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

Firsov, Alexander A.; Smirnova, Maria; Lubenko, Irene Yu; Vostrov, Sergey N.; Portnoy, Yury A.; Zinner, Stephen H.

doi:10.1093/jac/dkl387

Cited by 93 publications

(67 citation statements)

References 27 publications

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“…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]. Longer exposure inside the selection window should allow greater mutant amplification [36].…”

Section: Dynamic Models and The Window Hypothesismentioning

confidence: 54%

“…value or the AUC 24 /MPC value is more predictive with individual isolates when measured in vitro [35,39].…”

Section: Dynamic Models and The Window Hypothesismentioning

confidence: 96%

“…However, position in the window may be important for determining the effect of exposure time, because many more mutants-both in amount and type-are found in the lower portion of the window than in the upper portion, and because drug concentrations near the top of the window may be more effective at killing some mutant types [10]. The evolution of mutants may be a complex process that sometimes exhibits a correlation between time inside the window and outgrowth of mutants [35] and sometimes does not [26,33,34].…”

Section: Dynamic Models and The Window Hypothesismentioning

confidence: 99%

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Mutant Selection Window Hypothesis Updated

Drlica¹,

Zhao²

2007

Clinical Infectious Diseases

346

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: Dynamic Models and The Window Hypothesismentioning

confidence: 54%

“…value or the AUC 24 /MPC value is more predictive with individual isolates when measured in vitro [35,39].…”

Section: Dynamic Models and The Window Hypothesismentioning

confidence: 96%

Section: Dynamic Models and The Window Hypothesismentioning

confidence: 99%

See 1 more Smart Citation

Mutant Selection Window Hypothesis Updated

Drlica¹,

Zhao²

2007

Clinical Infectious Diseases

346

338

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“…From a practical perspective, to maintain drug levels above MPC is often more stringent than necessary and increases risk of toxicity. However, the MPC‐based PK/PD measurement, AUC 24 /MPC, has been tested to be more accurate than AUC 24 /MIC in predicting resistance occurrence (Firsov et al, 2006; Olofsson et al, 2006; Drlica and Zhao, 2007), and in vivo experiments also prove the usefulness to control the frequency of resistant mutant development by maintaining drug levels above MPC for certain time of period (Croisier et al, 2004; Etienne et al, 2004). Given the high plasma drug exposure potential and wide safety margin of CD101, and the fact that CD101 and MCF have the same MPC value suggests a possible advantage of CD101 in preventing resistance to currently approved echinocandin drugs.…”

Section: Discussionmentioning

confidence: 99%

CD101: a novel long‐acting echinocandin

Zhao

Perez

Jiménez‐Ortigosa

et al. 2016

Cellular Microbiology

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SummaryCD101 is a novel echinocandin drug being developed to treat severe fungal infections including invasive candidiasis. We have performed a series of studies to evaluate the antifungal properties of CD101 against both echinocandin‐susceptible and ‐resistant Candida strains. Antifungal susceptibility testing performed on a collection of 95 Candida strains including 30 caspofungin‐resistant isolates containing fks mutations demonstrated comparable antifungal potency of CD101 relative to micafungin (MCF) across different Candida species. Comparable kinetic inhibition of glucan synthase activity was also observed for CD101 and MCF on both wild‐type (WT) and resistant fks mutant Candida strains. Similarly, both drugs yielded nearly identical values for a mutant prevention concentration. In a murine model of invasive candidiasis, CD101 displayed better or at least comparable efficacy relative to MCF in treating WT or fks mutant Candida albicans. An exceptional long‐lived pharmacokinetic profile was observed in mice following a single dose of CD101. Collectively, CD101 has great potential not only in treating invasive Candida infections but also in preventing emergence of resistance to currently approved echinocandin drugs.

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“…25 Testing involving S. aureus for vancomycin and using in vitro dynamic models revealed that mutants are selectively amplified when concentrations are between the MIC and the MPC. 26 Stepwise accumulation of drug resistance on the MSW was examined in fluoroquinolone resistance of Haemophilus influenzae. 27 Observations strongly suggested that these vancomycin-intermediate S. aureus isolates represent the progeny of a single MRSA strain that emerged in vivo under the selective pressure of vancomycin therapy.…”

Section: Discussionmentioning

confidence: 99%