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149 Treatment and Prophylaxis of Bacterial Infections

construction sites or to wear protective gear if this is not possible. Using a mask in encounters with high risk of aerosol transmission is recom­ mended. There is a general recommendation against getting new pets for the first 6–12 months after transplant. Avoiding tick and mosquito bites is particularly important. Different professional societies provide advice to transplant recipients. In the United States, the American Society of Transplantation (AST) (myast.org) and the Centers for Dis­ ease Control and Prevention (cdc.gov) are useful resources. Available and required immunizations vary by country, and recommendations are modified as new vaccines and new data become available. Articles published in 2023 are provided in the “Further Reading” section, but updated information may be found in the AST website, and the CDC also presents the guidelines of the Advisory Committee on Immuniza­ tion Practices. Specific prophylaxes against many infections have been presented in the text; a summary is presented in Table 148-3. ■ ■FURTHER READING Amengual JE, Pro B: How I treat posttransplant lymphoproliferative disorder. Blood 142:1426, 2023. Dadwal SS et al: American Society of Transplantation and Cellular Therapy Series, 2: Management and prevention of aspergillosis in hematopoietic cell transplantation recipients. Transplant Cell Ther 27:201, 2021. Fishman JA: Infection in organ transplantation. Am J Transplant 17:856, 2017. Hakki M et al: American Society for Transplantation and Cellular Therapy Series, 3: Prevention of cytomegalovirus infection and dis­ ease after hematopoietic cell transplantation. Transplant Cell Ther 27:707, 2021. Kaul DR et al: Ten years of donor-derived disease: A report of the dis­ ease transmission advisory committee. Am J Transplant 21:689, 2021. Reynolds G et al: Vaccine schedule recommendations and updates for patients with hematologic malignancy post-hematopoietic cell trans­ plant or CAR T-cell therapy. Transpl Infect Dis 25(suppl 1):e14109, 2023. Stewart AG, Kotton CN: What’s new: Updates on cytomegalovirus in solid organ transplantation. Transplantation 108:884, 2024. Timsit JF et al: Diagnostic and therapeutic approach to infectious diseases in solid organ transplant recipients. Intensive Care Med 45:573, 2019. Viganò M et al: Vaccination recommendations in solid organ trans­ plant adult candidates and recipients. Vaccines (Basel) 11:1611, 2023. Wolfe CR et al: Donor-derived guidelines: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 33:e13547, 2019. Section 4 Therapy for Bacterial Diseases

Treatment and

Prophylaxis of Bacterial Infections David C. Hooper, Erica S. Shenoy,

Alyssa R. Letourneau, Ramy H. Elshaboury Antimicrobial agents have had a major impact on human health. Together with vaccines, they have contributed to reduced mortality, extended life span, and enhanced quality of life. Among drugs used in human medicine, however, they are distinctive in that their use

promotes the occurrence of drug resistance in the pathogens they are designed to treat as well as in other “bystander” organisms. Indeed, the history of antimicrobial development has been driven in large part by the medical need engendered by the emergence of resistance to each generation of agents. Thus, the careful and appropriate use of antimicrobial drugs is particularly important not only for optimizing efficacy and minimizing adverse effects but also for minimizing the risk of resistance and preserving the value of existing agents. Although this chapter focuses on antibacterial agents, the optimal use of all antimicro­ bials depends on an understanding of each drug’s mechanism of action, spectrum of activity, mechanisms of resistance, pharmacology, and adverse effect profile. This information is applied in the context of the patient’s clinical presentation, underlying conditions, and epidemiology to define the site and likely nature of the infection or other condition and thus to choose the best therapy. Gathering of microbiologic infor­ mation is especially important for refining therapeutic choices based on the documented pathogen and susceptibility data whenever possible; this information also makes it possible to choose more targeted therapy, thereby reducing the risk of selection of resistant bacteria that can occur with use of agents with a broader spectrum of activity than needed for the patient. Durations of therapy are chosen according to the nature of the infection and the patient’s response to treatment and are informed by clinical studies when they are available, with the understanding that shorter courses are less likely than longer courses to promote the emergence of resistance. This chapter and the one that follows provide specific information that is necessary for making informed choices among antibacterial agents. The mechanisms of action of antibacterial agents are discussed in detail in the text of this chapter, and mecha­ nisms of resistance are discussed in detail in Chap. 150. Both types of mechanisms, which are related to each other, are summarized for the most commonly used groups of agents in Table 150-1. A schematic of antibacterial targets is provided in Fig. 150-1.

CHAPTER 149 MECHANISMS OF ACTION

(SEE TABLE 150-1) Multiple essential components of bacterial cell structures and metabo­ lism have been the targets of antibacterial agents used in clinical medicine, and the interaction of an agent with its target results in either inhibition of bacterial growth and replication (bacteriostatic effect) or bacterial killing (bactericidal effect). In general, targets have been cho­ sen because they either do not exist in mammalian cells and physiol­ ogy or are sufficiently different from their mammalian counterparts to allow selective bacterial targeting. Treatment with bacteriostatic agents is effective when the patient’s host defenses are sufficient to contribute to eradication or sufficient reduction of the infecting pathogen. In patients with impaired host defenses (e.g., neutropenia) or infections at body sites with impaired or limited host defenses (e.g., meningitis and endocarditis), bactericidal agents are generally preferred. Treatment and Prophylaxis of Bacterial Infections ■ ■INHIBITION OF CELL WALL SYNTHESIS The bacterial cell wall, which is external to the cytoplasmic membrane and has no counterpart in mammalian cells, protects bacterial cells from lysis under low osmotic conditions. The cell wall is a crosslinked peptidoglycan composed of a polymer of alternating units of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM), four-amino-acid stem peptides linked to each NAM, and a peptide cross-bridge that links adjacent stem peptides to form a net-like structure. Several steps in peptidoglycan synthesis are targets of anti­ bacterial agents. Inhibition of cell-wall synthesis generally results in a bactericidal effect that is linked to cell lysis. This effect results not only from the blocking of new cell-wall formation but from the uninhibited action of cell wall–remodeling enzymes called autolysins, which cleave peptidoglycan as part of normal cell-wall growth and cell division. In gram-positive bacteria, the peptidoglycan is the most external cell structure, but in gram-negative bacteria, an asymmetric lipid outer membrane is external to the peptidoglycan and contains diffusion channels called porins. The space between the outer membrane and the peptidoglycan and cytoplasmic membrane is referred to as the periplasmic space. Most antibacterial drugs enter the gram-negative

bacterial cell through a porin channel, since the outer membrane is a major diffusion barrier. Although the peptidoglycan layer is thicker in gram-positive (20–80 nm) than in gram-negative (1 nm) bacteria, peptidoglycan itself constitutes only a limited diffusion barrier for antibacterial agents.

β-Lactams  The β-lactam drugs, including penicillins, cepha­ losporins, monobactams, and carbapenems, target transpeptidase enzymes (also called penicillin-binding proteins [PBPs]) involved in the stem-peptide cross-linking step. Inhibitors of β-lactamases—bacterial enzymes that can degrade β-lactams—are used in combination with some β-lactams to expand their spectrum of activity. Glycopeptides and Lipoglycopeptides  The glycopeptides, including vancomycin and teicoplanin, and the lipoglycopeptides, including telavancin, dalbavancin, and oritavancin, bind the two terminal d-alanine residues of the stem peptide, hindering the glyco­ syltransferase involved in polymerizing NAG–NAM units as well as transpeptidases. Vancomycin also binds to the lipid II intermediate that delivers cell-wall precursor subunits. The additional binding of teicoplanin, telavancin, dalbavancin, and oritavancin to the bacterial cytoplasmic membrane contributes to their increased potency. Both β-lactams and glycopeptides interact with their targets external to the cytoplasmic membrane. Bacitracin (Topical) and Fosfomycin  These agents interrupt enzymatic steps in the production of peptidoglycan precursors in the cytoplasm. ■ ■INHIBITION OF PROTEIN SYNTHESIS Most inhibitors of bacterial protein synthesis target bacterial ribo­ somes, whose differences from eukaryotic ribosomes allow selective antibacterial action. Some inhibitors bind to the 30S ribosomal sub­ unit and others to the 50S subunit. Most protein synthesis–inhibiting agents are bacteriostatic; aminoglycosides are an exception and are bactericidal. PART 5 Infectious Diseases Aminoglycosides  Aminoglycosides (amikacin, gentamicin, kana­ mycin, netilmicin, streptomycin, tobramycin, and plazomicin) bind irreversibly to 16S ribosomal RNA (rRNA) of the 30S ribosomal subunit, blocking the translocation of peptidyl transfer RNA (tRNA) from the A (aminoacyl) to the P (peptidyl) site and, at low concentra­ tions, causing misreading of messenger RNA (mRNA) codons, and thus cause the introduction of incorrect amino acids into the peptide chain; at higher concentrations, translocation of the peptide chain is blocked. Cellular uptake of aminoglycosides is dependent on the elec­ trochemical gradient across the bacterial membrane. Under anaerobic conditions, this gradient is reduced, with a consequent reduction in the uptake and activity of the aminoglycosides. Spectinomycin is a related aminocyclitol antibiotic that also binds to 16S rRNA of the 30S ribo­ somal subunit but at a different site. This drug inhibits translocation of the growing peptide chain but does not trigger codon misreading and produces only a bacteriostatic effect. Tetracyclines  Tetracyclines (doxycycline, minocycline, tetracy­ cline) bind reversibly to the 16S rRNA of the 30S ribosomal subunit and block the binding of aminoacyl tRNA to the ribosomal A site, thereby inhibiting peptide elongation. Active transport of tetracyclines into bacterial but not mammalian cells contributes to the selectivity of these agents. Tigecycline, a derivative of minocycline and the only available glycylcycline, acts similarly to the tetracyclines but is distinctive for its ability to circumvent the most common mechanisms of resistance to the tetracyclines. Other new tetracycline derivatives—eravacycline, a fluorocycline, and omadacycline, an aminomethylcycline—like tigecy­ cline are notable for being little affected by prior common tetracycline resistance mechanisms. Macrolides and Ketolides  In contrast to the aminoglycosides and tetracyclines, the macrolides (azithromycin, clarithromycin, and erythromycin) and ketolides (telithromycin) bind to the 23S rRNA of the 50S ribosomal subunit. These agents block translocation of the

growing peptide chain by binding to the tunnel from which the chain exits the ribosome. Lincosamides  Clindamycin is the only lincosamide in clinical use. It binds to the 23S rRNA of the 50S ribosomal subunit, interacting with both the ribosomal A and P sites and blocking peptide bond formation. Streptogramins  The only streptogramin in clinical use is a com­ bination of quinupristin, a group B streptogramin, and dalfopristin, a group A streptogramin. Both components bind to 23S rRNA of the 50S ribosome: dalfopristin binds to both the A and P sites of the peptidyl transferase center, and quinupristin binds to a site that overlaps the macrolide-binding site, blocking the emergence of nascent peptide from the ribosome. The combination is bactericidal, but macrolideresistant bacteria exhibit cross-resistance to quinupristin, and the remaining activity of dalfopristin alone is only bacteriostatic. Chloramphenicol  Chloramphenicol binds reversibly to the 23S rRNA of the 50S subunit in a manner that interferes with the proper positioning of the aminoacyl component of tRNA in the A site. This site of binding is near those of the macrolides and lincosamides. Oxazolidinones  Linezolid and tedizolid are the only oxazolidi­ nones in clinical use. They bind directly to the A site in the 23S rRNA of the 50S ribosomal subunit and block binding of aminoacyl tRNA, inhibiting the initiation of protein synthesis. Pleuromutilins  Lefamulin is the only systemic pleuromutilin in clinical use. It binds to the peptidyl transferase center of the 50S ribo­ somal subunit and prevents the correct positioning of tRNAs, thereby inhibiting peptide bond formation and protein synthesis. Mupirocin  Mupirocin (pseudomonic acid) is used topically. It competes with isoleucine for binding to isoleucyl tRNA synthetase, depleting stores of isoleucyl tRNA and thereby inhibiting protein synthesis. ■ ■INHIBITION OF BACTERIAL METABOLISM Available inhibitors (antimetabolites) target the pathway for synthesis of folate, which is a cofactor in a number of one-carbon transfer reac­ tions involved in the synthesis of some nucleic acids, including the pyrimidine thymidine and all purines (adenine and guanine), as well as some amino acids (methionine and serine) and acetyl coenzyme A. Two sequential steps in folate synthesis are targeted. The selective antibacterial effect stems from the inability of mammalian cells to syn­ thesize folate; they depend instead on exogenous sources. Antibacterial activity, however, may be reduced in the presence of high exogenous concentrations of the end products of the folate pathway (e.g., thymi­ dine and purines) that may occur in some infections, resulting from local breakdown of leukocytes and host tissues. Sulfonamides  Sulfonamides, including sulfadiazine, sulfisoxazole, and sulfamethoxazole, inhibit dihydropteroate synthetase (DHPS), which adds p-aminobenzoic acid (PABA) to pteridine, producing dihy­ dropteroate. Sulfonamides are structural analogues of PABA and act as competing enzyme substrates. Trimethoprim  Subsequent steps in folate synthesis are catalyzed by dihydrofolate synthase, which adds glutamate to dihydropteroate, and dihydrofolate reductase (DHFR), which then generates the final product, tetrahydrofolate. Trimethoprim is a structural analogue of pteridine and inhibits DHFR. Trimethoprim is available alone but is most often used in combination products that also contain sulfa­ methoxazole and thus block two sequential steps in folate synthesis. ■ ■INHIBITION OF DNA AND RNA SYNTHESIS OR ACTIVITY A variety of antibacterial agents act on these processes. Quinolones  The quinolones include nalidixic acid, the first agent in the class, and newer, more widely used fluorinated derivatives (fluoroquinolones), including norfloxacin, ciprofloxacin, levofloxacin, moxifloxacin, gemifloxacin, and delafloxacin. The quinolones are

synthetic compounds that inhibit bacterial DNA synthesis by interact­ ing with the DNA complexes of two essential enzymes, DNA gyrase and DNA topoisomerase IV, which alter DNA topology. Quinolones trap enzyme–DNA complexes in such a way that they block movement of the DNA replication apparatus and can generate lethal double-strand breaks in DNA, resulting in bactericidal activity. Although mammalian cells also have type II DNA topoisomerases related to gyrase and topoi­ somerase IV, the structures of the mammalian enzymes are sufficiently different from those of the bacterial enzymes that quinolones have substantially selective antibacterial activity. Rifamycins  Rifampin, rifabutin, and rifapentine are semisynthetic derivatives of rifamycin B and bind the β subunit of bacterial RNA polymerase, thereby blocking elongation of mRNA. Their action is highly selective for the bacterial enzyme over mammalian RNA polymerases. Nitrofurantoin  The reduction of nitrofurantoin, a nitrofuran com­ pound, by bacterial enzymes produces highly reactive derivatives that are thought to cause DNA strand breakage. Nitrofurantoin is used only for the treatment of lower urinary tract infections. Metronidazole  Metronidazole is a synthetic nitroimidazole with activity limited to anaerobic bacteria and certain anaerobic proto­ zoa. Reduction of its nitro group by the electron-transport system in anaerobic bacteria produces reactive intermediates that damage DNA and result in bactericidal activity. Both nitrofurantoin and metronida­ zole have selective antibacterial activity because the reducing activity needed to produce active derivatives is generated only by bacterial and not mammalian enzymes. ■ ■DISRUPTION OF MEMBRANE INTEGRITY The integrity of the bacterial cytoplasmic membrane—and, in gramnegative bacteria, the outer membrane—is important for bacterial viability. Two bactericidal drugs have membrane targets. Polymyxins  The polymyxins, including polymyxin B and poly­ myxin E (colistin), are cationic cyclic polypeptides that disrupt the cytoplasmic membrane and the outer membrane (the latter by binding lipopolysaccharides, which are negatively charged). Daptomycin  Daptomycin is a lipopeptide that binds the cytoplas­ mic membrane of gram-positive bacteria in the presence of calcium, generating a channel that leads to leakage of cytoplasmic potassium ions and membrane depolarization. PHARMACOKINETICS AND PHARMACODYNAMICS The term pharmacokinetics describes the disposition of a drug in the human body, whereas pharmacodynamics describes the drug action on the pathogen in relation to pharmacokinetic factors. An understand­ ing of the principles governing these two areas is required for effective drug selection, dosing, and prevention of toxicities. ■ ■PHARMACOKINETICS The process of drug disposition consists of four principal phases: absorption, distribution, metabolism, and excretion. These phases determine the time course of drug concentrations in serum, tissues, and body fluids. Absorption  When a drug is administered, absorption is defined as the percentage of the dose that reaches the vasculature. The fraction of a drug, however, that reaches the systemic circulation or the phar­ macologic site of action is termed bioavailability. The bioavailability is more relevant when non-IV routes are used—e.g., the oral, IM, SC, and topical routes. For example, since IV administration provides direct access to the systemic circulation, the bioavailability is therefore 100%. IV and oral dosing for highly bioavailable agents can result in equivalent systemic and tissue concentrations; examples of such agents include metronidazole, fluoroquinolones, tetracyclines, and linezolid. Additionally, many factors can influence oral bioavailability, including

the timing of food consumption relative to drug administration, drugmetabolizing enzymes, efflux transporters, concentration-dependent solubility, and acid degradation. Underlying conditions such as diar­ rhea or ileus can also affect the site of drug absorption and thereby alter its bioavailability. Certain orally administered drugs may have lower bioavailability because of the first-pass effect—the process by which drugs are absorbed in the small intestine through the portal circulation and directly transported to the liver for metabolism before reaching their intended site of action.

Distribution  Distribution describes the process of drug transfer reversibly between the general circulation and body tissues and fluids. After absorption into the systemic circulation and the central compart­ ment (the extensively perfused organs), the drug also distributes into the peripheral compartment (less well-perfused tissues). The volume of distribution (Vd) is a pharmacokinetic parameter that describes the amount of drug in the body at a given time relative to the measured serum concentration. Properties such as the drug’s lipophilicity, parti­ tion coefficient within different body tissues, protein binding, blood flow, penetration of the blood-brain barrier, and pH can affect the Vd and subsequently the concentration in various tissues. Drugs with a small Vd are limited to certain areas within the body (typically extracel­ lular fluid), whereas those with a higher Vd penetrate extensively into tissues and organs. Some antibacterial drugs can bind to serum pro­ teins, resulting in typically lower Vd as only the unbound (free) frac­ tion of the drug distributes into body tissues and fluids. Furthermore, only the unbound fraction of the drug is considered therapeutically active and available to exert antibacterial effects. CHAPTER 149 Metabolism  Metabolism is the chemical transformation of a drug by the body. This modification can occur within several areas; the liver is the organ most commonly involved. Drugs are metabolized by enzymes, but enzyme systems have a finite capacity to metabolize a substrate. If a drug is given in a dose at which the concentration does not exceed the rate of metabolism, the metabolic process is generally linear. If the dose exceeds the amount that can be metabolized, drug accumulation and potential toxicity may occur over time. Drugs are metabolized through phase I or phase II reactions. In phase I reactions, the drug is made more polar through dealkylation, hydroxylation, oxidation, and deamination. Polarity increases water solubility and facilitates removal from the body (e.g., renal elimination). Phase II reactions, which include glucuronidation, sulfation, and acetylation, result in larger and more polar compounds than the parent drug. Both phases usually inactivate the parent drug, although some drugs are rendered more active. The hepatic cytochrome P450 (CYP) enzyme system is mostly responsible for phase I reactions. CYP3A4 is a com­ mon subfamily within this system that is responsible for the majority of phase I metabolism. Antibacterial drugs can be substrates, inhibitors, or inducers of a particular CYP enzyme. Inducers, e.g., rifampin, can increase the production of CYP enzymes and consequently increase the metabolism of other drugs. Inhibitors, such as macrolides, cause a decrease in enzyme activity and therefore an increase in the concentra­ tion of the interacting drug by decreasing the rate of its metabolism. Treatment and Prophylaxis of Bacterial Infections Excretion  Excretion describes the body’s mechanisms of drug elim­ ination. Drugs can be eliminated through more than one mechanism. Renal clearance is the most common route and includes elimination through glomerular filtration, tubular secretion, and/or passive diffu­ sion. Some agents undergo nonrenal clearance and rely on the biliary tract or the intestine for excretion. Rate of excretion affects the half-life of a drug—i.e., defined as the time it takes for the blood concentration of a drug to decrease by one-half. This value can range from minutes to days. Half-life and overall drug clearance time can be extended if the organ responsible for clearance is impaired. For example, patients with renal or hepatic impairment may require dose adjustments that take delayed clearance into account to prevent drug accumulation and toxicity. For example, the majority of β-lactam agents are cleared pre­ dominantly through glomerular filtration, and in the presence of renal impairment, the dosing interval is typically increased to account for the increased half-life.

■ ■PHARMACODYNAMICS The term pharmacodynamics describes the relationship between the drug concentrations that determine its efficacy and those that may produce toxic effects. For an antibacterial agent, the pharmacodynamic focus is the level of drug exposure needed for optimal antibacterial effect in relation to the minimal inhibitory concentration (MIC)—the lowest drug concentration that inhibits the growth of a microorganism under standardized laboratory conditions. Antibacterial effect usually correlates with one or more of the following parameters: (1) concentra­ tion-dependent killing (defined as the ratio of peak drug concentration to the MIC), (2) time-dependent killing (defined as duration of drug concentrations above the MIC), or (3) the area under the concentra­ tion–time curve to the MIC (AUC/MIC), a measure of the overall drug exposure during the dosing interval (Fig. 149-1).

For concentration-dependent killing agents, as the designation implies, the higher the drug peak concentration (Cmax) at the site of action, the higher the rate and extent of bacterial killing. Aminogly­ cosides fit into the Cmax/MIC model of pharmacodynamics activity, and a particular measured peak serum concentration is often tar­ geted to achieve optimal killing. In contrast, time-dependent killing agents reach a ceiling at which higher concentrations do not result in increased effect(s). Rather, these agents are active against bacteria when the drug concentration exceeds the MIC for a desired period of time. The T > MIC predicts clinical efficacy for all β-lactams. The longer the concentration of the β-lactam remains above the MIC for an infect­ ing pathogen during the dosing interval, the greater the killing effect. Fluoroquinolones and vancomycin exemplify agents for which the AUC/MIC is a predictor of efficacy. For example, studies have found that an AUC/MIC ratio of >30 will maximize killing of Streptococcus pneumoniae by fluoroquinolones, whereas AUC/MIC ratios >125 are required to exert their optimal effects against gram-negative patho­ gens. Finally, for some antibacterial drugs such as aminoglycosides, a postantibiotic effect—the delayed regrowth of surviving bacteria after exposure to an antibiotic—supports less frequent dosing, increased drug-free intervals, and likely decreased drug-related toxicities. PART 5 Infectious Diseases APPROACH TO THERAPY The approach to antibiotic therapy is driven by host factors, site of infection, and local resistance profiles of suspected or known patho­ gens. Further, national and local drug shortages and formulary restric­ tions can affect available therapies. Regular monitoring of the patient and collection of laboratory data should be undertaken to streamline antibacterial therapy as appropriate and to investigate the possibility of treatment failure if the patient fails to respond appropriately. ■ ■EMPIRICAL AND DIRECTED THERAPY Therapy is considered empirical when the causative agent has yet to be determined and therapeutic decisions are based on the severity of illness, Peak (Cmax/MIC) Drug concentration AUC/MIC MIC T > MIC Time FIGURE 149-1  Pharmacokinetic and pharmacodynamic model predicting efficacy of antibacterial drugs. AUC, area under the time–concentration curve; Cmax, peak serum concentration of drug; MIC, minimal inhibitory concentration; T > MIC, duration of drug concentrations above the MIC.

the clinician’s assessment of likely pathogens in light of the clinical syn­ drome, the patient’s medical conditions and prior therapy, and relevant epidemiologic factors. For patients with severe illness, empirical therapy often takes the form of an antibacterial combination that provides broad coverage of diverse agents and thus ensures adequate treatment of possible pathogens while additional data are being collected. Directed therapy is predicated on identification of the pathogen, determination of its susceptibility profile, and establishment of the extent of the infection. Directed therapy generally allows the use of more targeted and narrowerspectrum antibacterial agents than does empirical therapy. Information on epidemiology, exposures, and local antibacterial susceptibility patterns can help guide empirical therapy. When empiri­ cal treatment is clinically appropriate, care should be taken to obtain clinical specimens for microbiologic analysis before the initiation of therapy and to adjust therapy as new information is obtained about the patient’s clinical condition and the causal pathogens. Change to directed therapy can limit unnecessary risks of drug side effects as well as selection for antibacterial resistance and the risk of Clostridioides difficile infection and disease. ■ ■SITE OF INFECTION The site of infection is a consideration in antibacterial therapy, largely because of the differing abilities of drugs to penetrate and achieve ade­ quate concentrations at particular body sites. For example, to be effective in the treatment of meningitis, an agent must (1) be able to cross the blood-brain barrier and reach adequate concentrations in the cerebrospi­ nal fluid (CSF) and (2) be active against the relevant pathogen(s). Dexa­ methasone, administered with or 15–20 min before the first dose of an antibacterial drug, has been shown to improve outcomes in patients with some types of acute bacterial meningitis, but its use may reduce penetra­ tion of some antibacterial agents, such as vancomycin, into the CSF. In this case, rifampin is added because its penetration is not reduced by dexamethasone. Infections at sites where pathogens are protected from normal host defenses, penetration of an antibacterial drug is limited, or local conditions (e.g., low pH) limit activity of some agents include, in addition to meningitis, osteomyelitis, prostatitis, intraocular infections, and abscesses. In such cases, consideration must be given to the route of drug delivery (e.g., intravitreal injections) as well as to interventions to drain, debride, or otherwise reduce bacterial load and necrotic material that can reduce antibacterial activity. ■ ■HOST FACTORS Host factors, including immune function, pregnancy, allergies, age, renal and hepatic function, drug–drug interactions, comorbid condi­ tions, and occupational or social exposures, should be considered. Immune Dysfunction  Patients with deficits in immune function that blunt the response to bacterial infection, including neutropenia, deficient humoral immunity, and asplenia (either surgical or functional), are all at increased risk of severe bacterial infection. Such patients should be treated aggressively and often broadly in the early stages of suspected infection pending results of microbiologic tests. For asplenic patients, treatment should include coverage of encapsulated organisms, particu­ larly S. pneumoniae, that may cause rapidly life-threatening infection. For neutropenic patients, initial treatment typically includes antibacterial agents with broad activity against gram-negative bacteria. Pregnancy  Pregnancy affects decisions regarding antibacterial therapy in two respects. First, pregnancy is associated with an increased risk of particular infections (e.g., those caused by Listeria). Second, the potential risks to the fetus that are posed by specific drugs must be considered. As for other drugs, the safety of the vast majority of anti­ bacterial agents in pregnancy has not been established, and such agents are grouped in categories B and C by the U.S. Food and Drug Admin­ istration (FDA). Drugs in categories D and X are contraindicated in pregnancy or lactation due to established risks. Note that in accordance with the Pregnancy and Lactation Labeling Final Rule (PLLR), drugs submitted to the FDA for approval after 2015 do not use the pregnancy risk categories. The risks associated with antibacterial use in pregnancy and during lactation are summarized in Table 149-1.

TABLE 149-1  Risks Associated with Use of Antibacterial Drugs in Pregnancy and Lactation PREGNANCY CATEGORYa ANTIBACTERIAL DRUG FETAL RISK RECOMMENDATIONb BREAST-FEEDING RISK RECOMMENDATIONb B Azithromycin Limited human data. Animal data suggest low risk. Limited human data; probably compatible Cephalosporins (including cephalexin, cefuroxime, cefixime, cefpodoxime, cefotaxime, ceftriaxone) Compatible Compatible Ceftazidime-avibactam No human data; no fetal harm in animal studies Ceftazidime is excreted into human milk in low concentrations. Avibactam is excreted into the milk of lactating rats; no human studies have been conducted. Ceftolozane-tazobactam Compatible Unknown Clindamycin Compatible Compatible Ertapenem No human data; probably compatible Limited human data; probably compatible Erythromycin Compatible (except for estolate salt) Compatible Meropenem and meropenem-vaborbactam No human data. Animal data suggest low risk. No human data; probably compatible Metronidazole Human data suggest low risk. Interrupt breast-feeding for 12–24 h after single 2-g dose. Limited human data; potential toxicity in divided doses Nitrofurantoin Human data suggest risk in third trimester. Limited human data; probably compatible. Higher risk associated with younger infants and those with G6PD deficiency Penicillins (including amoxicillin, ampicillin, cloxacillin) Compatible Compatible Quinupristin-dalfopristin Compatible. Maternal benefit must far outweigh risk to embryo/fetus. Vancomycin Compatible Limited human data; probably compatible C Chloramphenicol Compatible Limited human data; potential toxicity Fluoroquinolones Human data suggest low risk. Limited human data; probably compatible Clarithromycin Limited human data. Animal data suggest high risk. No human data; probably compatible Imipenem-cilastatin Limited human data. Animal data suggest low risk. Limited human data; probably compatible Linezolid Compatible. Maternal benefit must far outweigh risk to embryo/fetus. Telavancin No human data. Animal studies have revealed evidence of teratogenicity.c No human data. Animal studies have revealed evidence of teratogenicityc Tedizolid Limited data. Embryo-fetal studies in mice, rats, and rabbits have demonstrated fetal developmental toxicities. Use only if benefit outweighs risk. Dalbavancin Limited human data. At high doses in animal studies, delayed fetal maturation, increased embryo and offspring death. Use only if benefit outweighs risk. Oritavancin Limited human data. Studies in rats and rabbits demonstrated no harm at 25% of recommended human dose. Use only if benefit outweighs risk. C/D Amikacin Human data suggest low risk. Compatible Gentamicin Human data suggest low risk. Compatible D Kanamycin Human data suggest risk. Limited human data; probably compatible Streptomycin Human data suggest risk. Compatible Sulfonamides Human data suggest risk in third trimester. Limited human data; potential toxicity. Avoid in ill, stressed, premature infants and in infants with hyperbilirubinemia or G6PD deficiency. Tetracyclines Contraindicated in second and third trimesters Compatible Tigecycline Human data suggest risk in second and third trimesters. Not assignedd Cefiderocol No controlled data in human pregnancy; animal studies have not provided evidence of fetal harm. Eravacycline No controlled data in human pregnancy; animal data indicate drug crosses placenta and is associated with risk at higher doses, Imipenem-cilastatin-relebactam No controlled data in human pregnancy; animal studies have not revealed teratogenicity but have shown evidence of increased fetal loss. Lefamuline No controlled data in human pregnancy; animal studies have revealed evidence of fetal harm.

No human data; potential toxicity CHAPTER 149 No human data; potential toxicity Treatment and Prophylaxis of Bacterial Infections Excreted in the breast milk of rats; unknown in humans; caution use Excreted in the breast milk of animals; unknown in humans; caution use Excreted in the breast milk of rats; unknown in humans; caution use No human data; potential toxicity Unknown if excreted in human milk; excreted in animal milk. Unknown if excreted in human milk; excreted in animal milk. Not recommended during and for a period after treatment. Imipenem and cilastatin are excreted into human milk; no data on relebactam in human milk. Relebactam is excreted in animal milk. No human data regarding potential effect on infant. Unknown if excreted in human milk; excreted in animal milk. Breast-feeding is not recommended during use and for 2 days afterward. (Continued)

TABLE 149-1  Risks Associated with Use of Antibacterial Drugs in Pregnancy and Lactation PREGNANCY CATEGORYa ANTIBACTERIAL DRUG FETAL RISK RECOMMENDATIONb BREAST-FEEDING RISK RECOMMENDATIONb Meropenem-vaborbactam No controlled data in human pregnancy; animal studies have revealed evidence of fetal harm (related to vaborbactam component). Omadacycline No controlled data in human pregnancy; however, as this is a tetracycline class antibiotic, may cause deciduous tooth discoloration and bone growth inhibition in second and third trimester of pregnancy; animal data have demonstrated embryofetal lethality, teratogenicity, and embryofetal toxicity. Plazomicin No controlled data in human pregnancy; however, aminoglycoside antibiotics are known to cause fetal harm in pregnancy. aCategory B: Either animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well-controlled studies in pregnant women; or animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester. Category C: Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Category D: There is positive evidence of human fetal risk based on adverse-reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. bFetal risk recommendation and breast-feeding risk recommendation adapted from GG Briggs et al (eds): Drugs in Pregnancy and Lactation, 9th ed. Philadelphia, Lippincott Williams and Wilkins, 2011; and the U.S. Food and Drug Administration (Drugs@FDA). cA registry has been established to monitor pregnancy outcomes of pregnant women exposed to telavancin. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves by calling 1-855-633-8479. dThe U.S. Food and Drug Administration is phasing out use of pregnancy categories A, B, C, D, and X. eA pregnancy pharmacovigilance program is available: If this drug is inadvertently administered during pregnancy or if a patient becomes pregnant while receiving this drug, healthcare providers or patients should report drug exposure by calling 1-855-5NABRIVA (1-855-56227482) to enroll. Abbreviation: G6PD, glucose-6-phosphate dehydrogenase. Allergies  Allergies to antibiotics are among the most common allergies reported, and an allergy history should be obtained whenever possible before therapy is chosen. A detailed allergy history can shed light on the type of reaction experienced previously and on whether rechallenge with the same or a related medication is advisable (and, if so, under what circumstances). Allergies to the penicillins are most common. Although as many as 10% of patients may report an allergy to penicillin, studies suggest that >90% of these patients could tolerate a penicillin or cephalosporin. Adverse effects and intolerances (Table 149-2) should be distinguished from true allergies to ensure appropri­ ate selection of antibacterial therapy. PART 5 Infectious Diseases Drug–Drug Interactions  Patients commonly receive other drugs that may interact with antibacterial agents. A summary of the most common drug–drug interactions, by antibacterial class, is provided in Table 149-3. Exposures  Exposures, both occupational and nonoccupational, may provide clues to likely pathogens. When relevant, inquiries about exposure to ill contacts, animals, insects, and water should be included in the history, along with sites of residence and travel within a relevant time frame. Other Host Factors  Age, renal and hepatic function, and comor­ bid conditions are all considerations in the choice of, and schedule for, therapy. Dose adjustments should be made accordingly. In patients with decreased or unreliable oral absorption, intravenous therapy may be preferred to ensure adequate blood levels of drug and delivery of the antibacterial agent to the site of infection. In general, initial treatment for severe and life-threatening infections is given by intravenous injec­ tion to assure prompt and adequate drug delivery. ■ ■DURATION OF THERAPY Whether empirical or directed, the duration of therapy should be established in most clinical situations. Guidelines that synthesize available literature and expert opinion provide recommendations on therapy duration that are based on infecting organism, organ system, and patient factors. For example, the American Heart Association has published guidelines endorsed by the Infectious Diseases Society of America (IDSA) on diagnosis, antibacterial therapy, and manage­ ment of complications of infective endocarditis. Additional guidelines from the IDSA in collaboration with other specialty societies, such as the Society of Healthcare Epidemiology of America, the American Thoracic Society, and the European Society for Clinical Microbiology

(Continued) Meropenem is excreted in human milk; it is unknown if vaborbactam is excreted in human milk. Data on excretion of vaborbactam in animal milk are unknown. Unknown if excreted in human milk; data not available regarding excretion in animal milk. Not recommended during and for a period after treatment. Unknown if excreted in human milk; excreted in animal milk. and Infectious Diseases, exist for a range of infectious syndromes and specific pathogens. In general, where data on adequate durations of therapy exist, shorter courses are preferred to reduce the likelihood of drug adverse effects and selection of resistant bacteria. ■ ■FAILURE OF THERAPY If a patient does not respond to therapy, investigations often should include imaging and the collection of additional specimens for micro­ biologic testing as indicated. Failure to respond can be the result of an antibacterial regimen that does not address the underlying causative organism, the development of resistance during therapy, or the existence of a focus of infection at a site poorly penetrated by systemic therapy. Some infections may also require surgical interventions (e.g., large abscesses, myonecrosis). Fever due to allergic drug reactions may com­ plicate assessment of the patient’s response to antibacterial treatment. ■ ■EXPERT GUIDANCE Selected websites with the most up-to-date information and guidance for the clinician include the following: • Johns Hopkins ABX Guide (www.hopkins-abxguide.org) • IDSA Practice Guidelines (https://www.idsociety.org/ practice-guideline/practice-guidelines) • OneHealth Trust Resistance Map (https://resistancemap.onehealthtrust

.org/index.php) • Centers for Disease Control and Prevention Antibiotic/Antimicro­ bial Resistance (www.cdc.gov/drugresistance/) CLINICAL USE OF ANTIBACTERIAL AGENTS The clinical application of antibacterial therapy is guided by the spectrum of the agent and the suspected or known target pathogen. Infections for which specific antibacterial agents are among the drugs of choice are listed, along with associated pathogens and susceptibility data, in Table 149-4. Resistance rates of specific organisms are dynamic and should be taken into account in the approach to antibacterial therapy. While national resistance rates can serve as a reference, the most useful reference for the clinician is the most recent local labora­ tory antibiogram, which provides details on local resistance patterns, often on an annual or semiannual basis. ■ ■a-LACTAMS The β-lactam class of antibiotics consists of penicillins, cephalospo­ rins, carbapenems, and monobactams. The term β-lactam reflects

TABLE 149-2  Common Adverse Reactions to Antibacterial Agents ANTIBACTERIAL(S) POTENTIAL ADVERSE EFFECTS COMMENTS β-Lactams Hypersensitivity reactions Ranges from rash to anaphylaxis. Cross-reactivity among β-lactams is related to chemical structure and side chain similarity. Neurotoxicity More commonly described with cefepime and imipenem, but likely a class effect. Risk is increased in patients with history of seizures, renal impairment, and advanced age. Neutropenia/hematologic reactions May be related to high doses and prolonged duration Vancomycin Nephrotoxicity Risk increases with vancomycin trough levels >20 μg/mL or concomitant administration with other potentially nephrotoxic agents. The effect is usually reversible. “Red man syndrome” Can be managed with a slower vancomycin infusion and pretreatment with antihistamine Telavancin QT prolongation Interference with coagulation tests May falsely affect INR, PT, aPTT. Perform these tests before the next dose of telavancin (when serum drug levels are at their nadir). Taste disturbances Nephrotoxicity Oritavancin Interference with coagulation tests May falsely affect INR, PT, aPTT. Perform these tests at least 24 h after the dose is administered. Gastrointestinal distress Dalbavancin Gastrointestinal distress Daptomycin Myopathy Monitor CPK levels during therapy. Rhabdomyolysis has been reported but appears to be rare. Eosinophilic pneumonia Aminoglycosides Nephrotoxicity Associated with prolonged use; usually reversible Ototoxicity Can cause both vestibular and cochlear toxicity. Ototoxicity may be irreversible. Fluoroquinolones QTc prolongation Moxifloxacin appears more likely than other quinolones to exert this effect. Risk of arrhythmia increases when these drugs are given concomitantly with other QTc-prolonging agents. Tendinitis Risk is greater among the elderly and patients receiving steroids. Dysglycemia Exacerbation of myasthenia gravis Rifampin Hepatotoxicity Risk is greater when drug is given with other antituberculosis agents. When rifampin is given alone, LFT values may be transiently elevated without symptoms. Orange discoloration of body fluids Tetracyclines, including tigecycline, eravacycline, and omadacycline Photosensitivity Gastrointestinal distress High incidence of diarrhea, nausea, vomiting Macrolides Gastrointestinal distress Erythromycin is occasionally used as a therapeutic agent for some gastric motility disorders. QTc prolongation Azithromycin use is associated with an increased risk of death from cardiovascular causes among patients at high baseline risk. Metronidazole Peripheral neuropathy Associated with prolonged use Clindamycin Diarrhea and pseudomembranous colitis Linezolid, tedizolid Myelosuppression Associated with prolonged use Optic and peripheral neuropathy Associated with prolonged use Lactic acidosis TMP-SMX Hypersensitivity reactions Allergy usually associated with sulfonamide moiety Nephrotoxicity Associated with high doses Hematologic effects Associated with prolonged use Nitrofurantoin Pneumonitis and other pulmonary reactions Associated with prolonged use Peripheral neuropathy Associated with accumulation of nitrofurantoin in renal failure. Avoid use in renal impairment. Fosfomycin Gastrointestinal effects Polymyxins Nephrotoxicity Associated with high dose Neurotoxicity Neuromuscular blockade and muscle weakness are well described and usually reversible. Quinupristindalfopristin Arthralgias and myalgias Chloramphenicol Bone marrow suppression Aplastic anemia or hematopoietic toxicity Pleuromutilin Gastrointestinal Diarrhea QTc prolongation When used in conjunction with CYP3A4 substrates Note: All systemic antibiotics have the potential to alter abdominal flora and induce Clostridioides difficile infection. Abbreviations: aPTT, activated partial thromboplastin time; CPK, creatine phosphokinase; INR, international normalized ratio; LFT, liver function test; PT, prothrombin time; TMP-SMX, trimethoprim-sulfamethoxazole.

CHAPTER 149 Treatment and Prophylaxis of Bacterial Infections

TABLE 149-3  Important Antibacterial Drug Interactions ANTIBACTERIAL(S) INTERACTING AGENT(S) POTENTIAL EFFECT AND MANAGEMENT Nafcillin Warfarin, cyclosporine, tacrolimus Decreased effects of interacting drug via CYP3A4 induction. Monitor levels of affected drug closely if drugs are given concomitantly. Ceftriaxone Calcium-containing IV solutions Concomitant use is contraindicated in neonates (<28 days); the combination can lead to precipitation of ceftriaxone-calcium particulate. Ceftriaxone and calcium-containing solutions can be given to infants >28 days of age provided they are given sequentially and the lines are thoroughly flushed between infusions, or infused via separate lines. Carbapenems Valproic acid Diminished levels of valproic acid. Monitor valproic acid levels closely if drugs are given concomitantly and consider alternative therapies. Linezolid, tedizolid Serotonergic and adrenergic agents (e.g., SSRIs, vasopressors) Quinupristindalfopristin Substrates of CYP3A4 (e.g., warfarin, ritonavir, cyclosporine, diazepam, verapamil) Fluoroquinolones Theophyllinea Can result in theophylline toxicity Sucralfate; antacids containing aluminum, calcium, or magnesium; ferrous sulfate– and zinc-containing multivitamins Tizanidinea Can result in increased levels of tizanidine and hypotensive, sedative effects. Monitor for side effects if drugs are given concomitantly. QTc-prolonging drugs (e.g. azoles, sotalol, amiodarone, dofetilide, fluoxetine) Rifampin Substrates of CYP3A4 (e.g., warfarin, ritonavir, cyclosporine, diazepam, verapamil, protease inhibitors, voriconazole)   Substrates of CYP2C19 (e.g., omeprazole, lansoprazole)   Substrates of CYP2C9 (e.g., warfarin, tolbutamide) PART 5 Infectious Diseases   Substrates of CYP2C8 (e.g., repaglinide, rosiglitazone)   Substrates of CYP2B6 (e.g., efavirenz)   Hormone therapy (e.g., norethindrone) Can result in decreased levels of hormone. If oral contraceptive and rifampin are given concomitantly, use alternative or additional forms of birth control. Tetracyclines Antacids or drugs containing calcium, magnesium, iron, or aluminum Warfarin Increased effect of warfarin. Monitor levels closely if drugs are given concomitantly. Eravacycline: Strong CYP3A4 inducers (e.g., rifampin) Macrolidesb Substrates of CYP3A4 (e.g., warfarin, ritonavir, cyclosporine, diazepam, verapamil, amiodarone)   QTc-prolonging agents (e.g., fluoroquinolones, sotalol)   Protease inhibitors (e.g., ritonavir) Can result in increased levels of both macrolides and protease inhibitors. Avoid concomitant use if possible.   Cimetidine Cimetidine can increase levels of macrolides. Metronidazole Ethanol Can result in disulfiram-like reaction. Ethanol may be present in some formulations of oral drug suspensions (e.g., ritonavir). Warfarin Can increase warfarin effects. Monitor INR closely if drugs are given concomitantly. TMP-SMX Warfarin Increased effect of warfarin. Monitor levels closely if drugs are given concomitantly. Phenytoin Increased levels of phenytoin. Monitor levels closely if drugs are given concomitantly. Methotrexate Increased levels of methotrexate and prolonged exposure. Monitor levels closely if drugs are given concomitantly. Oritavancin Substrates of CYP3A4 (e.g., cyclosporine, warfarin) and CYP2D6 (e.g., aripiprazole) Substrates of CYP2C19 (e.g., omeprazole) and CYP2C9 (e.g., warfarin) Lefamulin QTc-prolonging drugs (e.g., azoles, sotalol, amiodarone, dofetilide, fluoxetine) Strong CYP3A4 inducers (e.g., rifampin) Reduced lefamulin efficacy Strong CYP3A4 strong inhibitors (e.g., ritonavir) Increased lefamulin exposure aDrug reaction described with ciprofloxacin only. bClarithromycin and erythromycin are potent CYP3A4 inhibitors; the probability of a drug interaction with azithromycin is lower. Abbreviations: INR, international normalized ratio; SSRI, selective serotonin-reuptake inhibitor; TMP-SMX, trimethoprim-sulfamethoxazole.

Increased levels of serotonergic and adrenergic agents. Monitor for serotonin syndrome. Tedizolid may have less potential than linezolid to cause this drug interaction. Can result in increased levels of interacting drug Can result in decreased oral absorption of fluoroquinolones. Administer fluoroquinolone

2 h before or 6 h after interacting drug. Increased risk of cardiotoxicity and arrhythmias. Monitor QTc. Can result in decreased levels of interacting drug. Avoid concomitant use if possible. If giving drugs concomitantly, monitor drug levels if possible. Can result in decreased oral absorption of tetracyclines. Administer tetracycline 2 h before or 6 h after interacting drug. Reduced eravacycline efficacy Avoid concomitant administration if possible. Increased risk of cardiotoxicity and arrhythmias. Monitor QTc. Can result in decreased levels of interacting drug. Avoid concomitant use if possible. If giving drugs concomitantly, monitor drug levels if possible. Increased risk of cardiotoxicity and arrhythmias. Monitor QTc.

TABLE 149-4  Drug Indications for Specific Infections, Associated Pathogens, and Sample Susceptibility Rates ANTIMICROBIAL(S) INFECTIONS Penicillin G Syphilis; yaws; leptospirosis; streptococcal infections; pneumococcal infections; actinomycosis; oral and periodontal infections; meningococcal meningitis and meningococcemia; viridans streptococcal endocarditis; clostridial myonecrosis; tetanus; rat-bite fever; Pasteurella multocida infections; erysipeloid (Erysipelothrix rhusiopathiae) Ampicillin, amoxicillin Salmonellosis; acute otitis media; Haemophilus influenzae meningitis and epiglottitis; Listeria monocytogenes meningitis; Enterococcus faecalis UTI Nafcillin, oxacillin MSSA bacteremia and endocarditis Staphylococcus aureus (72%); coagulase-negative staphylococci (49%) Piperacillintazobactam Intraabdominal infections (facultative enteric gram-negative bacilli and obligate anaerobes); infections caused by mixed flora (aspiration pneumonia, diabetic foot ulcers); infections caused by Pseudomonas aeruginosa Cefazolin E. coli UTI; surgical prophylaxis; MSSA bacteremia and endocarditis E. coli (80%) Cefoxitin, cefotetan Intraabdominal infections and pelvic inflammatory disease Bacteroides fragilis (60%)b Ceftriaxone Gonococcal infections; pneumococcal meningitis; viridans streptococcal endocarditis; salmonellosis and typhoid fever; health care–associated infections caused by nonpseudomonal facultative gram-negative enteric bacilli Ceftazidime, cefepime Health care–associated infections caused by facultative gram-negative bacilli and Pseudomonas spp. Ceftaroline CAP caused by S. pneumoniae, MSSA, H. influenzae, K. pneumoniae, Klebsiella oxytoca, and E. coli; acute bacterial skin and skin-structure infections caused by MSSA, MRSA, Streptococcus pyogenes, Streptococcus agalactiae, E. coli, K. pneumoniae, and K. oxytoca Ceftazidimeavibactam, meropenemvaborbactam Complicated UTIs (ceftazidime-avibactam and meropenem-vaborbactam) and complicated intraabdominal infections (ceftazidime-avibactam in combination with metronidazole) caused by resistant gram-negative organisms, including Pseudomonas, and some anaerobes Ceftolozanetazobactam Complicated UTIs and complicated intraabdominal infections (in combination with metronidazole) caused by resistant gram-negative organisms, including Pseudomonas, and some anaerobes Imipenem, meropenem Intraabdominal infections, infections caused by Enterobacter spp. and ESBLproducing gram-negative bacilli Ertapenem CAP; complicated UTIs, including pyelonephritis; acute pelvic infections; complicated intraabdominal infections; complicated skin and skin-structure infections, excluding diabetic foot infections accompanied by osteomyelitis or caused by P. aeruginosa Aztreonam Infections caused by facultative gram-negative bacilli and Pseudomonas in penicillin-allergic patients Vancomycin Bacteremia, endocarditis, and other invasive disease caused by MRSA; pneumococcal meningitis; oral formulation for CDAD Telavancin Health care– and ventilator-associated pneumonia or skin and soft tissue infections caused by MRSA Dalbavancin, oritavancin Complicated skin and soft tissue infections S. aureus: rarely reported for dalbavancin.g Rarely reported for oritavancin.h Daptomycin VRE infections; MRSA bacteremia E. faecalis (99.9%);i E. faecium (99.7%);i S. aureus (99.9%)g Gentamicin, tobramycin, amikacin Combined with penicillin for staphylococcal, enterococcal, or streptococcal endocarditis; combined with β-lactam for gram-negative bacteremia; pyelonephritis Azithromycin, clarithromycin, erythromycin Legionella, Campylobacter, and Mycoplasma infections; CAP; GAS pharyngitis in penicillin-allergic patients; bacillary angiomatosis; gastric infections due to Helicobacter pylori; MAI infections Clindamycin Severe, invasive GAS infections (with a β-lactam); infections caused by obligate anaerobes; infections caused by susceptible staphylococci Doxycycline, minocycline Acute bacterial exacerbations of chronic bronchitis; granuloma inguinale; brucellosis (with streptomycin); tularemia; glanders; melioidosis; spirochetal infections caused by Borrelia (Lyme disease and relapsing fever; doxycycline); infections caused by Vibrio vulnificus; some Aeromonas infections; infections due to Stenotrophomonas (minocycline); plague; ehrlichiosis; chlamydial infections (doxycycline); granulomatous infections due to Mycobacterium marinum (minocycline); rickettsial infections; mild CAP; skin and soft tissue infections caused by gram-positive cocci (e.g., CA-MRSA infections); leptospirosis; syphilis; and actinomycosis in the penicillin-allergic patient

COMMON PATHOGENS (% SUSCEPTIBLE);

RESISTANCE AS NOTEDa Neisseria meningitidis; viridans streptococci (60%); Streptococcus pneumoniae (97% nonmeningitis; 74% meningitis) Escherichia coli (52%); H. influenzae (72%); Salmonella spp. (89%) P. aeruginosa (78%) S. pneumoniae (87% meningitis; 99% nonmeningitis); E. coli (88%); Klebsiella pneumoniae (85%) P. aeruginosa (82% for ceftazidime, 85% for cefepime) Mostly susceptible; four strains of MRSA with ceftaroline MICs >4 μg/mL reported in isolates from a single Greek hospitalc; additional case reports, including in patients without prior exposure to ceftarolined,e P. aeruginosa (84–97%)f MDR Enterobacterales, including carbapenem-resistant Enterobacterales that produce KPCs No activity against metallo-β-lactamases (e.g., NDM) CHAPTER 149 P. aeruginosa (>86% overall; 60–80% of ceftazidime- and meropenem-resistant strains)f MDR Enterobacterales No activity against KPC-producing organisms Treatment and Prophylaxis of Bacterial Infections P. aeruginosa (84%); Acinetobacter calcoaceticus-baumannii complex (84%) (meropenem susceptibilities reported) Enterobacter cloacae (88%); K. pneumoniae (98%)   S. aureus (100%); E. faecalis (93%); E. faecium (41%) S. aureus: none reported E. coli (gentamicin, 90%); P. aeruginosa (amikacin, 93%; gentamicin, 89%); A. calcoaceticus-baumannii complex (gentamicin, 83%) S. pneumoniae (60%); group A streptococci (82%); H. pylori (75%)j S. aureus (73%) S. pneumoniae (54%); S. aureus (97%) (Continued)

TABLE 149-4  Drug Indications for Specific Infections, Associated Pathogens, and Sample Susceptibility Rates ANTIMICROBIAL(S) INFECTIONS Tigecycline CAP caused by S. pneumoniae, H. influenzae, or Legionella pneumophila; complicated skin infections caused by E. coli, MRSA, MSSA, S. pyogenes, Streptococcus anginosus, S. agalactiae, B. fragilis; complicated intraabdominal infections caused by E. coli, vancomycin-susceptible E. faecalis, Citrobacter freundii, E. cloacae, K. pneumoniae, K. oxytoca, Bacteroides spp., Clostridium perfringens, and Peptostreptococcus spp. TMP-SMX Community-acquired UTI; CA-MRSA skin and soft tissue infections E. coli (73%); S. aureus (94%) Sulfonamides Nocardial infections; leprosy (dapsone); toxoplasmosis (sulfadiazine) Unknown Ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin CAP (levofloxacin and moxifloxacin); UTI; bacterial gastroenteritis; health care–associated gram-negative enteric infections; Pseudomonas infections (ciprofloxacin and levofloxacin); skin and skin-structure infections (delafloxacin) Rifampin Staphylococcal foreign body infections (in combination with other antistaphylococcal agents); Legionella pneumonia; Mycobacterium tuberculosis; atypical nontuberculous mycobacterial infection; pneumococcal meningitis when organisms are susceptible or response is delayed Metronidazole Obligate anaerobic gram-negative bacteria (e.g., Bacteroides spp.); abscess in lung, brain, or abdomen; bacterial vaginosis; CDAD Linezolid, tedizolid VRE; uncomplicated and complicated skin and soft tissue infections caused by MSSA and MRSA; CAP with concurrent bacteremia; health care–associated pneumonia Chloramphenicol Infections due to gram-positive and gram-negative organisms resistant to standard alternatives (e.g., Burkholderia) Colistin Infections due to gram-negative bacilli resistant to all other chemotherapy

(e.g., P. aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia) Quinupristindalfopristin VRE; complicated skin and skin-structure infections due to MSSA and S. pyogenes PART 5 Infectious Diseases Mupirocin Topical application to nares for S. aureus decolonization S. aureus (74–100%)l Nitrofurantoin UTI caused by most gram-negative bacilli and some gram-positive organisms; prophylaxis in recurrent cystitis Fosfomycin UTI caused by most gram-negative bacilli and some gram-positive organisms; prophylaxis in recurrent cystitis Cefiderocol Complicated UTIs and/or pyelonephritis caused by multidrug-resistant gram-negative bacteria, including extended-spectrum β-lactamase- or carbapenemase-producing organisms and multidrug-resistant P. aeruginosa,

A. baumannii, Stenotrophomonas maltophilia, and Burkholderia cepacia Eravacycline Complicated intraabdominal infections caused by E. coli, K. pneumoniae,

C. freundii, E. cloacae, K. oxytoca, E. faecalis, E. faecium, S. aureus, S. anginosus group, C. perfringens, Bacteroides spp., and Parabacteroides distasonis Imipenem-cilastatinrelebactam Complicated intraabdominal infections, pneumonia, and complicated UTI including pyelonephritis caused by multidrug-resistant organisms including Enterobacterales and against some imipenem-nonsusceptible P. aeruginosa Lefamuline Community acquired pneumonia caused by MRSA, S. pneumoniae, and atypical CAP pathogens Meropenemvaborbactam Complicated UTI caused by KPC-producing Enterobacterales Identified in KPC-producing strains of K. pneumoniaeo Omadacycline Community-acquired bacterial pneumonia caused by S. pneumoniae, S. aureus (methicillin-susceptible isolates), H. influenzae, Haemophilus parainfluenzae,

K. pneumoniae, L. pneumophila, M. pneumoniae, and Chlamydophila pneumoniae Plazomicin Complicated UTIs caused by carbapenemase-producing Enterobacteriaceae Resistance uncommon except in infrequent isolates with plasmid-encoded ribosome modifying methylases aUnless otherwise noted, susceptibility rates are based on isolates from the Massachusetts General Hospital Clinical Microbiology Laboratory collected between January and December 2022. Local rates will vary. bJA Karlowsky et al: Antimicrob Agents Chemother 56:1247, 2012. cRE Mendes et al: J Antimicrob Chemother 67:1321, 2012. dSW Long et al: Antimicrob Agents Chemother 58:6668, 2014. eM Nigo et al: Antimicrob Agents and Chemother 61:e01235, 2017. fD Van Duin, RA Bonomo: Clin Infect Dis 63:234, 2016. gSP McCurdy et al: Antimicrob Agents Chemother 59:5007, 2015. hJA Karlowsky et al: Diag Microbiol Infect Dis 87:349, 2017. iHS Sader et al: J Chemother 23:200, 2011. jJ Torres et al: J Clin Microbiol 39:2677, 2001. kWS Oh et al: Antimicrob Agents Chemother 49:5176, 2005. lAE Simor et al: Antimicrob Agents Chemother 51:3880, 2007. mS Demirci-Duarte et al: Diagn Microbiol Infect Dis 98:115098, 2020. nLJ Scott: Drugs 79:315, 2019. oSun et al Antimicrob Agents Chemother 61:e01694, 2017. Abbreviations: CA-MRSA, community-acquired MRSA; CAP, community-acquired pneumonia; CA-UTI, community-acquired UTI; CDAD, Clostridioides difficile–associated diarrhea; ESBL, extended-spectrum β-lactamase; GAS, group A streptococcal; KPCs, Klebsiella pneumoniae carbapenemases; MAI, Mycobacterium avium-intracellulare; MDR, multidrug-resistant; MIC, minimal inhibitory concentration; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; NDM, New Delhi metalloβ-lactamase; TMP-SMX, trimethoprim-sulfamethoxazole; UTI, urinary tract infection; VRE, vancomycin-resistant Enterococcus. the drugs’ four-membered lactam ring, which is their core structure. The differing side groups among the agents of this family determine the spectrum of activity. All β-lactams exert a bactericidal effect by inhibiting bacterial cell-wall synthesis. The β-lactams are classified as time-dependent killing agents; therefore, their clinical efficacy is best

(Continued) COMMON PATHOGENS (% SUSCEPTIBLE);

RESISTANCE AS NOTEDa Mostly susceptible, although case reports of resistance

in A. baumannii and K. pneumoniae S. pneumoniae (100% levofloxacin); E. coli (75% for ciprofloxacin and 70% for levofloxacin); P. aeruginosa (78% for ciprofloxacin and 70% for levofloxacin); Salmonella spp. (79% for ciprofloxacin and 77% for levofloxacin) S. aureus (99%), although staphylococci rapidly develop resistance with monotherapy Mostly susceptible; resistance very rare Mostly susceptible; resistance occasionally seen in VRE Unknown P. aeruginosa (case reports, outbreaks) E. faecalis (<20%);k E. faecium (>90%)k E. coli (97%); E. faecalis (99%) Considered low prevalencem Very low resistance rates in initial studies Resistance noted in both gram-negative and gram-positive bacterian Low resistance rates in initial studies Low resistance rates in target pathogens in initial studies Broad spectrum overall, but resistance can occur in

gram-negative isolates; not active against Pseudomonas correlated with the proportion of the dosing interval during which drug levels remain above the MIC for the targeted pathogen. Penicillins and β-Lactamase Inhibitors  Penicillin, the first β-lactam, was discovered in 1928 by Alexander Fleming. Natural

Treatment and Prophylaxis of Bacterial Infections

CHAPTER 149 penicillins, such as penicillin G, are active against non-β-lactamaseproducing gram-positive and gram-negative bacteria, anaerobes, and some gram-negative cocci. Penicillin G is used for penicillin-susceptible streptococcal infections, pneumococcal and meningococcal menin­ gitis, enterococcal endocarditis, and syphilis. The antistaphylococcal penicillins, which have potent activity against methicillin-susceptible Staphylococcus aureus (MSSA), include nafcillin, oxacillin, dicloxa­ cillin, and flucloxacillin. Aminopenicillins, such as ampicillin and amoxicillin, provide added coverage beyond penicillin against gramnegative cocci, such as Haemophilus influenzae, and some Entero­ bacterales, including Escherichia coli, Proteus mirabilis, Salmonella, and Shigella. The aminopenicillins are hydrolyzed by many common β-lactamases. These drugs are commonly used for infections caused by susceptible enterococcal and streptococcal species. IV ampicillin is commonly used in meningitis and endocarditis. Oral amoxicillin may be an option for otitis media, respiratory tract infections, and urinary tract infections. The antipseudomonal penicillins include ticarcillin and piperacillin. These penicillin groups generally offer adequate anaerobic coverage; the exceptions are Bacteroides species (such as Bacteroides fragilis), which produce β-lactamases and are generally resistant. The rising prevalence of β-lactamase-producing bacteria has led to the increased use of β-lactam–β-lactamase inhibitor combina­ tions, such as ampicillin-sulbactam, amoxicillin-clavulanate, ticar­ cillin-clavulanate, piperacillin-tazobactam, ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, and imipenemrelebactam. The β-lactamase inhibitors themselves do not have antibacterial activity (with the exception of sulbactam, which has activity against Acinetobacter baumannii) but typically inhibit the S. aureus class A β-lactamase, β-lactamases of H. influenzae and Bacte­ roides species, and a number of plasmid-encoded β-lactamases. These combination agents are typically used when broader-spectrum cover­ age is needed—e.g., in pneumonia and intraabdominal infections. Piperacillin-tazobactam is a useful agent for febrile neutropenia, when local P. aeruginosa susceptibility rates are high. Avibactam, vabor­ bactam, and relebactam inhibit a broader spectrum of β-lactamases than the other inhibitors, including extended-spectrum β-lactamases (ESBLs), AmpC β-lactamases, and some carbapenemases (see Chap. 150). Sulbactam combined with the inhibitor durlobactam is limited to treatment for Acinetobacter infections. Cephalosporins  The cephalosporin drug class encompasses sev­ eral generations distinguished by spectrum of antibacterial activity. The first generation (cefazolin, cefadroxil, and cephalexin) largely has activity against gram-positive bacteria, with some additional activity against E. coli, P. mirabilis, and Klebsiella pneumoniae. First-generation cephalosporins are commonly used for infections caused by MSSA and streptococci (e.g., skin and soft tissue infec­ tions). Cefazolin is recommended for surgical prophylaxis against skin organisms. The second generation (cefamandole, cefuroxime, cefaclor, cefprozil, cefuroxime axetil, cefoxitin, and cefotetan) has additional activity against H. influenzae and Moraxella catarrha­ lis. Cefoxitin and cefotetan have potent activity against anaerobes as well, although there is some increased resistance seen for B. fragilis. Second-generation cephalosporins have been used to treat community-acquired pneumonia because of their activity against S. pneumoniae, H. influenzae, and M. catarrhalis. They are also used for other mild or moderate infections, such as acute otitis media and sinusitis. The third-generation cephalosporins are character­ ized by greater potency against gram-negative bacilli and reduced potency against gram-positive cocci. These cephalosporins, which include cefoperazone, cefotaxime, ceftazidime, ceftriaxone, cefdinir, cefixime, and cefpodoxime, are used for infections caused by Entero­ bacterales, although resistance is an increasing concern. Ceftriaxone penetrates the CSF and can be used to treat meningitis caused by H. influenzae, N. meningitidis, and susceptible strains of S. pneumoniae. It is also used for the treatment of later-stage Lyme disease, gono­ coccal infections, and streptococcal endocarditis. It is noteworthy that ceftazidime is the only third-generation cephalosporin with activity against Pseudomonas aeruginosa, but it lacks activity against gram-positive bacteria. This drug is frequently used for pulmonary infections in cystic fibrosis, postneurosurgical meningitis, and febrile neutropenia. The fourth generation of cephalosporins includes cefepime and cefpirome, broad-coverage agents with potent activ­ ity against both gram-negative bacilli, including P. aeruginosa, and gram-positive cocci. The fourth generation has clinical applications similar to those of the third generation and may offer additional activity over the first, second, and third generations in the presence of certain β-lactamases. These agents can be used in bacteremia, febrile neutropenia, and intraabdominal and urinary tract infections. Ceftaroline, a fifth-generation cephalosporin, differs from the other cephalosporins in its added activity against methicillin-resistant S. aureus (MRSA), which is resistant to all other β-lactams. Ceftaro­ line’s gram-negative activity is similar to that of the third-generation cephalosporins but does not include P. aeruginosa. Ceftaroline may be used in community-acquired pneumonia and skin infec­ tions, and emerging data support its use in more severe infections such as bacteremia. Adverse reactions to ceftaroline have included hypersensitivity reactions and neutropenia. Ceftolozane-tazobactam and ceftazidime-avibactam are novel cephalosporin–β-lactamase inhibitor combinations with activity against gram-negative bacteria, including Pseudomonas, and some anaerobes. Both agents have been studied in complicated intraabdominal infections and complicated urinary tract infections. Ceftolozane-tazobactam is thought to be stable against many ESBL-producing organisms because of the tazobactam component. The addition of avibactam to ceftazidime yields a combination agent with activity against AmpC-, ESBL-, and K. pneumoniae carbapenemase (KPC)–producing organisms. These cephalosporin–β-lactamase inhibitor combinations may be of clinical benefit in multidrug-resistant gram-negative infections. Cefiderocol is a novel cephalosporin with enhanced uptake through bacterial iron uptake pathways and stability to a broad range of β-lactamases. It has been studied in complicated urinary tract infections and hospitalacquired and ventilator-associated pneumonia and may provide most benefit for multidrug-resistant gram-negative bacterial infections. Carbapenems  Carbapenems, including doripenem, imipenem, meropenem, and ertapenem, offer the most reliable coverage for strains containing ESBLs. All carbapenems have broad activity against gram-positive cocci, gram-negative bacilli, and anaerobes. None is active against MRSA, but all are active against MSSA, Strep­ tococcus species, and Enterobacterales. Ertapenem is the only car­ bapenem that has poor activity against P. aeruginosa and Acinetobacter. Imipenem is active against penicillin-susceptible Enterococcus faecalis but not Enterococcus faecium. Carbapenems are not active against Enterobacterales containing carbapenemases. Stenotrophomonas maltophilia and some Bacillus species are intrinsically resistant to carbapenems because of a zinc-dependent carbapenemase. Addi­ tion of vaborbactam to meropenem and relebactam to imipenem results in inhibition of AmpC β-lactamases, ESBLs, and KPCs but not metallo-carbapenemases, such as NDM (New Delhi metalloβ-lactamases). Carbapenems may decrease the concentration of valproate products, and caution should be used in patients on this combination of therapy. Monobactams  Aztreonam is the sole monobactam in clinical use. Its activity is limited to gram-negative bacteria and includes P. aerugi­ nosa and most other Enterobacterales. It is inactivated by ESBLs and carbapenemases. The principal use for aztreonam is as an alternative to penicillins, cephalosporins, or carbapenems in patients with a seri­ ous β-lactam allergy. Aztreonam is structurally related to ceftazidime and should be used cautiously in individuals with a serious ceftazidime allergy. It is used in febrile neutropenia and intraabdominal infections when other β-lactams cannot be used. Aztreonam is sometimes used in combination with avibactam for the treatment of NDM carbapenemase gram-negative bacterial infections. Adverse Reactions to β-Lactam Drugs  Agents within the β-lactam class are known for several adverse effects. Gastrointesti­ nal side effects, mainly diarrhea, are common, but hypersensitivity

reactions constitute the most common adverse effect of β-lactams. The reactions’ severity can range from rash to anaphylaxis, but the rate of true anaphylactic reactions is only 0.05%. An individual with an accelerated IgE-mediated reaction to one β-lactam agent may still receive another agent within the class, but caution should be used and a β-lactam that has a dissimilar side chain and a low level of cross-reac­ tivity would be the preferred choice. For example, the second-, third-, and fourth-generation cephalosporins and the carbapenems display very low cross-reactivity in patients with penicillin allergy. Aztreonam is the only β-lactam that has no cross-reactivity with the penicillin group. In cases of severe allergy, desensitization (a graded challenge) to the indicated β-lactam, with close monitoring, may be warranted if other antibacterial options are not suitable.

β-Lactams can rarely cause serum sickness, Stevens-Johnson syn­ drome, nephropathy, hematologic reactions, and neurotoxicity. Neu­ tropenia appears to be related to high doses or prolonged use. Neutropenia and interstitial nephritis caused by β-lactams generally resolve upon discontinuation of the agent. Imipenem and cefepime are associated with an increased risk of seizure, but this risk is likely a class effect and related to high doses or doses that are not adjusted in renal impairment. ■ ■SULBACTAM-DURLOBACTAM Durlobactam is a novel diazabicyclooctane non-β-lactam β-lactamase inhibitor combined with the β-lactamase inhibitor sulbactam for treat­ ment of multidrug-resistant Acinetobacter infections. It was approved in the United States in 2023 for treatment of hospital-acquired and ventilator-associated pneumonia caused by Acinetobacter baumanniicalcoaceticus complex. Adverse reactions include abnormal liver func­ tion tests, diarrhea, anemia, and hypokalemia. PART 5 Infectious Diseases ■ ■GLYCOPEPTIDES AND LIPOGLYCOPEPTIDES Vancomycin is a glycopeptide antibiotic with activity against staphylo­ cocci (including MRSA and coagulase-negative staphylococci), strep­ tococci (including S. pneumoniae), and enterococci. It is not active against gram-negative organisms. Vancomycin also displays activity against Bacillus species, Corynebacterium jeikeium, and gram-positive anaerobes such as Peptostreptococcus, Actinomyces, Clostridium, and Propionibacterium species. Vancomycin has several important clini­ cal uses. It is used for serious infections caused by MRSA, including health care–associated pneumonia, bacteremia, osteomyelitis, and endocarditis. It is also commonly used for skin and soft tissue infec­ tions. Oral vancomycin is not absorbed systemically and is reserved for the treatment of C. difficile infection. Vancomycin is also an alternative for the treatment of infections caused by MSSA in patients who cannot tolerate β-lactams. Resistance to vancomycin is a rising concern. Strains of vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant enterococci (VRE) are not uncommon. Vanco­ mycin appears to be a concentration-dependent killer, with the AUC/ MIC ratio being the best predictor of efficacy (Fig. 149-1). Guidelines recommend targeting a vancomycin trough level of 15–20 μg/mL in MRSA infections in order to maintain an AUC/MIC ratio >400. When using vancomycin, clinicians should monitor for nephrotoxic­ ity. The risk of nephrotoxicity increases when trough levels are >20 μg/mL. Concomitant therapy with other nephrotoxic agents, such as aminoglycosides, also increases the risk. Ototoxicity was reported with early formulations of vancomycin but is currently uncommon because purer formulations are available. Both of these adverse effects are reversible upon discontinuation of vancomycin. Clinicians should be aware of vancomycin infusion reaction (formerly known as “red man syndrome”), a common reaction that presents as a rapid onset of erythematous rash or pruritus on the head, face, neck, and upper trunk. This reaction is caused by histamine release from basophils and mast cells and can be treated with diphenhydramine and slowing of the vancomycin infusion. Telavancin, dalbavancin, and oritavancin are structurally similar to vancomycin and are referred to as lipoglycopeptides. They have anti­ bacterial activity against S. aureus (including MRSA and some strains of VISA and vancomycin-resistant S. aureus [VRSA]), streptococci,

and enterococci. Oritavancin may have activity against some strains of VRE. These lipoglycopeptide agents also provide coverage against anaerobic gram-positive organisms except for Lactobacillus and some Clostridium species. The clinical efficacy of telavancin has been demonstrated in both skin and soft tissue infections and nosocomial pneumonia, and the efficacy of dalbavancin and oritavancin has been shown in skin and soft tissue infections. The vancomycin resistance phenotype may reduce the potency of all three lipoglycopeptides, but the rate of resistance to these drugs among S. aureus and enterococcal isolates has been low. Adverse effects of telavancin include nephrotox­ icity, metallic taste, and gastrointestinal side effects. Clinicians should be aware of the potential for electrocardiographic QTc prolongation that can increase the risk of cardiac arrhythmias when telavancin is used concomitantly with other QTc-prolonging agents. Telavancin may interfere with certain coagulation tests (e.g., causing false eleva­ tions in prothrombin time). Dalbavancin and oritavancin have safety profiles similar to that of vancomycin, with common effects reported as headache and gastrointestinal side effects. These glycolipopeptides should be used cautiously in patients with hypersensitivity reactions to vancomycin, as cross-allergy may be possible. ■ ■LIPOPEPTIDES Daptomycin is a lipopeptide antibiotic with activity against a broad range of gram-positive organisms. It is active against staphylococci (including MRSA and coagulase-negative staphylococci), streptococci, and enterococci. Daptomycin remains active against enterococci that are resistant to vancomycin. In addition, it exhibits activity against Bacillus, Corynebacterium, Peptostreptococcus, and Clostridium species. Daptomycin’s pharmacodynamic parameter for efficacy is concentrationdependent killing. Resistance to daptomycin is rare, but MICs may be higher for some VISA strains. Daptomycin can be used in skin and soft tissue infections, bacteremia, endocarditis, and osteomyelitis. It is an important alternative for MRSA and other gram-positive infections when bactericidal therapy is needed and vancomycin cannot be used. Daptomycin is generally well tolerated, and its main toxicity consists of elevation of creatine phosphokinase (CPK) levels and myopathy. CPK should be monitored during daptomycin treatment, and the drug should be discontinued if muscular toxicities occur. There have also been case reports of reversible eosinophilic pneumonia associated with daptomycin use. ■ ■AMINOGLYCOSIDES The aminoglycosides are a class of antibacterial agents with concen­ tration-dependent activity against most gram-negative organisms. The most commonly used aminoglycosides are gentamicin, tobramycin, and amikacin, although others, such as streptomycin, kanamycin, neomycin, and paromomycin, may be used in special circumstances. Plazomicin is a new aminoglycoside that is less affected by common resistance mechanisms and is approved for treatment of complicated urinary tract infections and acute pyelonephritis. Aminoglycosides have a significant dose-dependent postantibiotic effect; i.e., they have an antibacterial effect even after serum drug levels fall below inhibitory concentrations. The postantibiotic effect and concentration-dependent killing form the rationale behind extended-interval aminoglycoside dosing, in which a larger dose is given once daily rather than smaller doses multiple times daily. Aminoglycosides are active against gramnegative bacilli, such as Enterobacterales, P. aeruginosa, and Acineto­ bacter. They also enhance the activity of cell wall–active agents such as β-lactams or vancomycin against some gram-positive bacteria, including staphylococci and enterococci. This combination therapy is termed synergistic because the effect of both agents provides a killing effect greater than would be predicted from the effects of either agent alone. Amikacin and streptomycin have activity against Mycobacte­ rium tuberculosis, and amikacin has activity against nontuberculous mycobacteria, including Mycobacterium avium complex and Mycobac­ terium abscessus. The aminoglycosides do not have activity against anaerobes, S. maltophilia, or Burkholderia cepacia complex. Amino­ glycosides are used in clinical practice in a variety of infections caused by gram-negative organisms, including bacteremia and urinary tract

infections. They are frequently used in combination for the treatment of P. aeruginosa infection. When used in combination with a cell wall– active agent, gentamicin and streptomycin are also important for the treatment of gram-positive bacterial endocarditis. All aminoglycosides can cause nephrotoxicity and ototoxicity. The risk of nephrotoxicity is not well defined; however, some studies have indicated that the effect may be related to the duration of therapy as well as to the concomitant use of other nephrotoxic agents. Nephrotoxicity is usually reversible, but ototoxicity can be irreversible. ■ ■MACROLIDES AND KETOLIDES The macrolides (azithromycin, clarithromycin, and erythromycin) and ketolides (telithromycin) are classes of antibiotics that inhibit protein synthesis. Compared with erythromycin (the older antibi­ otic), azithromycin and clarithromycin have better oral absorption and tolerability. Azithromycin, clarithromycin, and telithromycin all have broader spectra of activity than erythromycin, which is less frequently used. These agents are commonly used in the treat­ ment of upper and lower respiratory tract infections caused by S. pneumoniae, H. influenzae, M. catarrhalis, and atypical organisms (e.g., Chlamydophila pneumoniae, Legionella pneumophila, and Myco­ plasma pneumoniae); group A streptococcal pharyngitis in penicillinallergic patients; and nontuberculous mycobacterial infections (e.g., caused by Mycobacterium marinum and Mycobacterium chelonae) as well as in the prophylaxis and treatment of M. avium complex infection in patients with HIV/AIDS and in combination therapy for Helicobacter pylori infection and bartonellosis. Enterobacterales, Pseudomonas species, and Acinetobacter species are intrinsically resistant to macrolides as a result of decreased membrane perme­ ability, although azithromycin is active against gram-negative diar­ rheal pathogens. The major adverse effects of this drug class include nausea, vomiting, diarrhea and abdominal pain, prolongation of QTc interval, exacerbation of myasthenia gravis, and tinnitus and reversible deafness, especially in the elderly. Azithromycin specifi­ cally has been associated with an increased risk of death, especially among patients with underlying heart disease, because of the risk of QTc interval prolongation and torsades de pointes arrhythmia. Erythromycin, clarithromycin, and telithromycin inhibit the CYP3A4 hepatic drug-metabolizing enzyme and can result in increased levels of coadministered drugs, including benzodiazepines, statins, war­ farin, cyclosporine, and tacrolimus. Azithromycin does not inhibit CYP3A4 and therefore does not interact with these drugs. ■ ■CLINDAMYCIN Clindamycin is a lincosamide antibiotic and is bacteriostatic against some organisms and bactericidal against others. It is used most often to treat bacterial infections caused by anaerobes (e.g., B. fragilis, Clostridium perfringens, Fusobacterium species, Prevotella melanino­ genicus, and Peptostreptococcus species) and susceptible staphylococci and streptococci. Clindamycin is used for treatment of dental infec­ tions, anaerobic lung abscess, and skin and soft tissue infections. It is used together with bactericidal agents (penicillins or vancomycin) to inhibit new toxin synthesis in the treatment of streptococcal or staphylococcal toxic shock syndrome. Other uses include treatment of infections caused by Capnocytophaga canimorsus, combination therapy for babesiosis and occasionally malaria, and therapy for toxoplas­ mosis. Clindamycin has excellent oral bioavailability. Adverse effects include nausea, vomiting, diarrhea, C. difficile–associated diarrhea and pseudomembranous colitis, maculopapular rash, and rarely StevensJohnson syndrome. ■ ■TETRACYCLINES The older (doxycycline, minocycline, and tetracycline) and newer (tigecycline, eravacycline, and omadacycline) tetracyclines inhibit protein synthesis and are bacteriostatic. These drugs have wide clini­ cal uses. They are used in the treatment of skin and soft tissue infec­ tions caused by gram-positive cocci (including MRSA), spirochetal infections (e.g., Lyme disease, syphilis, leptospirosis, and relapsing fever), rickettsial infections (e.g., Rocky Mountain spotted fever,

scrub typhus), atypical pneumonia, sexually transmitted infections (e.g., Chlamydia trachomatis infection, lymphogranuloma venereum, and granuloma inguinale), infections with Nocardia and Actinomyces, brucellosis, tularemia, Whipple’s disease, and malaria. Tigecycline, eravacycline, and omadacycline are also used in combination with other agents for treatment of M. abscessus. Tigecycline is a glycylcy­ cline derived from minocycline and is available only in IV formula­ tion. It is indicated in the treatment of complicated skin and soft tissue infections, complicated intraabdominal infections, and communityacquired bacterial pneumonia in adults. Tigecycline has activity against MRSA, vancomycin-sensitive enterococci, many Enterobacte­ rales, and Bacteroides species; it has no activity against P. aeruginosa. This drug has been used in combination with colistin for the treat­ ment of serious infections with multidrug-resistant gram-negative organisms. A pooled analysis of 13 clinical trials found an increased risk of death and treatment failure among patients given tigecycline alone; as a result, the FDA mandated a black box warning. Eravacy­ cline is a fluorocycline derivative available in IV formulation with a similar spectrum but more potent than tigecycline in vitro. It has been approved for complicated intraabdominal infections. Omadacycline is an aminomethylcycline derivative available in both IV and oral formulations. It has activity similar to that of tigecycline against grampositive pathogens but is less active against gram-negative pathogens. Omadacycline has been approved for treatment of bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Tetracyclines have reduced absorption when orally coad­ ministered with calcium- and iron-containing compounds, including milk, and doses should be spaced at least 2 h apart. The major adverse reactions to old and new tetracyclines are nausea, vomiting, diarrhea, and photosensitivity. Tetracyclines have been associated with fetal bone-growth abnormalities and should be avoided during pregnancy and in the treatment of children <8 years old.

CHAPTER 149 ■ ■TRIMETHOPRIM-SULFAMETHOXAZOLE Trimethoprim-sulfamethoxazole (TMP-SMX) is an antibiotic with two components that each inhibit a separate step in folate synthesis and produce antibacterial activity. TMP-SMX is active against grampositive bacteria such as staphylococci and streptococci; however, its use against MRSA is usually limited to community-acquired infections, and its activity against Streptococcus pyogenes may not be reliable. This drug is also active against many gram-negative bacteria, including H. influenzae, E. coli, P. mirabilis, Neisseria gonorrhoeae, and S. maltophilia. TMP-SMX is not active against anaerobes or P. aeruginosa. It has many uses because of its wide spectrum of activity and high oral bioavailability. Urinary tract infections, skin and soft tissue infections, and respiratory tract infections are among the com­ mon uses. Another important indication is for both prophylaxis and treatment of Pneumocystis jirovecii infections in immunocompro­ mised patients. Resistance to TMP-SMX has limited its use against many Enterobacterales. Resistance rates among urinary isolates of E. coli are almost 25% in the United States. The most common adverse reactions associated with TMP-SMX are gastrointestinal effects such as nausea, vomiting, and diarrhea. In addition, rash is a common allergic reaction and may preclude the subsequent use of other sulfonamides. With prolonged use, leukopenia, thrombocyto­ penia, and granulocytopenia can develop. TMP-SMX can also cause nephrotoxicity, hyperkalemia, and hyponatremia, which are more common at high doses. TMP-SMX has several important interactions with other drugs (Table 149-3), including warfarin, phenytoin, and methotrexate. Treatment and Prophylaxis of Bacterial Infections ■ ■FLUOROQUINOLONES The fluoroquinolones include norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, gemifloxacin, and delafloxacin. Cipro­ floxacin and levofloxacin have the broadest spectrum of activity against gram-negative bacteria, including P. aeruginosa (similar to that of third-generation cephalosporins). Because of the risk of selection of resistance during fluoroquinolone treatment of serious pseudomonal infections, these agents are usually used in combination with an

antipseudomonal β-lactam. Levofloxacin, moxifloxacin, gemifloxacin, and delafloxacin have additional gram-positive activity, including that against S. pneumoniae and some strains of MSSA, and with the excep­ tion of delafloxacin, these agents are used for treatment of communityacquired pneumonia. Strains of MRSA are commonly resistant to all fluoroquinolones except delafloxacin. Moxifloxacin is used as one component of second-line regimens for multidrug-resistant tubercu­ losis. Fluoroquinolones are no longer used for treatment of gonorrhea because of common resistance in N. gonorrhoeae. Fluoroquinolones exhibit concentration-dependent killing, are well absorbed orally, and have elimination half-lives that usually support once- or twicedaily dosing. Oral coadministration with compounds containing high concentrations of aluminum, magnesium, or calcium can reduce fluoroquinolone absorption. The penetration of fluoroquinolones into prostate tissue supports their use for bacterial prostatitis. Fluoroquino­ lones are generally well tolerated but can cause central nervous system (CNS) stimulatory effects, including seizures; peripheral neuropathy; glucose dysregulation; and tendinopathy associated with Achilles ten­ don rupture, particularly in older patients, organ transplant recipients, and patients taking glucocorticoids. Other potential effects on connec­ tive tissues include an association with increased risk of aortic aneu­ rysm. Worsening of myasthenia gravis also has been associated with quinolone use. Moxifloxacin causes modest prolongation of the QTc interval and should be used with caution in patients receiving other QTc-prolonging drugs.

■ ■RIFAMYCINS The rifamycins include rifampin, rifabutin, and rifapentine. Rifampin is the most commonly used rifamycin. For almost all therapeutic indications, it is used in combination with other agents to reduce the likelihood of selection of high-level rifampin resistance. Rifampin is used foremost in the treatment of mycobacterial infections—specifically, as a mainstay of combination therapy for M. tuberculosis infection or as a single agent in the treatment of latent M. tuberculosis infection. In addition, it is often used in the treatment of some nontuberculous mycobacterial infections. Rifampin is used in combination regimens for the treatment of staphylococcal infections, particularly prostheticvalve endocarditis and bone infections with retained hardware. It is a component of combination therapy for brucellosis (with doxycycline) and leprosy (with dapsone for tuberculoid leprosy and with dapsone and clofazimine for lepromatous disease). Rifampin can be used alone for prophylaxis in close contacts of patients with H. influenzae or N. meningitidis meningitis. The drug has high oral bioavailability, which is further enhanced when it is taken on an empty stomach. Rifampin has several adverse effects, including elevated aminotrans­ ferase levels (14%), rash (1–5%), and gastrointestinal events such as nausea, vomiting, and diarrhea (1–2%). Its many clinically relevant interactions with other drugs (Table 149-3) mandate the clinician’s careful review of the patient’s medications before rifampin initiation to assess safety and the need for additional monitoring, including monitoring of drug levels. PART 5 Infectious Diseases ■ ■METRONIDAZOLE Metronidazole is used in the treatment of anaerobic bacterial infections as well as infections caused by protozoa (e.g., amebiasis, giardiasis, trichomoniasis). It is the agent of choice as a component of combina­ tion therapy for polymicrobial abscesses in the lung, brain, or abdo­ men, the etiology of which often includes anaerobic bacteria, and for bacterial vaginosis, pelvic inflammatory disease, and anaerobic infec­ tions, such as those due to Bacteroides, Fusobacterium, and Prevotella species. This drug is an alternative agent for treatment of mild to moderate C. difficile–associated diarrhea. Metronidazole is bactericidal against anaerobic bacteria and exhibits concentration-dependent kill­ ing. It has high oral bioavailability and tissue penetration, including penetration of the blood-brain barrier. The majority of Actinomyces, Propionibacterium, and Lactobacillus species are intrinsically resistant to metronidazole. The major adverse effects include nausea, diarrhea, and a metallic taste. Concomitant ingestion of alcohol may result in a disulfiram-like reaction, and patients are usually instructed to avoid

alcohol during treatment. Long-term treatment carries the risk of leukopenia, neutropenia, peripheral neuropathy, and CNS toxicity manifesting as confusion, dysarthria, ataxia, nystagmus, and oph­ thalmoparesis. Through metronidazole’s effect on the CYP2C9 drugmetabolizing enzyme, its coadministration with warfarin can result in decreased metabolism and enhanced anticoagulant effects that require close monitoring. Concomitant administration of metronidazole with lithium can result in increased serum levels of lithium and associated toxicity; coadministration with phenytoin can result in phenytoin tox­ icity and possibly decreased levels of metronidazole. ■ ■OXAZOLIDINONES Linezolid is a bacteriostatic agent and is indicated for serious infections due to resistant gram-positive bacteria, such as MRSA and VRE. The intrinsic resistance of gram-negative bacteria is mediated primarily by endogenous efflux pumps. Linezolid has excellent oral bioavailability. Adverse effects include myelosuppression and ocular and peripheral neuropathy with prolonged therapy. Peripheral neuropathy may be irreversible. Linezolid is a weak, reversible monoamine oxidase inhibi­ tor, and coadministration with sympathomimetics and foods rich in tyramine should be avoided. Linezolid has been associated with sero­ tonin syndrome when coadministered with selective serotonin reup­ take inhibitors. Tedizolid has properties similar to those of linezolid, but with lower dosing due to greater potency, it may be less likely to cause adverse hematologic and neuropathic effects. ■ ■PLEUROMUTILINS Lefamulin is the only member of the pleuromutilin class approved for systemic use; it is available in IV and oral formulations. Lefamulin has in vitro activity against S. aureus (including MRSA), S. pneumoniae, H. influenzae, and atypical respiratory pathogens, including L. pneu­ mophila, M. pneumoniae, and C. pneumoniae, and has been approved for treatment of community-acquired bacterial pneumonia. Adverse effects are most commonly gastrointestinal, including diarrhea (12%), nausea (5%), and vomiting (3%). Prolongation of QTc interval and hepatic transaminase elevations occur in some patients. There can be interactions with drugs that are either inducers or inhibitors of CYP3A4 or P-glycoprotein transporter. ■ ■NITROFURANTOIN Nitrofurantoin’s antibacterial activity results from the drug’s conver­ sion to highly reactive intermediates that can damage bacterial DNA and other macromolecules. Nitrofurantoin is bactericidal, and its action is concentration dependent. It displays activity against a range of gram-positive bacteria, including S. aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, E. faecalis, Streptococcus agalactiae, group D streptococci, viridans streptococci, and corynebacteria, as well as gram-negative organisms, including E. coli, Enterobacter, Salmonella, and Shigella species. Nitrofurantoin is used primarily in the treatment of urinary tract infections and is preferred in the treatment of such infections in pregnancy. It may be used for the prevention of recurrent cystitis. Recently, there has been interest in the use of nitrofurantoin for treatment of urinary tract infections caused by ESBL-producing Enterobacterales such as E. coli, although resistance has been growing in Latin America and parts of Europe. Coadministration with magne­ sium should be avoided because of decreased absorption, and patients should be encouraged to take the drug with food to increase its bio­ availability and decrease the risk of adverse effects, which include nau­ sea, vomiting, and diarrhea. Nitrofurantoin may also cause pulmonary fibrosis and drug-induced hepatitis. Because the risk of adverse reac­ tions increases with age, the use of nitrofurantoin in elderly patients is not recommended. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at elevated risk for nitrofurantoin-associated hemolytic anemia. ■ ■POLYMYXINS Colistin and polymyxin B act by disrupting bacterial cell membrane integrity and are active against the nonenteric pathogens P. aeruginosa and A. baumannii but not against Burkholderia. These drugs also

exhibit activity against many Enterobacterales, with the exceptions of Proteus, Providencia, and Serratia species. They lack activity against gram-positive bacteria. Polymyxins are bactericidal and are available in IV formulations. Colistimethate is converted to the active form (colistin) in plasma. Polymyxins are most often used for infections due to pathogens resistant to multiple other antibacterial agents, including urinary tract infections, hospital-acquired pneumonia, and bloodstream infections. Nebulized formulations have been used for adjunctive treatment of refractory ventilator-associated pneumonia as well as a prevention strategy for patients with bronchiectasis and/ or cystic fibrosis. The most important adverse effect is dose-depen­ dent reversible nephrotoxicity. Neurotoxicity, including paresthesias, muscle weakness, and confusion, is reversible and less common than nephrotoxicity. ■ ■QUINUPRISTIN-DALFOPRISTIN Quinupristin-dalfopristin contains two members of the streptogramin class of antibiotics and kills bacteria by inhibiting protein synthesis. The antibacterial spectrum of quinupristin-dalfopristin includes staph­ ylococci (including MRSA), streptococci, and E. faecium (but not E. faecalis). This drug combination is also active against Corynebacterium species and L. monocytogenes. Quinupristin-dalfopristin is not reliably active against gram-negative organisms. It exhibits concentrationdependent killing, with an AUC/MIC ratio predicting efficacy. The clinical use of quinupristin-dalfopristin is largely for infections due to vancomycin-resistant E. faecium and other gram-positive bacterial infections. The drug has demonstrated efficacy in a variety of infec­ tions, including urinary tract infections, bone and joint infections, and bacteremia. Adverse effects associated with quinupristin-dalfopristin include infusion-related reactions, arthralgias, and myalgias. The arthralgias and myalgias may be severe enough to warrant drug discontinuation. Quinupristin-dalfopristin inhibits the CYP3A4 drugmetabolizing enzyme, with consequent drug interactions (Table 149-3). ■ ■FOSFOMYCIN Fosfomycin is a phosphonic acid antibiotic that has greater activity in acidic environments and is excreted in its active form in the urine. The oral formulation is primarily for prophylaxis and treatment of uncom­ plicated cystitis and should be avoided if there is concern about pyelo­ nephritis. The drug is administered as a single 3-g dose that results in high urine concentrations for up to 48 h. Fosfomycin is active against S. aureus, vancomycin-susceptible enterococci and VRE, and a wide range of gram-negative organisms, including E. coli, Enterobacter spe­ cies, Serratia marcescens, P. aeruginosa, and K. pneumoniae. Notably, the vast majority of ESBL-producing Enterobacterales are susceptible to fosfomycin. A. baumannii and Burkholderia species are resistant. The emergence of resistance to fosfomycin has not been observed during treatment of cystitis but has been documented during IV treat­ ment of respiratory tract infections and osteomyelitis. The few adverse effects that have been reported include nausea and diarrhea. ■ ■CHLORAMPHENICOL The use of chloramphenicol is limited by its potentially serious tox­ icities. When other agents are contraindicated or ineffective, chloram­ phenicol represents an alternative treatment for infections, including meningitis caused by susceptible bacteria such as N. meningitidis, H. influenzae, and S. pneumoniae. It has also been used for the treatment of anthrax, brucellosis, Burkholderia infections, chlamydial infections, clostridial infections, ehrlichiosis, rickettsial infections, and typhoid fever. Adverse reactions include aplastic anemia, myelosuppression, and gray baby syndrome. Chloramphenicol inhibits the CYP2C19 and CYP3A4 drug-metabolizing enzymes and consequently increases levels of many classes of drugs. APPROACH TO PROPHYLAXIS

OF INFECTION Antibacterial prophylaxis is indicated only in selected circumstances (Table 149-5) and should be supported by well-designed studies or expert panel recommendations. In all cases, the risk or severity

of the infection to be prevented should be greater than the adverse consequences of antibacterial therapy, including the potential for selection of resistance. In addition, the timing and duration of antibacterial treatment should be targeted for maximal effect and minimal required exposure. Prophylaxis of surgical infections tar­ gets bacteria that may contaminate the wound during the surgical procedure, including the skin flora of the patient or operating team and the air in the operating room. Delivery of the antibacterial drug within 1 h before the surgical incision is most effective because it maximizes tissue concentrations. For prolonged procedures, redosing may be necessary to maintain effective blood and tissue levels until the wound is closed. Additional dosing is not recommended after the incision is closed, and antimicrobials should be discontinued after incisional closure in the operating room. In patients with nasal car­ riage of S. aureus, preoperative decolonization with nasal mupirocin reduces the rate of S. aureus surgical-site infections and is generally recommended for high-risk procedures such as cardiac surgery and orthopedic implantation of prosthetic devices. For dental procedures, preprocedure antibacterial drugs are recommended for select patient populations to prevent transient bacteremia during the procedure and the seeding of certain high-risk cardiac lesions. Prophylaxis is also used in nonprocedural settings in certain patients who have recurrent infections or who are at risk of serious infection from a spe­ cific exposure (e.g., close contact with a patient with meningococcal meningitis). Extension of prophylaxis beyond the period of infection risk does not add further benefit and may increase the risk of resis­ tance selection or C. difficile disease.

CHAPTER 149 ANTIMICROBIAL STEWARDSHIP In an era of increasing prevalence of multidrug-resistant bacteria and with a substantial amount of inappropriate antimicrobial use, the need for rational antimicrobial prescribing has never been greater (Chap. 150). Antimicrobial stewardship describes the practice of promoting the selection of the appropriate drug, dosage, route, and duration of therapy. Antimicrobial stewardship programs implement a variety of strategies to (1) improve patient care through appropriate antimicrobial use; (2) preserve a vital health care resource by curbing the development of resistance within patient populations; (3) reduce the incidence of adverse effects; and (4) control costs. The Centers for Disease Control and Prevention (CDC) guidelines, The Joint Commission (TJC) Medication Management Standards, and the Centers for Medicare and Medicaid Services (CMS) Conditions of Participation, as well as the 2015 National Action Plan for Combating Antibiotic-Resistant Bacteria, have all supported antimicrobial stew­ ardship in various health care settings. Antimicrobial stewardship programs are typically multidisciplinary and often include infectious disease physicians, clinical pharmacists (usually with special training in infectious disease), clinical microbiologists, information systems specialists, infection prevention and control practitioners, and epi­ demiologists. These teams employ a variety of approaches to achieve the program’s goals. Treatment and Prophylaxis of Bacterial Infections Established strategies of antimicrobial stewardship programs include (1) prospective audit of antimicrobial use, with intervention and feedback; (2) formulary restriction; and (3) preauthorization. Prospective audit and feedback are usually undertaken by an infectious disease physician or a pharmacist. In this process, orders for broadspectrum antimicrobials (e.g., carbapenems) or agents for which more cost-effective alternatives may exist (e.g., daptomycin, ceftazidimeavibactam) are reviewed on a regular basis for appropriateness. In circumstances when antimicrobial use can be further optimized, the stewardship program team can intervene to recommend an alternative. This process has been successful in several quasi-experimental studies, resulting in declines in use of broad-spectrum drugs when unnecessary and decreases in adverse events, such as C. difficile infection. Formulary restriction is the inclusion of a limited set of antimicrobial agents in a hospital formulary for the purpose of limiting indiscriminate use of antimicrobials in the absence of demonstrated benefit. Such restriction also serves to avoid unnecessary drug expenditure. Preauthorization is the practice of requiring clinicians to obtain approval before using

TABLE 149-5  Prophylaxis of Bacterial Infections in Adults CONDITION ANTIBACTERIAL AGENTSa TIMING OR DURATION OF PROPHYLAXIS Surgical Clean (cardiac, thoracic, neurologic, orthopedic, vascular, plastic) Cefazolin (vancomycin,b clindamycin) 1 h before incision; re-dose with long procedures Clean (ophthalmic) Topical neomycin–polymyxin B–gramicidin, topical moxifloxacin Clean-contaminated (head and neck) Cefazolin + metronidazole, ampicillin-sulbactamc (clindamycin) 1 h before incision; re-dose with long procedures Clean-contaminated (hysterectomy, gastroduodenal, biliary, unobstructed small intestine, urologic) Cefazolin, ampicillin-sulbactamc (clindamycin + aminoglycoside, aztreonam, or fluoroquinolone) Clean-contaminated (colorectal, appendectomy) Cefazolin + metronidazole, ampicillin-sulbactam,c ertapenem (clindamycin + aminoglycoside, aztreonam, or fluoroquinolone) Dirty (ruptured viscus) Therapeutic regimen directed at anaerobes and gram-negative bacteria (e.g., ceftriaxone + metronidazole) Dirty (traumatic wound) Therapeutic regimen: cefazolin (clindamycin ± aminoglycoside, aztreonam, or fluoroquinolone) Nonsurgical Dental, oral, or upper respiratory procedures in patients with high-risk cardiac lesions (prosthetic valves, congenital heart defects, prior endocarditis) Amoxicillin PO, ampicillin IM (clindamycin PO, IV) Oral agents 1 h before procedure; injection 30 min before procedure Recurrent S. aureus skin infectionsd Mupirocine Intranasal application for 5 days Recurrent cellulitis associated with lymphatic disruptiond Benzathine penicillin IM monthly, oral penicillin or erythromycin twice daily Recurrent cystitis in womend Nitrofurantoin, TMP-SMX, fluoroquinolone After sexual intercourse or 3 times weekly for up to 1 year Bite wounds Amoxicillin-clavulanate (doxycycline, moxifloxacin) 3–5 days PART 5 Infectious Diseases Recurrent spontaneous bacterial peritonitis in cirrhotic patientsd Fluoroquinolonef Undefined Recurrent pneumococcal meningitis in patient with CSF leak or humoral immune defectd Penicillin Undefined Exposure to patient with meningococcal meningitis Rifampin, ciprofloxacin 2 days (rifampin), single dose (ciprofloxacin) High-risk neutropenia (ANC, ≤100/μL for >7 days)d Levofloxacin or ciprofloxacinf Until neutropenia resolves or fever dictates use of other antibacterials aRegimens in parentheses are alternatives for patients allergic to β-lactams. bVancomycin may be given together with cefazolin to patients known to be colonized with methicillin-resistant Staphylococcus aureus. cCefoxitin or cefotetan may also be considered. dNot considered routine for all patients, but an acceptable consideration among alternative approaches. eUsually coupled with bathing with chlorhexidine-containing skin antiseptic. fChoice of fluoroquinolone prophylaxis must be balanced against the risk of selection of resistance. Abbreviations: ANC, absolute neutrophil count; CSF, cerebrospinal fluid; TMP-SMX, trimethoprim-sulfamethoxazole. selected antimicrobials. Approval may be provided electronically with sophisticated Computerized Provider Order Entry (CPOE) software, after specific criteria for use are met, or after communication with an infectious disease specialist as designated by the stewardship program. These strategies have led to a decrease in C. difficile infections and to improvements in drug susceptibility patterns. Additional strategies used in specific health care settings are guide­ lines and pathways, dose optimization, parenteral-to-oral conversion, antibiotic time-out, and de-escalation of therapy. Documentation of the indication for which each antimicrobial is prescribed is also encouraged. Finally, antimicrobial stewardship teams provide ongoing education of best practices. An evolving and increasingly active area of clinical research to identify best practices, antimicrobial stewardship continues to grow as an essential service in various health care settings. The IDSA, in collaboration with several other professional organiza­ tions, has published guidelines for developing institutional antimicro­ bial stewardship programs (www.idsociety.org/Antimicrobial_Agents/). Acknowledgment The authors thank Christy A. Varughese for her significant contributions to this chapter in the previous editions. ■ ■FURTHER READING Barlam TF et al: Implementing an antibiotic stewardship program: Guidelines by the Infectious Diseases Society of America and the

Every 5–15 min for 5 doses immediately prior to procedure 1 h before incision; re-dose with long procedures 1 h before incision; re-dose with long procedures 1 h before incision; re-dose with long procedures; continue for 3–5 days after procedure 1 h before incision; re-dose with long procedures; continue for 3–5 days after procedure Undefined Society for Healthcare Epidemiology of America. Clin Infect Dis 62:e51, 2016. Bratzler DW et al: Clinical practice guidelines for antimicrobial pro­ phylaxis in surgery. Surg Infect (Larchmt) 14:73, 2013. Calderwood MS et al: Strategies to prevent surgical site infections in acute care hospitals: 2022. Update. Infect Control Hospital Epidemiol 44:695, 2023. Grayson ML et al (eds): Kucers’ The Use of Antibiotics. A Clinical Review of Antibacterial, Antifungal, Antiparasitic and Antiviral Drugs, 7th ed. Boca Raton, CRC Press, 2018. Infectious Diseases Society of America: Practice guidelines by organ system. Available at https://www.idsociety.org/practice-guideline/ practice-guidelines/. Jeffries MN et al: Consequences of avoiding β-lactams in patients with β-lactam allergies. J Allergy Clin Immunol 137:1148, 2016. Labreche MJ et al: Recent updates on the role of pharmacokinetics– pharmacodynamics in antimicrobial susceptibility testing as applied to clinical practice. Clin Infect Dis 61:1446, 2015. Rotschafer J et al (eds): Antibiotic Pharmacodynamics. Methods in Pharmacodynamics and Toxicology. New York, Humana Press, 2016. Shenoy ES et al: Evaluation and management of penicillin allergy: A review. JAMA 321:188, 2019. Tamma PD et al: Infectious Diseases Society of America 2023 guidance on the treatment of antimicrobial resistant gram-negative infections. Clin Infect Dis 18:ciae403, 2024.