Chapter 163: Pharmacology of Antimicrobials

Effective antibacterial drugs can either inhibit the growth of (bacteriostatic) or kill (bactericidal) bacteria. Antibacterial effects result from the inhibition of cell wall synthesis, inhibition of intrabacterial protein synthesis, alteration in nucleic acid metabolism, or intrabacterial enzyme inhibition (Table 163-1). The drug mechanism of action does not necessarily correlate with bacteriostatic or bactericidal effects, because the latter are affected also by the concentration of antibiotic to which bacteria are exposed. Drugs of choice for most infections are not based on a bacteriostatic or bactericidal effect of an agent, but rather are chosen based on whether the drug reaches the site of infection in adequate quantities, the spectrum of the agent, its safety, and cost.

CELL WALL ACTIVE AGENTS

β-Lactam (penicillins, cephalosporins) and glycopeptide antibiotics (vancomycin, telavancin, teicoplanin) bind to receptors in the bacterial cell wall. The target receptors for penicillins and cephalosporins are called penicillin-binding proteins. Autolytic enzymes within the cell wall bind to penicillin-binding proteins; once activated, the enzymes damage the peptidoglycan component of the cell wall, creating weakening and eventual cell lysis. Glycopeptide antibiotics bind to a terminal dipeptide (alanine-alanine) in the cell wall peptidoglycan and prevent the necessary cross-linking for a competent cell wall structure. At usual doses, β-lactam and glycopeptide antibiotics are bactericidal. Resistance arises due to mutations in the penicillin-binding proteins, leading to reduced β-lactam binding (e.g., by oxacillin-resistant Staphylococcus aureus or penicillin-resistant Streptococcus pneumoniae) or changes to the terminal dipeptide (e.g., by vancomycin-resistant Enterococcus faecium) that reduce the level of binding. Daptomycin inserts a lipophilic part of the molecule into the cell wall of gram-positive bacteria, depolarizing the cell wall, which causes the leakage of intracellular content and a bactericidal effect.

The emergence of multidrug-resistant organisms (most commonly in species of Pseudomonas, Acinetobacter, and Klebsiella) has led to the renewed use of older, but more toxic drugs such as colistin and polymyxin B. These agents interact with the lipids within the cell wall, increasing cell wall permeability, which leads to a bactericidal effect because of the leakage of intracellular contents.

PROTEIN SYNTHESIS INHIBITORS

Several classes of antibacterial drugs bind to ribosomes within bacteria, blocking necessary protein synthesis. Aminoglycosides and tetracyclines (including tigecycline) bind to the 30S ribosomal subunit, whereas macrolide antibiotics and clindamycin bind to the 50S subunit. Ribosomal binding inhibits transfer RNA function, decreasing the amount of protein synthesis. Ribosomal-binding drugs enter through the cell wall and bind in adequate concentrations to reversibly inhibit protein synthesis. Resistance mechanisms arise with reduced cell wall permeability, an active efflux pump that removes the antibiotic from the cell, or ribosomal-binding site mutations that decrease antibiotic affinity.

NUCLEIC ACID INHIBITORS

Fluoroquinolone antibiotics inhibit DNA gyrase, the enzyme responsible for DNA unwinding for transcription and recoiling during bacterial replication. Fluoroquinolones must reach the nucleus of the bacterial cell to provoke these effects; resistance can arise when cell wall permeability is reduced, active efflux occurs, or a DNA gyrase mutation has arisen that reduces fluoroquinolone binding. Rifampin is a broad-spectrum antimicrobial agent active against many gram-positive and gram-negative bacteria and mycobacteria. Rifampin (or rifampicin) inhibits RNA synthesis by binding to DNA-dependent RNA polymerase, thereby blocking the initiation of RNA chain formation. Nitrofurantoin is modified by bacterial metabolism to a compound that damages DNA. Susceptible bacteria rarely become resistant to nitrofurantoin.

ENZYME INHIBITORS

Sulfonamides and trimethoprim block sequential steps in the formation of folic acid. Sulfonamides inhibit dihydropteroate synthase, the enzyme that converts p-aminobenzoic acid to dihydrofolic acid; trimethoprim inhibits dihydrofolate reductase, the enzyme that converts dihydrofolic to tetrahydrofolic acid. Together, this paired action is an effective bactericidal process and not far removed from the intracellular actions of methotrexate. Fosfomycin inactivates enolpyruvate transferase, inhibiting cell wall synthesis; it is gaining resurgent popularity for single-dose treatment (3 grams orally) of uncomplicated urinary tract infections given the activity against the common pathogens involved. Resistance to these drugs arises by enzyme mutations that reduce the affinity of sulfonamide, trimethoprim, or fosfomycin to their respective enzyme targets.¹ These antibacterial drug mechanisms of action are summarized in Figure 163-1. Table 163-2 summarizes the classification, names, and routes of the most common antibiotics within each antibiotic class.¹

Drugs of choice for specific infections are based on clinical effectiveness and adverse events. Successful effectiveness is based on the knowledge of the likely bacterial pathogen responsible for a specific infection type and the usual antimicrobial spectrum of antibiotics. Alternate drugs of choice are selected in cases of resistance to an initial drug, a history of intolerance or allergy to the drug of choice, or because of a higher risk of adverse events. Taking into account those infections most likely to be present in ED patients and the most likely pathogens involved in these infections, Table 163-3 summarizes drugs of choice for common infections.²

Adequate drug dosage takes into account achievable serum and tissue levels plus the concentrations necessary (determined in the laboratory) to inhibit the growth of susceptible bacteria. Standard dosing guidelines usually result in successful treatment when a susceptible organism is present and barriers to drug penetration (i.e., abscess) are absent. If antibiotic penetration issues exist, such as in suspected meningitis, endocarditis, or osteomyelitis, give the highest doses recommended to improve effect.

Dosage adjustments of many antibiotics are necessary for patients with renal disease to prevent adverse events from drug accumulation, most notably when using IV administration. Oral doses are typically lower, so toxic drug accumulation is less likely in those with renal dysfunction. Dosage modifications in liver disease are less clear because of limited ways to accurately assess decreases in drug elimination characteristics or rate. Fosfomycin in single-dose use for urinary tract infection requires no adjustment. Guidelines for dosing adjustment, primarily with IV therapy, are summarized in Table 163-4.³

Allergic reactions and direct pharmacologic-based toxicity are the two general categories of adverse drug reactions to antibiotics.

Allergic reactions are not dose related, are unpredictable, and cannot be studied effectively in animal models. Allergic reactions vary from mild skin rashes to life-threatening events, such as toxic epidermal necrolysis or anaphylactic reactions. Drug fever, hepatitis, and interstitial nephritis are also examples of allergic drug reactions.

Direct dose-related toxicity is the result of the pharmacologic properties of the drug. These reactions are possible in any recipient if the dose or accumulated drug in the body is high. Dose-related adverse events typically are reversible once the antibiotic is discontinued. There is some predictability to these reactions, such as renal dysfunction caused by an aminoglycoside; these drugs are ideal candidates for appropriate dose adjustments of antibiotics (Table 163-4).

Certain adverse effects of antibiotics, such as pseudomembranous colitis, do not fall into either category; all antibiotics can cause this side effect. The common allergic and dose-related adverse effects of antibacterial drugs are summarized in Table 163-5.³

DRUG ALLERGY

In general, previous allergy is a contraindication for use. This circumstance is most pertinent for patients with a penicillin or cephalosporin allergy; between 1% and 10% of patients report a penicillin allergy. Some agents exhibit cross-reactivity; those with penicillin or amoxicillin allergy have a higher risk of the same with oral first-generation cephalosporins, likely due to similarities in antibiotic side chain structure, with about a 10% cross-reactivity occurrence. However, true allergies, as documented by antibiotic skin tests, are less common than often stated, so obtaining a clear description is important before choosing alternate therapy. For example, a patient with a history of respiratory distress, wheezing, angioedema, or hives (an immediate-type hypersensitivity) during a previous course of β-lactam treatment may be at higher risk for a life-threatening reaction upon re-exposure to another β-lactam, particularly if the patient reacts to skin tests with the other β-lactam. Unfortunately, with the exception of penicillin, these antibiotic skin tests are not commercially available and not used in clinical practice. So in this case, it would be wise to avoid a penicillin or first-generation cephalosporin, although a carbapenem or third-generation cephalosporin would have little cross-reactivity. On the other hand, if the patient history is a mild maculopapular rash while taking amoxicillin or other penicillin (a delayed-type hypersensitivity reaction), treatment later with a cephalosporin would not likely provoke an allergic event. Similarly, a fainting spell with injection may not represent a drug allergy at all, although it clearly was an adverse event for that treatment interval. Note that sulfa moieties are contained in many other drugs, such as furosemide, thiazides, sulfonylureas (glyburide), and celecoxib. Despite package labeling that suggests cross-sensitivity in a patient who is allergic to sulfonamides is a risk, the frequency of any allergic reaction upon exposure to one of the nonantibiotic sulfas is not common. A patient allergic to sulfonamides is at a higher risk to develop another allergic reaction to another drug, including penicillins.⁴ Several of the human immunodeficiency virus protease inhibitor agents also contain a sulfa moiety (amprenavir, fosamprenavir, tipranavir, darunavir), but the risk of cross-reactivity in a sulfonamide-allergic patient is not well known.⁴

DRUG INTERACTIONS

Drug interactions with antibacterial drugs derive from two mechanisms. The first mechanism is an inhibition of absorption of oral antibiotics. The best example of this interaction occurs when any of the tetracycline or fluoroquinolone antibiotics are given at the same time as divalent cations (Ca²⁺, Mg²⁺, Fe²⁺). This reduces absorption, so these agents must not be given orally with calcium or iron preparations or with antacids.

Second, certain antibiotics can slow the metabolism of other drugs by inhibiting several of the hepatic cytochrome P450 enzymes in the liver. In particular, ciprofloxacin, clarithromycin, and trimethoprim-sulfamethoxazole are drugs that are able to provoke this enzyme inhibition. Summaries of these antibiotic contraindications and drug interactions are included in Tables 163-6 and 163-7.³

The mechanism of action of antifungal agents is primarily based on actions that decrease cell wall integrity. Amphotericin B and its lipid-based derivatives bind to cell wall ergosterol, increasing cell wall permeability that eventually results in cell lysis. Triazole antifungals (e.g., fluconazole, itraconazole) block ergosterol synthesis by inhibition of a fungal cytochrome P450–dependent enzyme. Echinocandin antifungals (caspofungin, micafungin, and anidulafungin) are other enzyme inhibitors; in this case, the inhibition is of β-glucan synthetase. β-Glucan, like ergosterol, is another necessary component of the cell wall of several fungal species. Flucytosine is an antimetabolite that disrupts DNA function after conversion intracellularly to 5-fluorouracil. These mechanisms of action of antifungal agents are illustrated in Figure 163-2. These agents for systemic fungal infections are summarized in Table 163-8. Multiple topical antifungal preparations are available, as summarized in Table 163-9, and are indicated for Candida or tinea infections.^1,3

Of the various lipid-based amphotericin B preparations, liposomal amphotericin B (AmBisome^®) is preferred because of a lower rate of infusion-related reactions and a lower frequency of renal dysfunction compared with the other lipid products. Because amphotericin B has the broadest antifungal spectrum of all these systemic agents, it is the preferred drug for empiric therapy until further diagnostics determine the pathogen involved. All amphotericin B infusions, whether conventional (infused over 4 hours) or lipid-based (infused over 2 hours), can be preceded by acetaminophen (650 milligrams PO) and diphenhydramine (Benadryl^®, 25 to 50 milligrams PO or IV) given 30 minutes prior to attenuate development of fever and rash.

In addition to infusion-related reactions, amphotericin B also causes renal dysfunction. The lipid-based products reduce but do not eliminate the risk of renal toxicity. The kidney dysfunction created includes renal tubular acidosis and renal wasting of bicarbonate, potassium, and magnesium. When using this antifungal, monitor electrolyte levels and supplement as needed. Amphotericin B may elevate blood urea nitrogen and serum creatinine, although slightly less when using lipid-based products. If this occurs, reduce the daily dose or extend the infusion intervals to every other day if the creatinine level rises to >2.5 to 3.0 milligrams/dL.

Fluconazole, itraconazole, voriconazole, posaconazole, caspofungin, and micafungin do not provoke the renal dysfunction associated with amphotericin B. Occasionally, liver function test elevations and hepatitis result from triazole therapy, so patients on prolonged courses of these drugs should have liver function tests assessed monthly.

Triazoles (particularly itraconazole) can interact with other drugs metabolized by the cytochrome P450 system. In particular, warfarin, phenytoin, cyclosporine, and tacrolimus levels routinely increase in patients on itraconazole. Fluconazole is a less potent inhibitor of cytochrome P450, so interactions are less frequent. Flucytosine can cause reversible bone marrow suppression, with leukopenia and thrombocytopenia. Dose-modification issues are relevant for fluconazole and flucytosine. For creatinine clearance <50 mL/min, reduce fluconazole to 200 milligrams daily and flucytosine to 25 to 37.5 milligrams/kg every 12 hours; for creatinine clearance <10 mL/min, reduce flucytosine to 25 to 37.5 milligrams/kg every 24 hours.³

The pregnancy category for the amphotericin products is category B; for the triazoles, caspofungin, and flucytosine, the category is C.

Advances in antiviral agents can treat infections caused by herpes simplex virus I and II, varicella-zoster virus, cytomegalovirus, influenza A and B, human immunodeficiency virus, and hepatitis B and C. Table 163-10 summarizes the mechanism of action of the agents and spectrum of use for these drugs outside of human immunodeficiency virus and hepatitis.¹ Human immunodeficiency virus care is discussed elsewhere in the text, including postexposure prophylaxis. Uses for the non–human immunodeficiency virus antiviral agents for patients in the ED are summarized in Table 163-11. Table 163-12 summarizes the drugs available and common side effects of drugs for hepatitis B and hepatitis C; dosing is usually outside ED care and not reviewed.^1,3,5,6

Acyclovir, valacyclovir, famciclovir, and valganciclovir are oral drugs for the treatment of herpes simplex virus and cytomegalovirus infections. Of all, the absorption of acyclovir is less than others, requiring higher doses to achieve adequate blood and tissue levels to inhibit viral replication.

The development of new agents for hepatitis B and C infections has been similar to that of several of the antiretroviral drug classes. Effective drugs are analogues of nucleotides or nucleosides that result in nucleic acid polymerase inhibition (for example, entecavir for hepatitis B or simeprevir for hepatitis C) or directly inhibit RNA polymerase (sofosbuvir for hepatitis C). These agents are used in combination (for example, sofosbuvir with ribavirin and peginterferon).

HYPERSENSITIVITY SYNDROME

Used in human immunodeficiency virus care, abacavir (Ziagen^®, also contained in Trizivir^® and Epzicom^®) causes a hypersensitivity syndrome. This is more common in individuals who are positive for the major histocompatibility complex class I allele HLA-B^*5701, and this allele is now screened before a patient is placed on abacavir.⁵ The syndrome is characterized by rash and other systemic complaints. The reaction is reversible with discontinuation of abacavir. However, if the patient then takes abacavir again, life-threatening cardiovascular and respiratory insufficiency can develop.

Many other infrequent adverse reactions are possible but beyond the scope of one chapter. Multiple online sources can aid if needed.^3,5