Levofloxacin pharmacodynamics against Stenotrophomonas maltophilia in a neutropenic murine thigh infection model: implications for susceptibility breakpoint revision

Background: Levofloxacin displays in vitro activity against Stenotrophomonas maltophilia (STM); however, current susceptibility breakpoints are supported by limited data. We employed the murine neutropenic thigh infection model to assess levofloxacin pharmacodynamics against STM. Methods: Twenty-six clinical STM were studied using the neutropenic murine thigh infection model. Human simulated regimens (HSR) of levofloxacin 750mg q24h were administered over 24 h. Efficacy was measured as the change in log10 cfu/thigh at 24 h compared with 0 h. Composite cfu data were fitted to an Emax model to determine the fAUC/MIC needed for stasis and 1 log10 reduction at 24 h. Monte Carlo simulation was performed to determine PTA. Results: Levofloxacin MICs ranged from 0.5-8 mg/L. Mean bacterial burden at 0 h was 6.21 +/- 0.20 log10 cfu/thigh. In the 24 h controls, bacterial growth was 1.64 +/- 0.66 log(10) cfu/thigh. In isolates with levofloxacin MICs <= 1, 2 and >= 4 mg/L, changes in bacterial density following levofloxacin HSR were #1.66 +/- 0.89, 0.13 +/- 0.97 and 1.54 +/- 0.43 log10 cfu/thigh, respectively. The E-max model demonstrated strong agreement between fAUC/MIC and change in bacterial density (R-2 = 0.82). The fAUC/MIC exposure needed for stasis and 1 log10 reduction was 39.9 and 54.9, respectively. PTAs for the 1 log(10) reduction threshold were 95.8, 72.2, and 26.6% at MICs of 0.5, 1 and 2 mg/L, respectively. Conclusions: These are the first data to describe fAUC/MIC thresholds predictive of cfu reductions for levofloxacin against STM. Due to poor in vivo efficacy and PTA at MICs >= 2 mg/L, reassessment of the current susceptibility breakpoint is warranted.