Pharmacodynamic principles of antimicrobial therapy in the prevention of resistance

Pharmacodynamic properties can be used to divide antibiotics into two major classes based on their mechanism of bactericidal action: (1) concentration-dependent drugs, such as aminoglycosides and fluoroquinolones, and (2) concentration-independent drugs, including the beta-lactams. Antibiotics also differ in the postantibiotic effect (PAE) that they exert. In general, concentration-dependent drugs have a more prolonged PAE than concentration-independent drugs, particularly against Gram-negative pathogens. Pharmacodynamic classifications have important implications for the planning of drug regimens. For concentration-dependent drugs, peak concentration to minimal inhibitory concentration (MIC) ratios of approximately 10 are associated with clinical success. Therefore, high drug levels should be the goal of therapy. This is best achieved by high doses taken once daily. This approach, however, is not feasible for the fluoroquinolones owing to dose-limiting CNS toxicity. Concentration-independent agents are most effective when the duration of serum concentrations is higher than the pathogen's MIC (time >MIC) for a significant proportion of the dosing interval. Frequent dosing or continuous infusions can increase the time >MIC. Concentrations of antibiotics that are sublethal can permit the emergence of resistant pathogens. Optimization of antibiotic regimens on the basis of pharmacodynamic principles could thus significantly diminish the emergence of antibiotic resistance.