Multidrug- and rifampicin-resistant tuberculosis in the post-BPaLM era: from genomic resistance prediction to precision treatment, therapeutic failure and transmission control — a comprehensive review

Abstract Background Multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) remains a leading cause of death from antimicrobial resistance. The six-month, all-oral regimen of bedaquiline, pretomanid, linezolid and moxifloxacin (BPaLM) has transformed care. It is shorter, safer and more effective than earlier regimens. Yet its long-term success is fragile. Resistance to the newest drugs is already emerging, and access to fast, accurate resistance testing is uneven. Objective This review examines how genomic resistance prediction, precision treatment, the management of therapeutic failure and transmission control can be joined into a single, practical framework for the post-BPaLM era. Methods We conducted a comprehensive narrative review. We searched five databases and hand-searched key references, WHO guidance and pivotal trials. We then purposively synthesized 47 authenticated sources. They spanned randomized trials, genomic and bioinformatic studies, molecular epidemiology, mechanistic work and World Health Organization (WHO) guidance. Results BPaLM achieves favorable outcomes in about 89% of patients, against roughly half with older regimens. Whole-genome and targeted sequencing can predict resistance for much of the drug panel, although genotype–phenotype concordance is still incomplete for several newer drugs. Bedaquiline resistance, driven mainly by Rv0678 variants, and its cross-resistance with clofazimine are the most pressing threats. Linezolid toxicity still limits treatment and calls for dose personalization and monitoring. Genomic surveillance can detect transmission clusters early and feed data back into stewardship. Machine learning adds value, with the strongest current evidence in resistance prediction. Conclusion We propose a closed loop for the post-BPaLM era. Rapid sequencing should guide personalized regimens. Toxicity and resistance should be watched in real time. Genomic surveillance should protect the new drugs at the population level. Equity of access must underpin all of it.