The in vitro activity of BMS-284756, a new des-fluorinated quinolone

Weller, T. M. A.; Andrews, J. M.; Jevons, G.; Wise, R.

doi:10.1093/jac/49.1.177

Cited by 34 publications

(22 citation statements)

References 9 publications

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“…This quinolone exhibits potent activity against S. aureus, and some investigators have suggested that it might be useful with ciprofloxacin-resistant S. aureus [56][57][58][59]. 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].…”

Section: Potential Applicationsmentioning

confidence: 99%

Mutant Selection Window Hypothesis Updated

Drlica¹,

Zhao²

2007

Clinical Infectious Diseases

347

338

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The mutant selection window hypothesis postulates that, for each antimicrobial-pathogen combination, an antimicrobial concentration range exists in which selective amplification of single-step, drug-resistant mutants occurs. This hypothesis suggests an antimutant dosing strategy that is keyed to the upper boundary of the selection window: the mutant prevention concentration. Correlations are described between the mutant prevention concentration-a static parameter that is measured with agar plates-and fluctuating drug concentrations that restrict mutant amplification in vitro and in animals. When drug resistance is acquired stepwise, the mutant selection window increases, making the suppression of each successive mutant increasingly more difficult. For agents that kill drug-resistant mutants in a drug concentration-dependent manner, the use of the area under the 24-h time-drug concentration curve value divided by the value of the mutant prevention concentration is suggested as an index for designing antimutant dosing regimens. The need for such regimens is emphasized by a clinical example in which acquisition of drug resistance occurs concurrently with eradication of susceptible bacterial cells. These data support using the mutant selection window to optimize antimicrobial dosing regimens.Antimicrobial resistance is a complex problem that is likely to require attention at many levels [1]. Issues concerning dosing are addressed by the mutant selection window hypothesis [2,3]. This hypothesis maintains that drug-resistant mutant subpopulations present prior to initiation of antimicrobial treatment are enriched and amplified during therapy when antimicrobial concentrations fall within a specific range (the mutant selection window). The upper boundary of the mutant selection window is the MIC of the least drugsusceptible mutant subpopulation, a value called the mutant prevention concentration (MPC) [4]. The lower boundary of the mutant selection window is the lowest concentration that exerts selective pressure, often approximated by the minimal concentration that inhibits colony formation by 99% (MIC 99 ). Two principles emerge from the hypothesis. First, traditional dos-

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Section: Potential Applicationsmentioning

confidence: 99%

Mutant Selection Window Hypothesis Updated

Drlica¹,

Zhao²

2007

Clinical Infectious Diseases

347

338

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“…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).…”

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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

Antimicrob Agents Chemother

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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.

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“…It displays a high degree of in vitro activity against a broad range of gram-positive and gram-negative bacterial pathogens, including anaerobes (6,12,13,15,17,24,25,29,30).…”

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confidence: 99%