The changing face of antibiotic prescribing: the mutant selection window.

OBJECTIVE: To describe the mutant selection window, discuss supporting evidence and limitations, and suggest potential applications for clinical practice. DATA SOURCES: A MEDLINE search (1990-December 2003) of the English-language literature was conducted using the key words antibiotic, antimicrobial, resistance, mutant, selection window, prevention, MPC, and MSW in various combinations. Original investigations and reviews evaluating the mutant selection window, including abstracts and proceedings, were considered for inclusion. Published articles were also cross-referenced, and experts were contacted to locate additional pertinent data. STUDY SELECTION AND DATA EXTRACTION: All data sources identified were evaluated and all information deemed relevant was included. DATA SYNTHESIS: Until recently, physicians have had few ways to preserve antimicrobials from resistance other than by prescribing the agents less often. The mutant selection window hypothesis may modify this paradigm by shifting the focus to dosing strategies that reduce the growth of resistant mutants. Conventional dosing strategies have been formulated on the likelihood of curing an individual patient. Unfortunately, doses that cure patients appear to enrich resistant subpopulations of bacteria, thus promoting resistance. Antimicrobial-pathogen combinations can be identified that minimize mutant selection and cure patients while possibly restricting the progression of resistance.
CONCLUSIONS: The mutant selection window hypothesis provides a framework for considering the contribution of dosing to resistance, and it offers ideas for restricting the enrichment of resistant mutants and antimicrobial resistance.