title: Pharmacokinetic mismatch does not lead to emergence of isoniazid- or rifampin-resistant Mycobacterium tuberculosis but to better antimicrobial effect: a new paradigm for antituberculosis drug scheduling.
abstract: Multidrug resistant-tuberculosis is a pressing problem. One of the major mechanisms proposed to lead to the emergence of drug resistance is pharmacokinetic mismatch. Stated as a falsifiable hypothesis, the greater the pharmacokinetic mismatch between rifampin and isoniazid, the higher the isoniazid- and rifampin-resistant subpopulation sizes become with time. To test this, we performed hollow-fiber-system studies for both bactericidal and sterilizing effects in experiments of up to 42 days. We mimicked pharmacokinetics of 600-mg/day rifampin and 300-mg/day isoniazid administered to patients. Rifampin was administered first, followed by isoniazid 0, 6, 12, and 24 h later. The treatment was for drug-susceptible Mycobacterium tuberculosis in some experiments and hollow fiber systems with inoculum preseeded with isoniazid- and rifampin-resistant isogenic Mycobacterium tuberculosis strains in others. Analysis of variance revealed that the 12-h and 24-h-mismatched regimens always killed better than the matched regimens during both bactericidal and sterilizing effects (P < 0.05). This means that either the order of scheduling or the sequential administration of drugs in combination therapy may lead to significant improvement in microbial killing. Rifampin-resistant and isoniazid-resistant subpopulations were not significantly higher with increased mismatching in numerous analysis-of-variance comparisons. Thus, the pharmacokinetic mismatch hypothesis was rejected. Instead, sequential administration of anti-tuberculosis (TB) drugs (i.e., deliberate mismatch) following particular schedules suggests a new paradigm for accelerating M. tuberculosis killing. We conclude that current efforts aimed at better pharmacokinetic matching to decrease M. tuberculosis resistance emergence are likely futile and counterproductive.
authors: Department of Medicine, UT Southwestern Medical Center at Dallas, Texas 75390-8507, USA.
authors: Shashikant
authors: S
authors: Srivastava
authors: Carleton
authors: C
authors: Sherman
authors: Claudia
authors: C
authors: Meek
authors: Richard
authors: R
authors: Leff
authors: Tawanda
authors: T
authors: Gumbo
mesh_terms: D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007538:Isoniazid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000472:pathogenicity; D012293:Rifampin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid; D012293:Rifampin