Levofloxacin pharmacodynamics against Stenotrophomonas maltophilia in a neutropenic murine thigh infection model: implications for susceptibility breakpoint revision
| Autor: | Joseph L. Kuti, Andrew J Fratoni, David P. Nicolau |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Microbiology (medical)
medicine.medical_specialty Stenotrophomonas maltophilia Levofloxacin Microbial Sensitivity Tests Thigh Gastroenterology Mice In vivo Internal medicine Medicine Animals Humans Pharmacology (medical) Log10 reduction Pharmacology biology business.industry Breakpoint biology.organism_classification Anti-Bacterial Agents Infectious Diseases medicine.anatomical_structure Pharmacodynamics business medicine.drug |
| Zdroj: | The Journal of antimicrobial chemotherapy. 77(1) |
| ISSN: | 1460-2091 |
| Popis: | 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 750 mg 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 log10 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 Emax model demonstrated strong agreement between fAUC/MIC and change in bacterial density (R2 = 0.82). The fAUC/MIC exposure needed for stasis and 1 log10 reduction was 39.9 and 54.9, respectively. PTAs for the 1 log10 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|