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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin
Antimicrobial Agents and Chemotherapy, Volume 51, No. 11, Year 2007
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Description
Rifampin is a cornerstone of modern antituberculosis therapy. However, rifampin's half-life of 3 h is believed to limit its utility for intermittent therapy, so new congeners with long half-lives are being developed. Using an in vitro pharmacokinetic-pharmacodynamic model of tuberculosis, we examined the relationships between rifampin exposure, microbial killing of log-phase-growth Mycobacterium tuberculosis, and suppression of resistance. Rifampin's microbial killing was linked to the area under the concentration-time curve-to-MIC ratio. The suppression of resistance was associated with the free peak concentration (Cmax)-to-MIC ratio and not the duration that the rifampin concentration was above MIC. Rifampin prevented resistance to itself at a free Cmax/MIC ratio of ≥175. The postantibiotic effect duration was ≥5.2 days and was most closely related to the Cmax/MIC ratio (r2 = 0.96). To explain rifampin's concentration-dependent effect, we examined the kinetics of rifampin entry into M. tuberculosis. Rifampin achieved concentration-dependent intracellular steady-state concentrations within 15 min. Our results suggest that doses of rifampin higher than those currently employed would optimize the effect of rifampin, if patients could tolerate them. Another major implication is that in the design of new rifampin congeners for intermittent therapy, the important properties may include (i) the efficient entry of the rifamycin into M. tuberculosis, (ii) the achievement of a free Cmax/MIC of >175 that can be tolerated by patients, and (iii) a long postantibiotic effect duration. Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Authors & Co-Authors
Gumbo, Tawanda
United States, Dallas
Ut Southwestern Medical Center
Louie, Arnold
United States, Albany
Ordway Research Institute, Inc.
Liu, Weiguo
United States, Albany
Ordway Research Institute, Inc.
Parsons, Linda M.
United States, Albany
New York State Department of Health
Salfinger, Max
United States, Albany
New York State Department of Health
Drusano, George Louis
United States, Albany
Ordway Research Institute, Inc.
Statistics
Citations: 338
Authors: 6
Affiliations: 3
Identifiers
Doi:
10.1128/AAC.01533-06
ISSN:
00664804