Multidrug-resistant tuberculosis not due to noncompliance but to between-patient pharmacokinetic variability

Abstract

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.

Figure 1.

Pharmacokinetics of drugs within each hollow fiber system (HFS) and effect of nonadherence during bactericidal effect. A, Pharmacokinetics of isoniazid, rifampin, and pyrazinamide in HFS. B, Time kill curves for the bactericidal effect with different degrees of nonadherence. Abbreviations: CFU, colony-forming unit; M. tuberculosis, Mycobacterium tuberculosis.

Figure 2.

Effect of the nonadherence dosing schedule during bactericidal activity. The color-coded solid boxes represent the days when corresponding treatment was administered for each pattern of nonadherence. A, 80% nonadherence. B, 60% nonadherence. C, Delivery of the cumulative 28-day dose as an 80% start-stop nonadherence (20% adherence) demonstrated decreased killing after therapy was stopped. D, Rifampin-resistant subpopulations as measured by growth on the standard 0.2-mg/L concentration as well as the recently proposed 0.625-mg/L concentration [14]. E, Isoniazid-resistant subpopulation utilizing 2 susceptibility breakpoints. Abbreviations: CFU, colony-forming unit; M. tuberculosis, Mycobacterium tuberculosis.

Figure 3.

Time kill curves for different degrees of nonadherence during sterilizing activity. Abbreviations: CFU, colony-forming unit; M. tuberculosis, Mycobacterium tuberculosis.

Figure 4.

Effect of different patterns of nonadherence during sterilizing activity. Days when treatment was administered are color coded. A, By the end of the study, the start-stop-start-stop strategy had slightly better kill than the random nonadherence pattern. B, For 60% nonadherence, the start-stop led to faster kill than the random pattern during therapy but was different by day 56. C, Delivering the entire 28-day dose in 40% of 28 days and then stopping and repeating this starting day 28 took longer to sterilize compared with daily dosing with 100% adherence. Abbreviations: CFU, colony-forming unit; M. tuberculosis, Mycobacterium tuberculosis.

Figure 5.

Outcomes in 10 000 in silico tuberculosis patients from Khayelitsha, South Africa. A, Rates of M. tuberculosis kill in sputum of all patients. B, Rates of sputum conversion in patients with low rifampin concentrations. C, Time to emergence of drug resistance in patients failing therapy. Abbreviations: CFU, colony-forming unit; CI, confidence interval; M. tuberculosis, Mycobacterium tuberculosis.