Mutant Selection Window Hypothesis: A Framework for Anti-mutant Dosing of Antimicrobial Agents

Stochastic bacterial population dynamics restrict the establishment of antibiotic resistance from single cells

“…The MSW hypothesis has gained support from in vitro and animal model studies, and has been extended to consider time-varying drug concentrations (reviewed in ref. 17).…”

Mutant Prevention Concentrations of Four Carbapenems against Gram-Negative Rods

“…The mutant selection window may be used to design dosing strategies for monotherapy and in the initial application of new compounds. The MPC and MPC/MIC make no contribution if the bacterial population is already fully resistant (7,8).The numbers of ß-lactamase-producing members of the Enterobacteriaceae family resistant to various ␤-lactams, extended-spectrum cephalosporins, and even carbapenems are on the rise, as are the numbers of fluoroquinolone-and aminoglycoside-resistant strains (6). There is also an alarming increase in the incidence of multidrug-resistant Gram-negative nonfermenters, such as Pseudomonas aeruginosa and Acinetobacter baumannii, and strains resistant to all known antibiotics except, in some cases, polymyxin B have appeared (11).…”

“…As far as we know, MPC studies on the activities of carbapenems, such as imipenem, meropenem, ertapenem, and doripenem, against Gram-negative rods have not yet been published. MPCs and MPC/MIC ratios (the mutant selection window hypothesis) are difficult to test clinically (7)(8)(9)(25)(26)(27). The only published study tested the treatment of Staphylococcus aureus with rifampin and confirmed the outcome predicted by the mutant selection window hypothesis.…”

“…The mutant selection window may be used to design dosing strategies for monotherapy and in the initial application of new compounds. The MPC and MPC/MIC make no contribution if the bacterial population is already fully resistant (7,8).…”