title: Impact of nonlinear interactions of pharmacokinetics and MICs on sputum bacillary kill rates as a marker of sterilizing effect in tuberculosis.
abstract: The relationships between antituberculosis drug exposure and treatment effects on humans receiving multidrug therapy are complex and nonlinear. In patients on treatment, an analysis of the rate of decline in the sputum bacillary burden reveals two slopes. The first is the α-slope, which is thought to reflect bactericidal effect, followed by a β-slope, which is thought to reflect sterilizing activity. We sought to characterize the effects of standard first-line treatment on sterilizing activity. Fifty-four patients receiving combination therapy for pulmonary tuberculosis in a clinical trial had drug concentrations measured and Mycobacterium tuberculosis isolates available for MIC identification. Sputum sample cultures were performed at baseline and weekly for 8 weeks. A time-to-event model based on the days to positivity in the liquid cultures was used to estimate the β-slope. The pharmacokinetic parameters of rifampin, isoniazid, ethambutol, and pyrazinamide were determined for each patient. Multivariate adaptive regression splines analyses, which simultaneously perform linear and nonlinear analyses, were used to identify the relationships between the predictors and the β-slope. The potential predictors examined included HIV status, lung cavitation, 24-h area under the concentration-time curve (AUC), peak drug concentration (Cmax), AUC/MIC ratio, Cmax/MIC ratio, and the time that that concentration persisted above MIC. A rifampin Cmax of >8.2 mg/liter and a pyrazinamide AUC/MIC of >11.3 were key predictors of the β-slope and interacted positively to increase the β-slope. In patients with a rifampin AUC of <35.4 mg · h/liter, an increase in the pyrazinamide AUC/MIC and/or ethambutol Cmax/MIC increased the β-slope, while increasing isoniazid Cmax decreased it, suggesting isoniazid antagonism. Antibiotic concentrations and MICs interact in a nonlinear fashion as the main drivers of a sterilizing effect. The results suggest that faster speeds of sterilizing effect might be achieved by omitting isoniazid and by increasing rifampin, pyrazinamide, and ethambutol exposures. However, isoniazid and ethambutol exposures may only be of importance when rifampin exposure is low. These findings need confirmation in larger studies. (This study has been registered at controlled-trials.com under registration no. ISRCTN80852505.).
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chigutsa
authors.affiliation: Office of Global Health, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jotam G
authors.initials: JG
authors.lastname: Pasipanodya
authors.affiliation: School of Public Health, University of the Western Cape, Cape Town, South Africa.
authors.forename: Marianne E
authors.initials: ME
authors.lastname: Visser
authors.affiliation: DST/NRF Centre of Excellence for Biomedical TB Research/MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Paul D
authors.initials: PD
authors.lastname: van Helden
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.affiliation: DST/NRF Centre of Excellence for Biomedical TB Research/MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Sirgel
authors.affiliation: Office of Global Health, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa helen.mcilleron@uct.ac.za.
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
mesh_terms: D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D004203:Disinfection; D004336:Drug Antagonism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004977:Ethambutol / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000821:virology; D006801:Humans; D007538:Isoniazid / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D011718:Pyrazinamide / Q000493:pharmacokinetics / Q000627:therapeutic use; D012293:Rifampin / Q000493:pharmacokinetics / Q000627:therapeutic use; D013183:Sputum / Q000382:microbiology*; D013242:Sterilization; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin