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.
| 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 |
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.
