title: Concentration-Dependent Antagonism and Culture Conversion in Pulmonary Tuberculosis.
abstract: BACKGROUND
  There is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD) parameters could predict 2-month culture conversion.
  
  
  METHODS
  One hundred patients with pulmonary tuberculosis (65% human immunodeficiency virus coinfected) were intensively sampled to determine rifampicin, isoniazid, and pyrazinamide plasma concentrations after 7-8 weeks of therapy, and PK parameters determined using nonlinear mixed-effects models. Detailed clinical data and sputum for culture were collected at baseline, 2 months, and 5-6 months. Minimum inhibitory concentrations (MICs) were determined on baseline isolates. Multivariate logistic regression and the assumption-free multivariate adaptive regression splines (MARS) were used to identify clinical and PK/PD predictors of 2-month culture conversion. Potential PK/PD predictors included 0- to 24-hour area under the curve (AUC0-24), maximum concentration (Cmax), AUC0-24/MIC, Cmax/MIC, and percentage of time that concentrations persisted above the MIC (%TMIC).
  
  
  RESULTS
  Twenty-six percent of patients had Cmax of rifampicin <8 mg/L, pyrazinamide <35 mg/L, and isoniazid <3 mg/L. No relationship was found between PK exposures and 2-month culture conversion using multivariate logistic regression after adjusting for MIC. However, MARS identified negative interactions between isoniazid Cmax and rifampicin Cmax/MIC ratio on 2-month culture conversion. If isoniazid Cmax was <4.6 mg/L and rifampicin Cmax/MIC <28, the isoniazid concentration had an antagonistic effect on culture conversion. For patients with isoniazid Cmax >4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion.
  
  
  CONCLUSIONS
  PK/PD analyses using MARS identified isoniazid Cmax and rifampicin Cmax/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion.
authors.affiliation: Department of Medicine, Imperial College London, United Kingdom.|Wellcome Center for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.
authors.forename: Neesha
authors.initials: N
authors.lastname: Rockwood
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
authors.forename: Jotam G
authors.initials: JG
authors.lastname: Pasipanodya
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town.
authors.forename: Paolo
authors.initials: P
authors.lastname: Denti
authors.affiliation: Department of Science and Technology/National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research/ South African Medical Research Foundation Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Health Sciences, Stellenbosch University, Tygerberg.
authors.forename: Frederick
authors.initials: F
authors.lastname: Sirgel
authors.affiliation: Wellcome Center for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.|Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, and.
authors.forename: Maia
authors.initials: M
authors.lastname: Lesosky
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.|Department of Medicine, University of Cape Town, South Africa; and.
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
authors.affiliation: Department of Medicine, Imperial College London, United Kingdom.|Department of Medicine, University of Cape Town, South Africa; and.
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town.
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.affiliation: Department of Medicine, Imperial College London, United Kingdom.|Wellcome Center for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.|Department of Medicine, University of Cape Town, South Africa; and.|Francis Crick Institute, London, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D060085:Coinfection / Q000188:drug therapy* / Q000382:microbiology / Q000821:virology; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D007538:Isoniazid / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016015:Logistic Models; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification / Q000502:physiology; D011718:Pyrazinamide / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D012293:Rifampin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D013183:Sputum / Q000382:microbiology; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000150:complications* / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin
keywords: Mycobacterium tuberculosis; drug–drug antagonism.; minimum inhibitory concentrations; pharmacokinetic-pharmacodynamic variability; tuberculosis treatment outcomes