific agents. Specific identification of an organism from the Gram stain may not be possible. For example, gram-positive cocci in pairs or short chains may represent aerobic streptococci (including Streptococcus pneumoniae or enterococci), anaerobic streptococci, or even staphylococci. The classic grapelike clusters of staphylococci are quite helpful if detected but may not be present. Nevertheless, the Gram stain indicates that antibiotic therapy in these instances must be directed against gram-positive organisms. The technique and interpretation of Gram stains are discussed in Chap. 25. B. It is important to obtain appropriate cultures (aerobic, anaerobic) of bodily fluids, exudates, and blood before starting antibiotic treatment. 1. When the pretreatment cultures become available, the initial antibiotic regimen often can be altered (see sec. IX). If cultures are not obtained, it is difficult to determine which drugs to continue or discontinue in the patient who responds clinically to multiple antibiotics. 2. Follow-up cultures are much less reliable than pretreatment cultures. Because antibiotics may rapidly sterilize blood and urine cultures and alter surface bacterial flora (e.g., sputum or wound swabs) quickly after their initiation, subsequent cultures usually do not reflect the initial causative organisms.

4 III. 3. Anaerobic cultures. It is important to obtain anaerobic cultures when anaerobic infections are considered (e.g., abscesses that are incised and drained or aspirated). See Chap. 25. Question 3. What organisms are most likely to be causing the infection? Often the clinician must start antibiotics empirically. Based on clinical information and Gram stains, an educated guess about the likely pathogens is desirable in order to select an antibiotic with good activity against the most likely pathogen(s). A. Focal findings (i.e., genitourinary, pulmonary, skin, or biliary) will strongly influence the decision about whether coverage will be directed against gram-positive, gram-negative, or anaerobic organisms. 1. Table 28A-2 (Table Not Available) lists the common organisms seen in focal infections. Presumptive antibiotic therapy must cover these organisms. 2. Gram stains of clinical specimens may provide additional clues that certain organisms among those listed in Table 28A-2 (Table Not Available) are more likely to be causative agents. 3. Table 28A-3 lists the antibiotics of choice for common organisms. Using focal findings, Gram stains, and the information obtained in Table 28A-2 (Table Not Available) and in Table 28A-3, a rational choice can be made. 4. Examples using Table 28A-2 (Table Not Available) and Table 28A-3 a. A patient develops a fever and shaking chills on the third postoperative day following a hernia repair. Clinical evaluation reveals a postoperative incision with erythema, tenderness, and induration at the margins of the incision site. No other focus of infection can be found, and there is some purulent drainage from the wound. The Gram stain of the wound drainage reveals gram-positive cocci. Although hospital-acquired infections after this surgery can occasionally be caused by gram-negative bacilli, it is quite uncommon, and the Gram stain indicates otherwise. Table 28A-2 (Table Not Available) indicates P1062 P1063 P1064 P1068

5 that wound infections commonly involve Staphylococcus aureus and streptococci. Because the infection was hospital-acquired, the S. aureus is presumed to be a penicillinase producer. To provide adequate antibiotic therapy while awaiting cultures, Table 28A-3 suggests a penicillinase-resistant penicillin both for the S. aureus (e.g., oxacillin) as well as for most streptococci. It is unlikely that methicillin-resistant S. aureus (MRSA) would be a factor in this clinical situation but, if a particular hospital had a nosocomial outbreak of MRSA, vancomycin could be used while awaiting cultures and therapy modified after culture data became available. b. A 55-year-old woman with a prior history of gallstones presents with right-upper-quadrant abdominal pain, fever, chills, leukocytosis, and hyperbilirubinemia. Her presentation is consistent with acute cholecystitis and possibly an early cholangitis. Table 28A-2 (Table Not Available) indicates that Escherichia coli, Klebsiella spp. and, much less commonly, Enterobacter spp. are the major pathogens. Enterococci can usually be ignored unless culture is proven. Several antibiotic options are possible to use in this setting; this topic is reviewed in detail in Chap. 11. For the mildly ill patient, cefazolin alone would be reasonable for community-acquired infection, although cefoxitin is preferred by some in this setting. For the sicker patient, ceftriaxone would provide excellent gram-negative bacterial activity (with or without metronidazole for anaerobic activity, which is more of a concern in the elderly patient with biliary infection). c. A 70-year-old patient has a tender abdomen, with mild rebound left-lower-quadrant abdominal tenderness, fever, and leukocytosis. He has a past history of diverticulitis. After surgical evaluation, he is believed to have acute diverticulitis. Table 28A-2 (Table Not Available) indicates that the major potential pathogens are E. coli, Bacteroides fragilis, and Klebsiella spp. From Table 28A- 3 one can see that a cephalosporin is listed as the antibiotic of choice against E. coli (in non-uti) and Klebsiella spp. For serious B. fragilis infections, metronidazole is preferred, but for mild to moderate infections, as in our example, cefoxitin is an alternative. This cephalosporin is active against community-acquired E. coli and Klebsiella spp. and could be used as monotherapy. Ampicillin-sulbactam or piperacillintazobactam would be other alternatives for monotherapy. In a very ill patient with diverticulitis with a protracted course and with possible perforation, focal peritonitis, and possible intraabdominal abscess, several options are

6 available. A cephalosporin very active against E. coli and Klebsiella spp. (e.g., ceftriaxone) can be combined with metronidazole. Although triple antibiotics, ampicillin, metronidazole or clindamycin, and an aminoglycoside have often been used in this setting, some clinicians are concerned that aminoglycosides do not provide adequate tissue concentrations in severe intraabdominal infections, especially when early abscess formation is present. See related discussions in Chap. 11. d. See the example of an arteriovenous shunt infection discussed later under Using the Antibiotic Checklist. B. The age of the patient at times may provide important additional clues to the likely organisms or may affect the choice of agent. 1. In meningitis, neonates usually are infected with group B streptococci or enteric organisms. In children younger than 2 years, Haemophilus influenzae in the unvaccinated child is common but S. pneumoniae and Neisseria meningitidis also occur. The latter two organisms are the most common pathogens in adults. Recipients of the conjugated H. influenzae b vaccine are less likely to have invasive disease due to this pathogen. See Chap The choice and dosage of an antibiotic are also affected by age. For example, tetracycline should be avoided in children younger than 8 years because of its effect on teeth. If chloramphenicol must be used in the neonate, serum levels must be monitored to avoid the development of the gray-baby syndrome. The fluoroquinolones are avoided generally in children and prepubertal teenagers because they may affect cartilage and bone formation. See sec The elderly patient poses special problems. These topics have been reviewed elsewhere in detail [1] [2] [2A]. a. Infections occur more frequently in the elderly, in part because mechanical barriers such as skin and mucosa undergo structural and functional decline with age. Immune dysregulation and immunodeficiency are welldescribed P1069 phenomena accompanying aging. Age-related chronic diseases (e.g., diabetes, chronic pulmonary disease) may compromise host defenses. The elderly are hospitalized more often than young adults, and the incidence of nosocomial infections, often with resistant pathogens, is threefold higher in elderly patients [1]. b. The mortality for specific infections is higher in older patients versus younger. There is a threefold increase in death rates with pneumonia, sepsis, meningitis, and

7 endocarditis; a two- to eightfold increase with cholecystitis; a five- to tenfold increase with kidney infection; and a fifteen- to twentyfold increase with appendicitis [1]. In addition to the compromised host defenses and underlying chronic diseases, other factors help explain these higher death rates, including the atypical presentation of infections (see sec. d), delays in seeking help, and poorer tolerance to invasive diagnostic procedures and therapeutic interventions, among them surgery [1]. c. Morbidity rates are higher in the elderly with infections. Pneumonias are more apt to be associated with bacteremia and slow resolution; UTI is associated with bacteremias commonly; intraabdominal infection is more commonly associated with perforation, bacteremia, or abscess formation than in younger patients [1]. d. Infection in elderly persons may present atypically with minimal or subtle findings, often without signs pointing to a specifically involved organ system. This is particularly common in the so-called frail elderly (often older than 80 years, typically nursing home residents, with underlying debilitating illnesses as well as cognitive impairment). In these patients, any unexplained change in functional status (e.g., lethargy or agitation, anorexia, falls, confusion) should lead the clinician to consider and evaluate for infection [2]. Fever may be blunted or absent in up to one-third of infected elderly patients. Elderly patients may have lower baseline temperatures so that with an infection, their temperature may not elevate above 101 F (38 C). Therefore, in nursing home patients, in the setting of changes of functional status, an increase from baseline temperature of more than 1.4 F or an absolute oral temperature of greater than 100 F is highly suggestive of an underlying infection [2]. e. Clinical implications. Because of these special problems in the elderly and the higher death and morbidity rates, some experts emphasize [1] : (1) Early empiric antibiotics. (2) Initial broad-spectrum antibiotics. Focal infections may not be defined, hospital-acquired infections are common, and gram-negative infections in nursing home patients are common. (Antibiotics can be modified once culture data are back). (3) Careful selection and dosing of antibiotics. All elderly patients have some degree of renal impairment (see sec. VI.C) and may be on other drugs that may interact with antibiotics. Aminoglycosides should be used cautiously in these patients. See Chap. 28H.

8 (4) Compliance with oral antibiotics is a concern in the elderly [2A]. Reasons for noncompliance in the elderly include: forgetfulness, poor understanding of the drug regimen, impaired hearing or vision, polypharmacy, fear of side effects, disappearance of symptoms, complexity of the drug regimen, concerns regarding expense, inability to open child-resistant containers, and intentional nonadherence [2A]. Studies indicate that antimicrobial compliance is enhanced with once-per-day and twice-per-day dosing; some of the newer antibiotics with these easier dosing schedules may be more useful in the elderly because their use improves compliance, even though the newer agents may be more expensive than traditional agents [2A]. (5) Drug-drug interactions are a potential concern in the elderly patient on multiple medications [2A]. Similarly, adverse drug reactions also are a concern in these older patients with decreased renal function, problems with compliance, and often malnourished status [2A]. C. Severity of illness dictates not only whether antibiotic therapy should be initiated but also, at times, whether multiple agents should be used. In sepsis of unclear etiology, combinations of antibiotics often are indicated (see Chap. 2). In pelvic P1070 and other severe abdominal infections, multiple agents may be necessary to ensure sufficiently broad-spectrum coverage. D. Epidemiologic features 1. Hospital-acquired infections often are caused by gram-negative bacteria that are resistant to penicillin, ampicillin, erythromycin, and other antibiotics commonly used in the outpatient setting. The incidence of hospital-associated gram-negative bacteria resistant to cephalosporins and aminoglycosides varies among institutions, and local resistance patterns will affect the initial antibiotic choice. Because approximately 10-20% of these organisms may be sensitive only to an aminoglycoside, the latter is used often in the therapy of presumptive severe gram-negative infections in the hospital setting. This is even more likely if the patient has previously received antibiotics. Patients who develop infections in the intensive care or burn unit are especially likely to be infected with resistant gram-negative organisms. See also sec As noted, prior antibiotic use in a given patient may predispose to infections with more resistant organisms. Thus, a patient with one or more recent infections requiring gentamicin may, in a subsequent infection, be infected with an organism resistant to gentamicin.

9 IV. 3. All suspected staphylococcal infections, whether hospitalacquired or community-acquired, should be presumed to be penicillin-resistant for initial antibiotic therapy. When susceptibility studies are available, penicillin should be substituted if the staphylococcus is shown to be susceptible. If methicillin resistance to S. aureus or S. epidermidis organisms is shown or is highly suspected, vancomycin is used (see Chap. 28D). Therefore, susceptibility data for staphylococci should be carefully examined. 4. Is the patient at risk for recently emerging resistant bacteria, which may be community-acquired or hospital-acquired? In some geographic areas or special settings, in addition to high rates of ampicillin-resistant H. influenzae and MRSA, an increasing incidence of penicillin-resistant S. pneumoniae (see Chap. 28C), vancomycin-resistant enterococci (see Chap. 28O), and multidrug-resistant gram-negative bacilli are seen. See related discussion in sec. II under Miscellaneous Aspects of Antibiotic Use. E. Prior culture data often provide helpful clues. For example, an elderly man who recently had a positive culture for enterococci prior to removal of an indwelling catheter and who develops a UTI and sepsis associated with gram-positive cocci in an unspun urine Gram stain should have an antibiotic directed against enterococci (e.g., ampicillin) included in his empiric antibiotic regimen. Similarly, if prior cultures showed that the most recent gram-negative bacteria colonizing the urine was gentamicinresistant, the clinician should be concerned about a resistant gramnegative infection and should choose amikacin. Question 4. If several antibiotics are available to treat the likely or known pathogen, which agent is best for a particular patient? This question involves many variables. A. Is there an obvious drug of choice [3] (see Table 28A-3) and, if so, can this agent be used? B. Are there antibiotic allergies? For example, if a patient is allergic to a penicillin, the patient must be presumed to be allergic to all the penicillin derivatives unless appropriate skin tests can be done to test specifically for cross-reactivity. It is important to consider both trade and generic names of antibiotics when evaluating a patient's allergic history. See discussion of penicillin and other drug allergies in Chap. 27. C. Antibiotic penetration and ph. Will the antibiotic under consideration penetrate the infected area? This may be particularly important in infections involving the CNS, into which clindamycin, aminoglycosides, and first- and some second-generation cephalosporins penetrate poorly. Two other sites of poor penetration are the prostate and the obstructed biliary tree. The ph of the site of infection may affect antibiotic activity; for example, aminoglycosides are much more effective in a physiologic medium (ph 7.4) than in an acid environment (e.g., abscess). In pus or sputum, an acid ph may alter the activity of these antibiotics. D. Because of potential side effects, some agents may be contraindicated in certain settings. Examples include the following:

10 1. Chloramphenicol use is tempered by the rare occurrence of aplasia (probably 1/25,000-1/50,000 courses of therapy). 2. The dental effects of tetracycline limit its use in children younger than 8 years and during pregnancy. P The fluoroquinolones may affect cartilage formation and therefore are not recommended for use in prepubertal children [4] and pregnant women. 4. Certain antibiotics (e.g., the second- and third-generation cephalosporins, clindamycin) may pose a greater risk for the development of Clostridium difficile diarrhea than other antibiotics (e.g., aminoglycosides, aztreonam). In certain patients, this may be a consideration in the selection of one antibiotic over another. This topic is discussed in detail at the end of this chapter. E. Bactericidal versus bacteriostatic agents. The laboratory definitions and determination of bactericidal and bacteriostatic antibiotics are discussed in Chap Bacteriostatic agents primarily inhibit bacterial growth. Killing of the organism depends on host defense mechanisms. One of the disadvantages of bacteriostatic agents is that, in the setting of inadequate host mechanisms, any partially inhibited organisms may survive, replicate, and produce recurrent disease when the antibiotic is discontinued. 2. Bactericidal agents depend less on host factors. These agents are preferable if the host is compromised (e.g., neutropenic or immunosuppressed patients) or when host defense mechanisms do not operate well (e.g., in patients with bacterial endocarditis or meningitis). 3. Clinical implications. In minor infections of the healthy host, bacteriostatic or bactericidal agents are probably of equal efficacy. However, in severe, life-threatening infections (particularly bacteremias in leukopenic patients or patients with endocarditis or meningitis), bactericidal agents are necessary. A brief summary of antibiotics falling into these different categories is given in Table 28A-4. F. Cost of antibiotics. From the 1950s through the 1970s, the cost of an antibiotic and its administration seemed to have had little impact on the prescribing habits of house officers and most physicians. Now, with the spiraling costs of these agents and, in particular, the expense of hospitalization, the cost of administering antibiotics is an important consideration. This is a complex issue, and only a brief summary follows. A hospital's pharmacy and therapeutic committee (or formulary committee) will consider all these factors when evaluating new versus old agents. 1. The cost of the antibiotic itself is the easiest component to sort out. See Table 28A-5 (Table Not Available), See Table 28A-6 (Table Not Available), and See Table 28F-5. Generic

11 preparations should be ordered whenever possible (e.g., generic oral trimethoprim-sulfamethoxazole [TMP-SMX]; see Table 28A-5 (Table Not Available) ). It is essential that the clinician recognize that the cost per day of the antibiotic is only one component of the cost of antibiotic administration in hospitalized patients. Other factors include the following: 2. Frequency of administration per day. The more frequently the antibiotic is given (q4h versus q8h versus q24h), the more expensive it is to administer in P1072 terms of personnel time, intravenous materials used, and so on. In one study, the estimated average nonantibiotic cost associated with the mixing and administration of a single intravenous antibiotic dose was $3.35 [5]. Agents with longer half-lives may be more cost-effective. For example, if a third-generation cephalosporin is indicated, ceftriaxone may be a good choice because it can often be given once daily (see Chap. 28F). 3. Number of antibiotics. The use of multiple antibiotics often increases costs. In some situations, instead of using triple antibiotics for intraabdominal sepsis (e.g., ampicillin, gentamicin, clindamycin, or metronidazole), it may be appropriate and costeffective to use an expensive single agent (e.g., cefoxitin, cefotetan, ampicillin-sulbactam, or imipenem-cilastatin), which is less toxic than an aminoglycoside and does not require antibiotic serum monitoring. 4. Intravenous administration costs. In addition to the nursing time involved in giving the agent, the tubing, plastic bags, and infusion pumps all add to the costs of intravenous administration. 5. Intravenous versus intramuscular versus oral administration. Because less nursing time and materials are required, intramuscular administration is less expensive, and oral therapy (if appropriate) saves even more. The new oral fluoroquinolones (see Chap. 28S) are very exciting agents that often are costeffective if they are used appropriately instead of using a parenteral agent. However, the absorption of intramuscularly administered antibiotics may be impaired in diabetic patients [4]. P Monitoring of serum levels and toxicity. The potential for toxicity with certain agents (e.g., aminoglycosides, chloramphenicol) is real, and the toxicity, if it occurs, may prolong the patient's hospitalization, increase the level of care of the patient (e.g., dialysis), or be associated with increased

12 morbidity and even mortality. Monitoring for potential toxicities is expensive. Therefore, if an alternative choice of a "safer" agent is available, it often is wise as well as cost-effective to use the alternative. (See individual agent discussions.) 7. Outpatient oral therapy. Cost factors are less complex than in hospitalized patients but are still very important to control. For example, if a 55-year-old woman presents with an uncomplicated cystitis and no drug allergies, 10 days of generic TMP-SMX therapy will be approximately 10% of the cost of an unnecessarily broad-spectrum agent such as ciprofloxacin (250 mg bid) (see Table 28A-6) (Table Not Available). G. Narrow versus broad spectrum of activity. For empiric therapy, antibiotics with a broad spectrum of activity are used initially. Once susceptibility data are known, it is preferable to use as narrow-spectrum an agent as possible. A precise definition of the term broad-spectrum agent is one active against more than one of the major groups of infectious agents (i.e., bacteria, rickettsias, chlamydiae, mycoplasmas, viruses, fungi, protozoa, or spirochetes). Narrow-spectrum antibiotics are effective against only one or two varieties of microorganisms. For example, penicillin is active against bacteria and spirochetes. In routine clinical use, the term broadspectrum agent or wide-spectrum agent is used to refer to those antibiotics that are active against many gram-positive and gramnegative bacteria (e.g., the newer cephalosporins). A narrow-spectrum agent such as penicillin is active against fewer organisms (e.g., primarily grampositive bacteria). V. Question 5. Is an antibiotic combination appropriate? A. Current indications for antibiotic combinations. Although in vitro and animal studies support the use of antibiotic combinations, documentation of increased efficacy for human infections is difficult to obtain. Synergistic combinations in bacteremic leukopenic patients do seem to be associated with improved outcome when compared with single-agent therapy [4] [6]. 1. In the febrile leukopenic patient, two or sometimes three antibiotics often are used to provide activity against grampositive and gram-negative organisms and, it is hoped, to provide synergy against gram-negative bacilli [7] and cover, at times, gram-positive cocci. However, the optimal antibiotic regimen in this setting is unclear [4], and monotherapy often is useful. See Chap In infections in which multiple organisms are likely or proved (e.g., intraabdominal sepsis or pelvic abscess), more than one antibiotic may be required for adequate treatment. For example, therapy for an intraabdominal abscess and peritonitis often includes an aminoglycoside or cephalosporin (to treat the gramnegative aerobes) and clindamycin or metronidazole (to treat B. P1076

13 fragilis and other anaerobes). Although in the past a third agent (e.g., ampicillin) was added synergistically with gentamicin against enterococci, recently reviewers have suggested that therapy aimed at enterococci usually is not necessary. See Chap. 11 for a discussion of this topic. With the increased spectrum of activity of the newer cephalosporins (e.g., cefoxitin and cefotetan) and agents such as piperacillin-tazobactam, a single antibiotic may be useful in community-acquired mixed infections, saving the broader-acting imipenem-cilastatin for hospital-acquired infections. (See individual agent discussions.) 3. Synergism. When one antibiotic greatly enhances the activity of another, with more than an additive effect, this interaction is called synergy. Synergy can be measured in the laboratory by timed killing curves and checkerboard methods, but these tests are time-consuming and can be difficult to interpret. Examples of mechanisms of synergy include the following: a. Serial inhibition of microbial growth. Fixed combinations of trimethoprim (80 mg) and sulfamethoxazole (400 mg) will block successive steps in the synthesis of folic acid (see Chap. 28K). b. One antibiotic enhances the penetration of another. The synergistic interaction between penicillin and aminoglycosides may be mediated by this mechanism. It is believed that enterococci are impermeable to aminoglycosides. The penicillin alters the cell wall, allowing the aminoglycoside to penetrate the bacteria and thereby act effectively at the ribosomal level. 4. Limiting or preventing the emergence of resistance. This principle applies primarily to the treatment of tuberculosis. More than one agent is used routinely in an attempt to prevent the replication of preexisting resistant organisms (see Chap. 9). Whether or not two agents minimize the occurrence of resistance with gram-negative bacilli is unclear [6], but available data suggest that it does not. B. Antibiotic combinations commonly used are briefly outlined here: 1. Penicillin and gentamicin are synergistic against many enterococci. 2. Ticarcillin or piperacillin (and related penicillins) and aminoglycosides are synergistic against Pseudomonas aeruginosa and other gram-negative organisms (see Chap. 28E). 3. Cephalosporins and aminoglycosides may be synergistic against Klebsiella pneumoniae. P The drug combinations clavulanic acid-amoxicillin, clavulanic acid-ticarcillin, sulbactam-ampicillin, and tazobactam-piperacillin are discussed under the penicillins (see Chap. 28E). In these combinations, the clavulanic acid,

14 sulbactam, and tazobactam are inhibitors of beta-lactamase enzymes. They extend the activity of the antibiotic combined with these agents. C. Unique drug combination. Imipenem-cilastatin is another type of combination. The enzyme inhibitor (cilastatin) prevents metabolic breakdown of imipenem by the kidney (see Chap. 28G for a detailed discussion). D. Disadvantages of multiple antibiotics 1. An increased risk of drug sensitivities or toxicity is more likely when more agents are used. 2. An increased risk of colonization with a resistant bacterial organism may occur. If superinfection develops, such resistant organisms are more difficult to treat. 3. Possibility of antagonism a. Antagonism is present when the combined effect of two drugs is less than the effect of either drug alone; one of the drugs appears to interfere with the action of the second. How often this occurs clinically is unknown [6]. However, prior data suggest that the combination of tetracycline and penicillin for treatment of meningitis resulted in a poorer outcome than when penicillin was used alone, presumably due to the inhibition of growth by tetracycline, which interferes with the bactericidal action of penicillin. b. There has been recent interest in using the newer broadspectrum beta-lactams in combination with one another to obtain broad-spectrum coverage without exposing the patient to the possible toxicity of aminoglycosides, for example. Although this seems reasonable, there is in vitro and in vivo evidence that some beta-lactam-beta-lactam combinations may be antagonistic against certain organisms such as Enterobacter, Serratia, or Pseudomonas spp. This antagonism seems to be the result of the induction or derepression of chromosomally mediated beta-lactamases by one of the agents, leading to inactivation of the second antibiotic [4]. For example, antagonism has also been described when cefoxitin, cefamandole, or imipenem-cilastatin is combined with another cephalosporin or expanded penicillin. Apparently the cefoxitin or imipenem can induce a chromosomal beta-lactamase, which in turn may decrease the effectiveness of the cephalosporin or expanded penicillins [6]. (1) Moellering [4] concludes that the exact clinical significance of this phenomenon is not presently clear, but it must be kept in mind when one considers the clinical use of such drug combinations. (2) We tend to minimize the use of such combinations. 4. Higher costs. Combination antibiotics often are more expensive than single agents.

15 VI. 5. False sense of security. Although appealing at times, the use of multiple agents to treat all possible organisms often is not possible, practical, or necessary and may be associated with significant complications. Question 6. What are the important host factors? There may be special characteristics of the host that must be considered in choosing an antibiotic for use in individual patients. Some examples are given here. A. Genetic factors. Patients with glucose-6-phosphate dehydrogenase (G-6- PD) deficiency may develop hemolysis from sulfonamides, nitrofurantoin, and chloramphenicol [4]. B. Pregnancy and lactation. Certain drugs may pose special problems (e.g., the tetracyclines, which may cause hepatotoxicity in the mother and dentition problems in the infant). Because of the physiologic changes that occur in the mother during pregnancy (e.g., increases in total body water, with an increase in the apparent volume of distribution, increases in glomerular filtration rates and renal excretion of many antibiotics), overall serum drug levels of antibiotics are lower during gestation [7A]. Therefore, in critical infections, serum levels of antibiotics may need to be monitored and compensatory dosage adjustments may be necessary [7A]. 1. Placental transfer of antibiotics. Whenever possible, pregnant women should avoid all drugs because of the risk of fetal toxicity. Table 3-3 (on p. 71) shows the infant and maternal serum concentrations of selected antibiotics. This topic P1078 has been reviewed in detail [7A] [8] [9] and is summarized as follows: a. Antibiotics considered safe in pregnancy include the penicillins (with the possible exception of ticarcillin) [4], the cephalosporins, erythromycin base, and probably aztreonam. b. Antibiotics to be used with caution include the aminoglycosides, vancomycin, clindamycin, imipenemcilastatin, trimethoprim, and nitrofurantoin. c. Antibiotics contraindicated in pregnancy include chloramphenicol, erythromycin estolate, tetracycline, fluoroquinolones, and TMP-SMX (Bactrim, Septra). Although controversial, we would avoid metronidazole because of its carcinogenic potential (see Chap. 28P). Sulfonamides should be avoided in the last trimester of pregnancy. Some experts suggest avoiding ticarcillin as it has been shown to be teratogenic in rodents [4] See Chap. 28E. 2. Antibiotics in breast milk. Limited information is available regarding adverse effects in nursing neonates from antibiotics administered to their mothers. If possible, nursing mothers should avoid all drugs. As in pregnancy, chloramphenicol, tetracycline,

16 sulfonamides, and metronidazole should be avoided. Until further data are available, we suggest avoiding the use of fluoroquinolones. Table 3-4 (on p. 72) shows the concentrations of selected antibiotics in breast milk and milk-plasma ratios. The total daily dose a nursing baby receives often probably is not toxicologically significant. 3. The US Food and Drug Administration's (FDA's) use-inpregnancy drug-rating system is shown in Table 28A-7 (Table Not Available). These pregnancy categories are based on the degree to which available information has ruled out risk to the fetus balanced against the drug's potential benefits to the patients. This topic has recently been reviewed [7A]. The human embryo is most vulnerable to teratogenic insult during the first trimester (days 1-70 of gestation). During the second trimester (days of gestation), the fetal organs have been developed and growth continues; agents with antimetabolic activity, such as the folate antagonists, have the most theoretical potential for adverse effects. The third trimester (day 154 to delivery) is characterized by an impaired fetal ability to metabolize toxic agents and competition of the drugs with endogenous substances (e.g., bilirubin) for plasma proteinbinding sites [7A]. C. Renal function. Renal failure may affect not only the choice of antibiotic but also its dosages [10] [10A] (see discussions of individual agents). Consequently, renal function should be monitored in patients treated with antibiotics that are potentially nephrotoxic and primarily excreted by the kidney. These are summarized in Table 28A-8. Serum antibiotic levels, especially when aminoglycosides are used, should be monitored, as should serum creatinine, every 2-4 days. 1. Dosages of antibiotics excreted by the kidney are modified based on the patient's creatinine clearance. P The serum creatinine may not accurately reflect the patient's renal function, especially in the elderly, who may have decreased creatinine production. The creatinine clearance is a better measure of renal function. By modifying the equation of Cockcroft and Gault [11], it is possible to estimate the patient's creatinine clearance from the patient's age, gender, body weight (in kilograms), and serum creatinine [10] as follows: a. (1) Female estimated creatinine clearance = 85% of male value (2) Some prefer to use ideal body weight (IBW), which can be calculated as: (a) Male = 50 kg kg per each inch over 5 feet (in

17 height) (b) Female = 45.5 kg kg per each inch over 5 feet (3) In the obese patient, we use IBW to estimate the creatinine clearance. b. If the patient is oliguric, the creatinine clearance is estimated at < 10 ml/min [10]. c. Example: A 70-year-old man has a weight of 70 kg and a serum creatinine of 2.2. His estimated creatinine clearance is: d. In patients with severe hepatic insufficiency, this formula may overestimate the creatinine clearance. See sec. D.4. D. Liver function. The half-life of an antibiotic excreted by the liver may be prolonged if there is relative hepatic insufficiency [12] (see individual agent discussions of chloramphenicol, nafcillin, clindamycin, and erythromycin). Unfortunately, there is no easily performed laboratory test to assess for hepatic insufficiency (except possibly a prolonged prothrombin time) comparable to the serum creatinine test in renal failure. Table 28A-8 summarizes agents excreted primarily by the liver. Our understanding of modifying dosages in hepatic insufficiency is not as sophisticated as it is for renal insufficiency [12]. However, four issues deserve special emphasis in patients with hepatic insufficiency. 1. Aminoglycoside use may be associated with an increased risk of nephrotoxicity, as reviewed in Chap. 28H. 2. Beta-lactam antibiotic use in one study was associated with an increased risk of leukopenia when standard doses of betalactam antibiotics were used in patients with underlying liver disease [13]. The probable mechanism is P1080 impaired hepatic metabolism of the beta-lactam antibiotics, resulting in bone marrow suppression of white cell precursors from excessive antibiotic concentrations. The authors proposed a reduction in dosages of beta-lactam antibiotic when used in patients with significant hepatic dysfunction [13]. 3. Drugs primarily excreted or detoxified by the liver (e.g., chloramphenicol, clindamycin) need dose adjustments. Other drugs that should be used with caution or for which serum levels should be monitored include fluconazole, itraconazole, nitrofurantoin, and pyrazinamide [4] [14]. See Table 28A-8 and individual chapter discussions. 4. When selecting a dose for a potentially nephrotoxic drug, creatinine clearance (glomerular filtration rate [GFR]) should be estimated (just as in the elderly) even when the serum creatinine is normal [14].

18 VII. a. Normal GFR values are reliable in this setting. b. Low GFR may overestimate the true GFR (by two-to threefold) as measured by an inulin clearance. This may be accounted for by underproduction of creatinine resulting from diminished muscle mass or by a decreased rate of hepatic production of creatine, the substrate for the production of creatinine in muscle [14]. To provide a better estimate of GFR in this setting, determination of a creatinine index sometimes is suggested [14]. In practice for those with an estimated low GFR and severe hepatic disease, we assume their estimated creatinine clearance may be approximately 50% of the calculated estimate using the formula in sec. C.2. E. Humoral and cellular host defense mechanisms. Patients receiving corticosteroid therapy, chemotherapy, or radiation therapy, especially if they are leukopenic, are at risk for bacterial infections. Bactericidal antibiotics usually are preferred in such patients for previously stated reasons. F. Prosthetic devices predispose the host to infections that may be highly subacute at times [15]. See individual chapter topics (e.g., prosthetic valve endocarditis, Chap. 10). It often is necessary to remove the foreign body to cure an infection in the vicinity of a prosthetic heart valve or joint implant [4]. Question 7. What is the best route of administration? A. Parenteral antibiotics are almost always used in serious infections to ensure adequate blood levels. 1. Intravenous therapy is mandatory if hypotension is present or in a patient with a bleeding diathesis or thrombocytopenia and is preferred when high blood levels are important (e.g., in sepsis, meningitis, at least initial therapy of endocarditis, and gramnegative pneumonias). The absorption of intramuscularly administered antibiotics may be impaired in diabetic patients [4]. Therefore, intravenous therapy is preferred in diabetic patients with presumed or known bacteremia [4] or serious illness. 2. Intramuscular therapy. Many drugs cannot be tolerated by this route for more than a few doses. Some of the cephalosporins (e.g., cefazolin and ceftriaxone) provide excellent levels after intramuscular injection. Both procaine penicillin and aminoglycosides are well tolerated by intramuscular injection, although absorption of the latter can be unpredictable. Imipenem can be given IM. 3. Continuous versus intermittent bolus intravenous infusion. Whether intravenously administered antibiotics should be given by continuous infusion or by intermittent bolus remains controversial [4]. This is reviewed elsewhere [16] [16A]. a. Continuous infusions may result in less vein irritation and phlebitis. Prior animal model studies suggested that concentrations of penicillins and cephalosporins in fibrin clots were related to peak serum levels achieved; therefore, intermittent bolus therapy seemed appropriate

19 for endocarditis and tissue infections [4]. Recent data suggest that the clinical effectiveness of beta-lactam antibiotics is optimal when the concentration at the site of infection exceeds the minimum inhibitory concentration (MIC) of the infecting organism for a prolonged time (i.e., animal model data favors continuous infusion for serious systemic infections) [4]. This is called time-dependent bactericidal activity, which has little relationship to the magnitude of drug concentrations as long as the concentrations are above the MIC or really the minimal bactericidal concentration (MBC, see related discussion in Chap. 25 ) and includes the beta-lactam antibiotics and vancomycin [16A]. P1081 Multiple, small, frequent doses or continuous infusions produce similar or superior bactericidal effects compared with infrequently administered larger doses. The exception would be a beta-lactam with a prolonged halflife (e.g., ceftriaxone) that provides persistence of effective levels with infrequent dosing. At this point, while awaiting other clinical data, we do not advocate using continuous infusions of time-dependent antibiotics (e.g., beta-lactams). b. Intermittent infusions may be preferred for antibiotics that exhibit concentration-dependent bactericidal activity over a wide range of drug concentrations; i.e., the rate and extent of bactericidal action increase with increasing concentrations above the MBC up to a point of maximum effect, usually 5-10 times the MBC [16A]. The aminoglycosides and fluoroquinolones demonstrate this type of activity [4] [16A] ; the higher the drug level, the greater the rate of bacterial clearance, which slows as the drug level falls [16A]. (1) Potential implications. Large, infrequently administered doses of concentration-dependent agents (e.g., aminoglycosides) that achieve maximal concentrations at peak at the site of infection should produce optimal bactericidal effect [16A]. This is in large part the basis for once-daily regimens of aminoglycoside dosing, which is discussed in detail in Chap. 28H. (2) However, clinical studies that clearly prove this approach (e.g., once-daily aminoglycoside dosing) superior to other dosing regimens are still not available. Moellering emphasizes that "definitive clinical studies

20 providing unequivocal support for these concepts remain to be carried out" [4]. In his 1995 review, Levison concludes: "The optimal dosing interval of concentrationdependent antimicrobial agents remains an unanswered question for any individual patient and type of infection, and is under study for aminoglycosides" [16A]. Therefore, the long-term clinical implications of this dosing approach await further study. B. Oral absorption of an antibiotic, in general, is often too unpredictable to trust in serious infections. 1. Completion of antibiotic therapy. Well-absorbed oral agents may be used to complete a full course of therapy in uncomplicated infections. For example, in the patient with pyelonephritis, initially with dehydration, who is responding well after 1-4 days of intravenous therapy, one may elect to complete the course of therapy with oral therapy. A patient with a wound infection that required intravenous clindamycin may complete the course with oral clindamycin, as this is well absorbed. See specific discussions of oral cefuroxime (Chap. 28F), clindamycin (Chap. 28I), TMP-SMX (Chap. 28K), metronidazole (Chap. 28P), and the fluoroquinolones (Chap. 28S). The new erythromycinlike oral antibiotics (e.g., azithromycin and clarithromycin) are discussed in Chap. 28M. 2. Common outpatient infections. Many common minor infections respond to oral medications: pharyngitis, skin infections, UTIs, mycoplasmal pneumonia, and bronchitis. 3. Special situations. In special circumstances, well-absorbed oral agents may be used in serious infections; for example, TMP- SMX is available as an oral agent and has been used either initially or following intravenous therapy (e.g., in patients with AIDS and Pneumocystis carinii pneumonia). See Chap. 24. The new fluoroquinolones may allow oral therapy in certain settings (see Chap. 28S). C. Home intravenous antibiotics. In the mid-1970s, various groups began to report their experiences with self-administration of intravenous antibiotics at home. This approach is cost-effective but also has many difficult-to-measure variables in terms of the patient's being at his or her own home and often able to return to school, work, or social functions. 1. Types of infections. Patients with stable infections requiring prolonged intravenous therapy--for example, bone and joint infections, subacute endocarditis, and pulmonary infections in cystic fibrosis patients--are potential candidates. 2. Typical criteria for home intravenous therapy have been [17] [18] [19] [20] [21] reviewed elsewhere and usually include the following [22] : P1082