Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

83. Antimicrobial Regimen Selection

Grace C. Lee and David S. Burgess


KEY CONCEPTS

 Images Every attempt should be made to obtain specimens for culture and sensitivity testing prior to initiating antibiotics.

 Images Empirical antibiotic therapy should be based on knowledge of likely pathogens for the site of infection, information from patient history (e.g., recent hospitalizations, work-related exposure, travel, and pets), and local susceptibility.

 Images Patients with delayed dermatologic reactions (i.e., rash) to penicillin generally can receive cephalosporins. Patients with type I hypersensitivity reactions (i.e., anaphylaxis) to penicillins should not receive cephalosporins. Alternatives to the cephalosporins include aztreonam, quinolones, sulfonamide antibiotics, or vancomycin based on type of coverage indicated.

 Images Creatinine clearance should be estimated for every patient who is to receive antibiotics and the antibiotic dose interval adjusted accordingly. Hepatic function should be considered for drugs eliminated through the hepatobiliary system, such as clindamycin, erythromycin, and metronidazole.

 Images All concomitant drugs and nutritional supplements should be reviewed when an antibiotic is added to a patient’s therapy to ensure drug–drug interactions will be avoided.

 Images Combination antibiotic therapy may be indicated for polymicrobial infections (e.g., intra-abdominal, gynecologic infections), to produce synergistic killing (such as β-lactam plus aminoglycoside vs. Pseudomonas aeruginosa), or to prevent the emergence of resistance.

 Images All patients receiving antibiotics should be monitored for resolution of infectious signs and symptoms (e.g., decreasing temperature and white blood cell count) and adverse drug events.

 Images Antibiotics with the narrowest effective spectrum of activity are preferred. Antibiotic route of administration should be evaluated daily, and conversion from IV to oral therapy should be attempted as signs of infection improve for patients with functioning GI tracts (general exceptions are endocarditis and CNS infections).

 Images Patients not responding to an appropriate antibiotic treatment in 2 to 3 days should be reevaluated to ensure (a) the correct diagnosis, (b) that therapeutic drug concentrations are being achieved, (c) that the patient is not immunosuppressed, (d) that the patient does not have an isolated infection (i.e., abscess, foreign body), or (e) that resistance has not developed.


Choosing an antimicrobial agent to treat an infection is far more complicated than matching a drug to a known or suspected pathogen.1,2 Most clinicians generally follow a systematic approach to select an antimicrobial regimen (Table 83–1). Problems arise when this systematic approach is replaced by prescribing broad-spectrum therapy to cover as many organisms as possible. Consequences of not using the systematic approach include the use of more expensive and potentially more toxic agents, which can, in turn, lead to widespread resistance and difficult-to-treat superinfections. Another abuse of antimicrobial agents is administration when they are not needed such as when they are prescribed for self-limited clinical conditions that are most likely viral in origin (i.e., the common cold).

TABLE 83-1 Systematic Approach for Selection of Antimicrobials

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Initial selection of antimicrobial therapy is nearly always empirical, which is prior to documentation and identification of the offending organism. Infectious diseases generally are acute, and a delay in antimicrobial therapy can result in serious morbidity or even mortality. Thus, empirical antimicrobial therapy selection should be based on information gathered from the patient’s history and physical examination and results of Gram stains or of rapidly performed tests on specimens from the infected site. This information, combined with knowledge of the most likely offending organism(s) and an institution’s local susceptibility patterns, should result in a rational selection of antibiotics to treat the patient. This chapter introduces a systematic approach to the selection of antimicrobial therapeutic regimens.

CONFIRMING THE PRESENCE OF INFECTION

Fever

The presence of a temperature greater than the expected 37°C (98.6°F) “normal” body temperature is considered a hallmark of infectious diseases. Body temperature is controlled by the hypothalamus. In addition, the circadian rhythm, a built-in temperature cycle, is also operational. The daily temperature rhythm can vary for each individual. In a healthy person, the internal thermostat is set between the morning low temperature and the afternoon peak as controlled by the circadian rhythm. During fever, the hypothalamus is reset at a higher temperature level.

Fever is defined as a controlled elevation of body temperature above the normal range. The average normal body temperature range taken orally is 36.7°C to 37°C (98°F to 98.6°F). Body temperatures obtained rectally generally are 0.6°C (1°F) higher and axillary temperatures are 0.6°C (1°F) lower than oral temperatures, respectively. Skin temperatures are also less than the oral temperature but can vary depending on the specific measurement method.

Fever can be a manifestation of disease states other than infection. Collagen vascular (autoimmune) disorders and several malignancies can have fever as a manifestation. Fever of unknown or undetermined origin is a diagnostic dilemma and is reviewed extensively elsewhere.3

Many drugs have been identified as causes of fever.4 Drug-induced fever is defined as persistent fever in the absence of infection or other underlying condition. The fever must coincide temporally with the administration of the offending agent and disappear promptly on its withdrawal, after which the temperature remains normal. Possible mechanisms of drug-induced fever are either a hypersensitivity reaction or development of antigen–antibody complexes that result in the stimulation of macrophages and the release of interleukin 1 (IL-1). Although this is not a common drug effect (accounting for no more than 5% of all drug reactions), it should be suspected when obvious reasons for fever are not present. Almost any medication can produce fever, but β-lactam antibiotics, anticonvulsants, allopurinol, hydralazine, nitrofurantoin, sulfonamides, phenothiazines, and methyldopa appear to be responsible more often than others.

Noninfectious etiologies of fever can be referred to as “false-positives.” Although these certainly can confuse the clinician, even more troublesome are false-negatives: the absence of fever in a patient with signs and symptoms consistent with an infectious disease. Careful questioning of the patient or family is vital to assess the ingestion of any medication that can mask fever (e.g., aspirin, acetaminophen, nonsteroidal antiinflammatory agents, and corticosteroids). The use of antipyretics should be discouraged during the treatment of infection unless absolutely necessary because they can mask a poor therapeutic response. Moreover, elevated body temperature, unless very high (>40.5°C [105°F]), is not harmful and may be beneficial.

Signs and Symptoms

White Blood Cell Count

Most infections result in elevated white blood cell (WBC) counts (leukocytosis) because of the increased production and mobilization of granulocytes (neutrophils, basophils, and eosinophils), lymphocytes, or both to ingest and destroy invading microbes. The generally accepted range of normal values for WBC counts is between 4,000 and 10,000 cells/mm3 (4 × 109 and 10 × 109/L). Values above or below this range hold important prognostic and diagnostic value.

Bacterial infections are associated with elevated granulocyte counts, often with immature forms (band neutrophils) seen in peripheral blood smears. Mature neutrophils are also referred to as segmented neutrophils or polymorphonuclear (PMN) leukocytes. The presence of immature forms (left shift) is an indication of an increased bone marrow response to the infection. With infection, peripheral WBC counts can be very high, but they are rarely higher than 30,000 to 40,000 cells/mm3 (30 × 109 to 40 × 109/L). Because leukocytosis indicates the normal host response to infection, low leukocyte counts after the onset of infection indicate an abnormal response and generally are associated with a poor prognosis.

The most common granulocyte defect is neutropenia, a decrease in absolute numbers of circulating neutrophils. A thorough description of the consequences of neutropenia is given in Chapter 99. Lymphocytosis, even with normal or slightly elevated total WBC counts, generally is associated with tuberculosis and viral or fungal infections. Increases in monocytes can be associated with tuberculosis or lymphoma, and increases in eosinophils can be associated with allergic reactions to drugs or infections caused by metazoa. Many types of infections can be accompanied by a completely normal WBC count and differential.

Local Signs

The classic signs of pain and inflammation can manifest as swelling, erythema, tenderness, and purulent drainage. Unfortunately, these are only visible if the infection is superficial or in a bone or joint. The manifestations of inflammation in deep-seated infections (e.g., meningitis, pneumonia, endocarditis, and urinary tract infection) must be ascertained by examining tissues or fluids. For example, the presence of neutrophils in spinal fluid, lung secretions (sputum), or urine is highly suggestive of a bacterial infection.

Symptoms referable to an organ system must be sought out carefully because not only do they help in establishing the presence of infection, but they also aid in narrowing the list of potential pathogens. For example, a febrile patient with complaints of flank pain and dysuria can well have pyelonephritis. In this situation, enteric gram-negative bacilli, especially Escherichia coli, are the predominant pathogens. If a febrile patient has no symptoms suggestive of an organ system but only constitutional complaints, the list of possible infectious diseases is lengthy.3 A febrile individual with cough and sputum production probably has a pulmonary infection. What is not so evident, however, is the etiologic organism in this situation, because it can be caused by bacteria, mycobacteria, viruses, Chlamydia, or mycoplasmas.5 In this situation, attention to the patient’s history and background disease states is important. Even more important is a careful examination of the infected material (in this case sputum) to ascertain the identity of the pathogen.

IDENTIFICATION OF THE PATHOGEN

Microbiology Issues

Images Infected body materials must be sampled, if at all possible or practical, before institution of any antimicrobial therapy for two reasons. First, a Gram stain of the material might reveal bacteria, or an acid-fast stain might detect mycobacteria or actinomycetes. Second, a delay in obtaining infected fluids or tissues until after antimicrobial therapy is started might result in false-negative culture results or alterations in the cellular and chemical composition of infected fluids. This is particularly true in patients with urinary tract infections, meningitis, and septic arthritis.6

Blood cultures usually should be performed in the acutely ill febrile patient. Blood culture collection should coincide with sharp elevations in temperature, suggesting the possibility of microorganisms or microbial antigens in the bloodstream. Ideally, blood should be obtained from peripheral sites as two sets (one set consists of an aerobic bottle and one set an anaerobic bottle) from two different sites approximately 1 hour apart. In selected infections, bacteremia is qualitatively continuous (e.g., endocarditis), so cultures can be obtained at any time.7

In addition to the infected materials produced by the patient (e.g., blood, sputum, urine, stool, and wound or sinus drainage), other less accessible fluids or tissues must be obtained if they are suspected to be the infected site (e.g., spinal fluid in meningitis and joint fluid in arthritis). Abscesses and cellulitic areas also should be aspirated.

Interpreting Results

After a positive Gram stain, culture results, or both are obtained, the clinician must be cautious in determining whether the organism recovered is a true pathogen, a contaminant, or a part of the normal flora (see eChap. 24). The latter consideration is especially problematic with cultures obtained from the skin, oropharynx, nose, ears, eyes, throat, and perineum. These surfaces are heavily colonized with a wide variety of bacteria, some of which can be pathogenic in certain settings. For example, coagulase-negative staphylococci are found in cultures of all the aforementioned sites, yet are seldom regarded as pathogens unless recovered from blood, venous access catheters, or prosthetic devices.

Importantly, cultures of specimens from purportedly infected sites that are obtained by sampling from or through one of these contaminated areas might contain significant numbers of the normal flora. For urine cultures, the urinalysis should be used in combination with culture results to assess the presence of WBCs, nitrite, and leukocyte esterase to help confirm infection and rule out colonization.

Particularly problematic are expectorated sputum specimens that must be evaluated carefully by determination of the presence of squamous epithelial cells and leukocytes.5 A predominance of epithelial cells in sputum specimens reduces the likelihood that recovered bacteria are pathogenic, especially when multiple types of organisms are seen on Gram stain. In contrast, the discovery of leukocytes in large numbers with one predominant type of organism is a more reliable indicator of a valid collection. In general, however, sputum evaluation has poor sensitivity and specificity as a diagnostic test.5

Caution also must be used in the evaluation of positive culture results from normally sterile sites (e.g., blood, cerebrospinal fluid [CSF], or joint fluid). The recovery of bacteria normally found on the skin in large quantities (e.g., coagulase-negative staphylococci or diphtheroids) from one of these sites can be a result of contamination of the specimen rather than a true infection. However, these organisms can be pathogenic in certain settings.

Gram-staining techniques, culture methods, and serologic identification, as well as susceptibility testing, are discussed in detail in eChapter 24. Emphasis must be placed on the proper collection and handling of specimens and careful assessment of Gram stain or other test results in guiding the clinician toward appropriate selection of initial antimicrobial therapy.8

SELECTION OF PRESUMPTIVE THERAPY

Images To select rational antimicrobial therapy for a given clinical situation, a variety of factors must be considered. These include the severity and acuity of the disease, host factors, factors related to the drugs used, and the necessity for using multiple agents. In addition, there are generally accepted drugs of choice for the treatment of most pathogens (see Appendix 83–1).

Drugs of choice are compiled from a variety of sources and are intended as guidelines rather than as specific rules for antimicrobial use. These choices are influenced by local antimicrobial susceptibility data rather than information published by other institutions or national compilations. Each institution should publish an annual summary of antibiotic susceptibilities (antibiogram) for organisms cultured from patients. Antibiograms contain both the number of nonduplicate isolates for common species and the percentage susceptible to the antibiotics tested. To further guide empirical antibiotic therapy, some hospitals publish unit-specific antibiograms in unique patient care areas, such as intensive care units or burn units.

Susceptibility of bacteria can differ substantially among hospitals within a community. For example, the prevalence of hospital-acquired methicillin-resistant Staphylococcus aureus (HA-MRSA) in some centers is quite high, whereas in other centers the problem might be nonexistent. This particular situation will influence the selection of therapy for possible S. aureus infection, where the clinician must choose either a β-lactam or vancomycin. The problem of differing susceptibilities is not limited only to gram-positive bacteria but also is evident in gram-negative organisms, and all drug classes are affected.

Empirical therapy is directed at organisms that are known to cause the infection in question. These organisms are discussed for different sites of infection in Chapters 83 to 102. To define the most likely infecting organisms, a careful history and physical examination must be performed. The place where the infection was acquired should be determined, for example, the home (community acquired), nursing home environment, or hospital acquired (nosocomial). Nursing home patients can be exposed to potentially more resistant organisms because they are often surrounded by ill patients who are receiving antibiotics. Other important questions to ask infected patients regarding the history of present illness include the following:

   1. Are any other people sick at home, especially children?

   2. Are any unusual pets kept in the home such as pigeons?

   3. Where are you employed (i.e., are you exposed to contaminated meat or infectious biohazards)?

   4. Has there been any recent travel (i.e., to endemic areas of fungal infections or developing countries)?

Host Factors

Several host factors should be considered when evaluating a patient for antimicrobial therapy. The most important factors are drug allergies, age, pregnancy, genetic or metabolic abnormalities, renal and hepatic function, site of infection, concomitant drug therapy, and underlying disease states.

Allergy

Images Allergy to an antimicrobial agent generally precludes its use. Careful assessment of allergy histories must be performed because many patients confuse common adverse drug effects (i.e., GI disturbance) with true allergic reactions.9 Among the most commonly cited antimicrobial allergies are those to penicillin, penicillin-related compounds, or both. In the absence of complete penicillin skin testing capabilities, a rule of thumb for giving cephalosporins to patients allergic to penicillin is to avoid giving them to patients who give a good history for immediate or accelerated reactions (e.g., anaphylaxis, laryngospasm) and to give them under close supervision in patients with a history of delayed reactions, such as a rash.10 If a gram-negative infection is suspected or documented, therapy with a monobactam may be appropriate because cross-reactivity with other β-lactams is nonexistent.

Age

The patient’s age is an important factor both in trying to identify the likely etiologic agent and in assessing the patient’s ability to eliminate the drug(s) to be used. The best example of an age determinant of organisms is in bacterial meningitis, where the pathogens differ as the patient grows from the neonatal period through infancy and childhood into adulthood.6

For neonates, hepatic and liver functions are not well developed. Therefore, bilirubin excretion is decreased resulting in increased concentration of unconjugated bilirubin that can cause kernicterus. Neonates (especially when premature) can develop kernicterus when given sulfonamides. This results from displacement of bilirubin from serum albumin. In addition, neonates have more body water content that results in a larger volume of distribution leading to adjustments in antibiotic dosing regimens. Additional special drug considerations for pediatric patients include low frequency of adverse effects and compliance-enhancing features (e.g., absorption not affected by food, once- to twice-daily dosing, and good taste).11

The major physiologic change in persons older than 65 years of age is a decline in the number of functioning nephrons that, in turn, results in decreased renal function.12 This is usually manifested by an increased incidence of side effects caused by antimicrobials that are eliminated renally. For example, renal toxicity caused by aminoglycosides may be apparent much sooner during therapy than in younger patients.

Pregnancy

During pregnancy, not only is the fetus at risk for drug teratogenicity, but also the pharmacokinetic disposition of certain drugs can be altered.13 Penicillins, cephalosporins, and aminoglycosides are cleared from the peripheral circulation more rapidly during pregnancy. This is probably a result of marked increases in intravascular volume, glomerular filtration rate, and hepatic and metabolic activities. The net result is that maternal serum antimicrobial concentrations can be as much as 50% lower during this period than in the nonpregnant state. Increased dosages of certain compounds might be necessary to achieve therapeutic levels during late pregnancy.

Metabolic or Genetic Variation

Inherited or acquired metabolic abnormalities will influence the therapy of infectious diseases in a variety of ways. For example, patients with impaired peripheral vascular flow may not absorb drugs given by intramuscular injection. In addition, certain metabolic states can predispose patients to enhanced drug toxicity. For instance, patients who are phenotypically slow acetylators of isoniazid are at greater risk for peripheral neuropathy.14 Patients with severe deficiency of glucose-6-phosphate dehydrogenase can develop significant hemolysis when exposed to such drugs as sulfonamides, nitrofurantoin, nalidixic acid, antimalarials, and dapsone. Although mild deficiencies are found in African Americans, the more severe forms of the disease generally are confined to persons of eastern Mediterranean origin. Another example is the antiretroviral drug abacavir, which is associated with a severe hypersensitivity reaction, consisting of fever, rash, abdominal pain, and respiratory distress. This risk has been associated with the presence of a human leukocyte antigen allele HLA-B*5701. Routine screening for the presence of this allele before initiating treatment with abacavir is a recommendation in the current HIV treatment guidelines.

Organ Dysfunction

Images Patients with diminished renal or hepatic function or both will accumulate certain drugs unless the dosage is adjusted.15,16 Recommendations for dosing antibiotics in patients with liver dysfunction are not as formalized as guidelines for patients with renal dysfunction. Antibiotics that should be adjusted in severe liver disease include clindamycin, erythromycin, metronidazole, and rifampin. Significant accumulation can occur when both liver dysfunction and renal dysfunction are present for the following drugs: cefotaxime, nafcillin, piperacillin, and sulfamethoxazole.

Concomitant Drugs

Images Any concomitant therapy that the patient is receiving can influence the drug selection, dose, and monitoring. For instance, administration of isoniazid to a patient who is also receiving phenytoin can result in phenytoin toxicity secondary to inhibition of phenytoin metabolism by isoniazid. Furthermore, drugs that possess similar adverse effect profiles can increase the risk for effects (i.e., two drugs that cause nephrotoxicity or neutropenia). A detailed review of drug interactions is beyond the scope of this chapter, but an excellent textbook on this subject is available.17 Lists of potentially severe drug–drug interactions are provided in Table 83–2.

TABLE 83-2 Major Drug Interactions with Antimicrobials

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Concomitant Disease States

Concomitant disease states can influence the selection of therapy. Certain diseases will predispose patients to a particular infectious disease or will alter the type of infecting organism. For example, patients with diabetes mellitus and the resulting peripheral vascular disease often develop infections of the lower extremity soft tissue. Moreover, the alterations in peripheral blood flow associated with the disease and perhaps altered immunity make such infections more difficult to treat than in nondiabetics. Patients with chronic lung disease or cystic fibrosis develop frequent pulmonary infections that can be caused by somewhat different microorganisms than are found in otherwise normal hosts.

Patients with immunosuppressive diseases, such as malignancies or acquired immunologic deficiencies, are highly predisposed to infections, and the types of causative or pathogenic organisms can be vastly different from what would be expected (see Chap. 99). For instance, patients undergoing chemotherapy for acute forms of leukemia often are profoundly granulocytopenic and are predisposed to infections caused by bacteria and fungi.18 Patients with the acquired immunodeficiency syndrome (AIDS) often become infected with an enormous variety of organisms (see Chap. 102).

Many factors predisposing to infection are related to disruption of the host’s integumentary barriers. For example, trauma, burns, and iatrogenic wounds induced in surgery can lead to a substantial risk of infection depending on the severity and location of the injury or disruption. For a complete discussion of the various risks involved in surgical procedures, see Chapter 100.

Drug Factors

Pharmacokinetic and Pharmacodynamic Considerations

Integration of both pharmacokinetic and pharmacodynamic properties of an agent is important when choosing antimicrobial therapy to ensure efficacy and to prevent resistance.19 Early researchers relied solely on pharmacokinetic properties such as the area under the (drug concentration) curve (AUC), maximum observed concentration (peak), and drug half-life to optimize therapy. Pharmacodynamics is the study of the relationship between drug concentration and the effects on the microorganism. There is an important relationship between both pharmacokinetic and microbiologic parameters that has resulted in measurements such as AUC:minimal inhibitory concentration (MIC) ratio, peak:MIC ratio, and time (T) the concentration is above MIC (T > MIC).1923

Aminoglycosides exhibit concentration-dependent bactericidal effects. An example of the integration of pharmacokinetics and microbiologic activity is the use of high-dose, once-daily aminoglycosides. For these regimens, the drug is given as a single large daily dose to maximize the peak:MIC ratio. Aminoglycosides also possess a postantibiotic effect (persistent suppression of organism growth after concentrations decrease below the MIC) that appears to contribute to the success of high-dose, once-daily administration. Fluoroquinolones exhibit concentration-dependent killing activity, but optimal killing appears to be characterized by the AUC:MIC ratio.

β-Lactams display time-dependent bactericidal effects. Killing activity is enhanced only marginally if drug concentration exceeds the MIC. Therefore, the important pharmacodynamic relationship for these antimicrobials is the duration that drug concentrations exceed the MIC (T > MIC). Effective dosing regimens require serum drug concentrations to exceed the MIC for at least 40% to 50% of the dosing interval. Frequent small doses, continuous infusion, or prolonged infusion of β-lactams appears to be correlated with positive outcomes.

A detailed discussion on antimicrobial pharmacokinetics–pharmacodynamics is beyond the scope of this chapter. However, excellent sources of information on this topic are available.1923

Tissue Penetration

The importance of tissue penetration varies with site of infection. Some of the difficulties in interpreting data include a lack of correlation with clinical outcomes and poor understanding of whether the antimicrobial agents are present in a biologically active form. An example of the former problem is the recognized efficacy of drugs with low biliary fluid concentrations in the treatment of cholecystitis, cholangitis, or both and the absence of the enhanced efficacy of drugs whose primary route of elimination is biliary excretion of active drug. An example of the latter difficulty is with penetration to deep infections, such as abscesses, where various factors such as acid pH, WBC products, and various enzymes can inactivate even high concentrations of certain drugs.

The CNS is one body site where antimicrobial penetration is relatively well defined, and correlations with clinical outcomes are established.6,24 CSF concentrations of antimicrobial agents necessary to cure bacterial meningitis have been defined, and drugs that do not reach significant concentrations in the CSF should be either avoided or instilled directly, if feasible.

Caution must be exercised when selecting an antimicrobial agent for clinical use on the basis of tissue or fluid penetration. Body fluids where drug concentration data are clinically relevant include CSF, urine, synovial fluid, and peritoneal fluid. Apart from these areas, more attention should be paid to clinical efficacy, antimicrobial spectrum, toxicity, and cost than to comparative data on penetration into a given body site.

The proper route of administration for an antimicrobial depends on the site of infection. Parenteral therapy is warranted when patients are being treated for febrile neutropenia or deep-seated infections such as meningitis, endocarditis, and osteomyelitis. Severe pneumonia often is treated initially with IV antibiotics and switched to oral therapy as clinical improvement is evident.5,25 Patients treated in the ambulatory setting for upper respiratory tract infections (e.g., pharyngitis, bronchitis, sinusitis, and otitis media), lower respiratory tract infections, skin and soft-tissue infections, uncomplicated urinary tract infections, and selected sexually transmitted diseases can usually receive oral therapy.

Drug Toxicity

It is incumbent on health professionals to avoid toxic drugs whenever possible. Antibiotics associated with CNS toxicities, usually when not dose-adjusted for renal function, include penicillins, cephalosporins, quinolones, and imipenem. Hematologic toxicities generally are manifested with prolonged use of nafcillin (neutropenia), piperacillin (platelet dysfunction), cefotetan (hypoprothrombinemia), chloramphenicol (bone marrow suppression, both idiosyncratic and dose-related toxicity), and trimethoprim (megaloblastic anemia). Reversible nephrotoxicity classically is associated with aminoglycosides and vancomycin. Irreversible ototoxicity can occur with aminoglycosides. In the outpatient setting, patients must be counseled regarding photosensitivity with azithromycin, quinolones, tetracyclines, pyrazinamide, sulfamethoxazole, and trimethoprim. Lastly, all antibiotics have been implicated in causing diarrhea and colitis secondary to Clostridium difficile26 (see Chap. 91). List of potential antibiotic adverse drug reactions is provided in Table 83–3.

TABLE 83-3 Antimicrobial Adverse Drug Reactions

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Aside from consideration of drug toxicity, some antimicrobial use requires more intensive risk–benefit analysis. An example of this is the decision to use isoniazid prophylactically to prevent tuberculosis. Because the hepatotoxicity of isoniazid increases in frequency with age, older persons (>45 years of age) who are candidates for isoniazid prophylaxis (positive skin test) must have additional risk factors for tuberculosis to balance the potential toxic effects. These include evidence of recent skin test conversion, immunosuppression, or previous gastrectomy. Older patients without additional risk factors are more likely to suffer toxicity from isoniazid than derive benefit from its use.27

Combination Antimicrobial Therapy

Images In selecting a drug regimen for a given patient, consideration must be given to the necessity of using more than one drug.28 Combinations of antimicrobials generally are used to broaden the spectrum of coverage for empirical therapy, achieve synergistic activity against the infecting organism, and prevent the emergence of resistance.

Broadening the Spectrum of Coverage

Increasing the coverage of antimicrobial therapy generally is necessary in mixed infections where multiple organisms are likely to be present. This is the case in intraabdominal and female pelvic infections, in which a variety of aerobic and anaerobic bacteria can produce disease.29 Traditionally, a combination of a drug active against aerobic gram-negative bacilli (such as an aminoglycoside) and a drug active against anaerobic bacteria (such as metronidazole or clindamycin) is selected. Newer compounds, which possess good activity against both of these types of organisms, such as the β-lactam/β-lactamase inhibitor combinations, carbapenems, or glycylcyclines, might be adequate to replace the combination and thereby reduce the cost of therapy. The other clinical situation in which an increased spectrum of activity is desirable is with nosocomial infections.25

Synergism

The achievement of synergistic antimicrobial activity is advantageous for infections caused by enteric gram-negative bacilli in immunosuppressed patients. Laboratory tests to identify synergy between antibiotic combinations are described in eChapter 24. Traditionally, combinations of aminoglycosides and β-lactams have been used because these drugs together generally act synergistically against a wide variety of bacteria. However, the data supporting superior efficacy of synergistic over nonsynergistic combinations are weak. At best, it would appear that synergistic combinations produce better results in certain infections caused by Pseudomonas aeruginosa and Enterococcusspecies.3032

The most obvious example of the use of synergy is the treatment of enterococcal endocarditis. The causative organism is usually only inhibited by penicillins, but it is killed rapidly by the addition of streptomycin or gentamicin to a penicillin.7 The need for bactericidal activity in the treatment of endocarditis underscores the need for these synergistic combinations.

Preventing Resistance

The use of combinations to prevent the emergence of resistance is applied widely but not often realized. The only circumstance where this has been clearly effective is in the treatment of tuberculosis. The prevalence of resistance to a first-line drug such as isoniazid or rifampin in a population of organisms may be as high as 1 in 106 to 108. Because the bacterial load in a patient with active tuberculosis often exceeds this, two drugs are given to reduce the likelihood of encountering resistance to less than 1 in 10.27 There is ample evidence from in vitro data and experimental bacterial infections that combinations of drugs with different mechanisms are effective in the prevention of the emergence of resistance. Data from clinical trials, however, either are conflicting or do not convincingly support this concept.32


Clinical Controversy…

Despite evidence of potential advantages of definitive combination therapy for gram-negative infections from in vitro and animal studies, clinical data have been conflicting, and there is evidence that it may even be harmful. Currently, whether definitive combination antimicrobial therapy is more efficacious than monotherapy for infections with gram-negative bacteria remains a debate.

Disadvantages of Combination Therapy

Although there are potentially beneficial effects from combining drugs, there also are potential disadvantages, including increased cost, greater risk of drug toxicity such as nephrotoxicity with aminoglycosides, amphotericin, and possibly vancomycin, and superinfection with even more resistant bacteria.3032

The combination of two or more antibiotics can result in antagonistic effects. Clinically, the effect of antagonism may be evident when one drug induces β-lactamase production and another drug is β-lactamase unstable. Cefoxitin and imipenem are examples of drugs capable of inducing β-lactamases and may result in more rapid inactivation of penicillins when used together.

MONITORING THERAPEUTIC RESPONSE

Images After antimicrobial therapy has been instituted, the patient must be monitored carefully for a therapeutic response. Culture and sensitivity reports from specimens sent to the microbiology laboratory must be reviewed and the therapy changed accordingly. Use of agents with the narrowest spectrum of activity against identified pathogens is recommended. If anaerobes are suspected, even if they are not identified, anaerobic therapy should be continued.

Patient monitoring should include many of the same parameters used to diagnose the infection. The WBC count and temperature should start to normalize. Physical complaints from the patient also should diminish (i.e., decreased pain, shortness of breath, cough, or sputum production). Appetite should improve. However, radiologic improvement can lag behind clinical improvement.

Determinations of serum (or other fluid) levels of antimicrobials can be useful in ensuring outcome, preventing toxicity, or both. There are only a few antimicrobials that require serum concentration monitoring and then only in selected situations. These include the aminoglycosides, vancomycin, flucytosine, and chloramphenicol. Achievement of adequate aminoglycoside concentrations within the first few days of therapy of gram-negative infection has been correlated with better therapeutic outcome.33

Changes in the volume of distribution can have a significant impact on the efficacy, safety, or both of therapy. An unexpectedly low volume of distribution (such as in the dehydrated patient) will result in higher, potentially toxic drug concentrations, whereas a larger-than-expected volume of distribution (such as in patients with edema or ascites) will result in low, potentially subtherapeutic concentrations. The most effective methods use measured serum concentrations of the drugs rather than estimations from renal function tests to assess true drug clearance from the body.

Images As patients improve clinically, the route of administration should be reevaluated. Streamlining therapy from parenteral to oral (switch therapy) has become an accepted practice for many infections.5Criteria that should be present to justify a switch to oral therapy include (a) overall clinical improvement, (b) lack of fever for 8 to 24 hours, (c) decreased WBC count, and (d) a functioning GI tract. Drugs that exhibit excellent oral bioavailability when compared with IV formulations include ciprofloxacin, clindamycin, doxycycline, levofloxacin, metronidazole, moxifloxacin, linezolid, and trimethoprim–sulfamethoxazole.

FAILURE OF ANTIMICROBIAL THERAPY

Images A variety of factors may be responsible for an apparent lack of response to therapy. Patients who fail to respond over 2 to 3 days require a thorough reevaluation. It is possible that the disease is not infectious or is nonbacterial in origin, or there is an undetected pathogen in a polymicrobial infection. Other factors include those directly related to drug selection, the host, or the pathogen. Laboratory error in identification, susceptibility testing, or both (presence of inoculum effect or resistant subpopulations) is a rare cause of antimicrobial failure.

Failures Caused by Drug Selection

Factors related directly to the drug selection include an inappropriate drug selection, dosage, or route of administration. Malabsorption of a drug product because of GI disease (such as a short-bowel syndrome) or a drug interaction (such as complexation of fluoroquinolones with multivalent cations resulting in reduced absorption) can lead to potentially subtherapeutic serum concentrations. Accelerated drug elimination is also possible. This can occur in patients with cystic fibrosis or during pregnancy, when more rapid clearance or larger volumes of distribution can result in low serum concentrations, particularly for aminoglycosides. A common cause of failure of therapy is poor penetration into the site of infection. This is especially true for sites such as the CNS, eye, and prostate gland. Drug failure also can result from drugs that are highly protein bound or that are chemically inactivated at the site of infection.

Failures Caused by Host Factors

Host defenses must be considered when evaluating a patient who is not responding to antimicrobial therapy. Patients who are immunosuppressed (e.g., granulocytopenia from chemotherapy or AIDS) may respond poorly to therapy because their defenses are inadequate to eradicate the infection despite seemingly adequate drug regimens. A good example is the poor response of infection in granulocytopenic patients that is seen when their WBC counts remain low during therapy. This contrasts with a much better response when granulocyte counts increase during therapy.

Other host factors are related to the need for surgical drainage of abscesses or removal of foreign bodies, necrotic tissue, or both. If these situations are not corrected, they result in persistent infection and, occasionally, bacteremia despite adequate antimicrobial therapy.

Failures Caused by Microorganisms

There are two types of resistance, intrinsic and acquired resistance. Intrinsic resistance is when the antimicrobial agent never had activity against the bacterial species. For example, gram-negative bacteria are naturally resistant to vancomycin because the drug cannot penetrate the outer membrane of gram-negative bacteria. Acquired resistance is when the antimicrobial agent was originally active against the bacterial species but the genetic makeup of the bacteria has changed so the drug can no longer be effective.34

The strategies used by bacteria to develop acquired resistance are primarily classified into four general mechanisms of resistance: (a) alteration in the target site, (b) change in membrane permeability, (c) efflux pump, and (d) drug inactivation. Bacteria can use one or more of these mechanisms against a specific antibiotic class. Furthermore, a single mechanism of resistance can result in resistance to multiple related or unrelated classes of antibiotics.

Drug inactivation through either β-lactamases or aminoglycoside-modifying enzymes is the predominant mechanism of resistance. For example, β-lactamases can be either plasmid or chromosomally mediated. In addition, the expression of β-lactamases can be induced or constitutive. There are now multiple types and classes of β-lactamases identified, which is beyond the scope of this chapter. However, there are several outstanding papers discussing all of the different types of β-lactamases.3537

The increase in resistance among bacteria is believed to be a result of continued overuse of antimicrobials in the community, as well as in hospitals, and the increasing prevalence of immunosuppressed patients receiving long-term suppressive antimicrobials for the prevention of infections. These resistance patterns are regionally variable, and susceptibility patterns in the community (or hospital) should be monitored closely to promote rational antimicrobial selection.34

Enterococci have been isolated with multiple resistance patterns. They may be resistant to β-lactams (by virtue of β-lactamase production, altered penicillin-binding proteins [PBPs], or both), vancomycin (via alterations in peptidoglycan synthesis), and high levels of aminoglycosides (via enzymatic degradation). Pneumococci resistant to penicillins, certain cephalosporins, and macrolides are increasingly common. These organisms generally are susceptible to vancomycin, the new fluoroquinolones, and cefotaxime or ceftriaxone. However, antimicrobial agents such as linezolid, daptomycin, telavancin, and tigecycline have been targeted at resistant gram-positive bacteria.

Treatment of an infection caused by EnterobacterCitrobacterSerratia, or P. aeruginosa with a third-generation cephalosporin or aztreonam may produce an initial clinical response by eradicating all the susceptible bacteria in the population. Within a few days, however, the highly resistant subpopulations have a selective advantage and can overgrow the infection site to produce a relapse.37 These bacteria usually retain susceptibility to aminoglycosides, carbapenems, and fluoroquinolones but are resistant to all other β-lactams. Host defenses are extremely important in this scenario. Debilitated patients with pulmonary infections, abscesses, or osteomyelitis are at high risk for drug failure. In these situations, a combination regimen to prevent the emergence of resistance or the use of carbapenem or a fluoroquinolone may be warranted for empirical therapy.

ANTIMICROBIAL USE MANAGEMENT

Antibiotic Formulary

Institutions must decide which antibiotics to include on their formularies. The decision to have a formulary remains controversial; however, restricting choices does encourage familiarity with a core of antibiotics for residents and attending physicians. Open formularies allow the empirical use of any commercially available antibiotics, with recommended guidelines for changes when culture and sensitivity results are finalized. Many institutions have developed an antibiotic stewardship team.38,39 The team is generally a multidisciplinary group including representation from microbiology, infection control, administration, information technology, pharmacy including infectious disease-trained clinical pharmacists, and physicians from several disciplines, including infectious disease. The implementation of the guidelines and restrictions recommended by such groups requires the cooperation of the entire medical staff. Education is vital to the success of the antibiotic formulary.38,39

Antimicrobial Cycling

An interesting topic in formulary management that gained interest and scientific research is antimicrobial cycling. Antimicrobial cycling is a predetermined change in an antimicrobial recommendation for empirical therapy of a specific infection at a predetermined time. It also has been called rotation of antimicrobials. This strategy should not be confused with antimicrobial switch therapy, which involves changes in the route of administration of antimicrobial therapy (i.e., IV to oral).

Antimicrobial cycling is employed as a mechanism to reduce or prevent antimicrobial resistance. Proactive cycling is a planned switch to preempt resistance at a predetermined point or series of points with a predetermined schedule. Reactive cycling is a response to high or unacceptable resistance and is often a one-time switch. Most programs incorporate aspects of both types of cycling. Cycling implies returning to the original drug after other choices have been used. Rotation implies several planned changes.

Antimicrobial cycling is based on the assumptions (a) that the resistance problem is caused by the overuse of a particular agent or class of agents and (b) that discontinuation of the particular agent or class of agents will restore susceptibility. These assumptions correlate best with nosocomial gram-negative organisms that can rapidly develop resistance. Theoretically, antimicrobial agents should be sequenced in such an order that mechanisms of resistance do not overlap (i.e., changing drug classes).39,40 However, data have provided insufficient evidence to clearly demonstrate the usefulness of antibiotic cycling.

Keeping Current

Attention must be paid to the literature on antimicrobials to assist in the selection of therapy. The results from prospective, controlled, randomized clinical trials should be evaluated whenever possible when considering appropriate antimicrobial therapy. Results from prelicensing open trials offer only limited information that can be useful in this regard because patients in these trials generally are not seriously ill and are not infected with multiple resistant bacteria. Other confounding factors found in most clinical situations are excluded by virtue of the study design. Therefore, comparative data in more seriously ill patients are essential for the appropriate application of new agents.

Postmarketing trials are also important because results can demonstrate superiority of one regimen over another, in efficacy, safety, or cost-effectiveness. Appropriate antimicrobial therapy can change as new organisms are discovered, susceptibility patterns change, new drugs become available, and new clinical trial results are published. Classical thinking in the treatment of infectious diseases will continue to change and evolve to maintain antimicrobial efficacy. Optimal use of modern antimicrobials is just beginning to be defined.

ABBREVIATIONS

Images

REFERENCES

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   13. Crider KS, Cleves MA, Reefhuis J, et al. Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Arch Pediatr Adolesc Med 2009;163(11):978–985.

   14. Roy PD, Majumder M, Roy B. Pharmacogenomics of anti-TB drugs-related hepatotoxicity. Pharmacogenomics 2008;9:311.

   15. Gilbert B, Robbins P, Livornese LL. Use of antibacterial agents in renal failure. Infect Dis Clin North Am 2009;23(4):899–924.

   16. Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol 2008;64(12):1147–1161.

   17. Piscitelli SC, Rodvold KA. Drug Interactions in Infectious Diseases, 2nd ed. Totowa, NJ: Humana Press, 2005.

   18. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52(4):e56–e93.

   19. Drusano GL. Pharmacokinetics and pharmacodynamics of antimicrobials. Clin Infect Dis 2007;45:s89–s95.

   20. Ambrose PG, Bhavnani SM, Rubino CM, et al. Pharmacokinetics–pharmacodynamics of antimicrobial therapy: It’s not just for mice anymore. Clin Infect Dis 2007;44:79–86.

   21. Nightingale CH, Ambrose PG, Drusano GL, et al. Antimicrobial Pharmacodynamics in Theory and Clinical Practice, 2nd ed. New York: Marcel Dekker, 2007.

   22. DeRyke CA, Lee SY, Kuti JL, et al. Optimising dosing strategies of antibacterials utilizing pharmacodynamic principles. Drugs 2006;66:1–14.

   23. George JM, Towne TG, Rodvold KA. Prolonged infusions of β-lactam antibiotics: Implications for antimicrobial stewardship. Pharmacotherapy 2012;32(8):707–721.

   24. Sinner SW, Tunkel AR. Antimicrobial agents in the treatment of bacterial meningitis. Infect Dis Clin North Am 2004;18:581–602.

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   26. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society of Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31(5):431–455.

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   28. Ibrahim EH, Sherman G, Ward S, et al. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 2000;118(1):146–155.

   29. Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: Guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis 2010;50:133–164.

   30. Paul M, Leibovici L. Combination antimicrobial treatment versus monotherapy: The contribution of meta-analyses. Infect Dis Clin North Am 2009;23:277–293.

   31. Bliziotis IA, Samonis G, Vardakas KZ, et al. Effect of aminoglycoside and β-lactam combination therapy versus β-lactam monotherapy on the emergence of antimicrobial resistance: A meta-analysis of randomized, controlled trials. Antimicrob Agents Chemother 2005;41:149–158.

   32. Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for treatment of infections with gram-negative bacteria. Clin Microbiol Rev 2012;25(3):450–470.

   33. Turnidge J. Pharmacodynamics and dosing of aminoglycosides. Infect Dis Clin North Am 2003;17:503–528.

   34. Chen LF, Chopra T, Kaye KS. Pathogens resistant to antibacterial agents. Med Clin North Am 2011;95:647–676.

   35. Queenan AM, Bush K. Carbapenemases: The versatile β-lactamases. Clin Microbiol Rev 2007;20:440–458.

   36. Bush K, Jacoby GA. Updated functional classification of β-lactamases. Antimicrob Agents Chemother 2010;54(3):969–976.

   37. Jacoby GA. AmpC β-lactamases. Clin Microbiol Rev 2009;22:161–182.

   38. Fishman N, Patterson J, Saiman L, et al. Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infect Control Hosp Epidemiol 2012;33(4):322–327.

   39. Dellit TH, Owens RC, McGowan JE, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 2007;44:159–177.

   40. Brown EM, Nathwani D. Antibiotic cycling or rotation: A systematic review of the evidence of efficacy. J Antimicrob Chemother 2005;55:6–9.

Appendix 83–1

Drugs of Choice, First Choice, Alternative(s)

GRAM-POSITIVE COCCI

Enterococcus faecalis (generally not as resistant to antibiotics as Enterococcus faecium)

    • Serious infection (endocarditis, meningitis, pyelonephritis with bacteremia)

      Images Ampicillin (or penicillin G) + (gentamicin or streptomycin)

      Images Vancomycin + (gentamicin or streptomycin), daptomycin, linezolid, telavancin, tigecyclinea

    • Urinary tract infection

      Images Ampicillin, amoxicillin

      Images Fosfomycin or nitrofurantoin

E. faecium (generally more resistant to antibiotics than E. faecalis)

    • Recommend consultation with infectious disease specialist.

      Images Linezolid, quinupristin/dalfopristin, daptomycin, tigecyclinea

Staphylococcus aureus/Staphylococcus epidermidis

    • Methicillin (oxacillin)-sensitive

      Images Nafcillin or oxacillin

      Images FGC,b,c trimethoprim–sulfamethoxazole, clindamycin, BL/BLId

    • Hospital-acquired methicillin (oxacillin)–resistant

      Images Vancomycin ± (gentamicin or rifampin)

      Images Daptomycin, linezolid, telavancin, tigecycline,a trimethoprim–sulfamethoxazole, or quinupristin–dalfopristin

    • Community-acquired methicillin (oxacillin)–resistant

      Images Clindamycin, trimethoprim–sulfamethoxazole, doxycyclinea

      Images Daptomycin, linezolid, telavancin, tigecycline,a or vancomycin

Streptococcus (groups A, B, C, G, and Streptococcus bovis)

    • Penicillin G or V or ampicillin

    • FGC,b,c erythromycin, azithromycin, clarithromycin

Streptococcus pneumoniae

    • Penicillin-sensitive (minimal inhibitory concentration [MIC] >0.1 mcg/mL [mg/L])

      Images Penicillin G or V or ampicillin

      Images FGC,b,c doxycycline,a azithromycin, clarithromycin, erythromycin

    • Penicillin intermediate (MIC 0.1 to 1 mcg/mL [mg/L])

      Images High-dose penicillin (12 million units/day for adults) or ceftriaxonec or cefotaximec

      Images Levofloxacin,a moxifloxacin,a gemifloxacin,a or vancomycin

    • Penicillin-resistant (MIC ≥1.0 mcg/mL [mg/L])

      Images Recommend consultation with infectious disease specialist.

       – Vancomycin ± rifampin

       – Per sensitivities: cefotaxime, ceftriaxone,c levofloxacin,a moxifloxacin,a or gemifloxacina

Streptococcus, viridans group

    • Penicillin G ± gentamicine

    • Cefotaxime,c ceftriaxone,c erythromycin, azithromycin, clarithromycin, or vancomycin ± gentamicin

GRAM-NEGATIVE COCCI

Moraxella (Branhamella) catarrhalis

    • Amoxicillin–clavulanate, ampicillin–sulbactam

    • Trimethoprim–sulfamethoxazole, erythromycin, azithromycin, clarithromycin, doxycycline,a SGC,c,f cefotaxime,c ceftriaxone,c or TGCPOc,g

Neisseria gonorrhoeae (also give concomitant treatment for Chlamydia trachomatis)

    • Disseminated gonococcal infection

      Images Ceftriaxonec or cefotaximec

      Images Oral followupcefpodoxime,c ciprofloxacin,a or levofloxacina

    • Uncomplicated infection

      Images Ceftriaxone,c cefotaxime,c or cefpodoximec

      Images Ciprofloxacina or levofloxacina

Neisseria meningitides

    • Penicillin G

    • Cefotaximec or ceftriaxonec

GRAM-POSITIVE BACILLI

Clostridium perfringens

    • Penicillin G ± clindamycin

    • Metronidazole,a clindamycin, doxycycline,a cefazolin,c carbapenemh,i

Clostridium difficile

    • Oral metronidazolea

    • Oral vancomycin

GRAM-NEGATIVE BACILLI

Acinetobacter spp.

    • Doripenem, imipenem, or meropenem ± aminoglycosidej (amikacin usually most effective)

    • Ampicillin–sulbactam, colistin,i or tigecyclinea

Bacteroides fragilis (and others)

    • Metronidazolea

    • BL/BLI,d clindamycin, cefoxitin,c cefotetan,c or carbapenemh,i

Enterobacter spp.

    • Carbapenemh or cefepime ± aminoglycosidej

    • Ciprofloxacin,a levofloxacin,a piperacillin–tazobactam, ticarcillin–clavulanate

Escherichia coli

    • Meningitis

      Images Cefotaxime,c ceftriaxone,c meropenem

    • Systemic infection

      Images Cefotaximec or ceftriaxonec

      Images BL/BLI,d fluoroquinolone,a,k carbapenemh,i

    • Urinary tract infection

      Images Most oral agents: check sensitivities

      Images Ampicillin, amoxicillin–clavulanate, doxycycline,a or cephalexinc

      Images Aminoglycoside,j FGC,b,c nitrofurantoin, fluoroquinolonea,k

Gardnerella vaginalis

    • Metronidazolea

    • Clindamycin

Haemophilus influenzae

    • Meningitis

      Images Cefotaximec or ceftriaxonec

      Images Meropenemi

    • Other infections

      Images BL/BLI,d or if β-lactamase-negative, ampicillin or amoxicillin

      Images Trimethoprim–sulfamethoxazole, cefuroxime,c azithromycin, clarithromycin, or fluoroquinolonea,k

Klebsiella pneumoniae

    • BL/BLI,d cefotaxime,c ceftriaxone,c cefepimec

    • Carbapenem,h,i fluoroquinolonea,k

Legionella spp.

    • Azithromycin, erythromycin ± rifampin, or fluoroquinolonea,k

    • Trimethoprim–sulfamethoxazole, clarithromycin, or doxycyclinea

Pasteurella multocida

    • Penicillin G, ampicillin, amoxicillin

    • Doxycycline,a BL/BLI,d trimethoprim–sulfamethoxazole or ceftriaxonec

Proteus mirabilis

    • Ampicillin

    • Trimethoprim–sulfamethoxazole

Proteus (indole-positive) (including Providencia rettgeriMorganella morganii, and Proteus vulgaris)

    • Cefotaxime,c ceftriaxone,c or fluoroquinolonea,k

    • BL/BLI,d aztreonam,l aminoglycosides,j carbapenemh,i

Providencia stuartii

    • Amikacin, cefotaxime,c ceftriaxone,c fluoroquinolonea,k

    • Trimethoprim–sulfamethoxazole, aztreonam,l carbapenemh,i

Pseudomonas aeruginosa

    • Urinary tract infection only

      Images Aminoglycosidej

      Images Ciprofloxacin,a levofloxacina

    • Systemic infection

      Images Cefepime,c ceftazidime,c doripenem,i imipenem,i meropenem,i piperacillin–tazobactam, or ticarcillin–clavulanate + aminoglycosidej

      Images Aztreonam,l ciprofloxacin,a levofloxacin,a colistini

Salmonella typhi

    • Ciprofloxacin,a levofloxacin,c ceftriaxone,c cefotaximec

    • Trimethoprim–sulfamethoxazole

Serratia marcescens

    • Ceftriaxone,c cefotaxime,c cefepime,c ciprofloxacin,a levofloxacina

    • Aztreonam,l carbapenem,h,i piperacillin–tazobactam, ticarcillin–clavulanate

Stenotrophomonas (Xanthomonas) maltophilia (generally very resistant to all antimicrobials)

    • Trimethoprim–sulfamethoxazole.

    • Check sensitivities to ceftazidime,c doxycycline,a minocycline,a and ticarcillin–clavulanate.

MISCELLANEOUS MICROORGANISMS

Chlamydia pneumoniae

    • Doxycyclinea

    • Azithromycin, clarithromycin, erythromycin, or fluoroquinolonea,k

C. trachomatis

    • Azithromycin or doxycyclinea

    • Levofloxacin,a erythromycin

Mycoplasma pneumoniae

    • Azithromycin, clarithromycin, erythromycin, fluoroquinolonea,k

    • Doxycyclinea

SPIROCHETES

Treponema pallidum

    • Neurosyphilis

      Images Penicillin G

      Images Ceftriaxonec

    • Primary or secondary

      Images Benzathine, penicillin G

      Images Ceftriaxonec or doxycyclinea

Borrelia burgdorferi (choice depends on stage of disease)

    • Ceftriaxonec or cefuroxime axetil,c doxycycline,a amoxicillin

    • High-dose penicillin, cefotaximec

_______________

aNot for use in pregnant patients or children.

bFirst-generation cephalosporins—IV: cefazolin; orally: cephalexin, cephradine, or cefadroxil.

cSome penicillin-allergic patients may react to cephalosporins.

d β-Lactam/β-lactamase inhibitor combination—IV: ampicillin–sulbactam, piperacillin–tazobactam, and ticarcillin–clavulanate; orally: amoxicillin–clavulanate.

eGentamicin should be added if tolerance or moderately susceptible (MIC >0.1 mcg/mL [mg/L]) organisms are encountered; streptomycin is used but can be more toxic.

fSecond-generation cephalosporins—IV: cefuroxime; orally: cefaclor, cefditoren, cefprozil, cefuroxime axetil, and loracarbef.

gThird-generation cephalosporins—orally: cefdinir, cefixime, cefetamet, cefpodoxime proxetil, and ceftibuten.

hCarbapenem: doripenem, ertapenem, imipenem/cilastatin, and meropenem.

iReserve for serious infection.

jAminoglycosides: gentamicin, tobramycin, and amikacin; use per sensitivities.

kFluoroquinolones IV/orally: ciprofloxacin, levofloxacin, and moxifloxacin.

lGenerally reserved for patients with hypersensitivity reactions to penicillin.