Aeschlimann J R, Dresser L D, Kaatz G W, Rybak M J
Department of Pharmacy Services, Detroit Receiving Hospital and University Health Center, Michigan, USA.
Antimicrob Agents Chemother. 1999 Feb;43(2):335-40. doi: 10.1128/AAC.43.2.335.
NorA is a membrane-associated multidrug efflux protein that can decrease susceptibility to fluoroquinolones in Staphylococcus aureus. To determine the effect of NorA inhibition on the pharmacodynamics of fluoroquinolones, we evaluated the activities of levofloxacin, ciprofloxacin, and norfloxacin with and without various NorA inhibitors against three genetically related strains of S. aureus (SA 1199, the wild-type; SA 1199B, a NorA hyperproducer with a grlA mutation; and SA 1199-3, a strain that inducibly hyperproduces NorA) using susceptibility testing, time-kill curves, and postantibiotic effect (PAE) methods. Levofloxacin had the most potent activity against all three strains and was minimally affected by addition of NorA inhibitors. In contrast, reserpine, omeprazole, and lansoprazole produced 4-fold decreases in ciprofloxacin and norfloxacin MICs and MBCs for SA 1199 and 4- to 16-fold decreases for both SA 1199B and SA 1199-3. In time-kill experiments reserpine, omeprazole, or lansoprazole increased levofloxacin activity against SA 1199-3 alone by 2 log10 CFU/ml and increased norfloxacin and ciprofloxacin activities against all three strains by 0.5 to 4 log10 CFU/ml. Reserpine and omeprazole increased norfloxacin PAEs on SA 1199, SA 1199B, and SA 1199-3 from 0.9, 0.6, and 0.2 h to 2.5 to 4.5, 1.1 to 1.3, and 0.4 to 1.1 h, respectively; similar effects were observed with ciprofloxacin. Reserpine and omeprazole increased the levofloxacin PAE only on SA 1199B (from 1.6 to 5.0 and 3.1 h, respectively). In conclusion, the NorA inhibitors dramatically improved the activities of the more hydrophilic fluoroquinolones (norfloxacin and ciprofloxacin). These compounds may restore the activities of these fluoroquinolones against resistant strains of S. aureus or may potentially enhance their activities against sensitive strains.
NorA是一种与膜相关的多药外排蛋白，可降低金黄色葡萄球菌对氟喹诺酮类药物的敏感性。为了确定NorA抑制对氟喹诺酮类药物药效学的影响，我们使用药敏试验、时间-杀菌曲线和抗生素后效应（PAE）方法，评估了左氧氟沙星、环丙沙星和诺氟沙星在有无各种NorA抑制剂的情况下，对三株基因相关的金黄色葡萄球菌（SA 1199，野生型；SA 1199B，具有grlA突变的NorA高表达菌株；以及SA 1199-3，可诱导性高表达NorA的菌株）的活性。左氧氟沙星对所有三株菌株都具有最强的活性，添加NorA抑制剂对其影响最小。相比之下，利血平、奥美拉唑和兰索拉唑使SA 1199的环丙沙星和诺氟沙星的MIC和MBC降低了4倍，使SA 1199B和SA 1199-3的MIC和MBC降低了4至16倍。在时间-杀菌实验中，利血平、奥美拉唑或兰索拉唑单独使左氧氟沙星对SA 1199-3的活性提高了2 log10 CFU/ml，并使诺氟沙星和环丙沙星对所有三株菌株的活性提高了0.5至4 log10 CFU/ml。利血平和奥美拉唑使诺氟沙星对SA 1199、SA 1199B和SA 1199-3的PAE分别从0.9、0.6和0.2小时增加到2.5至4.
