Activity of moxifloxacin against intracellular community-acquired methicillin-resistant Staphylococcus aureus: Comparison with clindamycin, linezolid and co-trimoxazole and attempt at defining an intracellular susceptibility breakpoint

Abstract

Background: Co-trimoxazole, clindamycin and linezolid are used to treat community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections, but little is known about intracellular activity. Moxifloxacin is active against intracellular methicillin-susceptible S. aureus (MSSA), but CA-MRSA has not been studied. Methods: We used 12 clinical CA-MRSA, 1 MSSA overexpressing norA and 2 hospital-acquired MRSA (moxifloxacin MICs: 0.03 to 4 mg/L). Activity was assessed in broth and after phagocytosis by THP-1 macrophages or keratinocytes {concentration-dependent experiments [24 h of incubation] to determine relative potencies [EC50], static concentrations [Cs] and maximal relative efficacies [Emax (change in log10 cfu compared with initial inoculum)] and time-dependent experiments [0-72 h] at human Cmax}. Results: Concentration-dependent experiments: in broth, EC50 and Cs were correlated with the MIC for all antibiotics, but moxifloxacin achieved significantly (P<0.01) greater killing (more negative Emax) than the comparators; and in THP-1 cells and keratinocytes, moxifloxacin acted more slowly but still reached a near bactericidal effect (2 to 3 log10 cfu decrease) at 24 h with unchanged EC50 and Cs as long as its MIC was ≤0.125 mg/L (recursive partitioning analysis). Clindamycin and linezolid were static, and co-trimoxazole was unable to suppress the intracellular growth of CA-MRSA. At human Cmax in broth, moxifloxacin killed more rapidly and more extensively (≥5 log10 cfu decrease at 10 h) than clindamycin (4 log10 cfu at 48 h) or co-trimoxazole and linezolid (1-2 log10 cfu at 72 h). Conclusions: Moxifloxacin is active against both extracellular and intracellular CA-MRSA if the MIC is low, and is more effective than clindamycin, co-trimoxazole and linezolid. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.