Pretomanid resistance: An update on emergence, mechanisms and relevance for clinical practice

• Published in: International journal of antimicrobial agents 2023-10, Vol.62 (4), p.106953-106953, Article 106953
• Main Authors: Nguyen, Thi Van Anh, Nguyen, Quang Huy, Nguyen, Tran Nam Tien, Anthony, Richard M., Vu, Dinh Hoa, Alffenaar, Jan-Willem C.
• Format: Article
• Language: English
• Subjects: animals; antibiotic resistance; Drug susceptibility testing; drugs; Mechanisms; multiple drug resistance; Mycobacterium tuberculosis; Pretomanid; Resistance
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2023.106953

•Pretomanid resistance has been reported in in-vitro and animal models, but data from clinical trials are lacking.•Mutations in the fbiA, fbiB, fbiC, fbiD, ddn, fgd1 genes confer pretomanid resistance, but understanding of in-vivo molecular resistance mechanisms remains limited.•A reference antimicrobial susceptibility testing method for pretomanid is needed urgently to guide clinical use. Pretomanid (PA-824), a novel anti-tuberculosis (TB) nitroimidazoxazine, has been approved for multi-drug-resistant TB treatment for a few years. Pretomanid has been demonstrated to be highly active against Mycobacterium tuberculosis when combined with other anti-TB drugs. This review provides an update of the current knowledge on the modes of action, resistance mechanisms, emergence of drug resistance, and status of antimicrobial susceptibility testing for pretomanid and its relevance for clinical practice. Pretomanid resistance has been reported in in-vitro and animal models but not yet in clinical trials. Pretomanid-resistance-associated mutations have been reported in the fbiA, fbiB, fbiC, fbiD, ddn and fgd1 genes. However, understanding of in-vivo molecular resistance mechanisms remains limited, and complicates the development of accurate antimicrobial susceptibility testing methods for pretomanid. As such, no reference method for antimicrobial susceptibility testing of pretomanid has been established to guide clinical use. Further studies linking specific mutations, in-vitro susceptibility, drug exposure and resistance mechanisms to treatment failure with pretomanid should be prioritized.