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

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.

• Authors: Andrew J Fratoni, David P Nicolau, Joseph L Kuti
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 77 Issue 4 Pg. 1052-1060 (03 31 2022) ISSN: 1460-2091 [Electronic] England
• PMID: 35134195 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Anti-Bacterial Agents
• Minocycline

Topics

• Animals
• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Humans
• Mice
• Microbial Sensitivity Tests
• Minocycline (pharmacology, therapeutic use)
• Stenotrophomonas maltophilia
• Thigh (microbiology)