PHARMACODYNAMICS OF LEVOFLOXACIN, OFLOXACIN, AND CIPROFLOXACIN, ALONEAND IN COMBINATION WITH RIFAMPIN, AGAINST METHICILLIN-SUSCEPTIBLE ANDMETHICILLIN-RESISTANT STAPHYLOCOCCUS-AUREUS IN AN IN-VITRO INFECTION MODEL

The pharmacodynamic properties of levofloxacin (an optically active is omer of ofloxacin), ofloxacin, and ciprofloxacin, alone and in combina tion with rifampin, were evaluated over 24 to 48 h against clinical is olates of methicillin susceptible and -resistant Staphylococcus aureus (MSSA 1199 and MRSA 494, respectively) in an in vitro infection model . The incidence of the emergence of resistance among the test strains was also determined. The fluoroquinolones were administered to simulat e dosage regimens of 200 mg, 400 mg given intravenously (i.v.) every 1 2 h (q12h), and 400 and 800 mg given i.v. q24h. Rifampin was dosed at 600 mg i.v. q24h. Although the MICs and MBCs of the quinolones were si milar (less than or equal to 0.49 mu g/ml), levofloxacin was the most potent agent in time-kill studies on the basis of the time required to achieve a 99.9% reduction in the number of log(10) CFU per milliliter (e.g., with the regimen of levofloxacin [400 mg q24h, 6.5 h] versus o floxacin [12.5 h], P < 0.024, and levofloxacin versus ciprofloxacin [6 .5 versus 9.0 h], P < 0.0017) against MSSA 1199. The killing activity of levofloxacin was similar to that of ofloxacin against MRSA 494 (tim e to achieve a 99.9% reduction in the number of log(10) CFU per millil iter, 11.1 versus 13.8 h, respectively). Levofloxacin and ofloxacin do sed once daily demonstrated greater bactericidal activity than when th ey were dosed twice daily against MSSA 1199. Resistance to levofloxaci n or ofloxacin was not observed with any dosage regimen. Furthermore, resistance to ofloxacin was not detected when the half-life was reduce d from 6 to 3 h. Regrowth and stable resistance (65-fold increase in t he MIC for MSSA 1199; 16-fold increase in the MIC for MRSA 494) were n oted within 24 h of exposure to ciprofloxacin at 200 mg q12h. Combinat ion therapy with rifampin prevented the emergence of resistance to cip rofloxacin. Neither DNA gyrase alteration nor an energy-dependent effl ux process mediated by the norA gene appeared to be responsible for th e resistance observed. Our data suggest that with levofloxacin there i s a more rapid onset of bactericidal activity than with ofloxacin or c iprofloxacin against MSSA 1199 and that the activity; of levofloxacin is similar to that of ofloxacin but better than that of ciprofloxacin against MRSA 494. Resistance was noted only after exposure to the low dose of ciprofloxacin. Resistance to ofloxacin did not develop even wh en the pharmacokinetics of the drug were set to equal those of ciprofl oxacin, suggesting that ofloxacin differs from ciprofloxacin irrespect ive of time of exposure. The resistance to ciprofloxacin that develope d in our in vitro model may be mediated by the cfx-ofx locus, which ha s been shown to be associated with low-level fluoroquinolone resistanc e. Overall, levofloxacin demonstrated potent bactericidal activity aga inst S. aureus, without the emergence of resistance in our infection m odel. Quinolones dosed once daily were more effective than equivalent dosages administered twice daily. The addition of rifampin was not syn ergistic but prevented the emergence of ciprofloxacin resistance.