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THERAPEUTIC CONTROVERSIES

The Changing Face of Antibiotic Prescribing: The Mutant Selection Window

at time of writing, Internal Medicine Resident, North Florida/South Georgia Veterans Affairs Health-System, Gainesville, FL; now, Postdoctoral Fellow, Departments of Pharmacy Practice and Community Health and Family Medicine, Colleges of Pharmacy and Medicine, University of Florida, Gainesville

John G Gums, PharmD

Professor of Pharmacy and Medicine, Departments of Pharmacy Practice and Community Health and Family Medicine, College of Pharmacy and Medicine, University of Florida, Gainesville

Karl Drlica, PhD

Member, Public Health Research Institute, Newark, NJ

Reprints: Benjamin J Epstein PharmD, University of Florida, 625 S. W. 4th Ave., Gainesville, FL 32601, fax 352/379-7496, benjamin.epstein{at}med.va.gov

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.

Key Words: antimicrobial resistance, mutant prevention concentration, mutant selection window

Published Online, August 31, 2004. www.theannals.com, DOI 10.1345/aph.1E041

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