Mutant prevention concentration and mutant selection window for 10 antimicrobial agents against Rhodococcus equi

Area of Science:

• Microbiology
• Pharmacology
• Veterinary Medicine

Background:

• Rhodococcus equi causes significant infections in foals and humans.
• Antimicrobial resistance is a growing concern in treating R. equi infections.
• Understanding drug concentrations and mutant prevention is crucial for effective treatment.

Purpose of the Study:

• Determine mutant prevention concentration (MPC) and time above MPC for 10 antimicrobials against R. equi.
• Evaluate the efficacy of macrolide-rifampin combinations in preventing resistant mutant emergence.
• Assess pharmacokinetic parameters for predicting in vivo efficacy.

Main Methods:

• Agar plate assay to determine MPC for 10 antimicrobial agents against four R. equi strains.
• Calculation of pharmacodynamic parameters using published pharmacokinetic data.
• Evaluation of macrolide-rifampin combinations against R. equi.

Main Results:

• Significant differences in MPC observed among antimicrobial agents; clarithromycin had the lowest MPC, while rifampin and amikacin had the highest.
• Macrolide-rifampin combinations significantly reduced MPC and the MPC/MIC ratio.
• Only gentamicin and vancomycin predicted to exceed plasma MPC; clarithromycin and clarithromycin-rifampin predicted to exceed pulmonary MPC throughout dosing intervals.

Conclusions:

• Macrolide-rifampin combinations substantially decrease the emergence of R. equi resistant mutants.
• Clarithromycin-rifampin combination is a promising therapeutic strategy for pulmonary R. equi infections.
• Further research into optimal dosing regimens is warranted.