title: Investigation of Elimination Rate, Persistent Subpopulation Removal, and Relapse Rates of Mycobacterium tuberculosis by Using Combinations of First-Line Drugs in a Modified Cornell Mouse Model.
abstract: Currently, the most effective tuberculosis control method involves case finding and 6 months of chemotherapy. There is a need to improve our understanding about drug interactions, combination activities, and the ability to remove persistent bacteria using the current regimens, particularly in relation to relapse. We aimed to investigate the therapeutic effects of three main components, rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA), in current drug regimens using a modified version of the Cornell mouse model. We evaluated the posttreatment levels of persistent Mycobacterium tuberculosis in the organs of mice using culture filtrate derived from M. tuberculosis strain H37Rv. When RMP was combined with INH, PZA, or INH-PZA, significant additive activities were observed compared to each of the single-drug treatments. However, the combination of INH and PZA showed a less significant additive effect than either of the drugs used on their own. Apparent culture negativity of mouse organs was achieved at 14 weeks of treatment with RMP-INH, RMP-PZA, and RMP-INH-PZA, but not with INH-PZA, when conventional tests, namely, culture on solid agar and in liquid broth, indicated that the organs were negative for bacteria. The relapse rates for RMP-containing regimens were not significantly different from a 100% relapse rate at the numbers of mice examined in this study. In parallel, we examined the organs for the presence of culture filtrate-dependent persistent bacilli after 14 weeks of treatment. Culture filtrate treatment of the organs revealed persistent M. tuberculosis Modeling of mycobacterial elimination rates and evaluation of culture filtrate-dependent organisms showed promise as surrogate methods for efficient factorial evaluation of drug combinations in tuberculosis in mouse models and should be further evaluated against relapse. The presence of culture filtrate-dependent persistent M. tuberculosis is the likely cause of disease relapse in this modified Cornell mouse model.
authors.affiliation: Institute for Infection and Immunity, St. George's, University of London, London, United Kingdom ymhu@sgul.ac.uk.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Henry
authors.initials: H
authors.lastname: Pertinez
authors.affiliation: GlaxoSmithKline Research and Development, Diseases of Developing World, Tres Cantos, Madrid, Spain.
authors.forename: Fatima
authors.initials: F
authors.lastname: Ortega-Muro
authors.affiliation: GlaxoSmithKline Research and Development, Diseases of Developing World, Tres Cantos, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Alameda-Martin
authors.affiliation: Institute for Infection and Immunity, St. George's, University of London, London, United Kingdom.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Schipani
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Geraint
authors.initials: G
authors.lastname: Davies
authors.affiliation: Institute for Infection and Immunity, St. George's, University of London, London, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Coates
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004338:Drug Combinations; D005260:Female; D007538:Isoniazid / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011718:Pyrazinamide / Q000494:pharmacology*; D012008:Recurrence; D012293:Rifampin / Q000494:pharmacology*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D004338:Drug Combinations; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin