{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:51:25Z","timestamp":1791276685805,"version":"4.1.0"},"reference-count":16,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":35,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004417","name":"Global Fund to Fight AIDS, Tuberculosis, and Malaria","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004417","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI146095"],"award-info":[{"award-number":["R01AI146095"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Shortened all-oral regimens for multidrug- or rifampicin-resistant tuberculosis (MDR\/RR-TB) combine multiple QTc prolonging agents, including bedaquiline and delamanid, which act partly through hERG potassium channel binding. Promethazine, a first-generation antihistamine used for nausea during TB therapy, shares this mechanism. Whether adjunctive promethazine further raises the risk of clinically relevant QTc prolongation in this setting is unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted secondary analyses from a prospective observational cohort study of patients \u226515\u2005years in Lesotho who received a 9- to 12-month all-oral regimen (bedaquiline, linezolid, levofloxacin, clofazimine, delamanid) for pulmonary MDR\/RR-TB. We modelled time-varying promethazine exposure using the Andersen-Gill formulation of Cox regression, with time-to-first grade \u22653 (&amp;gt;500\u2005ms) QTc event as the outcome of interest. We conducted comparator analyses with time-varying exposure to metoclopramide, ondansetron, and episodes of nausea, dizziness, and vomiting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 247 participants (median age 41, 63.2% living with HIV), 62 (25.1%) received promethazine. Grade \u22653 QTc prolongation occurred in 10 (4.0%). Incident clinically significant QTc prolongation was higher during promethazine-exposed than unexposed periods (7.4 versus 1.3 per 10\u200a000 person-days; HR 7.0, 95% CI: 1.4\u201335.3). No comparable elevation was seen in analyses of exposure to metoclopramide (HR 1.0, 95% CI: 0.3\u20133.6), ondansetron, or episodes of nausea, dizziness, or vomiting (HR 1.5, 95% CI: 0.3\u20136.9).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Promethazine use was associated with increased risk of clinically relevant QTc prolongation within a QTc-burdened all-oral MDR\/RR-TB regimen. These findings provide preliminary evidence that clinicians may consider when selecting anti-emetics as part of MDR\/RR-TB therapy with a shortened all-oral regimen and highlight the importance of evaluating adjunctive medications in DR-TB care.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jacamr\/dlag215","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T18:26:05Z","timestamp":1789755965000},"source":"Crossref","is-referenced-by-count":0,"title":["Promethazine use and QT prolongation risk during treatment with a shortened all-oral regimen for MDR\/RR-TB"],"prefix":"10.1093","volume":"8","author":[{"given":"Edmund Q L","family":"Shen","sequence":"first","affiliation":[{"name":"Harvard Medical School, 641 Huntington Ave , Boston, MA 02115 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9814-0563","authenticated-orcid":false,"given":"Letizia","family":"Trevisi","sequence":"additional","affiliation":[{"name":"Department of Global Health and Social Medicine, Harvard Medical School , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephane","family":"Mpinda","sequence":"additional","affiliation":[{"name":"Partners In Health Lesotho , Maseru ,","place":["Lesotho"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8415-133X","authenticated-orcid":false,"given":"Allison","family":"Lahood","sequence":"additional","affiliation":[{"name":"Department of Global Health and Social Medicine, Harvard Medical School , Boston, MA ,","place":["USA"]},{"name":"Department of Epidemiology, Harvard School of Public Health , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Llang","family":"Maama","sequence":"additional","affiliation":[{"name":"National Tuberculosis and Leprosy Programme, Lesotho Ministry of Health , Maseru ,","place":["Lesotho"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meseret","family":"Tamirat","sequence":"additional","affiliation":[{"name":"Partners In Health Lesotho , Maseru ,","place":["Lesotho"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebakeng","family":"Phate","sequence":"additional","affiliation":[{"name":"Partners In Health Lesotho , Maseru ,","place":["Lesotho"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Oyewusi","sequence":"additional","affiliation":[{"name":"National Tuberculosis and Leprosy Programme, Lesotho Ministry of Health , Maseru ,","place":["Lesotho"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3038-0644","authenticated-orcid":false,"given":"Matthew","family":"Romo","sequence":"additional","affiliation":[{"name":"Department of Global Health and Social Medicine, Harvard Medical School , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elna","family":"Osso","sequence":"additional","affiliation":[{"name":"Department of Global Health and Social Medicine, Harvard Medical School , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L","family":"Rich","sequence":"additional","affiliation":[{"name":"Division of Global Health Equity, Department of Medicine, Brigham and Women\u2019s Hospital , Boston, MA ,","place":["USA"]},{"name":"Partners In Health , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3455-658X","authenticated-orcid":false,"given":"Carole D","family":"Mitnick","sequence":"additional","affiliation":[{"name":"Department of Global Health and Social Medicine, Harvard Medical School , Boston, MA ,","place":["USA"]},{"name":"Division of Global Health Equity, Department of Medicine, Brigham and Women\u2019s Hospital , Boston, MA ,","place":["USA"]},{"name":"Partners In Health , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwonjune Justin","family":"Seung","sequence":"additional","affiliation":[{"name":"Division of Global Health Equity, Department of Medicine, Brigham and Women\u2019s Hospital , Boston, MA ,","place":["USA"]},{"name":"Partners In Health , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly F","family":"Franke","sequence":"additional","affiliation":[{"name":"Department of Global Health and Social Medicine, Harvard Medical School , Boston, MA ,","place":["USA"]},{"name":"Department of Epidemiology, Harvard School of Public Health , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunda Kwabisha","family":"Mikanda","sequence":"additional","affiliation":[{"name":"Partners In Health Lesotho , Maseru ,","place":["Lesotho"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"2026100604020349800_dlag215-B1","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1016\/S1473-3099(20)30770-2","article-title":"QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial","volume":"21","author":"Dooley","year":"2021","journal-title":"Lancet Infect Dis"},{"key":"2026100604020349800_dlag215-B2","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1093\/cid\/ciae601","article-title":"The frequency and incidence of QT prolongation with extended use of bedaquiline or delamanid in a large, multi-country multidrug-resistant\/rifampicin-resistant tuberculosis cohort","volume":"81","author":"Khan","year":"2025","journal-title":"Clin Infect Dis"},{"key":"2026100604020349800_dlag215-B3","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1093\/cid\/ciae305","article-title":"Safety and effectiveness of 3 novel all-oral shortened regimens for rifampicin- or multidrug-resistant tuberculosis in Kazakhstan","volume":"79","author":"Rashitov","year":"2024","journal-title":"Clin Infect Dis"},{"key":"2026100604020349800_dlag215-B4","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.jemermed.2024.09.013","article-title":"Promethazine: a review of therapeutic uses and toxicity","volume":"70","author":"Le","year":"2025","journal-title":"J Emerg Med"},{"key":"2026100604020349800_dlag215-B5","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1016\/j.phrs.2009.05.008","article-title":"H(1) antihistamine drug promethazine directly blocks hERG K(+) channel","volume":"60","author":"Jo","year":"2009","journal-title":"Pharmacol Res"},{"key":"2026100604020349800_dlag215-B6","author":"European Medicines Agency"},{"key":"2026100604020349800_dlag215-B7","author":"European Medicines Agency"},{"key":"2026100604020349800_dlag215-B8","author":"Sauer"},{"key":"2026100604020349800_dlag215-B9","author":"M\u00e9decins Sans\u202fFronti\u00e8res"},{"key":"2026100604020349800_dlag215-B10","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1214\/aos\/1176345976","article-title":"Cox's regression model for counting processes: a large sample study","volume":"10","author":"Andersen","year":"1982","journal-title":"Ann Stat"},{"key":"2026100604020349800_dlag215-B11","doi-asserted-by":"publisher","first-page":"817","DOI":"10.2307\/1912934","article-title":"A heteroskedasticity-consistent covariance matrix estimator and a direct test for heteroskedasticity","volume":"48","author":"White","year":"1980","journal-title":"Econometrica"},{"key":"2026100604020349800_dlag215-B12","doi-asserted-by":"publisher","first-page":"385","DOI":"10.5588\/ijtld.14.0335","article-title":"QTc prolongation and treatment of multidrug-resistant tuberculosis","volume":"19","author":"Harausz","year":"2015","journal-title":"Int J Tuberc Lung Dis"},{"key":"2026100604020349800_dlag215-B13","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1213\/ANE.0000000000001673","article-title":"Cardiotoxic antiemetics metoclopramide and domperidone block cardiac voltage-gated Na+ channels","volume":"124","author":"Stoetzer","year":"2017","journal-title":"Anesth Analg"},{"key":"2026100604020349800_dlag215-B14","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.ejphar.2016.07.020","article-title":"Local-anesthetic like inhibition of the cardiac sodium channel Nav1.5 alpha-subunit by 5-HT3 receptor antagonists","volume":"789","author":"Van't Klooster","year":"2016","journal-title":"Eur J Pharmacol"},{"key":"2026100604020349800_dlag215-B15","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofab413","article-title":"QT interval prolongation in people treated with bedaquiline for drug-resistant tuberculosis under programmatic conditions: a retrospective cohort study","volume":"8","author":"Isralls","year":"2021","journal-title":"Open Forum Infect Dis"},{"key":"2026100604020349800_dlag215-B16","doi-asserted-by":"publisher","first-page":"H375","DOI":"10.1152\/ajpheart.00479.2017","article-title":"Ondansetron blocks wild-type and p.F503L variant small-conductance Ca(2+)-activated K(+) channels","volume":"315","author":"Ko","year":"2018","journal-title":"Am J Physiol Heart Circ Physiol"}],"container-title":["JAC-Antimicrobial Resistance"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jacamr\/article-pdf\/8\/5\/dlag215\/71619915\/dlag215.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jacamr\/article-pdf\/8\/5\/dlag215\/71619915\/dlag215.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:02:08Z","timestamp":1791273728000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jacamr\/article\/doi\/10.1093\/jacamr\/dlag215\/8868258"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":16,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,9,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jacamr\/dlag215","relation":{},"ISSN":["2632-1823"],"issn-type":[{"value":"2632-1823","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,10]]},"published":{"date-parts":[[2026,9,1]]},"article-number":"dlag215"}}