Mutant Selection Window Hypothesis Updated

Abstract

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-

Daily serum piperacillin monitoring is advisable in critically ill patients

“…(Table 1b) By contrast to that shown for fluoroquinolones [14], the possibility of selecting resistant mutants at serum piperacillin concentrations <4 MIC is not supported by experimental data. However, several authors have suggested that prolonged percentage of time during which the concentration remains above 4 MIC (T>4 MIC), instead of T>MIC, is an important pharmacokinetic/pharmacodynamic (PK/PD) parameter that better predicts treatment outcome with -lactams (especially for critically ill patients) [2,5,15].…”

CD101: a novel long‐acting echinocandin

“…A key consideration to this dilemma is that it lacks proper measures of how to overcome development of resistant mutant subpopulations with antifungal drugs. The mutant selection window hypothesis was recently raised to address the critical need of dosing strategy to restrict emergence of resistance to antibacterial agents (Zhao and Drlica, 2001; Drlica and Zhao, 2007; Zhao and Drlica, 2008). This hypothesis postulates that for each antimicrobial–pathogen combination, an antimicrobial range exists in which selective amplification of single‐step, drug‐resistant mutants occurs.…”

“…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.…”

Bacteriostatic versus bactericidal activity of ciprofloxacin in Escherichia coli assessed by flow cytometry using a novel far-red dye

“…1 In patients with serious bacterial infections, the use of maximum tolerable antibiotic doses improves therapeutic outcomes, and may prevent the development of resistance. 2 Bactericidal rather than bacteriostatic agents may be preferred, as these agents may limit the development of resistance. 3 However, even when bactericidal agents are used, the administered dose must be sufficient to achieve bactericidal activity, 1 because with some antibacterials (for example, aminoglycosides and fluoroquinolones) bacterial killing is concentrationdependent.…”