A Primer on Antimicrobials

Introduction

The serendipitous discovery of penicillin by Sir Alexander Fleming in 1928 was one of the greatest medical advances of the 20th century and marks the beginning of the antibiotic era. The term antibiotic originated with Selman Waksman in 1941, who defined it as any small molecule made by a microbe that antagonizes the growth of another microbe. With the widespread clinical use of antibiotics in the late 1940s came the ability to treat both minor and life-threatening infections. Antibiotics allow surgeons to perform complex procedures; have a major role in the success of organ transplantations; enable oncologists to prescribe lifesaving doses of chemotherapy, making bone marrow transplants feasible; and have greatly reduced the burden of major infectious diseases that have plagued humankind since antiquity, such as plague and tuberculosis (TB). Yet these pillars of modern medicine are threatened by the ongoing spread of antibiotic resistance, a major driver of which is the misuse of antibiotics. Thus, prescribing antibiotics judiciously is paramount to protect their long-term effectiveness and to prevent a return to the pre-antibiotic era.

The first effective antibacterial agent to be introduced was the sulfonamide prontosil in 1935, for which its discoverer, Domagk, was awarded the Nobel Prize in Medicine or Physiology in 1939. The life of Domagk’s own 6-year-old daughter was saved by the drug after she developed a severe staphylococcal infection. During World War II, the industrialization of penicillin production led to major improvements in morbidity and mortality for Allied soldiers. The period following the war until the early 1960s is often referred to as the golden age of antibiotic development, in which many new classes of antibiotics were introduced. But over the next 40 years the pace of antibiotic discovery slowed, with no new classes approved during that period. An innovation comeback in the early part of the 21st century resulted in several new agents being approved, although many of these were variants from existing classes with modified side chains.

This chapter describes our current antibacterial and antifungal armamentarium, as well as agents in late stages of clinical development, with an emphasis on mechanism of action, spectrum of activity, pharmacology, clinical indications, resistance mechanisms, and adverse events. An understanding of these principles will help the reader optimize their use of antibiotics while minimizing the risk for side effects and toxicities and limit the spread of antibiotic resistance. Antimycobacterial agents, antiparasitic agents, and antivirals are discussed in other chapters. In addition, antibiotic dosing was not addressed herein, and readers should refer to specific chapters for this information.

Antibacterial Agents

β-Lactams

β-lactam drugs, including penicillins, cephalosporins, monobactams, and carbapenems, are so named due to the presence of a β-lactam ring at the core of their chemical structure. They are bactericidal agents that inhibit cell wall synthesis by binding to penicillin-binding proteins (PBPs). The penicillins can be subdivided into the natural penicillins, such as penicillin G and bicillin; penicillinase-resistant penicillins, like nafcillin and oxacillin; aminopenicillins, which include ampicillin and amoxicillin; carboxypenicillins, like ticarcillin and carbenicillin; and the ureidopenicillins, which include piperacillin, azlocillin, and mezlocillin. Activity of the penicillins can be extended against aminopenicillin-resistant Gram-negative bacilli with the addition of a β-lactamase inhibitor, like tazobactam, clavulanate, or sulbactam. Cephalosporins are a diverse class of agents grouped by generations from first to fifth based on increasing activity against Gram-negative bacilli. The third-generation cephalosporin ceftazidime has been combined with the novel non–β-lactam β-lactamase inhibitor avibactam, leading to improved activity against most Enterobacteriaceae, including ceftazidime-resistant strains. Ceftazidime/avibactam also has activity against strains of carbapenemase-producing Klebsiella pneumoniae. Ceftolozane/tazobactam is another combination designed primarily to treat resistant Gram-negative bacilli, including Pseudomonas aeruginosa . The first fifth-generation drug, ceftaroline, is the only currently available cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA). Currently, aztreonam is the only available monobactam and is only effective against aerobic Gram-negative bacilli. Aztreonam/avibactam is under development primarily for carbapenem-resistant Enterobacteriaceae (CRE), and is notable for having activity against metallo-β-lactamases. Carbapenems, which include imipenem, doripenem, meropenem, and ertapenem, have the broadest spectrum activity of all the β-lactams. They have traditionally been used for polymicrobial infections and in patients with severe sepsis for whom there is a concern about antibiotic-resistant pathogens. Unfortunately, the efficacy of carbapenems has been decreasing due to the spread of carbapenemase-producing Gram-negative bacilli. Meropenem/vaborbactam was approved in 2017 for complicated urinary tract infections (UTIs) and currently is active against many CRE strains. Table 5.1 describes the most frequently used β-lactam agents in clinical practice. For a comprehensive list of all available antibiotics, the reader is encouraged to consult the latest version of the Sanford Guide.

TABLE 5.1

Properties of Frequently Used β-Lactam Antibiotics

Antibiotic	Spectrum of Activity	Pharmacology	Common Clinical Uses	Mechanism of Resistance	Adverse Events
Penicillin G	Strep, T. pallidum , anaerobes, some enterococci	PO, IV, or IM routes	Oral infections, syphilis, pharyngitis GAS	Penicillinases	Rash in 2%–3%
Ampicillin and amoxicillin	Same as penicillin G plus some GNB	Ampicillin IV or IM, amoxicillin PO	Enterococcal endocarditis, oral infections, GAS pharyngitis	Penicillinases	Rash in 5%–9%, Increased risk with EBV
Amoxicillin/Clavulanate	GPC as above, GNB, anaerobes	Less diarrhea with bid regimens	Mixed bacterial infections	Penicillinases	Hepatic injury, usually mild
Nafcillin	MSSA and some strep	>90% protein bound, need 12 g daily for bacteremia	Serious MSSA infections like bacteremia, endocarditis and osteomyelitis	mecA gene encodes the low-affinity penicillin binding protein, PBP 2a	Neutropenia, hypokalemia
Ampicillin/sulbactam	β-lactamase-producing GPC, anaerobes, GNB	IV or IM routes	Oral and neck infections, mixed skin infections; not active against P. aeruginosa	Not recommended for IAIs due to increasing resistance in E. coli caused by plasmid-mediated TEM-1 β-lactamase	GI symptoms
Piperacillin/tazobactam	GPC except MRSA, GNB including P. aeruginosa , anaerobes	Use 4.5 g IV q6h for nosocomial pneumonia; prolonged infusions probably more effective	UTIs, HAP/VAP, IAIs, mixed skin infections	β-lactamases	Thrombocytopenia, increased risk of AKI with vancomycin
Cefazolin	GPC including MSSA, some GNB	Use 2 g IV q8h for serious infections, e.g., bacteremia	Skin infections, bacteremia due to MSSA	β-lactamases and altered PBPs	Increased risk of CDI
Cefoxitin	GPC, some GNB, anaerobes except B. fragilis	High bile concentration	Mixed infections	Avoid treating B. fragilis due to increasing resistance	Increased risk for CDI
Ceftazidime	Many GPC and GNB, including some P. aeruginosa	Can be given by prolonged infusion	Nosocomial UTIs, susceptible P. aeruginosa infections	β-lactamases	Increased risk for CDI
Ceftriaxone	Many GPC and GNB except P. aeruginosa	Good CNS penetration; use 2 g IV q12h for meningitis	CAP, UTIs, combined with ampicillin for enterococcal endocarditis	β-lactamases	Cholelithiasis
Cefepime	Many GPC and GNB, including P. aeruginosa	Use 2 g IV q8h for serious P. aeruginosa infections	Pneumonia, UTIs	β-lactamases	Delirium especially in elderly
Ceftaroline	GPC, only cephalosporin active against MRSA, some GNB but not P. aeruginosa	Use q8h for serious infections, e.g., bacteremia and endocarditis	Skin infections, pneumonia especially MRSA		Neutropenia, direct Coombs test seroconversion, eosinophil PNA
Ceftolozane/tazobactam	GPC, GNB including MDR P. aeruginosa and ESBL producers	Decreased efficacy with CrCl <50 mL/min	MDR P. aeruginosa infections , combine with metronidazole for IAIs	AmpC and horizontally acquired β-lactamases	Cross reacts with β-lactam allergies
Ceftazidime/avibactam	GPC, ESBL- and carbapenemase-producing GNB, MDR P. aeruginosa	Infuse over 2 hours	Pneumonia, bacteremia, UTIs, combined with metronidazole for IAIs	Not active against metallo-carbapenemases	Similar to other cephalosporins
Aztreonam	Aerobic GNB	IV and inhaled formulations	UTIs, bacteremia, nosocomial pneumonia	β-lactamases Avoid empirical use	Cross-reacts with ceftazidime allergy
Meropenem	GPC, GNRs, including P. aeruginosa , anaerobes	Use prolonged infusions in critically ill patients	Serious nosocomial infections, mixed infections, IAIs, UTIs from MDR GNB	Carbapenemases	Seizures, increased risk for CDI
Imipenem	Same as for meropenem	Use prolonged infusions in critically ill patients	Same as for meropenem	Carbapenemases	Seizures, increased risk for CDI
Doripenem	Same as for meropenem	Use prolonged infusions in critically ill patients	Same as for meropenem	Carbapenemases	Increased risk for CDI
Ertapenem	GPC except enterococcus, GNB except P. aeruginosa , anaerobes	Can be given IV or IM	Polymicrobial infections, avoid in critically ill septic patients	Carbapenemases	Increased risk for CDI
Meropenem/vaborbactam	GPC, anaerobes, MDR GNB, including P . aeruginosa and Acinetobacter	Dose q12h with CrCl <30 mL/min	Polymicrobial infections, severe sepsis with MDR GNB	ompK36 mutations; can be used to treat ceftazidime/avibactam-resistant isolates	Headaches, increased risk for CDI

AKI , Acute kidney injury; bid , twice daily; CAP , community-acquired pneumonia; CDI , Clostridioides difficile infection; CNS , central nervous system; CrCl , creatinine clearance; ESBL , extended spectrum β-lactamase; EBV , Epstein–Barr virus; GAS , group A streptococcus; GI , gastrointestinal; GNB , Gram-negative bacilli; GPC , Gram-positive cocci; HAP , hospital-acquired pneumonia; IAIs , intraabdominal infections; IM , intramuscular; IV , intravenous; MDR , multidrug resistant; MSSA , methicillin-susceptible Staphylococcus aureus; PBPs , penicillin-binding proteins; po, : by mouth; Strep , Streptococcus spp.; UTI , urinary tract infection; VAP , ventilator-associated pneumonia.

Glycopeptides and Lipopeptides

Glycopeptides are bactericidal agents that inhibit cell wall synthesis by binding to precursors of the peptidoglycan chain. Vancomycin was the first glycopeptide and is one of the most commonly prescribed antibiotics for hospitalized patients. A second glycopeptide, teicoplanin, is available in Europe and Asia but not the United States. Vancomycin has activity against most Gram-positive organisms, including MRSA, with the exceptions of Leuconostoc spp., Listeria monocytogenes , and Lactobacillus spp. Certain species of Enterococcus faecalis have developed resistance to vancomycin (vancomycin-resistant Enterococcus [VRE]). Also, S. aureus isolates with intermediate susceptibility to vancomycin (vancomycin intermediate S. aureus [VISA]) have been reported, although fortunately they remain uncommon in clinical practice. Vancomycin is routinely used to treat serious Gram-positive infections such as meningitis, endocarditis, osteomyelitis, bacteremia, and skin infections, especially when MRSA coverage is needed or patient allergies preclude the use of β-lactam agents. The development of resistance to vancomycin is mediated in S. aureus by the acquisition of resistance genes, primarily mecA . Vancomycin trough levels should be monitored during treatment to reduce the risk for nephrotoxicity, especially for patients with underlying kidney disease or an elevated body mass index (BMI). An infusion-related reaction called red man syndrome can occur in some patients and is characterized by pruritus and an erythematous rash primarily on the face, neck, and upper torso. Red man syndrome can often be mitigated by slowing the infusion rate and does not indicate that the patient is allergic to vancomycin. Oral vancomycin is used to treat Clostridioides (formerly Clostridium ) difficile infection. It is not absorbed and therefore should not be used to treat systemic infections.

The lipoglycopeptides are semi-synthetic derivatives of vancomycin that have long half-lives, allowing them to be dosed less frequently. These include telavancin, dalbavancin, and oritavancin. Only available as intravenous (IV) formulations, they have all been approved for treating skin infections, and telavancin has the additional indication for hospital-acquired and ventilator-associated pneumonia caused by S. aureus . Also, oritavancin is active against VRE strains that harbor the vanA gene, but dalbavancin and telavancin are not. QT prolongation and nephrotoxicity have been associated with telavancin, and both telavancin and oritavancin can falsely increase results of coagulation tests. The high cost of these agents remains a salient issue and has limited their use.

Daptomycin, the only lipopeptide antibiotic, is a bactericidal agent that causes rapid depolarization of the bacterial cell membrane. It has broad activity against Gram-positive organisms, including S. aureus (both methicillin-sensitive S. aureus [MSSA] and MRSA), streptococci, and enterococcus (both vancomycin-susceptible strains and VRE). Daptomycin is approved to treat skin infections and S. aureus bacteremia, including cases complicated by right-sided infective endocarditis. It is also commonly used to treat infections caused by VRE, such as complicated UTIs and osteomyelitis. Notably, daptomycin should not be used to treat pneumonia, as it is inactivated by pulmonary surfactant. Myositis can occur, especially with prolonged courses and concurrent statin use, and weekly monitoring of creatinine phosphokinase (CPK) is advised.

Aminoglycosides

One of the earliest classes of antibiotics, the first aminoglycoside, streptomycin, was released in 1944 and was the first effective drug for TB. This was followed by neomycin, gentamicin, tobramycin, amikacin, and, most recently, plazomicin in 2018. Aminoglycosides are bactericidal agents that block protein synthesis using an oxygen-dependent mechanism. Thus aminoglycosides work poorly in anaerobic environments, such as abscesses. They exhibit concentration-dependent killing and have a significant postantibiotic effect. These properties have allowed the development of extended-interval dosing, which is generally perceived to be safer and possibly more effective than traditional short-interval dosing. It is recommended that drug levels be monitored during therapy to reduce the risk of nephrotoxicity. Aminoglycosides are usually used with another agent, such as a β-lactam, to prevent the development of resistance (which can occur rapidly with aminoglycoside monotherapy) and for synergistic effects. Also, when used as monotherapy, aminoglycosides are inactive against Gram-positive bacteria, as they are unable to diffuse through porins in the thick Gram-positive cell wall. They are most commonly used to treat pyelonephritis, UTIs, Gram-negative bacteremia, and in combination to treat infective endocarditis due to certain Gram-positive cocci. Plazomicin has enhanced activity against multidrug-resistant (MDR) Gram-negative pathogens, including CRE and Acinetobacter baumannii , and appears promising for the treatment of ventilator-associated pneumonia. It was also noninferior to meropenem for the treatment of complicated UTIs and acute pyelonephritis due to Enterobacteriaceae, including MDR strains. Bacterial resistance to aminoglycosides is due to the acquisition of aminoglycoside-modifying enzymes (AMEs). Adverse events associated with aminoglycosides include nephrotoxicity, which often improves once the drug is discontinued, and ototoxicity, which may be irreversible. Because they can cause neuromuscular blockade, aminoglycosides should be avoided in patients with myasthenia gravis and those taking calcium channel blockers. Plazomicin appears to have an improved safety profile, with a low incidence of nephrotoxicity and ototoxicity.

Quinolones

The first quinolone was nalidixic acid, which was discovered during the production of chloroquine and found to kill Gram-negative bacteria. The addition of fluoride to the drug gave further Gram-negative, Gram-positive, and some anaerobic activity and led to the development of the fluoroquinolones, including ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin, and, most recently, delafloxacin. They are bactericidal agents that block DNA synthesis by inhibiting two bacterial enzymes: DNA gyrase and topoisomerase IV. Like aminoglycosides, quinolones have a postantibiotic effect that lasts 2 to 6 hours after the dose is given. The bioavailability of quinolones is excellent, and they achieve high concentrations in the lung, kidney, bile, prostate, bone, and stool. Quinolones are available in oral, IV, and ocular formulations. The common uses for quinolones are described in Table 5.2 . Bacteria can become resistant to quinolones either through target-mediated resistance, which is the most common and is caused by specific mutations in DNA gyrase and topoisomerase IV; plasmid-mediated resistance from extrachromosomal elements that encode proteins that disrupt quinolone–enzyme interactions, alter drug metabolism, or increase quinolone efflux; or chromosome-mediated resistance, which causes an underexpression of porins or an overexpression of efflux pumps. Some common adverse events associated with quinolones include gastrointestinal symptoms, tendonitis (for which the risk is highest in the elderly and those on corticosteroids), QT prolongation, hypoglycemia, and C. difficile infection. The Food and Drug Administration (FDA) has issued several black box warnings for quinolones, including to avoid them in patients with myasthenia gravis and for an increased risk for mental health side effects, serious blood sugar disturbances, tendinitis and tendon rupture, irreversible neuropathy, and (in late 2018) aortic aneurysm or dissection. Because of the risks associated with quinolones, in 2016, the FDA recommended they should not be used for acute sinusitis, acute bronchitis, and uncomplicated UTIs when other treatment options are available. Antacids and products containing calcium, aluminum, magnesium, iron, or zinc can reduce the oral absorption of fluoroquinolones, and patients should be advised to not take them concurrently. Finally, there are many drugs that interact with quinolones, some of which include warfarin, theophylline, nonsteroidal antiinflammatory drugs (NSAIDs), cyclosporine, phenytoin, rifampin, and cycloserine.

TABLE 5.2

Clinical Uses for Quinolones ^a

Drug	Common Clinical Uses	Cost
Ciprofloxacin	UTIs, IAIs, HAP and GNB pneumonia, GNB bacteremia, bacterial gastroenteritis including Salmonella , anthrax treatment, and prophylaxis	$
Delafloxacin	Mixed skin infections including MRSA and MSSA	$$$
Gemifloxacin	Bronchitis and CAP	$
Levofloxacin	CAP, HAP, UTIs, AECOPD, bacterial sinusitis, GNB bacteremia	$
Moxifloxacin	CAP, aspiration pneumonia, IAIs, mixed bacterial infections	$$
Norfloxacin	UTIs, prostatitis	$
Ofloxacin	Eye infections, otitis media	$

AECOPD, Acute exacerbation of chronic obstructive pulmonary disease; CAP , community-acquired pneumonia; GNB , Gram-negative bacilli; HAP , hospital-acquired pneumonia; IAIs , intraabdominal infections; UTIs , urinary tract infections.

a Because of safety concerns, other agents are now recommended as first-line therapy for several common conditions (e.g., sinusitis, UTI, pneumonia) instead of quinolones.

Macrolides

The currently available macrolides include erythromycin, clarithromycin, and fidaxomicin; azithromycin, an azalide, is included as a macrolide in this chapter. Telithromycin was the first ketolide, which are similar in structure to macrolides. Its use was dramatically reduced in 2007 after an FDA warning about acute liver injury, which led to the withdrawal of the drug in the United States. Macrolides inhibit protein synthesis by binding to the bacterial ribosome and blocking translocation of the growing peptide chain. Azithromycin and clarithromycin have better oral absorption and tolerability than erythromycin, which was the first of the class to be developed and is mostly used now as a prokinetic agent. Azithromycin and clarithromycin are used to treat upper and lower respiratory tract infections, group A β-hemolytic streptococcal infections in penicillin-allergic patients, and in combination therapy to treat mycobacterial infections. Azithromycin has been the most commonly prescribed outpatient antibiotic in the United States for the past several years. Fidaxomicin is approved to treat C. difficile infection, although it is usually limited in use to recurrent infections due to the drug’s high cost. In addition to their antibacterial activity, macrolides have antiinflammatory and immunomodulatory properties. It is for these reasons that azithromycin is frequently prescribed for patients with bronchiectasis and cystic fibrosis. Resistance to macrolides most often occurs via the acquisition of methylases that change the drug-binding site on the ribosome. Adverse events include gastrointestinal symptoms and QT prolongation. QTc monitoring every 3 to 4 months is recommended for patients who are on macrolides long term.

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