title: A Multistrain Mathematical Model To Investigate the Role of Pyrazinamide in the Emergence of Extensively Drug-Resistant Tuberculosis.
abstract: Several infectious diseases of global importance-e.g., HIV infection and tuberculosis (TB)-require prolonged treatment with combination antimicrobial regimens typically involving high-potency core agents coupled with additional companion drugs that protect against thede novoemergence of mutations conferring resistance to the core agents. Often, the most effective (or least toxic) companion agents are reused in sequential (first-line, second-line, etc.) regimens. We used a multistrain model ofMycobacterium tuberculosistransmission in Southeast Asia to investigate how this practice might facilitate the emergence of extensive drug resistance, i.e., resistance to multiple core agents. We calibrated this model to regional TB and drug resistance data using an approximate Bayesian computational approach. We report the proportion of data-consistent simulations in which the prevalence of pre-extensively drug-resistant (pre-XDR) TB-defined as resistance to both first-line and second-line core agents (rifampin and fluoroquinolones)-exceeds predefined acceptability thresholds (1 to 2 cases per 100,000 population by 2035). The use of pyrazinamide (the most effective companion agent) in both first-line and second-line regimens increased the proportion of simulations in which the prevalence exceeded the pre-XDR acceptability threshold by 7-fold compared to a scenario in which patients with pyrazinamide-resistant TB received an alternative drug. Model parameters related to the emergence and transmission of pyrazinamide-resistant TB and resistance amplification were among those that were the most strongly correlated with the projected pre-XDR prevalence, indicating that pyrazinamide resistance acquired during first-line treatment subsequently promotes amplification to pre-XDR TB under pyrazinamide-containing second-line treatment. These findings suggest that the appropriate use of companion drugs may be critical to preventing the emergence of strains resistant to multiple core agents.
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Mariam O
authors.identifier: 0000-0002-2874-471X
authors.initials: MO
authors.lastname: Fofana
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Sourya
authors.initials: S
authors.lastname: Shrestha
authors.affiliation: TB Modelling Group, TB Centre, Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Gwenan M
authors.initials: GM
authors.lastname: Knight
authors.affiliation: Department of Epidemiology of Microbial Diseases, School of Public Health, Yale University, New Haven, Connecticut, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Cohen
authors.affiliation: TB Modelling Group, TB Centre, Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Richard G
authors.initials: RG
authors.lastname: White
authors.affiliation: Amsterdam Institute for Global Health and Development, Academic Medical Center, Amsterdam, Netherlands.|KNCV Tuberculosis Foundation, The Hague, Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Cobelens
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA ddowdy@jhsph.edu.|Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Dowdy
mesh_terms: D000995:Antitubercular Agents / Q000627:therapeutic use*; D001499:Bayes Theorem; D001682:Biological Availability; D003198:Computer Simulation; D004334:Drug Administration Schedule; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000502:physiology; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy* / Q000382:microbiology; D024841:Fluoroquinolones / Q000627:therapeutic use; D006801:Humans; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development; D011718:Pyrazinamide / Q000627:therapeutic use*; D012293:Rifampin / Q000627:therapeutic use; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D011718:Pyrazinamide; D012293:Rifampin
keywords: antimicrobial combinations; mathematical modeling; multidrug resistance; pyrazinamide; tuberculosis