Determination of the mutant selection window for clindamycin, doxycycline, linezolid, moxifloxacin and trimethoprim/sulfamethoxazole against community-associated meticillin-resistant Staphylococcus aureus (MRSA)

The risk that antimicrobials suitable for therapy of infections caused by community-associated meticillin-resistant Staphylococcus aureus (CA-MRSA) will allow the emergence of resistance has not been adequately studied. In this study, mutant prevention concentration (MPC) testing was used to investigate the propensity for future resistance induction in CA-MRSA by clindamycin, doxycycline, linezolid, moxifloxacin and trimethoprim/sulfamethoxazole. Four CA-MRSA isolates [two each of clones USA300 (10841 and NRS384) and USA400 (2833 and NRS123)] were tested as well as a single hospital-acquired strain (NRS385). A variable hierarchy of the tested antimicrobials with respect to the percentage of the dosage interval that concentrations fall within the mutant selection window (%TMSW) was determined, with all antimicrobials achieving %TMSW values >20%. Against the hospital-acquired strain, all antimicrobials except linezolid (%TMSW = 74.10%) and moxifloxacin (%TMSW = 21.65%) are predicted to attain concentrations below the minimum inhibitory concentration (MIC) and mutant selection window (MSW). No instance was observed in which the percentage of the dosage interval that concentrations exceed the MPC (%T > MPC) was found to be 100%. Therapeutic dosing of the tested agents is predicted to attain concentrations within the MSW to varying degrees in CA-MRSA. The risk that resistance to these antimicrobials will emerge in CA-MRSA with continued use warrants further investigation of their propensity to select resistant subpopulations.