Details

Autor(en) / Beteiligte

• Srivastava, Shashikant
• Pasipanodya, Jotam G.
• Meek, Claudia
• Leff, Richard
• Gumbo, Tawanda

Titel

Multidrug-Resistant Tuberculosis Not Due to Noncompliance but to Between-Patient Pharmacokinetic Variability

Ist Teil von

• The Journal of infectious diseases, 2011-12, Vol.204 (12), p.1951-1959

Ort / Verlag

Oxford: Oxford University Press

Erscheinungsjahr

2011

Link zum Volltext

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• 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 drugresistant 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 10 000 Cape Town, South Africa, tuberculosis patients. Results. Therapy failure was only encountered at extents of nnadherence > 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.