Restricting the Selection of Antibiotic‐Resistant Mutant Bacteria: Measurement and Potential Use of the Mutant Selection Window

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.

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Synergistic Combination of Linezolid and Fosfomycin Closing Each Other’s Mutant Selection Window to Prevent Enterococcal Resistance

Frontiers in Microbiology ◽

10.3389/fmicb.2020.605962 ◽

2021 ◽

Vol 11 ◽

Author(s):

Lifang Jiang ◽

Na Xie ◽

Mingtao Chen ◽

Yanyan Liu ◽

Shuaishuai Wang ◽

...

Keyword(s):

Ribosomal Proteins ◽

Bacterial Resistance ◽

Selection Index ◽

Resistance Mechanism ◽

Mutant Selection ◽

Selection Window ◽

Mutant Prevention Concentration ◽

Resistant Mutants ◽

Synergistic Combination ◽

Selection Of

Enterococci, the main pathogens associated with nosocomial infections, are resistant to many common antibacterial drugs including β-lactams, aminoglycosides, etc. Combination therapy is considered an effective way to prevent bacterial resistance. Preliminary studies in our group have shown that linezolid combined with fosfomycin has synergistic or additive antibacterial activity against enterococci, while the ability of the combination to prevent resistance remains unknown. In this study, we determined mutant prevention concentration (MPC) and mutant selection window (MSW) of linezolid, fosfomycin alone and in combination including different proportions for five clinical isolates of Enterococcus and characterized the resistance mechanism for resistant mutants. The results indicated that different proportions of linezolid combined with fosfomycin had presented different MPCs and MSWs. Compared with linezolid or fosfomycin alone, the combination can restrict the enrichment of resistant mutants at a lower concentration. A rough positive correlation between the selection index (SI) of the two agents in combination and the fractional inhibitory concentration index (FICI) of the combination displayed that the smaller FICI of linezolid and fosfomycin, the more probable their MSWs were to close each other. Mutations in ribosomal proteins (L3 and L4) were the mechanisms for linezolid resistant mutants. Among the fosfomycin-resistant mutants, only two strains have detected the MurA gene mutation related to fosfomycin resistance. In conclusion, the synergistic combination of linezolid and fosfomycin closing each other’s MSW could effectively suppress the selection of enterococcus resistant mutants, suggesting that the combination may be an alternative for preventing enterococcal resistance. In this study, the resistance mechanism of fosfomycin remains to be further studied.

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Searching for the Optimal Predictor of Ciprofloxacin Resistance in Klebsiella pneumoniae by UsingIn VitroDynamic Models

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02334-15 ◽

2015 ◽

Vol 60 (3) ◽

pp. 1208-1215 ◽

Cited By ~ 11

Author(s):

Elena N. Strukova ◽

Yury A. Portnoy ◽

Andrey V. Romanov ◽

Mikhail V. Edelstein ◽

Stephen H. Zinner ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Area Under The Curve ◽

Mutant Selection ◽

Content Type ◽

Selection Window ◽

Mutant Prevention Concentration ◽

Ciprofloxacin Resistance ◽

Resistant Mutants ◽

Time Courses ◽

Selection Of

There is growing evidence of applicability of the hypothesis of the mutant selection window (MSW), i.e., the range between the MIC and the mutant prevention concentration (MPC), within which the enrichment of resistant mutants is most probable. However, it is not clear if MPC-based pharmacokinetic variables are preferable to the respective MIC-based variables as interstrain predictors of resistance. To examine the predictive power of the ratios of the area under the curve (AUC24) to the MPC and to the MIC, the selection of ciprofloxacin-resistant mutants of threeKlebsiella pneumoniaestrains with different MPC/MIC ratios was studied. Each organism was exposed to twice-daily ciprofloxacin for 3 days at AUC24/MIC ratios that provide peak antibiotic concentrations close to the MIC, between the MIC and the MPC, and above the MPC. ResistantK. pneumoniaemutants were intensively enriched at an AUC24/MIC ratio of 60 to 360 h (AUC24/MPC ratio from 2.5 to 15 h) but not at the lower or higher AUC24/MIC and AUC24/MPC ratios, in accordance with the MSW hypothesis. AUC24/MPC and AUC24/MIC relationships with areas under the time courses of ciprofloxacin-resistantK. pneumoniae(AUBCM) were bell shaped. These relationships predict highly variable “antimutant” AUC24/MPC ratios (20 to 290 h) compared to AUC24/MIC ratios (1,310 to 2,610 h). These findings suggest that the potential of the AUC24/MPC ratio as an interstrain predictor ofK. pneumoniaeresistance is lower than that of the AUC24/MIC ratio.

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Susceptibility and PK/PD relationships of Staphylococcus aureus strains isolated from the milk of sheep and goats with clinical mastitis to five veterinary fluoroquinolones

Veterinary Record ◽

10.1136/vr.103964 ◽

2017 ◽

Vol 180 (15) ◽

pp. 376-376 ◽

Cited By ~ 4

Author(s):

J. M. Serrano-Rodríguez ◽

C. Cárceles-García ◽

C. M. Cárceles-Rodríguez ◽

M. L. Gabarda ◽

J. M. Serrano-Caballero ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Inhibitory Concentration ◽

Clinical Mastitis ◽

The Other ◽

Mutant Selection ◽

Sheep And Goats ◽

Selection Window ◽

Mutant Prevention Concentration ◽

Higher Doses ◽

Selection Of

Minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) of veterinary fluoroquinolones as enrofloxacin, its metabolite ciprofloxacin, danofloxacin, difloxacin and marbofloxacin against Staphylococcus aureus strains (n=24) isolated from milk of sheep and goats affected by clinical mastitis were evaluated. The authors have used the MIC and MPC, as well as the pharmacokinetic-pharmacodynamic relationships in plasma and milk. MIC values were significantly different between drugs, unlike MPC values. Lower MIC values were obtained for danofloxacin and difloxacin, middle and higher values for enrofloxacin, ciprofloxacin and marbofloxacin. However, differences in MPC values were not found between drugs. At conventional doses, the AUC24/MIC and AUC24/MPC ratios were close to 30–80 hours and 5–30 hours, with exception of danofloxacin, in plasma and milk. The time inside the mutant selection window (TMSW) was close to 3–6 hours for enrofloxacin, ciprofloxacin and marbofloxacin, near to 8 hours for danofloxacin and 12–22 hours for difloxacin. From these data, the mutant selection window could be higher for danofloxacin and difloxacin compared with the other fluoroquinolones tested. The authors concluded that enrofloxacin and marbofloxacin, at conventional doses, could prevent the selection of bacterial subpopulations of S aureus, unlike danofloxacin and difloxacin, where higher doses could be used.

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Quinolone-Resistant Haemophilus influenzae: Determination of Mutant Selection Window for Ciprofloxacin, Garenoxacin, Levofloxacin, and Moxifloxacin

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.11.4460-4462.2004 ◽

2004 ◽

Vol 48 (11) ◽

pp. 4460-4462 ◽

Cited By ~ 30

Author(s):

Xinying Li ◽

Noriel Mariano ◽

James J. Rahal ◽

Carl M. Urban ◽

Karl Drlica

Keyword(s):

Haemophilus Influenzae ◽

Wild Type ◽

Mutant Selection ◽

Stepwise Selection ◽

Type Selection ◽

Selection Window ◽

Fourth Step ◽

Selection Of

ABSTRACT Stepwise selection of ciprofloxacin-resistant Haemophilus influenzae mutants produced first-, second-, third-, and fourth-step substitutions in GyrA (S84Y), ParC (S84R), GyrA (D88N), and ParC (E88K), respectively. Successive mutations raised the mutant selection window. The wild-type selection window for garenoxacin, levofloxacin, and moxifloxacin was also measured.

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Enrichment of Fluoroquinolone-Resistant Staphylococcus aureus: Oscillating Ciprofloxacin Concentrations Simulated at the Upper and Lower Portions of the Mutant Selection Window

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01371-07 ◽

2008 ◽

Vol 52 (6) ◽

pp. 1924-1928 ◽

Cited By ~ 26

Author(s):

Alexander A. Firsov ◽

Irene Y. Lubenko ◽

Maria V. Smirnova ◽

Elena N. Strukova ◽

Stephen H. Zinner

Keyword(s):

Staphylococcus Aureus ◽

Dependent Manner ◽

Time Curve ◽

Mutant Selection ◽

Selection Window ◽

Lower Case ◽

Mutant Prevention Concentration ◽

Kill Curve ◽

Time Kill ◽

Selection Of

ABSTRACT The time inside the mutant selection window (MSW), T MSW, appears to be less predictive of the selection of fluoroquinolone-resistant Staphylococcus aureus than is the ratio of the area under the concentration-time curve (AUC) to the MIC. This observation might be attributed to the fact that T MSW does not consider the actual position of simulated antibiotic concentrations inside the MSW, which also might influence the amplification of resistant mutants. To test this hypothesis, the enrichment of ciprofloxacin-resistant S. aureus was studied at ciprofloxacin (CIP) concentrations that oscillate near the mutant prevention concentration (MPC), i.e., closer to the top of the MSW (“upper case”), and closer to the MIC, i.e., at the lower limit of the MSW (“lower case”) at the same T MSW. Two methicillin-resistant strains of S. aureus, ATCC 6538 and ATCC 43300 (MICs of 0.25 and 0.5 mg/liter, respectively, and MPCs of 4 and 2 mg/liter, respectively), were exposed to twice-daily CIP treatments for three consecutive days. With S. aureus ATCC 6538, the simulated ratios of the AUC at 24 h (AUC24) to the MIC were 50 and 260 h (T MSW 75% of the dosing interval). With S. aureus ATCC 43300, the simulated AUC24/MICs were 30 and 100 h (T MSW 56%). With each organism, mutants resistant to CIP were enriched in an AUC24/MIC-dependent manner: the higher the AUC24/MIC ratio, the lower the growth on CIP-containing plates. For example, the area under the time-kill curve of mutants resistant to 4× MIC of CIP in the upper case was three times smaller than that in the lower case for both S. aureus strains. Similar differences were seen at the higher (8× MIC) and lower (2× MIC) CIP concentrations. These data highlight differences in the selection of resistant S. aureus, depending on the position of simulated concentrations inside the MSW at a given T MSW. This explains why T MSW-based predictions of resistance are less accurate than those based on AUC/MIC and AUC/MPC.

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Inferring the selection window in antimicrobial resistance using deep mutational scanning data and biophysics-based fitness models

10.1101/189019 ◽

2017 ◽

Author(s):

Pouria Dasmeh ◽

Anh-Tien Ton ◽

Caroline Quach ◽

Adrian W.R. Serohijos

Keyword(s):

Antimicrobial Resistance ◽

Genetic Parameters ◽

Catalytic Efficiency ◽

Single Step ◽

Mutant Selection ◽

Selection Window ◽

Low Levels ◽

Lower Limits ◽

Selection Of

AbstractMutant-selection window (MSW) hypothesis in antimicrobial resistance implies a range for antimicrobial concentration that promotes selection of single-step resistant mutants. Since the inception and experimental verification, MSW has been at the forefront of strategies to minimize development of antimicrobial resistance (AR). Setting the upper and lower limits of MSW requires an understanding of the dependence of selection coefficient of arising mutations to antimicrobial concentration. In this work, we employed a biophysics-based and experimentally calibrated fitness model to estimate MSW in the case of Ampicillin and Cefotaxime resistance in E.coli TEM-1 beta lactamase. In line with experimental observations, we show that selection is active at very low levels of antimicrobials. Furthermore, we elucidate the dependence of MSW to catalytic efficiency of mutants, fraction of mutants in the population and discuss the role of population genetic parameters such as population size and mutation rate. Altogether, our analysis and formalism provide a predictive model of MSW with direct implications in the design of dosage strategies.

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In Vivo Validation of the Mutant Selection Window Hypothesis with Moxifloxacin in a Murine Model of Tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01123-07 ◽

2007 ◽

Vol 51 (12) ◽

pp. 4261-4266 ◽

Cited By ~ 24

Author(s):

Deepak Almeida ◽

Eric Nuermberger ◽

Sandeep Tyagi ◽

William R. Bishai ◽

Jacques Grosset

Keyword(s):

Drug Exposure ◽

Serum Concentrations ◽

Mutant Selection ◽

Drug Concentrations ◽

Selection Window ◽

Mutant Prevention Concentration ◽

Resistant Mutants ◽

Selection Of

ABSTRACT Combination therapy is the most effective strategy to prevent emergence of resistance during tuberculosis (TB) treatment. Another strategy, albeit theoretical, is to limit the time that drug concentrations fall in the “mutant selection window” (MSW) between the MIC and the mutant prevention concentration (MPC). Drug concentrations above the MPC prevent selective amplification of resistant mutants in vitro even with a single drug exposure. The MSW concept has been validated using fluoroquinolones against Mycobacterium tuberculosis in vitro but not in vivo. Using a mouse model in which serum moxifloxacin (MXF) concentrations were maintained above the MPC, we tested whether this strategy prevents selection of MXF-resistant mutants. Beginning 2 weeks after aerosol infection with M. tuberculosis, when the mean lung log10 CFU count was 7.9 ± 0.2, mice received either no treatment or MXF in the diet at 0.25% to approximate the conventional human dose or 1.5% to maintain serum concentrations above the MPC (8 μg/ml). After 56 days of treatment, lung CFU counts were 3.5 ± 0.8 and 0.9 ± 0.6 in 0.25% and 1.5% of the MXF-treated mice, respectively. In mice given 0.25% MXF, MXF-resistant mutants were selected by day 28 and detected in 16% (3/19) of mice tested on day 56. No selection of MXF-resistant mutants was detected in mice given 1.5% MXF. We conclude that maintaining serum concentrations of MXF above the MPC prevents selection of MXF-resistant mutants. Although this target cannot be achieved clinically with MXF, it might be possible with new fluoroquinolones with more potent activity and/or improved pharmacokinetics.

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Bacterial Resistance Studies UsingIn VitroDynamic Models: the Predictive Power of the Mutant Prevention and Minimum Inhibitory Antibiotic Concentrations

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00578-13 ◽

2013 ◽

Vol 57 (10) ◽

pp. 4956-4962 ◽

Cited By ~ 23

Author(s):

Alexander A. Firsov ◽

Elena N. Strukova ◽

Darya S. Shlykova ◽

Yury A. Portnoy ◽

Varvara K. Kozyreva ◽

...

Keyword(s):

Predictive Power ◽

Bacterial Resistance ◽

Area Under The Curve ◽

Mutant Selection ◽

Content Type ◽

E Coli ◽

Selection Window ◽

Mutant Prevention Concentration ◽

Time Courses ◽

Selection Of

ABSTRACTIn light of the concept of the mutant selection window, i.e., the range between the MIC and the mutant prevention concentration (MPC), MPC-related pharmacokinetic indices should be more predictive of bacterial resistance than the respective MIC-related indices. However, experimental evidence of this hypothesis remains limited and contradictory. To examine the predictive power of the ratios of the area under the curve (AUC24) to the MPC and the MIC, the selection of ciprofloxacin-resistant mutants of fourEscherichia colistrains with different MPC/MIC ratios was studied. Each organism was exposed to twice-daily ciprofloxacin for 3 days at AUC24/MIC ratios that provide peak antibiotic concentrations close to the MIC, between the MIC and the MPC, and above the MPC. ResistantE. coliwas intensively enriched at AUC24/MPCs from 1 to 10 h (AUC24/MIC from 60 to 360 h) but not at the lower or higher AUC24/MPC and AUC24/MIC ratios. AUC24/MPC and AUC24/MIC relationships of the areas under the time courses of ciprofloxacin-resistantE. coli(AUBCM) were bell-shaped. A Gaussian-like function fits the AUBCM-AUC24/MPC and AUBCM-AUC24/MIC data combined for all organisms (r2= 0.69 and 0.86, respectively). The predicted anti-mutant AUC24/MPC ratio was 58 ± 35 h, and the respective AUC24/MIC ratio was 1,080 ± 416 h. Although AUC24/MPC was less predictive of strain-independentE. coliresistance than AUC24/MIC, the established anti-mutant AUC24/MPC ratio was closer to values reported forStaphylococcus aureus(60 to 69 h) than the respective AUC24/MIC ratio (1,080 versus 200 to 240 h). This implies that AUC24/MPC might be a better interspecies predictor of bacterial resistance than AUC24/MIC.

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Testing the mutant selection window hypothesis in Staphylococcus aureus resistance studies with linezolid using a mixture of antibiotic-susceptible cells and resistant mutants in an in vitro dynamic model

10.26226/morressier.56d6be79d462b80296c97b28 ◽

2016 ◽

Author(s):

Kamilla Alieva

Keyword(s):

Staphylococcus Aureus ◽

Dynamic Model ◽

Mutant Selection ◽

Selection Window ◽

Resistant Mutants

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