Chapter 39: Antimicrobial Therapy

The discovery and rapid development of targeted antimicrobial agents, beginning in the 1930s, are among the most important scientific developments of 20th-century medicine. These drugs have forever changed the practice of medicine, and antimicrobials remain one of medicine’s most effective and widely used interventions. However, despite the impact of these drugs, choosing an appropriate antimicrobial can be a complex and difficult task. Optimal antimicrobial use requires appreciation of the complicated interactions between host, organism, and drug. This decision-making process, summarized in Table 39–1, begins with an accurate working diagnosis, based on the patient’s history, physical examination, exposure history, and initial laboratory tests. From this foundation, the clinician must consider the most likely organism(s) and that organism’s likely pattern of antimicrobial susceptibility. This information is considered in the context of numerous patient-specific factors, including age, immune status, relevant comorbidities, site of infection, and microbiology of his or her prior infections. Empiric therapy should be changed to definitive therapy as the clinical course evolves and additional laboratory data are available. Obtaining appropriate microbiologic specimens helps facilitate this transition.

For example, age impacts the likely pathogens; neonates are generally predisposed to infection with Escherichia coli and group B Streptococcus, while in older children, infections with Streptococcus pneumoniae and Staphylococcus aureus predominate. Children with chronic illness may have significant exposure to antimicrobials, and the effect of this on their microbial flora should be considered. Different exposures, based on environment, travel, diet, animal contact, or ill family members or other close contacts, may suggest a greater likelihood of certain organisms. Another important consideration is the pace and seriousness of the illness. A rapidly progressive and severe illness should be treated initially with broad-spectrum antimicrobials until a specific etiologic diagnosis is made. A mildly ill ambulatory patient should receive treatment with narrow-spectrum antimicrobials, per national guidelines when available. These many and often interconnected factors make the choice of empiric treatment challenging.

Once an appropriate initial antimicrobial is chosen, the clinician must consider the proper dose, route of administration, duration of therapy, and whether additional drugs are needed. Antimicrobial susceptibility, antimicrobial families, and dosing recommendations are listed in Tables 39–3, 39–4, 39–5. The need to balance a treatment’s efficacy with the toxicities and side effects inherent in the drugs chosen makes this process even more complex. Often, decisions of when not to use antimicrobials are important, as additional drugs and longer durations may harm patients.

Antimicrobials are the most commonly prescribed class of medication in both adults and children. Over 25% of pediatric outpatient visits result in an antimicrobial prescription, and nearly 60% of pediatric inpatients receive antimicrobials. Much of this use (up to 40%–60%) is inappropriate. We not only overprescribe but also choose unnecessarily broad agents, even though they are often less effective. For example, azithromycin and cefdinir are among the top prescribed antibiotics in outpatient pediatrics, despite that they are rarely first-line agents on pediatric national guidelines and often inferior to alternative oral agents.

Historically, overprescribing was viewed as an “insurance policy.” This approach was considered a cheap, safe, and reliable intervention that providers could offer to parents beyond reassurance. This era is over for six reasons. First, overuse leads to antibiotic resistance at a patient, hospital, and community level. Resistance is now commonplace and increasing to the point the efficacy of some antimicrobials may be limited or completely lacking for some infections. Second, overuse impacts the patient’s normal flora and creates a microbial “void” that multidrug-resistant organisms, Clostridioides difficile (formerly Clostridium difficile), yeasts, and molds can enter and become a reservoir for disease. In the United States, there are approximately 478,000 cases of C difficile colitis and 2 million antimicrobial resistant infections (with at least 23,000 deaths) per year. Third, patients experience adverse drug reactions regularly; an adverse reaction occurs in approximately 30% of antibiotic courses, resulting in over 150,000 unplanned pediatric medical visits per year. In many instances of inappropriate prescribing, more patients will experience harm from an antibiotic than will benefit from it—in other words, when the likelihood of benefit is low, the number needed to treat (NNT) to benefit a patient can be higher than the number needed to NNT to harm (NNH) a patient. Adverse events include device-related complications (such as infections and clots of central lines inserted for antimicrobial use, and intravenous extravasations) and drug adverse effects (such as fever, rash, hives, Stevens-Johnson syndrome, drug-induced hypersensitivity syndrome [DIHS], drug-induced lupus, antibiotic-associated diarrhea, neutropenia, thrombocytopenia, anemia, renal toxicity, and hepatitis). Fourth, the impact of overuse on a patient’s microbiome has been linked to untoward health effects, such as obesity in children and graft-versus-host disease in transplant recipients. Fifth, the drugs and their health consequences are expensive; for example, an episode of in-hospital C difficile has an attributable cost of $93,000. Sixth, provider’s perception that a parent wants an antibiotic for their child is often unfounded. Data indicate that instead of antibiotics, the majority of parents want reassurance that their concern for their child was justified, and they want guidance on what to do if their child becomes more ill or does not improve. This misconception is a main driver of overprescribing. Finally, many of these factors together may lead to poorer clinical outcomes.

To avoid complications and side effects, providers should use guideline-recommended drugs, for the shortest efficacious durations, stop drugs when infections are unlikely and cultures are negative, and choose oral therapies when possible. Many drugs including metronidazole, clindamycin, fluconazole, levofloxacin, rifampin, linezolid, and trimethoprim/sulfamethoxazole are more than 90% bioavailable orally (and ciprofloxacin is 80%) and thus can be used orally, with similar efficacy to IV therapy, if the gastrointestinal tract is intact. Even for drugs that are less bioavailable, transition to oral therapy is still appropriate as step-down therapy once the patient is clinically improved (eg, amoxicillin for pneumonia or cephalexin for osteomyelitis after initial inpatient IV therapy).

Because of the documented harms of unrestrained antimicrobial use, antimicrobial stewardship programs (ASPs) have been endorsed by the Infectious Disease Society of America, US News and World Report, Centers for Medicaid and Medicare Services, and some state legislatures. ASPs are effective at improving antimicrobial use in many hospitals, resulting in decreased use of antimicrobials, decreased drug-resistant infections, decreased C difficile colitis, decreased costs, and improved clinical outcomes. ASPs are typically collaborative and cross-disciplinary, involving infectious diseases physicians, pharmacists, data analysts, and multiple other stakeholders. ASP models vary by location, but they include local guideline and policy development, antibiotic use prior authorization programs (where a prescriber must seek permission to prescribe certain antimicrobials), postprescriptive review programs (where stewards review use and intervene when there is a question on appropriateness), IV to oral switch policies, prescriber feedback programs (where prescribing habits are compared and contrasted to others on either a unit, practice, or provider level), and multiple other interventions.

Cultures and other diagnostic material should be obtained prior to starting antimicrobial therapy. This is especially important for complicated situations, such as when the patient has a serious infection, is at risk for drug-resistant organisms, has failed prior treatment, has unusual exposures, or multiagent empiric therapy is anticipated. When cultures identify the causative organism, therapy should be tailored to susceptibility and an appropriate duration selected.

Clinical specimens for diagnostic testing should be evaluated in a laboratory using carefully defined procedures (as defined by the Clinical and Laboratory Standards Institute [CLSI] or European Committee on Antimicrobial Susceptibility Testing [EUCAST]). For most bacteria, growth in culture remains the gold standard for identification and susceptibility testing. Though laboratory techniques continue to improve, the growth rate of the organism remains a limiting factor—multiple days are often required for an organism to grow, be identified, and susceptibilities determined. Though traditional biochemical testing is still the mainstay for most organisms, there are now much more rapid methods, such as polymerase chain reaction (PCR) panels and mass spectrometry-based identification. For detection of some mechanisms of resistance, such as mecA detection indicating methicillin-resistant S aureus (MRSA), rapid PCR methods are available in many clinical laboratories. However, most antimicrobial susceptibility testing is still done by determination of the minimum inhibitory concentration (MIC) for the organism-drug pair (eg, S pneumoniae and penicillin) in a culture-based system. The MIC represents the amount of antibiotic (in mcg/mL) necessary to inhibit growth of the organism under specific laboratory conditions. The organism is then deemed susceptible, intermediate, or resistant based on CLSI or EUCAST published breakpoints. Breakpoints are determined based on achievable levels of drug in the serum at recommended dosing in healthy adults. In certain circumstances, the levels in other body fluids are considered, such as in cerebral spinal fluid (CSF, eg, S pneumoniae) or in urine. In general, however, breakpoints do not consider drug penetration into certain infected spaces (like bone, lung, kidney parenchyma), a particular dosing strategy, or a patient’s immune status. Providers must interpret microbiologic data as these data pertain to a particular patient or clinical scenario. For example, for osteomyelitis higher doses of cephalexin are used (100–150 mg/kg/day divided in three to four doses) to achieve sufficiently high antibiotic levels within bone for extended periods. Conversely, many drugs are highly concentrated in urine and can be used to successfully treat some urinary pathogens that are classified as “resistant” per published breakpoints (eg, a patient may have a good clinical response to cephalexin for a urinary tract infection (UTI) with E coli determined to be cephalexin-resistant in the laboratory). Ultimately, the true test of therapeutic efficacy is patient response. Patients who do not respond to seemingly appropriate therapy require reassessment, including reconsideration of the diagnosis, repeat cultures, and consideration of surgical debulking of the infection. Thus, antimicrobial susceptibility testing, although an essential part of therapeutic decision making, must be considered in context with drug concentrations at the site of infection, immune status, patient age, comorbid conditions, and pharmacodynamics.

When considering efficacy of antibiotics, there are three pharmacodynamic/pharmacokinetic models used to predict cure (Figure 39–1). Common to all these concepts is that the concentration of drug in the space of the infection must exceed the MIC. If an isolate is available, the MIC may be exactly determined in the clinical laboratory. Alternatively, general knowledge of the likely MIC based on historical data for the pathogen can be used to choose an antimicrobial. Apart from simply exceeding the MIC, efficacy is then correlated with either the time that the MIC is exceeded (time over MIC), the peak concentration over the MIC (peak over MIC), or a combination of both, described as “the area under the curve” (AUC) over the MIC (see Figure 39–1). Time over the MIC, which applies to all β-lactams, is calculated as the percentage of a 24-hour day that the drug concentration exceeds the MIC. Time over MIC targets can range from 30% to 40% to more than 90%, depending on the severity and site of infection and the immune status of the host. The typical target for peak over MIC (applicable to aminoglycosides) is a peak of 8- to 10-fold greater than the MIC, though this is not always possible. Time-dependent drugs rapidly enter the microbe at high concentrations, and even when the drug is gone, the surviving microbes take hours to recover the ability to replicate. This is called postantibiotic effect (PAE) and allows dosing at extended intervals, such as once daily. For most other drugs, the AUC over the MIC is the best predictor of bacterial killing because it incorporates both this PAE and the required time above MIC. These efficacy parameters are affected by achievable drug concentrations, protein binding of the drug (protein-bound drug is not active), and the drug half-life. These parameters can be modified to increase efficacy by altering the dose, the route, or the interval.

Other patient factors affect dosing, most notably organ dysfunction, concomitant medications, obesity, and age. Drug metabolism (usually renal or hepatic), interactions, and side effects are addressed in the drug descriptions and tables in this chapter. Obesity affects drug distribution. For example, aminoglycosides do not rapidly distribute into fat, so an obese patient dosed by body weight may have supratherapeutic aminoglycoside levels. Age affects metabolism and excretion of all drugs, and absorption of oral drugs. Infants and toddlers may lack proteins necessary to transport drug, and their kidneys are relatively immature, both of which impact dosing.

Antimicrobials are primarily used to treat active infections. However, they are also used to prevent new infections through preexposure prophylaxis (malaria prevention in travelers, dental prophylaxis to prevent endocarditis in patients with prosthetic valves, etc), postexposure prophylaxis (household meningococcal exposure, chlamydia disease in sexual partners, etc), and prophylaxis to prevent conversion of latent to active disease (latent Mycobacterium tuberculosis infection, recurrent herpes simplex virus [HSV] infection, etc). Surgical prophylaxis is another common use of antimicrobials, with the goal to achieve high drug levels in the tissue at the time of incision and—along with good surgical technique—to minimize viable bacterial contamination of the wound. For most surgeries, a single dose is all that is necessary. A list of microbes and disease states for which prophylaxis may be considered is in Table 39–2.

Recommendations for choosing antibiotics for specific conditions are based on the patient’s age, diagnosis, site of infection, severity of illness, local antimicrobial susceptibility patterns, antimicrobial susceptibility of patient-specific bacterial isolates (historical and current), history of drug allergy, and potential drug interactions and side effects, as discussed above. Tables 39–3, 39–4, 39–5 provide further information, including dosing. Always consult the package insert for detailed prescribing information. Empiric and definitive therapies for many particular clinical entities are addressed throughout this textbook and in Table 39–6. Mechanisms of action and efficacy parameters are noted later and indicated in Figure 39–2.

β-LACTAM ANTIBIOTICS

β-Lactam antimicrobials include the penicillins, cephalosporins, carbapenems, monobactams (Step 1, Figure 39–2), and many β-lactamase inhibitors (Step 3, Figure 39–2), (Step 1, Figure 39–2). They are characterized by a four-member β-lactam ring, but otherwise they are structurally distinct, with differences in their ability to bind their target, the penicillin-binding proteins (PBPs, also called transpeptidases). Bacteria have a large variety and number of PBPs, so the spectrum of β-lactam activity is related to the binding affinity to the key PBPs in a given bacterial isolate. Binding of PBPs by β-lactams prevents cross-linking of the peptidoglycan layer of the cell wall, resulting in bacterial death. Efficacy is related to time over the MIC. Bacteria protect themselves from β-lactams mainly by (1) producing β-lactamases that hydrolyze the β-lactam ring, (2) altering the PBP to change the β-lactam–PBP-binding affinity, or (3) creating changes in porins or efflux pumps to decrease the intracellular concentration of drug. There are many different types of β-lactamases that vary from very narrow penicillinases (such as that produced routinely by S aureus) to more sophisticated and broad types produced by gram negatives, of which there are thousands. Among these are the inducible β-lactamases (IBL) that become clinically apparent only after β-lactam use. IBLs are common in some species of Serratia, Pseudomonas, Proteus, Citrobacter, Enterobacter, Morganella, and Aeromonas, and species-level lists can be found in the literature. There are also the extended spectrum β-lactamases (ESBLs), which are primarily produced by Klebsiella spp. and E coli. These are of particular concern because the plasmids (see Figure 39–2) encoding them are transmissible between organisms and often harbor other types of resistance. Of increasing concern are the plasmids encoding carbapenem resistance, because they often contain other types of resistance mutations and have the potential to lead to infections that are untreatable with current drugs.

Although allergy to β-lactam antimicrobials is reported commonly by parents, this history is not highly predictive of an allergic reaction. A history of anaphylactic-type reactions warrants caution or avoidance of cephalosporins and penicillins until evaluated by an allergist. However, because patients labeled with a penicillin allergy may receive inferior treatment strategies, confirming the details of the history is important. Patients unlikely to have a true allergy should be “de-labeled,” and those with a history consistent with a concerning reaction should be referred for allergy testing.

β-LACTAM: PENICILLINS

Penicillins & Aminopenicillins

Penicillins, amoxicillin, and ampicillin are the drugs of choice to treat infections with most streptococci (including group A Streptococcus, group B Streptococcus, and Pneumococcus), most enterococci, Treponema pallidum, Neisseria meningitides, Leptospira, Streptobacillus moniliformis (rat-bite fever), Actinomyces, many oral anaerobes, and most Clostridium and Bacillus species. They are also used for prophylaxis in patients with rheumatic fever or asplenia. Amoxicillin and ampicillin are considered first line for community-acquired pneumonia and otitis media. They penetrate all tissues relatively well, and amoxicillin offers adequate oral bioavailability (it has the best bioavailability among β-lactams that, as a class, are generally poorly absorbed). More time above the MIC is achieved with higher, more frequent dosing; for example, amoxicillin dosed 90 mg/kg divided three times daily for S pneumoniae (with MIC of 1–2 mcg/mL) will achieve 7–8 hours of time over the MIC, while if divided only two times a day, it will exceed the MIC for only 5–6 hours.

The common β-lactamase inhibitors are themselves β-lactams in structure (including sulbactam, clavulanic acid, and tazobactam, though not avibactam or vaborbactam), but they do not typically have antibacterial activity. Instead, they act as “decoys,” binding bacterial β-lactamases so that their companion drug is free to bind the target PBP. They are available in combination aminopenicillins in amoxicillin-clavulanic acid (oral) and ampicillin/sulbactam (IV), offering expanded activity to methicillin-susceptible S aureus (MSSA), Moraxella catarrhalis, Klebsiella spp., and β-lactamase–producing gram negatives (such as some Haemophilus influenzae, E coli) and anaerobes (such as Bacteroides fragilis and Fusobacteria spp.). This makes them useful for treating mixed infections, for example dog bites or tonsillar and parapharyngeal abscesses, orbital cellulitis, step-down therapy for ruptured appendicitis, and refractory sinusitis and otitis media. Notably, they offer no advantage in the treatment of S pneumoniae or other streptococci, as these organisms do not produce β-lactamases. Piperacillin/tazobactam similarly expands coverage, including possible coverage for P aeruginosa. This drug has a niche in complex abdominal infections and hospital-associated pneumonia, but it should be used sparingly due to its broad spectrum and risk of acute kidney injury (AKI), particularly if used with vancomycin. While the penetration of the penicillins and aminopenicillins is good into most spaces, the penetration of the β-lactamase inhibitors is poorly understood. Combinations of β-lactam with β-lactamase inhibitor are notorious for causing diarrhea, particularly amoxicillin/clavulanic acid, and care with dosing clavulanic acid is advised.

Penicillinase-Resistant Penicillins

The penicillinase-resistant penicillins were developed as anti-MSSA antibiotics to combat the narrow-spectrum β-lactamase (penicillinase) produced by nearly all MSSA. These drugs, which include nafcillin, oxacillin, methicillin, and dicloxacillin, offer structural protection to the β-lactam ring so that it is unavailable to penicillinases. They are associated with renal and hepatic toxicity, which does limit their use. Drug fever, rashes, and neutropenia are also common. Oxacillin and methicillin are renally excreted, whereas nafcillin is excreted through the biliary tract. Nafcillin is a venous irritant, making it difficult to maintain peripheral intravenous access; it also causes damage with extravasation, so it is best used with large or central lines. Because of their expense and side-effect profiles, these drugs have largely been supplanted by cefazolin (IV) and cephalexin (oral), but the IV forms retain a niche in the treatment of endocarditis and central nervous system (CNS) infections caused by MSSA. Dicloxacillin is used as step-down oral therapy when appropriate and for outpatient treatment of skin/soft tissue infections (SSTI) in adults.

β-LACTAM: CEPHALOSPORINS

Cephalosporins are often categorized in “generations,” which is not a chemical relationship, but rather represents similarity in antimicrobial spectra based on binding to various PBPs. All the resistance mechanisms mentioned above for β-lactams also apply to cephalosporins. Gram-negative organisms have an ever-expanding variety of β-lactamases, the most problematic of which in routine practice are the inducible and extended spectrum β-lactamases (IBLs and ESBLs). No cephalosporins approved for use in the United States have activity against enterococci.

The first-generation cephalosporins include cefazolin (IV) and cephalexin (oral), which are mainly used to treat infections with MSSA or as empiric therapy for UTIs. They are highly effective treatments for SSTI, as they also have activity against group A streptococci, and in initial and oral step-down treatment of musculoskeletal infections in children. Because of its high concentration in urine, cephalexin is considered first line for UTIs and often achieves adequate killing in organisms deemed “resistant.” In the laboratory, cephalothin is commonly used as a surrogate for cefazolin/cephalexin susceptibility.

The second-generation cephalosporins include cefuroxime (IV) and cefprozil and cefuroxime (oral). These have somewhat reduced, but acceptable, activity against gram-positive cocci, and greater activity against some gram-negative rods compared with first-generation cephalosporins, but not as much as the third-generation cephalosporins described below. They are active against H influenzae and M catarrhalis, including strains that produce β-lactamases capable of inactivating ampicillin. Cefoxitin and cefotetan, which are considered second generation, offer activity against anaerobes, making them potentially useful in the treatment of nonperforated appendicitis, pediatric cholangitis, and pelvic inflammatory disease; however, increasing resistance and short half-life (cefoxitin) are limitations.

Third-generation cephalosporins have substantially less activity against MSSA compared to first-generation cephalosporins, though notably increased activity against S pneumoniae. They also have increased activity against aerobic gram-negative bacteria that harbor narrow-spectrum β-lactamases. The most common intravenous forms are ceftriaxone and cefotaxime; due to production issues, availability of cefotaxime is currently limited. Ceftazidime provides similar coverage (with decreased S pneumoniae coverage compared to ceftriaxone) but provides some activity against P aeruginosa, though resistance may be induced quickly. These IV formulations have good CNS penetration. Cefpodoxime, cefixime, and cefdinir are oral options but are limited by low serum levels.

Cefepime is considered a fourth-generation cephalosporin. It retains considerable activity against MSSA while also being active against P aeruginosa and some other IBL producers, such as Enterobacter spp. It is a zwitterion and as such efficiently penetrates the gram-negative outer cell membrane. Despite its efficacy against IBL-producing organisms, cefepime is hydrolyzed by ESBLs so generally confers no advantage in that situation.

Ceftaroline is the only cephalosporin able to treat MRSA based on its ability to bind the PBP (PBP2a) in MRSA (encoded by mecA); it does not, however, have activity against P aeruginosa. Ceftaroline was recently approved in children.

There are now two cephalosporins combined with β-lactamase inhibitors, ceftazidime/avibactam (approved in pediatrics) and ceftolozane/tazobactam. These have activity against P aeruginosa, and variable coverage against many other highly resistant gram negatives.

The oral cephalosporins, except cephalexin, have very poor serum levels and may not achieve adequate time over the MIC for sufficient killing. In general, they are poorly absorbed, highly protein bound, often are given at ineffectively long intervals. In general, they should not be widely used. For organisms susceptible to amoxicillin, oral cephalosporins are pharmacokinetically inferior and should be used only to patients with penicillin allergy. For example, high-dose amoxicillin is more effective than cefdinir for infections where S pneumoniae is the most likely pathogen. In general, longer time above the MIC is achieved in the middle ear and urine compared to other locations for β-lactams, improving likelihood of cure in those locations.

β-LACTAM: MONOBACTAMS

Aztreonam is the only monobactam approved for use in the United States. Aztreonam is active against aerobic gram-negative rods, including P aeruginosa. Aztreonam has activity against H influenzae and M catarrhalis, including those that are β-lactamase producers. The most common uses of aztreonam are as an aerosol for therapy of P aeruginosa infection in patients with cystic fibrosis, and as an alternative therapy for severely β-lactam allergic patients, as there is little cross-reactivity between aztreonam and other β-lactams, except ceftazidime as they share a common side chain.

β-LACTAM: CARBAPENEMS

Meropenem, ertapenem, doripenem, and imipenem comprise the carbapenems, which are very broad antimicrobials effective against gram-negative aerobes, most anaerobes, and many gram-positive organisms. They have some activity against MSSA (but not MRSA), S pneumoniae, E faecalis (but not E faecium), and various other gram positives. Except for ertapenem, they have good activity against P aeruginosa and retain activity against many multidrug-resistant gram negatives, including and those with IBLs and ESBLs. Imipenem is sold in combination with cilastatin, which inhibits the metabolism of imipenem in the kidneys resulting in high serum and urine levels. An increased frequency of seizures is encountered when CNS infections are treated with carbapenems, particularly imipenem; carbapenems also decrease valproic acid levels. Because carbapenems are active against so many species of bacteria, there is a strong temptation to use them as single-drug empiric therapy. However, overuse is linked to the development of multidrug resistance. Hospitals that use carbapenems heavily encounter resistance in many different species of gram-negative rods. This resistance can develop in a single patient within days due to bacteria developing a porin/efflux mechanism. Carbapenem use should therefore be reserved only for patients with confirmed (or at high risk for) infection due to highly resistant organisms. Bacteria with β-lactamases capable of attacking the carbapenems now exist and are spreading worldwide; organisms harboring these plasmids often have many resistance mechanisms and are susceptible to few (if any) remaining treatment options. To address some of these resistance mechanisms, meropenem is now available with a β-lactamase inhibitor, vaborbactam, though this is not yet approved in children.

GLYCOPEPTIDE AGENTS

Glycopeptides include vancomycin, telavancin, oritavancin, and dalbavancin (Step 2, Figure 39–2). They are characterized by their large molecular size, which prevents them from penetrating the outer membrane of gram-negative organisms. Like the β-lactams, they also are active on the cell wall, inhibiting peptidoglycan synthesis by preventing cross-linking at the terminal amino acids (D-alanine). It is debated if their efficacy is most related to time over the MIC or AUC over MIC. Bacteria protect themselves mainly through (1) changing the terminal amino acid to D-lactate so that vancomycin cannot bind or (2) thickening the cell wall (vancomycin-intermediate and resistant S aureus) such that the glycopeptide cannot bind a sufficient number of targets to prevent cross-linking. They have notable nephrotoxicity and are a common cause of drug-related AKI. Red-man syndrome (flushing and itching with infusion), which is not an allergic response, can be mitigated with slower infusions (over 2 hours) and premedication with diphenhydramine or hydrocortisone. All the glycopeptides have similar spectra of activity, including MRSA, coagulase negative staphylococci, ampicillin-resistant enterococci, and resistant S pneumoniae. Oral vancomycin is not systemically absorbed but effectively kills C difficile in the GI tract. IDSA guidelines recommend oral vancomycin preferentially over metronidazole for severe or recurrent C difficile enteritis in pediatrics and for all cases in adults. The glycopeptides differ in dosing strategies, with telavancin dosed once daily, and both dalbavancin and oritavancin dosed once weekly. These three drugs are not Food and Drug Administration (FDA) approved for use in children.

The empiric use of vancomycin has increased tremendously over the past decade. Thus, vancomycin-resistant enterococci (VRE) are now problematic, particularly in inpatient units, intensive care units, and oncology wards. Vancomycin-intermediate and vancomycin-resistant S aureus exist, which is of concern because of the inherent virulence of many S aureus strains. Vancomycin use should be monitored carefully in hospitals and intensive care units. Vancomycin should not be used empirically when an infection is mild or when other antimicrobial agents are likely to be effective, and it should be stopped promptly if infection is caused by organisms susceptible to other antimicrobials. Attention to obtaining cultures prior to vancomycin initiation is required, as susceptibility to oral alternatives is not predictable.

Efficacy of vancomycin requires sufficient drug exposure (typically approximated by achieving trough levels of 15–20 mcg/mL for CNS infections, endocarditis, and bone infections, 10–15 mcg/mL for other infections); this can be difficult to achieve in some pediatric ages. Thus monitoring and dose adjustment are necessary. Continuous infusion can be used if sufficient levels are not achievable with every 6 hour dosing. The trough concentrations are usually drawn before the fourth dose but should be drawn sooner if the patient is at risk of AKI. A high trough can cause renal injury and will be observed when renal function is impaired. Serum creatinine should be checked in all patients administered vancomycin to monitor for AKI. Some experts argue that vancomycin should be dosed based on AUC (goal 400–600 mg*h/L), though in pediatrics this requires multiple serum drug levels and some dosing expertise, as trough levels may not be a good predictor of AUC. For patients receiving antimicrobials for weeks to months, weekly clinical and laboratory assessment, including drug levels, creatinine, and complete blood count will facilitate detection of toxicity.

DAPTOMYCIN

Daptomycin is unique in being a lipopeptide that inserts into the lipid-rich cell inner membrane of gram-positive bacteria (Step 4, Figure 39–2). This results in depolarization and cell death. It is unclear if efficacy correlates with the time that intracellular levels exceed the MIC or whether AUC over MIC is most important. Microbes protect themselves by changing the charge of their cell membranes, such that daptomycin cannot penetrate the inner membrane. Since daptomycin cannot penetrate the gram-negative outer cell membrane (envelope), it is only active against gram-positive organisms and has a clinical niche against MRSA and vancomycin-resistant E faecium. Daptomycin may insert itself into lipid layers of human cells, particularly muscle, causing creatinine phosphokinase (CPK) elevation. Rhabdomyolysis has been reported and monitoring of CPK in children is recommended. Because daptomycin is a lipid-like molecule, pulmonary surfactant envelops the drug rendering it inactive, so it is typically not used for lung infections.

TRIMETHOPRIM/SULFAMETHOXAZOLE

Sulfonamides—the oldest class of antimicrobials—are usually used in a fixed combination with trimethoprim (TMP-SMX) to inhibit two steps in the folate synthesis pathway (which then inhibits DNA biosynthesis, step 8, Figure 39–2) for greater efficacy (Step 5, Figure 39–2). AUC over MIC correlates with efficacy. Resistance is usually related to alterations in the binding targets or decreased drug concentrations due to efflux or decreased entry. TMP-SMX is particularly associated with drug hypersensitivity reactions and, more rarely, severe skin reactions such as Stevens-Johnson syndrome. It also may cause hematologic abnormalities that can be severe. It should not be used in patients with G6PD deficiency. TMP-SMX is most often used clinically to treat MRSA SSTIs, UTIs, and susceptible strains of Haemophilus spp., Shigella spp., or Salmonella spp. TMP-SMX is a mainstay in prophylaxis and treatment of Pneumocystis jirovecii infection, and in treatment of Nocardia spp., brucellosis, and Stenotrophomonas maltophilia. As an intravenous formulation, it requires large volume infusion over 2 hours every 6–12 hours, so is rarely given via this route (especially given its high oral bioavailability). Pathogens with significant resistance include group A Streptococcus, S pneumoniae, and various gram negatives.

METRONIDAZOLE

Metronidazole is a prodrug that is only converted to its active form by anaerobic and amoebic and other protozoal organisms (Step 6, Figure 39–2). It is unclear if these active intermediates bind DNA, RNA, or essential proteins that result in cell death. Effective killing is related to the AUC over MIC. It has a PAE and a long half-life so could be dosed less frequently than the current recommendation of three to four times daily. In pediatric appendicitis, it often is dosed once daily. Resistance mechanisms are not well investigated, but they likely relate to lack of conversion to active drug. It is most active against gram-negative and gram-positive anaerobic rods, such as Bacteroides, Fusobacterium, Clostridium, Prevotella, and Porphyromonas. Gram-positive anaerobic cocci such as Peptococcus and Peptostreptococcus are often more susceptible to penicillin or to clindamycin. Metronidazole is the drug of choice for bacterial vaginosis and among the recommended options for C difficile enterocolitis. It is active against many parasites, including Giardia lamblia and Entamoeba histolytica. Metronidazole is highly bioavailable and has excellent tissue penetration, including to the CNS.

MACROLIDES

The macrolide antimicrobials in common use include erythromycin, azithromycin, and clarithromycin (Step 6, Figure 39–2). They inhibit protein synthesis by blocking RNA translation and assembly of the 50S ribosomal subunit. Efficacy is related to AUC over MIC. Microbes protect themselves by altering the macrolide binding site with methylation or through efflux of the drug. Because of ease of dosing and tolerability, azithromycin is the most commonly prescribed macrolide worldwide, and is one of the most commonly prescribed antimicrobials in the United States. This likely indicates overuse, as macrolides are rarely considered first-line agents in national treatment guidelines, and high rates of resistance have developed among S pneumoniae, for which it is commonly prescribed. Gastrointestinal side effects are common with the macrolides, particularly with erythromycin, which is sometimes used as a promotility agent. Exposure to macrolides early in life is associated with infantile hypertrophic pyloric stenosis, though azithromycin is thought to pose a lower risk than erythromycin. They all prolong the QTc interval, a consideration in at-risk patients.

Azithromycin has a large volume of distribution and a long half-life; after a 5-day treatment course, intracellular drug is present for approximately 10 days. Azithromycin is used to treat Campylobacter, Shigella, and Salmonella infections, including typhoid fever resistant to ampicillin and TMP-SMX, and is thus used for presumed bacterial traveler’s diarrhea. All macrolides are active against many bacteria that are intrinsically resistant to cell wall–active antimicrobials, and are the drugs of choice for Bordetella pertussis, Legionella pneumophila, Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Chlamydia trachomatis infections. Azithromycin and clarithromycin also have activity against some mycobacteria. Resistance among other common pathogens, such as S pneumoniae, group A Streptococcus, S aureus, and Haemophilus spp., limits efficacy of azithromycin efficacy for otitis media, sinusitis, and community-acquired pneumonia (except for Mycoplasma).

LINCOSAMIDES

Clindamycin targets protein synthesis through inhibiting peptidyl transferase at the 50S ribosomal subunit (Step 6, Figure 39–2). Its efficacy is related to the AUC over MIC. Resistance, which is mediated by methylation of the binding site, may be constitutive or may be detected only after induction with erythromycin (using a D-test). Efflux of drug is another mechanism of resistance. Clindamycin is highly bioavailable and penetrates most body tissues well except for spinal fluid and urine; it should not be used for infection in those spaces. Though clindamycin is not used to treat CNS bacterial infections, it does achieve sufficient CNS levels to treat CNS toxoplasmosis (the parasiticidal concentration is 6 ng/mL), though it is not considered a first-line agent. It is active against many anaerobes and gram-positive aerobic organisms, including S pneumoniae, S pyogenes, and MRSA, though resistance is becoming more prevalent. It is not active against enterococci. Because of its unique spectrum of activity, it is often used to treat mixed aerobic gram-positive and anaerobic infections, such as sinusitis, dental, oral, and neck abscesses; pelvic inflammatory disease; and deep infections from pressure ulcers. Because it inhibits protein synthesis (and thus toxin production), it is often used as an adjunct to treat serious toxin-mediated diseases such as toxic shock syndrome. It also is considered to be more active than β-lactams against nonreplicating bacteria that may be present in undrained abscesses. Clindamycin is associated with C difficile–related pseudomembranous colitis in adults, but this relationship is uncommon in children, although diarrhea is a frequent side effect. Though clindamycin is an old drug, it is often more expensive than alternatives and has palatability issues.

OXAZOLIDINONES

Linezolid is the first oxazolidinone in use (Step 6, Figure 39–2). It targets the 50S-ribosomal RNA subunit to prevent initiation of protein synthesis. Cross-resistance with other ribosomally active antimicrobials is uncommon, though a unique mutation of the binding site has made resistance increasingly common. Efficacy is related to AUC over MIC. Linezolid has broad gram-positive activity, including some anaerobes, but it is typically reserved for particular drug-resistant organisms (eg, VRE) when first-line agents are contraindicated (eg, for MRSA when vancomycin is avoided due to significant renal insufficiency) or when oral therapy is desired and no other oral options are available. It has very limited gram-negative activity. Linezolid comes in an IV formulation, but it is highly bioavailable and is usually used orally. Linezolid is safe and well tolerated in children, but neutropenia and thrombocytopenia are common and frequently dose limiting. A complete blood count should be monitored in patients at increased risk for these problems and in patients receiving therapy for 2 weeks or longer. Linezolid is an inhibitor of monoamine oxidase (MAO) and should not be used in patients taking MAO inhibitors.

TETRACYCLINES

Tetracyclines, including doxycycline, minocycline, tigecycline, and eravacycline, interact with transfer RNA (tRNA) at the 30S ribosomal subunit to prevent protein synthesis (Step 6, Figure 39–2). Resistance occurs when the microbe develops proteins that protect the tRNA target or when it encodes efflux pumps to decrease intracellular drug concentrations. Efficacy is related to AUC over MIC. Tetracyclines are broadly effective but are most commonly used against B pertussis, many species of Rickettsia, Chlamydia/Chlamydophila, and Mycoplasma. Doxycycline can also be used for eradication of C trachomatis in pelvic inflammatory disease and nongonococcal urethritis. Among tetracyclines, doxycycline is often preferred because it is better tolerated than tetracycline, its twice-daily administration is convenient, and it can be taken with food. Notable side effects of the tetracyclines are staining of permanent teeth, so long courses (longer than 21 days for doxycycline) are generally not given to children younger than 8 years if an alternative exists. However, a single course of a tetracycline does not pose a significant risk of tooth staining. Increased photosensitivity is a notable side effect, and minocycline (commonly used for acne) has a particular association with DIHS.

Doxycycline is used for therapy of Q fever and rickettsial infections (Rocky Mountain spotted fever, ehrlichiosis, anaplasmosis, rickettsialpox) and endemic and murine typhus. It is also first line for treatment of Borrelia spp. (Lyme disease, relapsing fever). Doxycycline can also be used as an alternative to macrolides for M pneumoniae and C pneumoniae infections and for treatment of psittacosis, brucellosis, and P multocida infection. Doxycycline also retains good activity against MRSA.

Tigecycline is a glycylcycline (an analogue of tetracycline) that is active against many gram-negative aerobes, anaerobes, and gram-positive cocci including MRSA and enterococci. Tigecycline is not active against P aeruginosa but is useful against VRE and resistant gram negatives other than P aeruginosa. It is inferior to other agents for bacteremia if the organism is susceptible to alternative antibiotics. It is approved for children over 8 years.

AMINOGLYCOSIDES

The aminoglycosides include gentamicin, tobramycin, amikacin, and streptomycin (Step 6, Figure 39–2). They bind to ribosomal RNA in the 30S subunit to inhibit protein synthesis. A high peak above MIC is required for efficacy. Because microbes will not replicate for a long time after aminoglycoside exposure (post-antibiotic effect), aminoglycosides can be dosed once daily. However, once-daily dosing is still controversial in pediatrics due to faster clearance in children. Variation in dosing strategies exists due to lack of consensus. While efficacy is associated with an adequate peak to MIC ratio (with a goal peak of at least eight times the MIC to achieve a longer PAE), toxicity is associated with a high trough. Renal toxicity is most common, followed by ototoxicity. Bacteria gain resistance either through bacterial enzymatic modification of the aminoglycoside to limit binding to its target or through changes in drug entry due to alterations in porin channels. Aminoglycosides are active against gram-negative bacteria. When used together with β-lactams and vancomycin, which damage cell walls against some gram positives, there is a synergistic effect such that aminoglycosides enter bacteria more efficiently. Synergy is described for group B streptococci, enterococci, staphylococci, and Listeria monocytogenes at a low aminoglycoside dose. All aminoglycosides are active against pseudomonas, but especially tobramycin. Amikacin is less susceptible to microbial modification, so organisms resistant to other aminoglycosides may remain susceptible to amikacin. Addition of an aminoglycoside to another active agent, such as described for a β-lactam for gram-negative infections, such as for P aeruginosa, is generally considered to add more toxicity than benefit. However, this remains appropriate for empiric therapy in patients at risk for resistant gram-negative bacteria while awaiting speciation and susceptibilities. Tobramycin and amikacin have inhaled formulations, and though relative penetration to alveoli is not clear, they are used in patients with cystic fibrosis. Streptomycin is still used for tuberculosis in endemic areas of the world, but ototoxicity otherwise limits its usefulness. As a group, the aminoglycosides do not penetrate CSF well; thus, treatment with a third-generation cephalosporin is preferred for CNS infection. Aminoglycosides also are not active in acidic environments, rendering them less active in abscesses and bone.

Because of their renal and ototoxicity, creatinine measurement and therapeutic drug level monitoring is necessary. Drug levels are usually checked between the third and fourth doses, but sooner in children at high risk for renal impairment. Efficacy of gentamicin and tobramycin are correlated with a peak of 8–12 mcg/mL for dosing every 8 hours or 20–30 mcg/mL for once daily dosing. The goal is for trough levels less than 2 mcg/mL, which correlates with less toxicity. For amikacin, desired peak for every 8 hour dosing is 20–35 mcg/mL and a trough less than 10 mcg/mL. In children expected to receive long-term therapy, drug levels and creatinine should be checked weekly and hearing screening should be considered, especially for those with elevated trough levels.

RIFAMYCINS

Rifamycins include rifampin, rifabutin, rifaximin, and rifamycin B (Step 7, Figure 39–2). They are the only antimicrobial inhibitors of RNA polymerase. They are active against a wide variety of organisms, including many mycobacteria. Resistance develops quickly (usually via a mutation in RNA polymerase) so they should not be used as monotherapy, except in select circumstances. Rifampin monotherapy is used as prophylaxis against disease in those exposed to H influenzae or N meningitides, as well as to treat latent M tuberculosis infection. It is also used as combination therapy to penetrate bacterial biofilms for patients with prosthetic material in place. Rifampin and rifabutin are used in combination therapy for active tuberculosis; rifabutin is often preferred in patients co-infected with human immunodeficiency virus (HIV) as rifampin decreases levels of some HIV medications. Most rifamycins, rifampin in particular, induce P450 enzymes, lowering the concentrations of many other drugs, including birth control, opiates, immune-suppressive agents, HIV medications, some chemotherapy agents, and some anesthetics, and thus their possible benefit must be weighed against the dangers of lowering levels of these other drugs. These drugs penetrate many tissue spaces and will turn body fluids such as tears, urine, and feces orange. This is an important and troubling side effect to warn patients about, and those with contact lenses should be counseled to wear glasses while on therapy to prevent staining. Oral preparations of rifamycins are highly bioavailable. Rifaximin, because it is nonabsorbable, avoids drug interactions or side effects and is used for the treatment and prevention of traveler’s diarrhea in people older than 12 years, though this will predispose to the acquisition of drug-resistant organisms (as do all antibiotics used for these indications).

FLUOROQUINOLONES

Fluoroquinolones include norfloxacin, ofloxacin, ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin drops (Step 8, Figure 39–2). They target bacterial topoisomerases, inhibiting DNA replication and repair. Efficacy is based on the AUC over MIC. Levofloxacin and ciprofloxacin are active against P aeruginosa, with moxifloxacin having reduced systemic activity against P aeruginosa. In addition to gram-negative activity, levofloxacin has activity against some strains of MRSA, S pneumoniae, and Enterococcus faecalis (not E faecium). They are also active against many atypical pathogens, such as Mycoplasma, Chlamydophila, and Legionella. Ofloxacin and levofloxacin are used for treatment of some cases of M tuberculosis and some atypical mycobacterial infections. Due to activity against N meningitides and Yersinia pestis, ciprofloxacin is an option for prophylaxis of exposed persons. Fluoroquinolones are often active against N gonorrhea (though increasing resistance described) and C trachomatis. They often are active against the common causes of traveler’s diarrhea, though increasing resistance has removed them as first-line agents (in favor of azithromycin) in many geographic areas. Bacteria become resistant by mutating the targeted topoisomerases to avoid binding or by efflux of drug. This class of drugs is highly associated with bacterial resistance and secondary C difficile infection. When these organisms acquire mutations that encode resistance, they often are accompanied by genes encoding resistance to other classes of antimicrobials. They also select for hypervirulent, hyperspreading strains of C difficile that endanger not only the patient receiving the fluoroquinolone but other patients on the same unit to whom the strain may spread. When an outbreak of C difficile infection is present in a hospital setting, stopping use of these drugs is an appropriate intervention. They are also associated with tendon rupture in adults, leading to an FDA warning to limit use, and with arthropathy in children, and can prolong the QTc interval. These drugs are highly bioavailable and generally should be used orally. One caveat is that they are inactivated by divalent cations, so they cannot be given with multivitamins, dairy containing products, or infant formulas, making them difficult to administer to infants and children. Due to the issues mentioned above, fluoroquinolones should be used sparingly in pediatrics (and adults). They do have a place in the treatment of organisms resistant to other classes of drugs.

ANTIFUNGALS

The principles of antifungal therapy are similar to those of antibacterials, though there are fewer classes of agents. Amphotericin B is a polyene that interacts with ergosterol to disrupt the fungal cell membrane; ergosterol is not a component of mammalian cell membranes. Amphotericin B also inhibits fungal ATPase. It is available in deoxycholate or liposomal/lipid complex formulations, the latter of which has reduced side effects, including less renal toxicity. Lipid-based and conventional amphotericin are not interchangeable for dosing purposes. Its efficacy parameter is peak to MIC. Amphotericin is active against a broad range of yeasts and molds, with some rare but important exceptions. It is also a mainstay of treatment for some protozoal infections, for example Leishmania spp.

The azoles, which are another important class of antifungals, include ketoconazole, fluconazole, itraconazole, voriconazole, and posaconazole. The azole efficacy parameter is AUC over MIC. Azoles work through inhibition of the enzymes that convert lanosterol to ergosterol. Their spectra of activity, tissue penetration, side effects, drug interactions, and bioavailability vary, all of which should be considered when choosing an agent and route of administration. For some drugs, monitoring of serum levels is indicated.

The echinocandins (micafungin, caspofungin, anidulafungin) are a third class of antifungals for systemic use. These drugs, which have become a mainstay for the treatment of yeasts, work through inhibition of enzymes important to cell membrane integrity (β-(1-3)-D-glucan). They generally provide more rapid and reliable killing of yeasts (eg, Candida spp.) than of molds (eg, Aspergillus spp.); they have minimal activity against most molds other than Aspergillus. Echinocandins cannot be used reliably for CNS or urinary tract infections due to poor CSF and urine drug penetration. Their spectra of activity and side-effect profiles are generally similar. Last, flucytosine is a less commonly used antifungal that inhibits fungal protein synthesis. Its niche is only as an adjunctive agent for some fungal CNS infections due to its high CNS penetration. Its use is severely limited due to cost and the common occurrence of neutropenia. Combination therapy remains controversial, though it can be considered in the situation of unknown/unpredictable susceptibilities, unclear tissue penetration, or bridge to an oral agent (as therapeutic levels of voriconazole or posaconazole are often difficult to obtain in children). Additional detail on antifungals and some antiparasitics is available in Chapter 43, and limited information is included in Tables 39–3, 39–4, 39–5.

ANTIVIRALS

Antivirals are a complex group of agents that target various stages in the viral life cycle. This cycle occurs solely within a eukaryotic host cell, since viral replication depends on host cell machinery. Individual antiviral drugs may target viral entry into host cells, intracellular viral uncoating, integration, nucleic acid replication, assembly/packaging, and viral release from the host cell. Viral life cycles also vary, sometimes requiring infection of specific cell types, presence of certain host proteins, and/or incorporation into host DNA. Last, many viruses, especially RNA viruses, develop resistant mutants quickly, making the development of antivirals challenging. Anti-HIV agents are discussed in Chapter 41; anti-influenza and anti-herpes (HSV, cytomegalovirus [CMV], Epstein-Barr virus [EBV]) agents in Chapter 40; and antihepatitis virus agents in Chapter 22. Limited information is included in Tables 39–3, 39–4, 39–5.