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

• Published in: Journal of antimicrobial chemotherapy 2012-11, Vol.67 (11), p.2700-2706
• Main Authors: ZHU, Yu-Lin, HU, Li-Fen, QING MEI, JUN CHENG, LIU, Yan-Yan, YING YE, LI, Jia-Bin
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - therapeutic use; Antibiotics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimicrobial agents; Bacterial diseases; Biological and medical sciences; Disease Models, Animal; Female; Human bacterial diseases; Indexing in process; Infectious diseases; Medical sciences; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Mutation; Pharmacology; Pharmacology. Drug treatments; Rabbits; Staphylococcal Infections - drug therapy; Staphylococcal infections, streptococcal infections, pneumococcal infections; Staphylococcus infections; Time Factors; Vancomycin - therapeutic use; Vancomycin Resistance
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dks280

To test the mutant selection window (MSW) hypothesis with Staphylococcus aureus exposed to vancomycin in an animal model and to compare in vivo and in vitro exposures that restrict the enrichment of resistant mutants. Local infection with S. aureus was established in rabbits, and the infected animals were treated with various doses of twice-daily vancomycin (half-life 6 h) for 3 consecutive days to provide antibiotic concentrations below the MIC, between the MIC and the mutant prevention concentration (MPC), and above the MPC. Changes in susceptibility and the numbers of surviving organisms were monitored daily on agar plates containing 2× and 4× MIC of vancomycin. S. aureus lost vancomycin susceptibility when drug concentrations at the site of infection fluctuated between the lower and upper boundaries of the MSW, defined in vitro as the MIC(99) and the MPC, respectively. Both boundaries were determined in vitro, before starting animal studies. The value at which resistant mutants are not enriched in vivo was estimated as an AUC(24)/MPC value of ∼15 h, where AUC(24) is the area under the drug concentration time curve in a 24 h interval. The estimated anti-mutant AUC/MIC ratio in vivo was ≥200 h. These findings support the MSW hypothesis and the anti-mutant AUC/MIC ratio estimated in vivo is consistent with that reported in in vitro studies. Keeping vancomycin concentrations above the MPC or AUC(24)/MPC >15 h is a straightforward way to restrict the acquisition of resistance.