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Dose ranging and fractionation of moxifloxacin against Stenotrophomonas maltophilia using an in vitro pharmacodynamic model

Abstract number: 1733_1559

Sevillano D., Alou L., Cafini F., López M., González N., Echeverría O., Torrico M., Prieto J., Gómez-Lus M.

Objectives: To explore the antibacterial activity of higher total daily doses of moxifloxacin (MXF) against S. maltophilia with or without expression of SmeABC or SmeDEF efflux pump systems.

Methods: Eight PFGE characterised isolates of S. maltophilia (MIC to MXF 0.03–8 mg/L) without QRDR mutations in gyrA and parC were exposed to MXF 200 mg o.d., MXF 400 mg o.d., MXF 400 mg b.i.d., and MXF 800 mg o.d. (AUC0–24/MIC ratio of 4.4–1186.3 h) using a two-compartment in vitro pharmacodynamic model with peripheral units containing a starting inoculum of 1–2×109 CFU of each strain. A sigmoid dose-response model was used to estimate the required AUC0–24/MIC to achieve a 50% (ED50) and 80% (ED80) of maximum antibacterial effect at 24 hours. Concentrations of MXF were determined by bioassay and were closed to target values.

Results: Only the strain with MIC to MXF of 0.03 (no SmeABC and SmeDEF expression) was eradicated at MXF 200 mg. The three strains with MIC to MXF of 0.12–0.5 mg/L (SmeDEF expression) was related to regrowth after MXF 400 mg administration but eradicated after MOX 400 mg b.i.d. or 800 mg o.d. These doses were more active (2.7–4.3 log cfu/mL reduction) than MXF 400 mg o.d. (0.6–1.2 log cfu/mL reduction) (p < 0.05) against strains with MIC to MXF of 1 mg/L (SmeDEF expression) or MIC to MXF of 2 mg/L (simultaneous SmeABC and SmeDEF expression) at 24 h. The activity of the MXF 400 b.i.d. regimen was higher than MXF 800 o.d. against strain with MIC to MXF >2 mg/L (1.7–2.4 vs. 0.7–0.8 log cfu/mL reduction). Sigmoid relationship between AUC/MIC and measurement of the antibacterial effect was more adequately described using AUBKC (r2 = 0.95). Values associated with ED50/ED80 at 24 h were 24/87 h.

Conclusions: Higher total daily doses of moxifloxacin (400 mg b.i.d. and 800 mg o.d.) than the usual moxifloxacin clinical dose (400 mg o.d.) improve significatively the antimicrobial activity against strains of S. maltophilia with MIC to MXF ≤ 2 mg/L independently of the efflux pump expression.

Session Details

Date: 31/03/2007
Time: 00:00-00:00
Session name: European Society of Clinical Microbiology and Infectious Diseases
Subject:
Location: ICC, Munich, Germany
Presentation type:
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