title: In silico evaluation and exploration of antibiotic tuberculosis treatment regimens.
abstract: BACKGROUND
  Improvement in tuberculosis treatment regimens requires selection of antibiotics and dosing schedules from a large design space of possibilities. Incomplete knowledge of antibiotic and host immune dynamics in tuberculosis granulomas impacts clinical trial design and success, and variations among clinical trials hamper side-by-side comparison of regimens. Our objective is to systematically evaluate the efficacy of isoniazid and rifampin regimens, and identify modifications to these antibiotics that improve treatment outcomes.
  
  
  RESULTS
  We pair a spatio-temporal computational model of host immunity with pharmacokinetic and pharmacodynamic data on isoniazid and rifampin. The model is calibrated to plasma pharmacokinetic and granuloma bacterial load data from non-human primate models of tuberculosis and to tissue and granuloma measurements of isoniazid and rifampin in rabbit granulomas. We predict the efficacy of regimens containing different doses and frequencies of isoniazid and rifampin. We predict impacts of pharmacokinetic/pharmacodynamic modifications on antibiotic efficacy. We demonstrate that suboptimal antibiotic concentrations within granulomas lead to poor performance of intermittent regimens compared to daily regimens. Improvements from dose and frequency changes are limited by inherent antibiotic properties, and we propose that changes in intracellular accumulation ratios and antimicrobial activity would lead to the most significant improvements in treatment outcomes. Results suggest that an increased risk of drug resistance in fully intermittent as compared to daily regimens arises from higher bacterial population levels early during treatment.
  
  
  CONCLUSIONS
  Our systems pharmacology approach complements efforts to accelerate tuberculosis therapeutic development.
authors.affiliation: Department of Chemical Engineering, University of Michigan, 2800 Plymouth Rd, Ann Arbor, MI, 48109, USA. epienaar@umich.edu.|Department of Microbiology and Immunology, University of Michigan Medical School, 6730 Medical Science Building II, Ann Arbor, MI, 48109, USA. epienaar@umich.edu.
authors.forename: Elsje
authors.initials: E
authors.lastname: Pienaar
authors.affiliation: Public Health Research Institute and New Jersey Medical School, Rutgers, The State University of New Jersey, 225 Warren Street, Newark, NJ, 07103, USA. dartoiva@njms.rutgers.edu.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dartois
authors.affiliation: Department of Chemical Engineering, University of Michigan, 2800 Plymouth Rd, Ann Arbor, MI, 48109, USA. linderma@umich.edu.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Linderman
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, 6730 Medical Science Building II, Ann Arbor, MI, 48109, USA. kirschne@umich.edu.
authors.forename: Denise E
authors.initials: DE
authors.lastname: Kirschner
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003198:Computer Simulation; D024881:Drug Resistance, Bacterial; D006099:Granuloma / Q000188:drug therapy / Q000382:microbiology; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009169:Mycobacterium tuberculosis / Q000254:growth & development; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid; D012293:Rifampin