In Vitro Pharmacodynamic Evaluation of the Mutant Selection Window Hypothesis Using Four Fluoroquinolones against Staphylococcus aureus

Abstract

Examination of time-kill curves of antibiotic-exposed bacteria using in vitro dynamic models allows pharmacokinetically related comparisons of antimicrobial effects but may or may not directly reflect the selective enrichment of resistant mutants. Bacterial resistance has been studied infrequently using these models. Limited observations reported from earlier timekill studies (3, 8, 21-23) precluded delineation of relationships of the area under the concentration-time curve (AUC)/MIC ratio with resistance because the ranges of the simulated AUCto-MIC ratios were too narrow. In fact, the first attempts to relate resistance to the AUC/MIC or peak concentration (C max )/MIC ratio were reported quite recently from studies that declared resistance analysis as a primary goal (1,7,17,18,20,(25)(26)(27)30,33,34; A. MacGowan and K. Bowker, Abstr. 41st Intersci. Conf. Antimicrob. Agents Chemother., poster A-440, 2001). Despite wide ranges of AUC/MIC ratios simulated in some recent studies (17)(18)(19)(20)27,33; MacGowan and Bowker, 41st ICAAC), reasonable relationships with resistance were not established. The relatively few studies of these relationships can be classified as those that directly attempt to relate resistance to the simulated pharmacokinetics but do not (17,20) and those that imply the existence of relationships with the AUC/MIC ratio measured within a 24-h dosing interval (AUC 24 /MIC) or with the C max /MIC ratio but do not actually report them (26,27,30). One study did report a complex effect of AUC 24 /MIC and duration of moxifloxacin treatment on bacterial resistance (MacGowan and Bowker, 41st ICAAC), but the three-dimensional plots masked rather than highlighted these links. For example, according to an analysis of these data (A. Firsov, S. Vostrov, I. Lubenko, S. Zinner, and Y. Portnoy, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. A-1210Chemother., abstr. A- , p. 10, 2002, the reported 72-h area under the population analysis profile-time curve as an index of pneumococcal resistance did not correlate with simulated AUC 24 /MIC ratios (r 2 , 0.04).

Mutant Selection Window Hypothesis Updated

“…A general relationship is sketched in figure 1B. Testing involving S. aureus and using in vitro dynamic models reveals that drug-resistant mutants fail to amplify when fluctuating fluoroquinolone concentrations are maintained above or below the selection window that has been determined using agar plates; as expected, mutants are selectively amplified when concentrations are between the MIC and the MPC [31]. Similar observations were obtained with S. pneumoniae [32] and by additional experments with S. aureus [26,33,34].…”

Moxifloxacin superior to vancomycin for treatment of bone infections—a study in rats

“…In numerous in-vitro and in-vivo studies, moxifloxacin was one of the most effective substances against gram-positive bacteria and in particular, it has been shown to be many times more effective against Staphylococci than older fluoroquinolones such as ciprofloxacin (Dalhoff 1999, Jones et al 1999, Hoogkamp-Korstanje et al 2000, Kaatz et al 2002, Ince et al 2003. On the basis of numerous studies, the risk of development of resistance during treatment with moxifloxacin appears to be much lower than during treatment with older quinolones (Pong et al 1999, Lister 2001, Firsov et al 2003.…”

Efficacy of moxifloxacin compared to teicoplanin in the treatment of implant‐related chronic osteomyelitis in rats

“…30 In contrast to other quinolones, moxifloxacin shows better antibacterial activity against MSSA and MRSA strains 18,19,55 and a lower risk of the development of resistance in comparison to other quinolones. 21,22 In conclusion, moxifloxacin is a good alternative to glycopeptide antibiotics, especially in the treatment of implant-related chronic osteomyelitis.…”