Antimicrobial agents have had a major impact on human health. Together with vaccines, they have contributed to reduced mortality, extended lifespan, and enhanced quality of life. Among drugs used in human medicine, however, they are distinctive in that their use promotes the occurrence of drug resistance in the pathogens they are designed to treat as well as in other “bystander” organisms. Indeed, the history of antimicrobial development has been driven in large part by the medical need engendered by the emergence of resistance to each generation of agents. Thus, the careful and appropriate use of antimicrobial drugs is particularly important not only for optimizing efficacy and minimizing adverse effects but also for minimizing the risk of resistance and preserving the value of existing agents. Although this chapter focuses on antibacterial agents, the optimal use of all antimicrobials depends on an understanding of each drug’s mechanism of action, spectrum of activity, mechanisms of resistance, pharmacology, and adverse effect profile. This information is then applied in the context of the patient’s clinical presentation, underlying conditions, and epidemiology to define the site and likely nature of the infection or other condition and thus to choose the best therapy. Gathering of microbiologic information is important for refining therapeutic choices on the basis of documented pathogen and susceptibility data whenever possible; this information also makes it possible to choose more targeted therapy, thereby reducing the risk of selection of resistant bacteria. Durations of therapy are chosen according to the nature of the infection and the patient’s response to treatment and are informed by clinical studies when they are available, with the understanding that shorter courses are less likely than longer ones to promote the emergence of resistance. This chapter provides specific information that is necessary for making informed choices among antibacterial agents.
MECHANISMS OF ACTION AND RESISTANCE
The mechanisms of action of and resistance to antibacterial agents are discussed in detail in the text and are summarized for the most commonly used groups of agents in Table 41-1. A schematic of antibacterial targets is provided in Fig. 41-1.
TABLE 41-1MECHANISMS OF ACTION OF AND RESISTANCE TO ANTIBACTERIAL AGENTS ||Download (.pdf) TABLE 41-1 MECHANISMS OF ACTION OF AND RESISTANCE TO ANTIBACTERIAL AGENTS
|ANTIBACTERIAL AGENT(S) ||MAJOR TARGET ||MECHANISM(S) OF ACTION ||MECHANISM(S) OF RESISTANCE |
|β-Lactams (penicillins, cephalosporins, monobactams, carbapenems) ||Cell wall synthesis ||Bind cell wall cross-linking enzymes (PBPs, transpeptidases) || |
Drug inactivation by β-lactamases
Altered PBP targets
Reduced diffusion through porin channels
|Glycopeptides (vancomycin, teicoplanin, telavancin, dalbavancin, oritavancin) ||Cell wall synthesis || |
Block cell wall glycosyltransferases by binding D-Ala-D-Ala stem-peptide terminus
Telavancin, dalbavancin, and oritavancin: affect membrane function
Oritavancin: inhibits transpeptidases
Altered D-Ala-D-Ala target (D-Ala-D-Lac)
Increased D-Ala-D-Ala target binding at sites distant from cell wall synthesis enzymes
|Bacitracin ||Cell wall synthesis ||Blocks lipid carrier of cell wall ...|