Pharmacokinetics/Pharmacodynamics Evaluation of Flomoxef against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli In Vitro and In Vivo in a Murine Thigh Infection Model.

Abstract

PURPOSE:

Although flomoxef (FMOX) has attracted substantial attention as an antibiotic against extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-producing E. coli), the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of FMOX against ESBL-producing E. coli is unclear. The aim of this study was to determine the PK/PD index of FMOX against ESBL-producing E. coli.

METHODS:

In vitro time-kill curve studies and in vivo PK/PD experiments were carried out.

RESULTS:

Time-kill curves exhibited a unique bactericidal activity: time-dependent activity at low concentrations and concentration-dependent activity at high concentrations. In neutropenic murine thigh infection experiments, the antibacterial activity of FMOX correlated with the time that the free drug concentration remaining above the minimum inhibitory concentration (MIC) (fT>MIC) and the ratio of the area under the free drug concentration-time curve for a 24 h period to the MIC (fAUC24/MIC). However, the burden of ESBL producing E. coli significantly reduced when the time intervals for administration were shorter among three dosage regimens with same magnitude of fAUC24/MIC, indicating that fT>MIC is significant PK/PD index. The target value of fT>MIC for 1 log10 kill reduction was 35.1%.

CONCLUSIONS:

fT>MIC is the most significant PK/PD index of FMOX against ESBL-producing E. coli and its target value is ≥ 40%.

• Authors: Sho Tashiro, Marina Hayashi, Wataru Takemura, Yuki Igarashi, Xiaoxi Liu, Yuki Mizukami, Nana Kojima, Yuki Enoki, Kazuaki Taguchi, Yuta Yokoyama, Tomonori Nakamura, Kazuaki Matsumoto
• Journal: Pharmaceutical research (Pharm Res) Vol. 38 Issue 1 Pg. 27-35 (Jan 2021) ISSN: 1573-904X [Electronic] United States
• PMID: 33404990 (Publication Type: Journal Article)

Chemical References

• Cephalosporins
• beta-Lactamases
• flomoxef

Topics

• Animals
• Area Under Curve
• Cephalosporins (pharmacology, therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Escherichia coli (drug effects, enzymology)
• Escherichia coli Infections (drug therapy, microbiology)
• Female
• Humans
• Mice
• Microbial Sensitivity Tests
• beta-Lactam Resistance (drug effects)
• beta-Lactamases (metabolism)