A Multistrain Mathematical Model To Investigate the Role of Pyrazinamide in the Emergence of Extensively Drug-Resistant Tuberculosis

Author:

Fofana Mariam O.1ORCID,Shrestha Sourya1,Knight Gwenan M.2,Cohen Ted3,White Richard G.2,Cobelens Frank45,Dowdy David W.16

Affiliation:

1. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

2. TB Modelling Group, TB Centre, Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom

3. Department of Epidemiology of Microbial Diseases, School of Public Health, Yale University, New Haven, Connecticut, USA

4. Amsterdam Institute for Global Health and Development, Academic Medical Center, Amsterdam, Netherlands

5. KNCV Tuberculosis Foundation, The Hague, Netherlands

6. Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Abstract

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 the de novo emergence 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 of Mycobacterium tuberculosis transmission 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.

Funder

B. Frank and Kathleen Polk Assistant Professorship in Epidemiology at Johns Hopkins Bloomberg School of Public Health

USAID/International Union Against Tuberculosis and Lung Disease

Johns Hopkins University Medical Scientist Training Program

Paul and Daisy Soros Fellowships for New Americans

Bill and Melinda Gates Foundation

RCUK | Medical Research Council

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

Reference50 articles.

1. World Health Organization. 2014. Antimicrobial resistance: global report on surveillance 2014. World Health Organization, Geneva, Switzerland. http://www.who.int/drugresistance/documents/surveillancereport/en/. Accessed 29 June 2015.

2. Drug combinations in antibacterial chemotherapy;Barber M;Proc R Soc Med,1965

3. Drug resistance in HIV-1

4. Tuberculosis

5. Combination Therapy for Malaria

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