Several infectious diseases of global importance — e.g. HIV, tuberculosis (TB) — require prolonged treatment with combination antimicrobial regimens, typically involving high-potency "core" agents coupled with additional "companion" drugs that protect against de novo emergence of mutations conferring resistance to the core agents. Often, the most effective (or least toxic) companion agents are re-used in sequential (first-line, second-line, etc...) regimens. We used a multi-strain model of M. 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 reported 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) — exceeded pre-defined acceptability thresholds (1-2 cases per 100,000 population by 2035). Using pyrazinamide (the most effective companion agent) in both first-line and second-line regimens increased the proportion of simulations exceeding the pre-XDR acceptability threshold seven-fold, compared to a scenario in which patients with pyrazinamide-resistant TB received an alternative drug. Model parameters related to emergence and transmission of pyrazinamide-resistant TB and resistance amplification were among those most strongly correlated with 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 appropriate use of companion drugs may be critical to preventing the emergence of strains resistant to multiple core agents.
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