Optimising dosing strategies of antibacterials utilising pharmacodynamic principles: impact on the development of resistance

Abstract

Evolving antimicrobial resistance is of global concern. The impact of decreased susceptibility to current antibacterials coupled with the decline in the marketing of new agents with novel mechanisms of action places a tremendous burden on clinicians to appropriately use available agents. Optimising antibacterial dose administration through the use of pharmacodynamic principles can aid clinicians in accomplishing this task more effectively. Methods to achieve this include: continuous or prolonged infusion, or the use of smaller doses administered more frequently for the time-dependent beta-lactam agents; or higher, less frequent dose administration of the concentration-dependent aminoglycosides and fluoroquinolones. Pharmacodynamic breakpoints, which are predictive of clinical and/or microbiological success in the treatment of infection, have been determined for many classes of antibacterials, including the fluoroquinolones, aminoglycosides and beta-lactams. Although surpassing these values may predict efficacy, it may not prevent the development of resistance. Recent studies seek to determine the pharmacodynamic breakpoints that prevent the development of resistance. Numerous studies to this point have determined these values in fluoroquinolones in both Gram-positive and Gram-negative bacteria. However, among the other antibacterial classes, there is a lack of sufficient data. Additionally, a new term, the mutant prevention concentration, has been based on the concentrations above which resistance is unlikely to occur. Future work is needed to fully characterise these target concentrations that prevent resistance.