Determination of the pharmacodynamic profile of daptomycin against Streptococcus pneumoniae isolates with varying susceptibility to penicillin in a murine thigh infection model.

Background: Daptomycin has demonstrated in vitro activity against gram-positive organisms, including Streptococcus pneumoniae. However, the pharmacodynamic (PD) profile of daptomycin is needed to relate the activity of the drug to biologically achievable concentrations.

Methods: The PD profile of daptomycin against four S. pneumoniae isolates was determined using the immunocompromised murine thigh model. Due to the high protein binding of this agent, PD parameters were calculated based on free drug exposures. Efficacy was assessed by the change in log colony-forming units (CFU) in thighs after 24 h of drug treatment.

Results: Daptomycin produced a 7.1 (95% confidence interval 7.0-7.2) log(10) CFU kill. The ratio between overall drug exposure and the minimum inhibitory concentration (MIC) (AUC/MIC) was the most predictive of the PD parameters. The S. pneumoniae AUC/MIC required for static effects was 12 (95% confidence interval 10-14). Eighty percent and 99% of maximal kill was achieved at ratios of 35 (95% confidence interval 32-39) and 184 (95% confidence interval 160-208), respectively.

Conclusions: Clinically achievable serum drug exposures produced by the lowest dose of daptomycin currently studied in humans (4 mg/kg/day) should result in a potent in vivo bactericidal effect against infections due to S. pneumoniae such as bacteremia, where serum drug concentrations adequately reflect the concentration at the site of infection.