Bactericidal Activities of BMS-284756, a Novel Des-F(6)-Quinolone, against
            <i>Staphylococcus aureus</i>
            Strains with Topoisomerase Mutations

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...

Section: Discussionmentioning

confidence: 99%

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

Zhao¹,

Eisner²,

Perl-Rosenthal³

et al. 2003

“…Genotyping of the levofloxacin-resistant variants in the starting cultures revealed a variety of mutations in grlA/B. The S80Y, S80F, E84K, and A116P grlA mutations observed have been associated with phenotypic levofloxacin resistance in S. aureus (15,22,35), but the P144S grlA and the E422D grlB mutations do not appear to contribute to resistance (16,26,33). Other resistant subpopulations did not have mutations in the sequenced regions of grlA/B or gyrA/B.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic Modeling of the Evolution of Levofloxacin Resistance in Staphylococcus aureus

Campion¹,

Chung

Titlow³

et al. 2005

Previously, we demonstrated the importance of low-level-resistant variants to the evolution of resistance in Staphylococcus aureus exposed to ciprofloxacin in an in vitro system and developed a pharmacodynamic model which predicted the emergence of resistance. Here, we examine and model the evolution of resistance to levofloxacin in S. aureus exposed to simulated levofloxacin pharmacokinetic profiles. Enrichment of subpopulations with mutations in grlA and low-level resistance varied with levofloxacin exposure. A regimen producing average steady-state concentrations (C avg ss ) just above the MIC selected grlA mutants with up to 16-fold increases in the MIC and often additional mutations in grlA/grlB and gyrA. A regimen providing C avg ss between the MIC and the mutant prevention concentration (MPC) suppressed bacterial numbers to the limit of detection and prevented the appearance of bacteria with additional mutations or high-level resistance. Regimens producing C avg ss above the MPC appeared to eradicate low-level-resistant variants in the cultures and prevent the emergence of resistance. There was no relationship between the time concentrations remained between the MIC and the MPC and the degree of resistance or the presence or type of mutations that appeared in grlA/B or gyrA. Our pharmacodynamic model described the growth and levofloxacin killing of the parent strains and the most resistant grlA mutants in the starting cultures and correctly predicted conditions that enrich subpopulations with low-level resistance. These findings suggest that the pharmacodynamic model has general applicability for describing fluoroquinolone resistance in S. aureus and further demonstrate the importance of low-level-resistant variants to the evolution of resistance.In previous work, we examined the evolution of resistance when ciprofloxacin-susceptible (S) Staphylococcus aureus strains were exposed in an in vitro hollow-fiber system to simulated clinical and experimental ciprofloxacin pharmacokinetic profiles (4). We found that with increasing average steady-state concentrations (C avg ss ), the rate of initial killing approached a maximum, and the rate of regrowth decreased. Enrichment of subpopulations with mutations in grlA and low-level resistance also varied depending on the pharmacokinetic environment. A regimen producing C avg ss slightly above the MIC selected resistant (R) variants with grlA mutations that did not evolve to higher levels of resistance. Clinical regimens which provided C avg ss intermediate between the MIC and mutant prevention concentration (MPC) resulted in the emergence of subpopulations with gyrA mutations and higher levels of resistance and a regimen producing C avg ss greater than or equal to the MPC selected grlA mutants, but the appearance of subpopulations with higher levels of resistance was delayed. A regimen designed to maintain ciprofloxacin concentrations entirely above the MPC appeared to eradicate low-level-resistant variants in the inoculum and prevent the emergence of high-level-re...

“…It has been shown to have activity against a wide range of clinical isolates (1,7,12,34), and in particular, garenoxacin has been shown to have good activity against Staphylococcus aureus, both methicillin sensitive and resistant (6), and the respiratory pathogens Streptococcus pneumoniae (26), Haemophilus influenzae, and Moraxella catarrhalis (8). The activity of garenoxacin has been further assessed against strains of S. aureus with specific topoisomerase mutations (21), and more recently, it has been shown that garenoxacin has similar potency against both topoisomerase IV and gyrase (16) (dual-targeting quinolone), thus requiring mutations in both topoisomerases for resistance to occur (29). Although horizontal transfer is a major reason for the spread of ciprofloxacin-resistant strains, the role of antimicrobial selection may also play an important role.…”

mentioning

confidence: 99%

Antimicrobial Activities of Garenoxacin (BMS 284756) against Asia-Pacific Region Clinical Isolates from the SENTRY Program, 1999 to 2001

Christiansen

Bell

Turnidge

et al. 2004

Between 1999 and 2001, 16,731 isolates from the Asia-Pacific Region were tested in the SENTRY Program for susceptibility to six fluoroquinolones including garenoxacin. Garenoxacin was four-to eightfold less active against Enterobacteriaceae than ciprofloxacin, although both drugs inhibited similar percentages at 1 g/ml. Garenoxacin was more active against gram-positive species than all other fluoroquinolones except gemifloxacin. For Staphylococcus aureus, oxacillin resistance was high in many participating countries (Japan, 67%; Taiwan, 60%; Hong Kong, 55%; Singapore, 52%), with corresponding high levels of ciprofloxacin resistance (57 to 99%) in oxacillin-resistant S. aureus (ORSA). Of the ciprofloxacin-resistant ORSA isolates, the garenoxacin MIC was >4 g/ml for only 9% of them. For Streptococcus pneumoniae, penicillin nonsusceptibility and macrolide resistance were high in many countries. No relationship was seen between penicillin and garenoxacin susceptibility, with all isolates being susceptible at <2 g/ml. There was, however, a partial correlation between ciprofloxacin and garenoxacin MICs. For ciprofloxacin-resistant isolates for which garenoxacin MICs were 0.25 to 1 g/liter, mutations in both the ParC and GyrA regions of the quinolone resistance-determining region could be demonstrated. No mutations conferring high-level resistance were detected. Garenoxacin shows useful activity against a wide range of organisms from the Asia-Pacific region. In particular, it has good activity against S. aureus and S. pneumoniae, although there is evidence that low-level resistance is present in those organisms with ciprofloxacin resistance.