title: 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.
abstract: NorA is a membrane-associated multidrug efflux protein that can decrease susceptibility to fluoroquinolones in Staphylococcus aureus. We have previously determined that NorA inhibition can increase fluoroquinolone killing activity and post-antibiotic effect. In the current investigation, we studied the killing activity and development of resistance for levofloxacin, ciprofloxacin and norfloxacin with or without the H+/K+ ATPase inhibitor omeprazole, in a wild-type strain of S. aureus (SA-1199) and its NorA hyperproducing mutant (SA-1199-3) in an in-vitro pharmacodynamic model with infected fibrin-platelet matrices. Each drug was administered every 12-24 h for 72 h and human pharmacokinetics were simulated. Levofloxacin was the most potent fluoroquinolone against both strains and its activity was not significantly affected by combination with omeprazole. The addition of omeprazole to ciprofloxacin significantly lowered colony counts at all time-points against both strains and decreased the time to 99.9% kill from 72.2 h to 33.8 h against SA-1199. The addition of omeprazole minimally increased norfloxacin activity against both strains. Omeprazole decreased the frequency of ciprofloxacin 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 levofloxacin regimens. The hydrophobic fluoroquinolones such as levofloxacin appear to circumvent NorA efflux, which may contribute to their better activity and decreased resistance rates against staphylococci. More durable and potent NorA inhibitor compounds are needed that can improve killing activity and prevent resistance.
authors.affiliation: Department of Pharmacy Services (1B), and College of Pharmacy and Allied Health Professions, Wayne State University, MI 48201, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Aeschlimann
authors.forename: G W
authors.initials: GW
authors.lastname: Kaatz
authors.forename: M J
authors.initials: MJ
authors.lastname: Rybak
mesh_terms: D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002939:Ciprofloxacin / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D004352:Drug Resistance, Microbial; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009643:Norfloxacin / Q000493:pharmacokinetics / Q000494:pharmacology; D015242:Ofloxacin / Q000493:pharmacokinetics / Q000494:pharmacology; D009853:Omeprazole / Q000493:pharmacokinetics / Q000494:pharmacology*; D013045:Species Specificity; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D002939:Ciprofloxacin; D004791:Enzyme Inhibitors; D064704:Levofloxacin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009643:Norfloxacin; D015242:Ofloxacin; D009853:Omeprazole; C075040:NorA protein, Staphylococcus