Prevention of the selection of resistant Staphylococcus aureus by moxifloxacin plus doxycycline in an in vitro dynamic model: an additive effect of the combination

Abstract

Twenty-four hour ratios of area under the curve (AUC 24) to MIC of 200–240 h providing quinolone concentrations above the mutant prevention concentration (MPC) protected from enrichment of resistant Staphylococcus aureus in our recent study that simulated the pharmacokinetics of moxifloxacin, gatifloxacin, levofloxacin and ciprofloxacin. These protective AUC 24/MICs might also be achieved by using antibiotic combinations, assuming additive effects of two anti-staphylococcal agents. To test this hypothesis, changes in S. aureus susceptibility were examined in a dynamic model that simulates 5-day treatment with moxifloxacin and doxycycline, alone and in combination at sub-optimal AUC 24/MICs of each agent. Significant increases in MIC were observed with monotherapy where moxifloxacin or doxycycline concentrations fell into the mutant selection window (MSW) for more than 80% of the dosing interval (AUC 24/MIC 60 h). Less pronounced changes in MIC occurred when the summed concentrations of moxifloxacin (AUC 24/MIC 30 and 60 h) and doxycycline (AUC 24/MIC 30 and 60 h) were inside the MSWs for the individual drugs for 30–50% of the dosing interval. No loss in susceptibility was found at moxifloxacin or doxycycline AUC 24/MIC 170 h combined with the smaller AUC 24/MIC (60 h) of the second compound. These data suggest that the total AUC 24/MIC of 230 h might protect against S. aureus resistance. As this value is very close to that predicted in monotherapy with moxifloxacin (220 h), an additive protective effect of quinolone+doxycycline on the selection of resistant S. aureus is proposed. The use of drug combinations may be useful for restricting the enrichment of resistant mutants with agents whose clinically achievable AUC 24/MICs do not provide concentrations above the MPC.