Minocycline pharmacodynamics against <i>Stenotrophomonas maltophilia</i> in the neutropenic murine infection model: implications for susceptibility breakpoints
Andrew J Fratoni, David P. Nicolau, Joseph L. Kuti
Abstract
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 (R2 = 0.376). The composite fAUC/MIC required for stasis and 1 log10 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 log10 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.