Abstract
ABSTRACTSeveral 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.
Highlights
Antimicrobial resistance has recently been labeled “a problem so serious that it threatens the achievements of modern medicine” [1]
If the concomitant use of PZA prevents the emergence of resistance to RIF and FQs, PZA resistance may be an important facilitator of the emergence of strains that are resistant to both RIF and FQs, which we define conventionally to be pre-extensively drug resistant TB strains
First- and second-line treatment may critically facilitate the emergence of strains that are resistant to multiple core agents
Summary
Antimicrobial resistance has recently been labeled “a problem so serious that it threatens the achievements of modern medicine” [1]. In combination therapy against HIV, nucleoside inhibitors often serve as companion agents to prevent resistance to the core drug classes of protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and integrase inhibitors [6] These companion drugs are frequently reused in sequential treatment regimens when alternative companion agents are less effective or more toxic. If the concomitant use of PZA prevents the emergence of resistance to RIF and FQs (an unproven hypothesis but one that is consistent with the principles of combination drug therapy), PZA resistance may be an important facilitator of the emergence of strains that are resistant to both RIF and FQs, which we define conventionally to be pre-extensively drug resistant (pre-XDR) TB strains To illustrate this concept, we constructed a dynamic model of M. tuberculosis transmission which incorporates resistance to RIF, PZA, and FQs (Fig. 1). We compared a baseline scenario in which PZA is recycled in first- and second-line regimens to a counterfactual scenario in which PZA is replaced by a hypothetical alternative drug of equal efficacy to demonstrate how the repeated use of companion drugs can facilitate the emergence of extensively drug-resistant strains
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
