Comparing the Synergistic and Antagonistic Interactions of Ciprofloxacin and Levofloxacin Combined with Rifampin against Drug-Resistant Staphylococcus aureus: A Time-Kill Assay

Background: Treatment of device-related infections by drug-resistant Staphylococcus aureus can be challenging, and combination therapy has been proposed as a potential solution. We compared the effectiveness of levofloxacin-rifampin and ciprofloxacin-rifampin combinations in killing methicillin-resistant S. aureus (MRSA) using a time-kill assay. Methods: We randomly selected 15 vancomycin-susceptible S. aureus (VSSA) strains, 3 vancomycin-intermediate S. aureus (VISA) strains, and 12 heterogeneous VISA (hVISA) strains from the Asian Bacterial Bank. Time-kill experiments were performed in duplicate for each isolate. Viable bacterial counts were determined at 0 h, 4 h, 8 h, and 24 h for the ciprofloxacin- and levofloxacin-rifampin combinations at 1x MIC and 0.5x MIC. We compared synergistic and antagonistic interactions between the two combinations. Results: The viable bacterial count significantly decreased after 24 h of exposure to ciprofloxacin-rifampin and levofloxacin-rifampin combinations, with synergy observed more frequently in isolates exposed to ciprofloxacin-rifampin (43.3%) than levofloxacin-rifampin (20.0%) (p = 0.0082). The synergistic interactions of both combinations were more frequently observed in resistant strains with high MICs of ciprofloxacin (>= 16 mg/L) and levofloxacin (>= 8 mg/L). Levofloxacin tended to exhibit more frequent antagonistic interactions with rifampin than ciprofloxacin, although there was no statistical difference in antagonism between the two combinations. Conclusions: Our study demonstrated that ciprofloxacin exhibits superior synergistic activity against MRSA strains, including VISA/hVISA, when combined with rifampin compared with levofloxacin. High MICs of fluoroquinolones were found to predict synergism. Our results suggest that ciprofloxacin may be a more effective choice than levofloxacin for combination therapy with rifampin in the treatment of MRSA infections.