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

Department of Medicine, University of Texas Southwestern Medical Center at Dallas, TX, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 12/2011; 204(12):1951-9. DOI: 10.1093/infdis/jir658
Source: PubMed


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.
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.
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.
These data, based on a preclinical model, demonstrate that nonadherence alone is not a sufficient condition for MDR-tuberculosis emergence.

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    • "First, it is most likely that there are inadequate antibiotic concentrations in TB pericardial fluid, especially of the primary sterilizing effect drugs rifampin and pyrazinamide, due to poor penetration, as we have shown elsewhere (Shenje et al., 2015). There is now sufficient hollow fiber and prospective clinical studies evidence to show that both the bactericidal activities and the sterilizing effect of antibiotics in TB is driven by high peak concentration and the area under the concentration-time curve of each drug, and that evolution-mandated pharmacokinetic variability drives many patients on recommended doses to not achieve optimal peak and area under the concentration–time curve concentrations (Shenje et al., 2015; Pasipanodya and Gumbo, 2011; Gumbo et al., 2015; Pasipanodya et al., 2013; Srivastava et al., 2011). Secondly, CART identified a CD4+ T cell count ≤199.5 as a major predictor. "
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    • "However, administration of the studied rifampicin and moxifloxacin doses resulted in large interindividual variability in exposures both in plasma and CSF [6]. Accumulating data suggest that exposure to TB drugs is relevant for outcome in pulmonary TB [7] [8] [9] [10] [11] [12]. "
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    • "Similarly, in bone/joint disease, the percentage of drug in foci in sclerotic bone is 0-8% for rifampin, 0-6% for pyrazinamide, and 0-23% for isoniazid [47]. These drug-concentration scenarios are known to lead to acquired drug resistance and poor efficacy [21,48]. Finally, it could be that for some syndromes such as meningitis, the M. tuberculosis genotypes that preferentially cause such disease are more difficult to kill and have a higher propensity to fail and develop drug resistance [49-52]. "
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