Minocycline pharmacodynamics against Stenotrophomonas maltophilia in the neutropenic murine infection model: implications for susceptibility breakpoints

Background Minocycline displays high susceptibility rates against Stenotrophomonas maltophilia at the current breakpoint of 4 mg/L. However, no pharmacodynamic data are available to guide dosing or justify this breakpoint. Methods The murine neutropenic thigh infection model was utilized to determine minocycline pharmacodynamics against four S. maltophilia through dose ranging and fractionation studies. The efficacy of a human simulated regimen (HSR) of 100 mg IV q12h was tested against 17 isolates with a range of minocycline MICs. Monte Carlo simulation was employed to assess the PTA for achieving defined pharmacodynamic thresholds in critically ill patients. Results The pharmacodynamic index best correlated with reductions in cfu was fAUC/MIC (R-2 = 0.376). The composite fAUC/MIC required for stasis and 1 log(10) reduction was 9.6 and 23.6, respectively. The minocycline 100 mg q12h HSR yielded no bacterial reduction at MICs >= 1 mg/L and mixed efficacy at 0.5 mg/L. Monte Carlo simulation of minocycline 200 mg IV q12h achieved the 1 log(10) kill threshold with PTAs of 93% and 51.7% at MICs of 0.5 and 1 mg/L, respectively, but 0.1% at the current breakpoint of 4 mg/L. Conclusions Clinically utilized minocycline dosing regimens fail to reach exposures predicted to be efficacious against S. maltophilia in critically ill patients at the current susceptibility breakpoint.

Automated summary

Minocycline shows high susceptibility rates against Stenotrophomonas maltophilia at the current breakpoint, but there is a lack of pharmacodynamic data to guide dosing. This study found that clinically utilized minocycline dosing regimens fail to reach effective exposures against S. maltophilia at the current susceptibility breakpoint.