Mutant Prevention Concentration of Garenoxacin (BMS-284756) for Ciprofloxacin-Susceptible or -Resistant Staphylococcus aureus

Abstract

The new quinolone garenoxacin (BMS-284756), which lacks a C-6 fluorine, was examined for its ability to block the growth of Staphylococcus aureus. Measurement of the MIC and the mutant prevention concentration (MPC) revealed that garenoxacin was 20-fold more potent than ciprofloxacin for a variety of ciprofloxacinsusceptible isolates, some of which were resistant to methicillin. The MPC for 90% of the isolates (MPC 90 ) was below published serum drug concentrations achieved with recommended doses of garenoxacin. These in vitro observations suggest that garenoxacin has a low propensity for selective enrichment of fluoroquinoloneresistant mutants among ciprofloxacin-susceptible isolates of S. aureus. For ciprofloxacin-resistant isolates, the MIC at which 90% of the isolates tested were inhibited was below serum drug concentrations while the MPC 90 was not. Thus, for these strains, garenoxacin concentrations are expected to fall inside the mutant selection window (between the MIC and the MPC) for much of the treatment time. As a result, garenoxacin is expected to selectively enrich mutants with even lower susceptibility.The fluoroquinolones are potent antibacterial agents that have been used successfully to control a variety of bacterial pathogens. Unfortunately, Staphylococcus aureus readily develops resistance to derivatives such as ciprofloxacin (1,3,18). In some surveys of hospital-acquired infection, more than 90% of the S. aureus isolates were found to be ciprofloxacin-resistant (1, 22). Nevertheless, many community-acquired infections due to S. aureus are still susceptible (8,14,17,20), raising the possibility that new quinolones may be active enough to treat S. aureus infections successfully.Fluoroquinolone activity can be measured in a variety of ways. For susceptible cells, activity is generally assessed in terms of the MIC, the concentration that prevents growth when 10 4 to 10 5 cells are applied to drug-containing agar. When large bacterial and patient populations are considered, activity can be assessed by the mutant prevention concentration (MPC) (5) to take into account subpopulations of resistant mutants that may be present prior to antimicrobial treatment. The MPC is defined as the MIC of the least susceptible singlestep mutant (12,24). For bacterial populations that already contain mutations that lower susceptibility, the MPC is equivalent to the MIC of the least-susceptible next single-step mutant. The MPC is approximated by the concentration that prevents growth when at least 10 10 cells are applied to agar plates (when 10 9 to 10 10 bacteria are treated with fluoroquinolone, the recovery of mutants is progressively reduced by increasing the drug concentration, as expected for concentrations that approach the MIC of the least susceptible mutant).In principle, the interval between the lowest concentration that blocks wild-type growth and the MPC represents a concentration window in which resistant mutants are selected (26,27). The properties of the selection window, when combined with drug pharm...

Comparative Study of the Mutant Prevention Concentrations of Moxifloxacin, Levofloxacin, and Gemifloxacin against Pneumococci

“…These results further suggest that GyrA was the most crucial target for development of high-level resistance reflected in high MIC and MPC values for these three fluoroquinolones and the only target sensitive to prolonged antibiotic pressure in MPC experiments. These results are in agreement with previous findings (1,4,18,23,25,27). No clear relationship was found between the MPCs or their ratios to the MICs and the existence of gyrB, parC, or parE mutations.…”

Mutant Selection Window Hypothesis Updated

“…However, determination of MPC with ciprofloxacin-resistant isolates indicates that garenoxacin resistance would be acquired as quickly as ciprofloxacin resistance by fully susceptible isolates [60,61]; in both cases, serum drug concentrations are within the selection window for much of the dosing period [62]. These same in vitro measurements indicate that garenoxacin trials with ciprofloxacin-susceptible isolates might be successful if drug concentrations at the site of mutant amplification are at least as high as serum concentrations (i.e., serum drug concentrations are above MPC for the entire dosing period) [62,63].…”

Comparative study of the mutant prevention concentrations of vancomycin alone and in combination with levofloxacin, rifampicin and fosfomycin against methicillin-resistant Staphylococcus epidermidis

“…The results of FIC indices were interpreted as synergistic (FICIp0.5), indifferent (0.5oFICIo4) and antagonistic (FICIX4) according to the most relevant criteria. 19 MPC determination and MIC retesting of putative mutants MPCs were determined as described by Zhao et al 20 Briefly, the tested bacteria were cultured in Mueller-Hinton broth and cultured for 24 h. The suspension was centrifuged (4000 g for 10 min) and re-suspended in Mueller-Hinton broth to yield a concentration of about 3 Â 10 10 CFU ml À1 . Finally, each agar plate containing known antibiotic concentrations was inoculated with about 3.0 Â 10 9 CFU of tested bacteria (100 ml bacterial suspension), with four plates (9 cm in diameter) for a given antibiotic concentration.…”