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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Multidrug-resistant tuberculosis not due to noncompliance but to between-patient pharmacokinetic variability
Journal of Infectious Diseases, Volume 204, No. 12, Year 2011
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Description
Background. It is believed that nonadherence is the proximate cause of multidrug-resistant tuberculosis (MDR-tuberculosis) emergence. The level of nonadherence associated with emergence of MDR-tuberculosis is unknown. Performance of a randomized controlled trial in which some patients are randomized to nonadherence would be unethical; therefore, other study designs should be utilized. Methods. We performed hollow fiber studies for both bactericidal and sterilizing effect, with inoculum spiked with 0.5% rifampin-and isoniazid-resistant isogenic strains in some experiments. Standard therapy was administered daily for 28-56 days, with extents of nonadherence varying between 0% and 100%. Sizes of drug-resistant populations were compared using analysis of variance. We also explored the effect of pharmacokinetic variability on MDR-tuberculosis emergence using computer-aided clinical trial simulations of 10000 Cape Town, South Africa, tuberculosis patients. Results. Therapy failure was only encountered at extents of nonadherence ≥60%. Surprisingly, isoniazid-and rifampin-resistant populations did not achieve ≥1% proportion in any experiment and did not achieve a higher proportion with nonadherence. However, clinical trial simulations demonstrated that approximately 1% of tuberculosis patients with perfect adherence would still develop MDR-tuberculosis due to pharmacokinetic variability alone. Conclusions. These data, based on a preclinical model, demonstrate that nonadherence alone is not a sufficient condition for MDR-tuberculosis emergence. © 2011 The Author.
Authors & Co-Authors
Srivastava, Shashikant
United States, Dallas
Ut Southwestern Medical Center
Pasipanodya, Jotam Garaimunashe
United States, Dallas
Ut Southwestern Medical Center
Meek, Claudia C.
United States, Dallas
Texas Tech University Health Sciences Center at Dallas
Leff, Richard D.
United States, Dallas
Texas Tech University Health Sciences Center at Dallas
Gumbo, Tawanda
United States, Dallas
Ut Southwestern Medical Center
Statistics
Citations: 229
Authors: 5
Affiliations: 2
Identifiers
Doi:
10.1093/infdis/jir658
ISSN:
00221899
Research Areas
Health System And Policy
Study Approach
Quantitative
Study Locations
South Africa