Treating tuberculosis without rifampicin: an open dilemma

Background: The World Health Organization recommends the same treatment regimens for rifampicin-monoresistant (RR) and multidrug-resistant (MDR) TB. Aside of resistance, rifampicin cannot be used in all patients because of allergy, intolerance or drug-to-drug interactions (here called "functional" rifampicin mono-resistance or fRR). Objectives: Given the uncertainty on the best way to treat these forms of TB, we performed a literature review assessing the epidemiology and diagnostic tools for RR and fRR-TB, as well as treatment options and costs of the potential treatments. Sources: We performed a narrative review of the English-language literature by using the terms "tuberculosis"/"rifampicin" and "mono-resistance"/"rifampicin"/"tuberculosis" in the time frame 1960-2025; secondary articles were also manually evaluated from selected papers' bibliographies. Content: We described the role of rifampicin in the antitubercular armamentarium, the epidemiology of RR, the laboratory methods used for detecting rifampicin resistance, the evolution of guidelines on the topic, as well as the studies that reported the use of non-standard regimens for patients with RR or fRR. We summarized the potential options with their pros and cons and suggested a potential flowchart in such scenarios. Implications: WHO-recommended regimens for RR/MDR are the key treatments for patients with RR or fRR-TB: despite the heterogeneity of available data, we identified scenarios where rifampicin can be substituted by alternative drugs and added to first-line antitubercular regimens.