Historically, treatment regimens for rifampicin-resistant tuberculosis were composed of five to seven older, second-line tuberculosis drugs, including injectable agents that resulted in frequent and sometimes permanent adverse effects in some patients, that were given for 18–24 months and were only modestly effective. The development of multiple novel and repurposed tuberculosis drugs has substantially changed the approach to rifampicin-resistant tuberculosis treatment, but children have not benefited equitably. On the basis of emerging results from pivotal trials, in December 2022, WHO recommended a 6-month, once-per-day regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) as a first-line treatment for individuals older than 14 years with rifampicin-resistant tuberculosis.1WHOWHO consolidated guidelines on tuberculosis. Module 4: treatment—drug-resistant tuberculosis treatment, 2022 update.https://www.who.int/publications/i/item/9789240063129Date: 2022Date accessed: March 5, 2023Google Scholar The inclusion of patients as young as 14 years in these pivotal trials, even though people aged 14–17 years were enrolled in small numbers, allowed WHO to extend their recommendation to this age group, thus avoiding unnecessary delays in access to this much-needed treatment innovation for older adolescents. Most older adolescents and adults aged 18 years or older treated for rifampicin-resistant tuberculosis can now expect to receive an effective, all-oral, once-per-day, four-drug regimen for 6 months. Although extrapolating the efficacy of BPaLM to children aged 13 years or younger with rifampicin-resistant tuberculosis is reasonable, two crucial barriers prevent paediatric access to this regimen. First, although pretomanid was approved by the US Food and Drug Administration in 2019 for use in adults as part of the bedaquiline, pretomanid, and linezolid regimen, paediatric evaluation has been substantially delayed. The pharmacokinetics and safety of a single dose of pretomanid in children and adolescents will be evaluated in the IMPAACT 2034 trial (NCT05586230), which is expected to open in 2023. A subsequent multidose pretomanid paediatric trial will be needed to substantiate these doses and evaluate its safety long term. Pretomanid is thus unlikely to be available for children for several years. Second, although linezolid has potent antimycobacterial activity, its use for 6 months results in frequent adverse effects, including myelosuppression and neuropathies. These adverse events are associated with longer duration and increased exposure.2Conradie F Bagdasaryan TR Borisov S et al.Bedaquiline–pretomanid–linezolid regimens for drug-resistant tuberculosis.N Engl J Med. 2022; 387: 810-823Crossref PubMed Scopus (34) Google Scholar For adults with rifampicin-resistant tuberculosis who typically have severe disease and traditionally poor outcomes, the risk–benefit profile of 6 months of linezolid is favourable. However, for children who tend to have paucibacillary, less severe tuberculosis, and better outcomes, this risk–benefit profile is less acceptable. Shorter linezolid durations would substantially improve this risk–benefit profile, reducing the risk of developing severe anaemia, peripheral neuropathy, and optic neuropathy, which, while rare, might have long-term consequences. Although some experts prescribe shorter, less intense regimens for rifampicin-resistant tuberculosis,3The Sentinel Project on Pediatric Drug-Resistant TuberculosisManagement of multidrug-resistant tuberculosis in children: a field guide.http://sentinel-project.org/2022/03/22/fifth-edition-of-management-of-multidrug-resistant-tuberculosis-in-children-a-field-guide-now-available/Date: 2022Date accessed: May 22, 2023Google Scholar WHO still recommends a 9–11-month treatment regimen for children, composed of a 4–6-month intensive phase with seven drugs (ie, bedaquiline, levofloxacin, clofazimine, pyrazinamide, ethionamide, high-dose isoniazid, and ethambutol) and a 6-month continuation phase with four drugs (ie, levofloxacin, clofazimine, pyrazinamide, and ethambutol).1WHOWHO consolidated guidelines on tuberculosis. Module 4: treatment—drug-resistant tuberculosis treatment, 2022 update.https://www.who.int/publications/i/item/9789240063129Date: 2022Date accessed: March 5, 2023Google Scholar Children respond as well as, or better than, adults to tuberculosis treatment. However, compared with adults, this currently recommended paediatric rifampicin-resistant tuberculosis treatment regimen includes more drugs than BPaLM (ie, seven vs four) and older drugs that are less well tolerated and less likely to be effective for a longer duration than BPaLM (ie, 9–11 months vs 6 months). Currently recommended regimens, although generally safe, are not always well tolerated, with clofazimine-associated skin discoloration and ethionamide-associated nausea and vomiting frequently causing challenges for children and caregivers. Despite the current recommendation that injectable agents be avoided, they are still used in some countries and result in a high risk of permanent sensorineural hearing loss. As children overall respond well to treatment, ensuring the safety and tolerability of regimens, especially to avoid adverse effects with potentially long-term consequences, is imperative. An attractive adaptation of the BPaLM regimen for children would substitute delamanid for pretomanid and shorten the duration of linezolid. Treatment with 6 months of bedaquiline, delamanid, and a fluoroquinolone with 2 months of linezolid could allow children access to an efficacious, all-oral regimen similar to that used in adults. Delamanid and pretomanid are in the same class of drugs (ie, nitroimidazoles) with similar mechanisms of action. At exposures expected with current dosing of both compounds, there appears to be minimal difference in activity in preclinical evaluations.4Mudde SE Upton AM Lenaerts A Bax HI De Steenwinkel JEM Delamanid or pretomanid? A Solomonic judgement!.J Antimicrob Chemother. 2022; 77: 880-902Crossref PubMed Scopus (9) Google Scholar There are no high-quality clinical data directly comparing the two drugs, but a reasonable assumption is that they will have similar activity. This assumption is further supported by preliminary results from the South African BEAT-Tuberculosis trial, which enrolled patients aged 6 years or older and showed that a 6-month delamanid-containing regimen was highly effective,5Conradie F. High rate of successful outcomes treating RR-TB with a delamanid–bedaquiline regimen in BEAT Tuberculosis: an interim analysis. Union World Conference on Lung Health 2022; Nov 8–11, 2022 (LBTB-2074-11).Google Scholar and from the BEAT-India trial.6Padmapriyadarsini C Vohra V Bhatnagar A et al.Bedaquiline, delamanid, linezolid and clofazimine for treatment of pre-extensively drug-resistant tuberculosis.Clin Infect Dis. 2022; 76: e938-e946Crossref PubMed Scopus (6) Google Scholar Delamanid is now recommended by WHO for children of all ages and is available in a dispersible tablet formulation. Furthermore, a shorter duration of linezolid would provide benefit while reducing the risk of adverse effects. The ZeNix trial showed that adults with rifampicin-resistant tuberculosis receiving regimens with 9 weeks of linezolid 600 mg once per day had excellent outcomes with less toxicity than higher doses and longer durations of linezolid.2Conradie F Bagdasaryan TR Borisov S et al.Bedaquiline–pretomanid–linezolid regimens for drug-resistant tuberculosis.N Engl J Med. 2022; 387: 810-823Crossref PubMed Scopus (34) Google Scholar This shorter linezolid duration would result in a more appropriate and favourable risk–benefit profile for most children with rifampicin-resistant tuberculosis. Ease of preparation and administration of any such regimen is also essential to address current poor acceptability in children as a result of complex regimens; these factors can lead to imperfect adherence and increased risk of poor outcomes. Bedaquiline is recommended as thrice-per-week dosing after a 2-week, once-per-day dosing loading phase, and delamanid is recommended as twice-per-day dosing. Once-per-day dosing for both drugs has now been studied in adults and is increasingly used, but also needs to be evaluated in children.7Salinger DH Nedelman JR Mendel C Spigelman M Hermann DJ Daily dosing for bedaquiline in patients with tuberculosis.Antimicrob Agents Chemother. 2019; 63: e00463-e00519Crossref PubMed Scopus (6) Google Scholar, 8von Groote-Bidlingmaier F Patientia R Sanchez E et al.Efficacy and safety of delamanid in combination with an optimised background regimen for treatment of multidrug-resistant tuberculosis: a multicentre, randomised, double-blind, placebo-controlled, parallel group phase 3 trial.Lancet Respir Med. 2019; 7: 249-259Summary Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 9Tanneau L Karlsson MO Rosenkranz SL et al.Assessing prolongation of the corrected QT interval with bedaquiline and delamanid coadministration to predict the cardiac safety of simplified dosing regimens.Clin Pharmacol Ther. 2022; 112: 873-881Crossref PubMed Scopus (3) Google Scholar, 10Mallikaarjun S Chapagain ML Sasaki T et al.Cumulative fraction of response for once- and twice-daily delamanid in patients with pulmonary multidrug-resistant tuberculosis.Antimicrob Agents Chemother. 2020; 65: e01207-e01220Crossref PubMed Scopus (10) Google Scholar Modelling and simulation with existing paediatric bedaquiline and delamanid pharmacokinetic data would enable selection of once-per-day dosing strategies for children for evaluation in a trial. Simple, once-per-day dosing strategies of the overall regimen would improve acceptability and adherence to this regimen. A trial addressing these targeted questions of safety, pharmacokinetics, outcomes, and acceptability of a once-per-day, simple regimen for children with rifampicin-resistant tuberculosis is a crucial priority. Although currently not possible to fully implement the novel BPaLM regimen for children, children receiving longer, more toxic regimens with higher pill burden than adults is unacceptable. A pragmatic alternative is available that should be evaluated immediately. To wait would be unacceptable. ES has received research funding from TB Alliance and Janssen Pharmaceuticals, has received financial compensation from WHO, and is a member of the Data Safety Monitoring Board for the BE-PEOPLE leprosy prevention study. SK has received grants, paid to her institution, from the National Institutes of Health, Unitaid, and CRDF Global and is a Data Safety Monitoring Board member for the DRAMATIC trial. AJG-P has received grants, paid to his institution, from Unitaid and the National Institutes of Health. PH has received research funding, paid to her institution. from TB Alliance and the National Institutes of Health. GH has received financial assistance from the EU (DCI-PANAF/2020/420–028) through the African Research Initiative for Scientific Excellence pilot programme. The content of this Comment is the sole responsibility of the authors and can under no circumstances be regarded as reflecting the position of the EU, the African Academy of Sciences, or the African Union Commission. The content of this Comment is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. All other authors declare no competing interests.