Pharmacodynamics: relation to antimicrobial resistance

Abstract

Antibiotic pharmacodynamics (PD) describes the impact of an antimicrobial agent on a target pathogen and is based on the drug's pharmacokinetics (PK) and microbiologic activity toward that pathogen, together with the pathogen's susceptibility to the drug. Patient or host factors play an important role in antibiotic PD by affecting drug PK and patient susceptibility to infection. The 3 PD parameters commonly used to predict antibiotic efficacy are (1) the ratio of maximum serum concentration to the minimum inhibitory concentration (MIC) (Cmax/MIC); (2) the ratio of the area under the plasma concentration versus time curve (AUC) versus MIC (AUC/MIC) and (3) the duration of the dosing interval that plasma concentrations exceed the MIC (T>MIC). The Cmax/MIC ratio has been shown to predict aminoglycoside efficacy, AUC/MIC best describes fluoroquinolone, glycopeptide, and ketolide efficacy, and T>MIC best describes the efficacy of beta-lactams and macrolides. Traditionally, PK and PD (PK/PD) parameters have been used to predict antibiotic efficacy, but there is now increasing interest in trying to use PK/PD parameters to minimize development of resistance. With respect to fluoroquinolone resistance, the "mutant selection window" hypothesis has been developed to describe how drug exposures below the mutant prevention concentration may create conditions for the selection of resistant bacterial strains. The AUC/MIC ratio has also been used to describe fluoroquinolone drug exposures associated with either increased or decreased risk of resistance emergence. The accessory gene regulator (agr) locus in Staphylococcus aureus-and particularly agr group II-has been associated with reduced susceptibility or resistance of S aureus to vancomycin. Recent experiments suggest that the AUC/MIC ratio may be used to identify vancomycin exposures associated with emergence of resistance in S aureus. More generally, AUC/MIC ratios may be additive, and combination therapies may represent 1 approach to lowering the emergence rate of bacterial resistance associated with antibiotic therapy. But, further work needs to be done before this conclusion can be verified.