Multidrug-resistant tuberculosis not due to noncompliance but to between-patient pharmacokinetic variability.
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 10 000 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.
Department of Medicine, University of Texas Southwestern Medical Center at Dallas, TX, USA.
Shashikant
S
Srivastava
Jotam G
JG
Pasipanodya
Claudia
C
Meek
Richard
R
Leff
Tawanda
T
Gumbo
D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D003198:Computer Simulation; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000494:pharmacology; D055118:Medication Adherence; D008954:Models, Biological; D009010:Monte Carlo Method; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011718:Pyrazinamide / Q000008:administration & dosage / Q000494:pharmacology; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*
D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin