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.
TABLE 163-1Mechanisms of Action of Antibacterial Drugs ||Download (.pdf) TABLE 163-1 Mechanisms of Action of Antibacterial Drugs
|Cell wall active agents ||Nucleic acid inhibitors |
|Penicillins ||Fluoroquinolones |
|Vancomycin ||Rifampin |
|Cephalosporins ||Nitrofurantoin |
|Teicoplanin ||Enzyme inhibitors |
|Telavancin ||Fosfomycin |
|Daptomycin ||Sulfonamides |
|Colistin ||Trimethoprim |
|Polymyxin B || |
|Protein synthesis inhibitors || |
|Aminoglycosides || |
|Macrolides || |
|Linezolid || |
|Tetracyclines (including tigecycline) || |
|Clindamycin || |
|Quinupristin/dalfopristin || |
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 ...