{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T08:46:49Z","timestamp":1766566009342,"version":"3.48.0"},"reference-count":23,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T00:00:00Z","timestamp":1748822400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Office of Orphan Products Development Grants Program"},{"DOI":"10.13039\/100000038","name":"US Food and Drug Administration","doi-asserted-by":"publisher","award":["R01FD005724"],"award-info":[{"award-number":["R01FD005724"]}],"id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>In vitro, meropenem is shown to restore the activity of rifampicin in rifampicin-resistant Mycobacterium tuberculosis strains. This phase 2a trial aimed to determine if addition of rifampicin increases the early bactericidal activity (EBA) of meropenem plus amoxicillin\/clavulanate in patients with rifampicin-resistant tuberculosis (RR-TB).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Individuals with RR-TB were randomized to either 2\u2005g meropenem infusion 3 times daily plus amoxicillin\/clavulanate 500\u2005mg\/125\u2005mg orally 3 times daily with 20\u2005mg\/kg rifampicin orally once daily (M-AC-R arm) or the same treatment without rifampicin (M-AC). Sputum samples were collected at baseline and throughout the 14-day treatment. Colony-forming unit (CFU) and time-to-positivity (TTP) data were analyzed using nonlinear mixed-effects modeling. Plasma samples at day 13 were used to derive rifampicin and meropenem pharmacokinetic parameters using noncompartmental analysis. Rifampicin minimum inhibitory concentrations (MICs) were determined from baseline sputum isolates with and without meropenem.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of the 52 participants enrolled, 38 participants completed the trial. The majority (67%) were male, and the median age was 37 years. The median (95% prediction interval) predicted 14-day EBA in CFU was 1.33 (\u22120.15 to 3.64) and 1.20 (0.05\u20132.66) log10 CFU\/mL, and TTP increased by 0.220 (0.098\u20130.551) and 0.216 (0.126\u20130.505) log10 hours for the M-AC-R and M-AC arms, respectively. No statistically significant difference was found between the 2 arms. Meropenem pharmacokinetics were similar in both arms, and rifampicin MICs were not meaningfully reduced by meropenem.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Adding rifampicin to meropenem plus amoxicillin\/clavulanate did not enhance short-term antibacterial activity in patients with RR-TB.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cid\/ciaf276","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T07:44:55Z","timestamp":1748591095000},"page":"e393-e400","source":"Crossref","is-referenced-by-count":0,"title":["A Phase 2a Study of the Early Bactericidal Activity of Rifampicin in Combination With Meropenem Plus Amoxicillin\/Clavulanate Among Adults With Rifampicin-Resistant Pulmonary Tuberculosis"],"prefix":"10.1093","volume":"81","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6389-5575","authenticated-orcid":false,"given":"Veronique","family":"de Jager","sequence":"first","affiliation":[{"name":"TASK , Cape Town ,","place":["South Africa"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7008-4946","authenticated-orcid":false,"given":"Laurynas","family":"Mockeliunas","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences, Uppsala University , Uppsala ,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huifang","family":"You","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences, Uppsala University , Uppsala ,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrika S H","family":"Simonsson","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences, Uppsala University , Uppsala ,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0678-9617","authenticated-orcid":false,"given":"Tarryn","family":"Collings","sequence":"additional","affiliation":[{"name":"TASK , Cape Town ,","place":["South Africa"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caryn M","family":"Upton","sequence":"additional","affiliation":[{"name":"TASK , Cape Town ,","place":["South Africa"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes A","family":"Bezuidenhout","sequence":"additional","affiliation":[{"name":"TASK , Cape Town ,","place":["South Africa"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikhil","family":"Gupte","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan E","family":"Dorman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Medical University of South Carolina , Charleston, South Carolina ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1440-9889","authenticated-orcid":false,"given":"Eric","family":"Nuermberger","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gyanu","family":"Lamichhane","sequence":"additional","affiliation":[{"name":"Taskforce to Study Resistance Emergence and Antimicrobial Development Technology, Department of Medicine, Johns Hopkins University , Baltimore, Maryland 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