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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Efflux-pump-derived multiple drug resistance to ethambutol monotherapy in mycobacterium tuberculosis and the pharmacokinetics and pharmacodynamics of ethambutol
Journal of Infectious Diseases, Volume 201, No. 8, Year 2010
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Description
Background. Ethambutol is used for the treatment of tuberculosis in cases where there is isoniazid resistance. We examined the emergence of drug resistance to ethambutol monotherapy in pharmacokinetic-pharmacodynamic studies of a hollow-fiber system. Methods. Dose-effect and dose-scheduling studies were performed with ethambutol and log-phase growth Mycobacterium tuberculosis to identify exposures and schedules linked to optimal kill and resistance suppression. In one study, after 7 days of daily ethambutol, 300 mg isoniazid per day was administered to each system to determine its early bactericidal activity. Results. Efflux-pump blockage reduced the mutation frequency to ethambutol 64-fold. In dose-effect studies, ethambutol had a maximal early bactericidal activity of 0.22 logl0 colony-forming units/mL/day, as is encountered in patients. By day 7, resistance to both ethambutol and isoniazid had increased. Previous exposure to ethambutol halted isoniazid early bactericidal activity. Daily therapy, as opposed to more intermittent therapy, was associated with the least proportion of efflux-pump-driven resistance, consistent with a time-driven effect. Microbial kill was best explained by the ratio of area under the concentration-time curve to minimum inhibitory concentration (r2 = 0.90). Conclusion. The induction of an efflux pump that reduces the effect of multiple drugs provides an alternative pathway to sequential acquisition of mutations in the development of multiple drug resistance. © 2010 by the Infectious Diseases Society of America. All rights reserved.
Authors & Co-Authors
Srivastava, Shashikant
United States, Dallas
Ut Southwestern Medical Center
Musuka, Sandirai
United States, Dallas
Ut Southwestern Medical Center
Sherman, Carleton M.
United States, Dallas
Ut Southwestern Medical Center
Meek, Claudia C.
United States, Lubbock
Texas Tech University
Leff, Richard D.
United States, Lubbock
Texas Tech University
Gumbo, Tawanda
United States, Dallas
Ut Southwestern Medical Center
Statistics
Citations: 119
Authors: 6
Affiliations: 2
Identifiers
Doi:
10.1086/651377
ISSN:
00221899
Research Areas
Cancer