Nemonoxacin Enhances Antibacterial Activity and Anti-Resistance Mutation Ability of Vancomycin against Methicillin-Resistant Staphylococcus aureus in an In Vitro Dynamic Pharmacokinetic/Pharmacodynamic Model

Reduced susceptibility and emergence of resistance to vancomycin in methicillin-resistant Staphylococcus aureus (MRSA) have led to the development of various vancomycin-based combinations. Nemonoxacin is a novel nonfluorinated quinolone with antibacterial activity against MRSA. The present study aimed to investigate the effects of nemonoxacin on antibacterial activity and the anti-resistant mutation ability of vancomycin for MRSA and explore whether quinolone resistance genes are associated with a reduction in the vancomycin MIC and mutant prevention concentration (MPC) when combined with nemonoxacin. Four isolates, all with vancomycin MICs of 2 mu g/mL, were used in a modified in vitro dynamic pharmacokinetic/pharmacodynamic model to investigate the effects of nemonoxacin on antibacterial activity (isolates M04, M23, and M24) and anti-resistant mutation ability (isolates M04, M23, and M25, all with MPCs of >= 19.2 mu g/mL) of vancomycin. The mutation sites of gyrA, gyrB, parC, and parE of 55 clinical MRSA isolates were sequenced. We observed that in M04 and M23, the combination of vancomycin (1 g given every 12 h [q12h]) and nemonoxacin (0.5 g once daily [qd]) showed a synergistic bactericidal activity and resistance enrichment suppression. All clinical isolates resistant to nemonoxacin harbored gyrA (S84 -> L) mutation; gyrA (S84 -> L) and parC (E84 -> K) mutations were the two independent risk factors for the unchanged vancomycin MPC in combination. Nemonoxacin enhances the bactericidal activity and suppresses resistance enrichment ability of vancomycin against MRSA, with an MIC of 2 mu g/mL. Our in vitro data support the combination of nemonoxacin and vancomycin for the treatment of MRSA infection with a high MIC.