scholarly journals Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to linezolid in an in vitro dynamic model

2017 ◽  
Vol 72 (11) ◽  
pp. 3100-3107 ◽  
Author(s):  
Alexander A Firsov ◽  
Kamilla N Alieva ◽  
Elena N Strukova ◽  
Maria V Golikova ◽  
Yury A Portnoy ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Dynamic Model ◽  
Mutant Selection ◽  
Selection Window

scholarly journals Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to daptomycin and vancomycin in an in vitro dynamic model

2006 ◽  
Vol 58 (6) ◽  
pp. 1185-1192 ◽  
Author(s):  
A. A. Firsov ◽  
M. V. Smirnova ◽  
I. Yu. Lubenko ◽  
S. N. Vostrov ◽  
Y. A. Portnoy ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Dynamic Model ◽  
Mutant Selection ◽  
Selection Window

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

2003 ◽  
Vol 47 (3) ◽  
pp. 1023-1027 ◽  
Author(s):  
Xilin Zhao ◽  
William Eisner ◽  
Nathan Perl-Rosenthal ◽  
Barry Kreiswirth ◽  
Karl Drlica
Keyword(s):  
Staphylococcus Aureus ◽  
Treatment Time ◽  
Mutant Selection ◽  
Selective Enrichment ◽  
Drug Concentrations ◽  
Selection Window ◽  
Mutant Prevention Concentration ◽  
Resistant Mutants

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 ciprofloxacin-susceptible isolates, some of which were resistant to methicillin. The MPC for 90% of the isolates (MPC90) 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 fluoroquinolone-resistant 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 MPC90 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.

scholarly journals Pharmacodynamic Modeling of Ciprofloxacin Resistance in Staphylococcus aureus

2005 ◽  
Vol 49 (1) ◽  
pp. 209-219 ◽  
Author(s):  
Jeffrey J. Campion ◽  
Patrick J. McNamara ◽  
Martin E. Evans
Keyword(s):  
Staphylococcus Aureus ◽  
Resistance Mechanism ◽  
Viable Count ◽  
Pharmacodynamic Modeling ◽  
Mutant Selection ◽  
High Density Culture ◽  
Low Level ◽  
Selection Window ◽  
Mutant Prevention Concentration

ABSTRACT Three pharmacodynamic models of increasing complexity, designed for two subpopulations of bacteria with different susceptibilities, were developed to describe and predict the evolution of resistance to ciprofloxacin in Staphylococcus aureus by using pharmacokinetic, viable count, subpopulation, and resistance mechanism data obtained from in vitro system experiments. A two-population model with unique growth and killing rate constants for the ciprofloxacin-susceptible and -resistant subpopulations best described the initial killing and subsequent regrowth patterns observed. The model correctly described the enrichment of subpopulations with low-level resistance in the parent cultures but did not identify a relationship between the time ciprofloxacin concentrations were in the mutant selection window (the interval between the MIC and the mutant prevention concentration) and the enrichment of these subpopulations. The model confirmed the importance of resistant variants to the emergence of resistance by successfully predicting that resistant subpopulations would not emerge when a low-density culture, with a low probability of mutants, was exposed to a clinical dosing regimen or when a high-density culture, with a higher probability of mutants, was exposed to a transient high initial concentration designed to rapidly eradicate low-level resistant grlA mutants. The model, however, did not predict or explain the origin of variants with higher levels of resistance that appeared and became the predominant subpopulation during some experiments or the persistence of susceptible bacteria in other experiments where resistance did not emerge. Continued evaluation of the present two-population pharmacodynamic model and development of alternative models is warranted.

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

2003 ◽  
Vol 47 (5) ◽  
pp. 1604-1613 ◽  
Author(s):  
Alexander A. Firsov ◽  
Sergey N. Vostrov ◽  
Irene Y. Lubenko ◽  
Karl Drlica ◽  
Yury A. Portnoy ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Half Life ◽  
Dynamic Models ◽  
Daily Administration ◽  
Human Pharmacokinetics ◽  
Mutant Selection ◽  
Dosing Interval ◽  
Selection Window ◽  
Mutant Prevention Concentration

ABSTRACT To study the hypothesis of the mutant selection window (MSW) in a pharmacodynamic context, the susceptibility of a clinical isolate of methicillin-resistant Staphylococcus aureus exposed to moxifloxacin (MOX), gatifloxacin (GAT), levofloxacin (LEV), and ciprofloxacin (CIP) was tested daily by using an in vitro dynamic model that simulates human pharmacokinetics. A series of monoexponential pharmacokinetic profiles that mimic once-daily administration of MOX (half-life, 12 h), GAT (half-life, 7 h), and LEV (half-life, 6.8 h) and twice-daily administration of CIP (half-life, 4 h) provided peak concentrations (C max) that either equaled the MIC, fell between the MIC and the mutant prevention concentration (MPC) (i.e., within or “inside” the MSW), or exceeded the MPC. The respective ratios of the area under the curve (AUC) over a 24-h dosing interval (AUC24) to the MIC varied from 13 to 244 h, and the starting inoculum was 108 CFU/ml (6 × 109 CFU per 60-ml central compartment). With all four quinolones, the greatest increases in MIC were observed at those AUC24/MIC values (from 24 to 62 h) that corresponded to quinolone concentrations within the MSW over most of the dosing interval (>20%). Less-pronounced increases in MIC were associated with the smallest simulated AUC24/MIC values (15 to 16 h) of GAT and CIP, whose C max exceeded the MICs. No such increases were observed with the smallest AUC24/MIC values (13 to 17 h) of MOX and LEV, whose C max were close to the MICs. Also, less pronounced but significant increases in MIC occurred at AUC24/MIC values (107 to 123 h) that correspond to quinolone concentrations partly overlapping the MIC-to-MPC range. With all four drugs, no change in MIC was seen at the highest AUC24/MIC values (201 to 244 h), where quinolone concentrations exceeded the MPC over most of the dosing interval. These “protective” AUC24/MIC ratios correspond to 66% of the usual clinical dose of MOX (400 mg), 190% of a 400-mg dose of GAT, 220% of a 500-mg dose of LEV, and 420% of two 500-mg doses of CIP. Thus, MOX may protect against resistance development at subtherapeutic doses, whereas GAT, LEV, and CIP provide similar effects only at doses that exceed their usual clinical doses. These data support the concept that resistant mutants are selectively enriched when antibiotic concentrations fall inside the MSW and suggest that in vitro dynamic models can be used to predict the relative abilities of quinolones to prevent mutant selection.

scholarly journals Influence of Inoculum Size on the Selection of Resistant Mutants of Escherichia coli in Relation to Mutant Prevention Concentrations of Marbofloxacin

2007 ◽  
Vol 51 (11) ◽  
pp. 4163-4166 ◽  
Author(s):  
Aude Ferran ◽  
Véronique Dupouy ◽  
Pierre-Louis Toutain ◽  
Alain Bousquet-Mélou
Keyword(s):  
Escherichia Coli ◽  
Bacterial Population ◽  
Inoculum Size ◽  
Pharmacodynamic Model ◽  
Initial Size ◽  
Mutant Selection ◽  
Selection Window ◽  
Resistant Mutants ◽  
Selection Of

ABSTRACT We demonstrate using an in vitro pharmacodynamic model that the likelihood of selection of Escherichia coli mutants resistant to a fluoroquinolone was increased when the initial size of the bacterial population, exposed to fluoroquinolone concentrations within the mutant selection window, was increased.

Mutant selection window of disinfectants for Staphylococcus aureus and Pseudomonas aeruginosa

2019 ◽  
Vol 17 ◽  
pp. 316-320
Author(s):  
Masato Kawamura ◽  
Shigeru Fujimura ◽  
Koichi Tokuda ◽  
Tetsuji Aoyagi ◽  
Shiro Endo ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Mutant Selection ◽  
Selection Window
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