Emergence of resistant Streptococcus pneumoniae in an in vitro dynamic model that simulates moxifloxacin concentrations inside and outside the mutant selection window: related changes in susceptibility, resistance frequency and bacterial killing

Zinner, Stephen H.; Lubenko, Irene Yu; Gilbert, Deborah; Simmons, Kelly; Zhao, Xilin; Drlica, Karl; Firsov, Alexander A.

doi:10.1093/jac/dkg401

Cited by 105 publications

(82 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Most of these resistant bacteria were still susceptible to the MPC of marbofloxacin for Escherichia coli ATCC 25922 (0.256 g/ml), suggesting that these resistant populations corresponded to those of the first-step mutants. The detection of first-step mutants when marbofloxacin concentrations were maintained within the MSW is in agreement with previous studies (5,10). However, resistant mutants emerged systematically in all three experiments carried out with 10 9 CFU/ml, but only in one of three for the 10 5 -CFU/ml inoculum and one of three for the 10 7 -CFU/ml inoculum.…”

supporting

confidence: 91%

“…The MIC and MPC define the bounds of the mutant selection window (MSW), a range of antibiotic concentrations favoring the selection of the first-step mutant subpopulation (9). Previous studies (5,10) have indicated that the growth of this first-step mutant subpopulation was prevented when fluoroquinolone concentrations exceeded the MPC for more than 80% of the dosage interval, i.e., when time within the MSW (T MSW ) was less than 20%. However, those studies tested only a single inoculum size, but the bacterial load increases during the time course of infections, and the likelihood of a mutant appearing may increase with inoculum size.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Ferran

Dupouy

Toutain

et al. 2007

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

supporting

confidence: 91%

mentioning

confidence: 99%

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

Ferran

Dupouy

Toutain

et al. 2007

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…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]. The principle has also been extended to S. aureus for vancomycin and daptomycin [35].…”

Section: Dynamic Models and The Window Hypothesissupporting

confidence: 62%

Mutant Selection Window Hypothesis Updated

Drlica¹,

Zhao²

2007

Clinical Infectious Diseases

346

338

View full text Add to dashboard Cite

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-

show abstract

“…This MSW hypothesis has been used to explain the results of several in vitro studies using an expanded-spectrum cephalosporin (22) and quinolones (7,10,35) against both gram-positive and gram-negative bacterial strains. For quinolones, this was achieved with dosing regimens producing ratios of the AUC at 24 h to MIC of Ͼ100 (10,33,36). In the present study, no distinction could be made between the effects of fTϾMIC and tMSW because of the relative high MPC values of the E. cloacae strain.…”

Section: Discussionmentioning

confidence: 71%

“…While the ratio of the area under the concentrationtime curve (AUC) at 24 h to MIC of Ն100 (10,33,36) or a peak-to-MIC ratio of 8 to 10 (3, 8) may significantly reduce the emergence of resistant subpopulations during treatment with fluoroquinolones and aminoglycosides, it has been reported that these indices do not appear to play an important role in the suppression of resistance during ␤-lactam therapy (33). However, recent findings have indicated the importance of a high-dose, short-elimination half-life regimen to minimize the emergence of cephalosporin-resistant Escherichia coli strains (25).…”

Section: To 10mentioning

confidence: 99%

Effect of Dosing and Dosing Frequency on the Efficacy of Ceftizoxime and the Emergence of Ceftizoxime Resistance during the Early Development of Murine Abscesses Caused by Bacteroides fragilis and Enterobacter cloacae Mixed Infection

Stearne¹,

Goessens²,

Mouton

et al. 2007

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The efficacy of ␤-lactams is thought to be dependent on the time that the unbound concentrations exceed the MIC (fT>MIC). However, the pharmacokinetic/pharmacodynamic index (PDI) that correlates best to the selection of resistance is not yet clear. The selection of ceftizoxime (CZX)-resistant Enterobacter cloacae mutant strains during the development of murine mixed-infection abscesses was studied to determine the PDI that is important for the emergence of resistance and the PDI value needed for the prevention of resistance. Studies were carried out 24 h after inoculation with Bacteroides fragilis ATCC 23745 and E. cloacae 22491. Six to 1,536 mg of CZX/kg of body weight/day given every 2 h (q2h), q4h, q6h, or q8h was started 30 min before inoculation and continued for 24 h. Resistant mutants were isolated to determine mutant frequencies (MF). The fT>MIC varied from 9 to 98% for E. cloacae, the peak concentration (unbound fraction) was 0.6 to 578 mg/liter, and the area under the concentration-time curve (unbound fraction) (fAUC) was 1.9 to 553 mg ⅐ h/liter. The fAUC-to-MIC ratio best explained the in vivo efficacy. CZX-resistant B. fragilis and E. cloacae mutants were isolated from untreated controls at an MF of 10 ؊5 to 10 ؊7 . The MF of resistant B. fragilis did not increase during therapy. The selection of resistant E. cloacae strains at an MF of 10 ؊1 to 10 ؊2 was related to the fT>MIC and the ratio of fAUC to MIC following an inverse U shape. However, the ratio of fAUC to MIC was the stronger driver of resistance. The highest MFs were 0.7 to 0.9 at an fAUC-to-MIC ratio of approximately 250. We conclude that the ratio of fAUC to MIC is the PDI that correlated best to the in vivo efficacy of CZX and probably also to the emergence of resistant E. cloacae mutants. An fAUC-to-MIC ratio of 1,000 was needed to prevent the emergence of this resistance.The emergence of resistant bacterial strains during ␤-lactam therapy is associated with the intensity of ␤-lactam use (12,20,32) and with prolonged antibiotic exposure (14). Until now, antibiotic dosing regimens used to treat infections have been based primarily on the pharmacokinetic/pharmacodynamic index (PDI) (18) that describes the optimal efficacy and/or prevention of toxicity. However, the increasing problem of emergence of resistance under the influence of antibiotic selection necessitates the need to determine the PDI that correlates best to the development of this resistance.To date, there have been very few studies that have investigated the PDI that is important for the emergence of ␤-lactam resistance. While the ratio of the area under the concentrationtime curve (AUC) at 24 h to MIC of Ն100 (10, 33, 36) or a peak-to-MIC ratio of 8 to 10 (3, 8) may significantly reduce the emergence of resistant subpopulations during treatment with fluoroquinolones and aminoglycosides, it has been reported that these indices do not appear to play an important role in the suppression of resistance during ␤-lactam therapy (33). However, recent findings have indicated the impo...

show abstract

Emergence of resistant Streptococcus pneumoniae in an in vitro dynamic model that simulates moxifloxacin concentrations inside and outside the mutant selection window: related changes in susceptibility, resistance frequency and bacterial killing

Cited by 105 publications

References 18 publications

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

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

Mutant Selection Window Hypothesis Updated

Effect of Dosing and Dosing Frequency on the Efficacy of Ceftizoxime and the Emergence of Ceftizoxime Resistance during the Early Development of Murine Abscesses Caused by Bacteroides fragilis and Enterobacter cloacae Mixed Infection

Contact Info

Product

Resources

About