Chapter 6: Principles of Antimicrobial Therapy

The successful treatment of infection relies on implementing fundamental principles of antimicrobial therapy, which involves first identifying the source and most probable causative pathogen through diagnostic methods such as Gram stain, culture, and sensitivity testing. Initial empiric treatment is often broad-spectrum, based on the infection site (e.g., meningitis, endocarditis, or urinary tract) and acquisition setting (community versus healthcare-acquired, the latter potentially requiring coverage for multidrug-resistant organisms). Once a patient is clinically improving, therapeutic monitoring ensures efficacy and manages potential toxicity, sometimes allowing for conversion from parenteral to a bioavailable oral regimen. Major antibiotic classes are defined by their mechanism of action, such as the beta-lactams (penicillins, cephalosporins, monobactams, and carbapenems) which inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs). Resistance to beta-lactams is often addressed by combining them with beta-lactamase inhibitors. Other classes inhibit protein synthesis, including macrolides (binding the 50S ribosomal subunit), aminoglycosides (binding the 30S ribosomal subunit and exhibiting concentration-dependent killing), and tetracyclines. Key agents for resistant Gram-positive bacteria, like MRSA, include the glycopeptide vancomycin (now frequently monitored via AUC-based dosing) and the lipopeptide daptomycin, which depolarizes the bacterial membrane. Additionally, fluoroquinolones inhibit bacterial DNA replication enzymes, but their use is limited by serious adverse event warnings. Resistance develops through various complex mechanisms, including enzymatic drug inactivation, reduced cell membrane permeability, active efflux pumps that expel the drug, or alterations to the target binding site. Given the widespread problem of resistance, antimicrobial stewardship programs are crucial for optimizing antibiotic usage by ensuring the selection of the correct drug, dosage, and duration for each patient.