The effects of NorA inhibition on the activities of levofloxacin, ciprofloxacin and norfloxacin against two genetically related strains of Staphylococcus aureus in an in-vitro infection model

NorA is a membrane-associated multidrug efflux protein that can decrease su sceptibility to fluoroquinolones in Staphylococcus aureus. We have previous ly determined that NorA inhibition can increase fluoroquinolone killing act ivity and post-antibiotic effect. In the current investigation, we studied the killing activity and development of resistance for levofloxacin, ciprof loxacin and norfloxacin with or without the H+/K+ ATPase inhibitor omeprazo le, in a wild-type strain of S. aureus (SA-1199) and its NorA hyperproducin g mutant (SA-1199-3) in an in-vitro pharmacodynamic model with infected fib rin-platetet matrices. Each drug was administered every 12-24 h for 72 h an d human pharmacokinetics were simulated. Levofloxacin was the most potent f luoroquinolone against both strains and its activity was not significantly affected by combination with omeprazole. The addition of omeprazole to cipr ofloxacin significantly lowered colony counts at all time-points against bo th strains and decreased the time to 99.9% kill from 72.2 h to 33.8 h again st SA-1199. The addition of omeprazole minimally increased norfloxacin acti vity against both strains. Omeprazole decreased the frequency of ciprofloxa cin resistance nearly 100-fold at the 24 h time-point, but the frequency of resistance was not significantly different for any of the fluoroquinolone regimens after this time-point. No resistance was detected during levofloxa cin regimens. The hydrophobic fluoroquinolones such as levofloxacin appear to circumvent NorA efflux, which may contribute to their better activity an d decreased resistance rates against staphylococci. More durable and potent NorA inhibitor compounds are needed that can improve killing activity and prevent resistance.