Testing the mutant selection window in rabbits infected with methicillin-resistant Staphylococcus aureus exposed to...

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Background:

• Antibiotic resistance is a growing global health threat.
• Staphylococcus aureus, particularly MRSA, is a major cause of difficult-to-treat infections.
• The mutant selection window (MSW) hypothesis proposes that antibiotic concentrations between the minimum inhibitory concentration (MIC) and the mutant prevention concentration (MPC) promote resistance development.

Purpose of the Study:

• To test the MSW hypothesis in a Staphylococcus aureus animal model using vancomycin.
• To compare in vivo and in vitro antibiotic exposures that prevent the emergence of resistant mutants.

Main Methods:

• A local S. aureus infection model was established in rabbits.
• Animals received varying doses of vancomycin twice daily for 3 days.
• Antibiotic concentrations were set below, between, and above the MIC and MPC.
• Bacterial susceptibility and survival were monitored daily using agar plates with vancomycin.

Main Results:

• Vancomycin resistance emerged when concentrations fluctuated within the MSW (MIC to MPC).
• The in vitro determined MIC(99) and MPC defined the MSW boundaries.
• In vivo, resistant mutants were not enriched when the area under the curve over 24 hours (AUC24) to MPC ratio exceeded approximately 15 h.
• The estimated in vivo anti-mutant AUC/MIC ratio was ≥200 h.

Conclusions:

• The study findings support the MSW hypothesis.
• The in vivo anti-mutant AUC/MIC ratio aligns with previous in vitro data.
• Maintaining vancomycin concentrations above the MPC or achieving an AUC24/MPC >15 h effectively restricts resistance acquisition.