Effects of NorA inhibitors on in vitro antibacterial activities and postantibiotic effects of levofloxacin, ciprofloxacin, and norfloxacin in genetically related strains of Staphylococcus aureus

NorA is a membrane-associated multidrug efflux protein that can decrease su sceptibility 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 wi th and without various NorA inhibitors against three genetically related st rains 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 ef fect (PAE) methods, Levofloxacin had the most potent activity against all t hree strains and,vas 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-fo ld decreases for both SA 1199B and SA 1199-3, In time-kill experiments rese rpine, omeprazole, or lansoprazole increased levofloxacin activity against SA 1199-3 alone by 2 log(10) CFU/ml and increased norfloxacin and ciproflox acin activities against all three strains by 0.5 to 4 log(10) CFU/ml. Reser pine 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. Reserpin e 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 dramati cally improved the activities of the more hydrophilic fluoroquinolones (nor floxacin and ciprofloxacin), These compounds may restore the activities of these fluoroquinolones against resistant strains of S, aureus or may potent ially enhance their activities against sensitive strains.