Effectiveness and Safety of Varying Doses of Linezolid With Bedaquiline and Pretomanid in Treatment of Drug-Resistant Pulmonary Tuberculosis: Open-Label, Randomized Clinical Trial
Treatment of drug-resistant tuberculosis with bedaquiline-pretomanid-linezolid regimen has demonstrated good treatment efficacy. Given linezolid's toxicity profile, prudence suggests reconsidering its dose and duration. We determined the effectiveness and safety of structured dose reduction of...
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| creator | Padmapriyadarsini, Chandrasekaran Oswal, Vikas S Jain, Chetankumar D Mariappan, Muthu Vijayalakshmi Singla, Neeta Kumar, Santosh Daniel, Bella Devaleenal Dave, Jigna D Vadgama, Parul Ramraj, Balaji Kant, Surya Bhatnagar, Anuj K Shanmugam, Sivakumar Paul, Dhamodharan Bharathi, Jeyadeepa Palav, Manasi Shah, Neha V Santhanakrishnan, Rameshkumar Dewan, Ravindra K Shekh, Nadim Rathinam, Prabhakaran Sisara, Arvind B Mankar, Shubhangi Dhakulkar Bajpai, Jyoti Mittal, Upasana Chauhan, Sandeep Kumar, Ravinder Parmar, Mallik Mattoo, Sanjay K Jaju, Jyoti |
| description | Treatment of drug-resistant tuberculosis with bedaquiline-pretomanid-linezolid regimen has demonstrated good treatment efficacy. Given linezolid's toxicity profile, prudence suggests reconsidering its dose and duration. We determined the effectiveness and safety of structured dose reduction of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant (pre-XDR) or treatment-intolerant/nonresponsive multidrug-resistant (MDRTI/NR) pulmonary tuberculosis.
Adults with pre-XDR or MDRTI/NR pulmonary tuberculosis were enrolled in a multicenter, parallel-group, randomized clinical trial in India. Patients were randomized to 26 weeks of bedaquiline, pretomanid, and daily linezolid, at 600 mg for 26 weeks (arm 1); 600 mg for 9 weeks followed by 300 mg for 17 weeks (arm 2); or 600 mg for 13 weeks followed by 300 mg for 13 weeks (arm 3). Study end points included sustained cure, bacteriological failure, toxicity, and death.
Of 403 patients enrolled, 255 (63%) were |
| doi_str_mv | 10.1093/cid/ciae388 |
| format | Article |
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Adults with pre-XDR or MDRTI/NR pulmonary tuberculosis were enrolled in a multicenter, parallel-group, randomized clinical trial in India. Patients were randomized to 26 weeks of bedaquiline, pretomanid, and daily linezolid, at 600 mg for 26 weeks (arm 1); 600 mg for 9 weeks followed by 300 mg for 17 weeks (arm 2); or 600 mg for 13 weeks followed by 300 mg for 13 weeks (arm 3). Study end points included sustained cure, bacteriological failure, toxicity, and death.
Of 403 patients enrolled, 255 (63%) were <30 years old, 273 (68%) had prior tuberculosis episodes, and 238 (59%) were malnourished. At the end of treatment, after excluding those with negative baseline cultures, cure was seen in 120 (93%), 117 (94%), and 115 (93%) in arms 1, 2, and 3 respectively. Myelosuppression seen in 85 patients each in arms 1 and 2 and 77 patients in arm 3, not significantly different. Peripheral neuropathy was noticed in 66 patients (30, 17, and 19 in arms 1, 2, and 3) at 10-26 weeks (P = .02). The linezolid dose was reduced because of toxicity in 13, 2, and 4 patients in arms 1, 2, and 3, respectively.
In adults with pre-XDR or MDRTI/NR pulmonary tuberculosis, structured linezolid dose reduction to 300 mg/d is as effective as the standard 600-mg dose but with fewer cases of peripheral neuropathy when given with bedaquiline and pretomanid.
Clinical Trial Registry of India (CTRI/2021/03/032189).</description><identifier>ISSN: 1058-4838</identifier><identifier>ISSN: 1537-6591</identifier><identifier>EISSN: 1537-6591</identifier><identifier>DOI: 10.1093/cid/ciae388</identifier><identifier>PMID: 39194339</identifier><language>eng</language><publisher>United States</publisher><subject>Adolescent ; Adult ; Antitubercular Agents - administration & dosage ; Antitubercular Agents - adverse effects ; Antitubercular Agents - therapeutic use ; Diarylquinolines - administration & dosage ; Diarylquinolines - adverse effects ; Diarylquinolines - therapeutic use ; Drug Therapy, Combination ; Female ; Humans ; India ; Linezolid - administration & dosage ; Linezolid - adverse effects ; Linezolid - therapeutic use ; Male ; Middle Aged ; Nitroimidazoles ; Oxazolidinones - administration & dosage ; Oxazolidinones - adverse effects ; Oxazolidinones - therapeutic use ; Treatment Outcome ; Tuberculosis, Multidrug-Resistant - drug therapy ; Tuberculosis, Pulmonary - drug therapy ; Young Adult</subject><ispartof>Clinical infectious diseases, 2024-12, Vol.79 (6), p.1375-1385</ispartof><rights>The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c177t-67b1a64d32933335c0b9d03c8e060cb12dd25907a94797c30b6a9a99df4a743</cites><orcidid>0000-0002-1324-4595</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39194339$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Padmapriyadarsini, Chandrasekaran</creatorcontrib><creatorcontrib>Oswal, Vikas S</creatorcontrib><creatorcontrib>Jain, Chetankumar D</creatorcontrib><creatorcontrib>Mariappan, Muthu Vijayalakshmi</creatorcontrib><creatorcontrib>Singla, Neeta</creatorcontrib><creatorcontrib>Kumar, Santosh</creatorcontrib><creatorcontrib>Daniel, Bella Devaleenal</creatorcontrib><creatorcontrib>Dave, Jigna D</creatorcontrib><creatorcontrib>Vadgama, Parul</creatorcontrib><creatorcontrib>Ramraj, Balaji</creatorcontrib><creatorcontrib>Kant, Surya</creatorcontrib><creatorcontrib>Bhatnagar, Anuj K</creatorcontrib><creatorcontrib>Shanmugam, Sivakumar</creatorcontrib><creatorcontrib>Paul, Dhamodharan</creatorcontrib><creatorcontrib>Bharathi, Jeyadeepa</creatorcontrib><creatorcontrib>Palav, Manasi</creatorcontrib><creatorcontrib>Shah, Neha V</creatorcontrib><creatorcontrib>Santhanakrishnan, Rameshkumar</creatorcontrib><creatorcontrib>Dewan, Ravindra K</creatorcontrib><creatorcontrib>Shekh, Nadim</creatorcontrib><creatorcontrib>Rathinam, Prabhakaran</creatorcontrib><creatorcontrib>Sisara, Arvind B</creatorcontrib><creatorcontrib>Mankar, Shubhangi Dhakulkar</creatorcontrib><creatorcontrib>Bajpai, Jyoti</creatorcontrib><creatorcontrib>Mittal, Upasana</creatorcontrib><creatorcontrib>Chauhan, Sandeep</creatorcontrib><creatorcontrib>Kumar, Ravinder</creatorcontrib><creatorcontrib>Parmar, Mallik</creatorcontrib><creatorcontrib>Mattoo, Sanjay K</creatorcontrib><creatorcontrib>Jaju, Jyoti</creatorcontrib><creatorcontrib>modified BPaL (mBPaL) Study Team</creatorcontrib><title>Effectiveness and Safety of Varying Doses of Linezolid With Bedaquiline and Pretomanid in Treatment of Drug-Resistant Pulmonary Tuberculosis: Open-Label, Randomized Clinical Trial</title><title>Clinical infectious diseases</title><addtitle>Clin Infect Dis</addtitle><description>Treatment of drug-resistant tuberculosis with bedaquiline-pretomanid-linezolid regimen has demonstrated good treatment efficacy. Given linezolid's toxicity profile, prudence suggests reconsidering its dose and duration. We determined the effectiveness and safety of structured dose reduction of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant (pre-XDR) or treatment-intolerant/nonresponsive multidrug-resistant (MDRTI/NR) pulmonary tuberculosis.
Adults with pre-XDR or MDRTI/NR pulmonary tuberculosis were enrolled in a multicenter, parallel-group, randomized clinical trial in India. Patients were randomized to 26 weeks of bedaquiline, pretomanid, and daily linezolid, at 600 mg for 26 weeks (arm 1); 600 mg for 9 weeks followed by 300 mg for 17 weeks (arm 2); or 600 mg for 13 weeks followed by 300 mg for 13 weeks (arm 3). Study end points included sustained cure, bacteriological failure, toxicity, and death.
Of 403 patients enrolled, 255 (63%) were <30 years old, 273 (68%) had prior tuberculosis episodes, and 238 (59%) were malnourished. At the end of treatment, after excluding those with negative baseline cultures, cure was seen in 120 (93%), 117 (94%), and 115 (93%) in arms 1, 2, and 3 respectively. Myelosuppression seen in 85 patients each in arms 1 and 2 and 77 patients in arm 3, not significantly different. Peripheral neuropathy was noticed in 66 patients (30, 17, and 19 in arms 1, 2, and 3) at 10-26 weeks (P = .02). The linezolid dose was reduced because of toxicity in 13, 2, and 4 patients in arms 1, 2, and 3, respectively.
In adults with pre-XDR or MDRTI/NR pulmonary tuberculosis, structured linezolid dose reduction to 300 mg/d is as effective as the standard 600-mg dose but with fewer cases of peripheral neuropathy when given with bedaquiline and pretomanid.
Clinical Trial Registry of India (CTRI/2021/03/032189).</description><subject>Adolescent</subject><subject>Adult</subject><subject>Antitubercular Agents - administration & dosage</subject><subject>Antitubercular Agents - adverse effects</subject><subject>Antitubercular Agents - therapeutic use</subject><subject>Diarylquinolines - administration & dosage</subject><subject>Diarylquinolines - adverse effects</subject><subject>Diarylquinolines - therapeutic use</subject><subject>Drug Therapy, Combination</subject><subject>Female</subject><subject>Humans</subject><subject>India</subject><subject>Linezolid - administration & dosage</subject><subject>Linezolid - adverse effects</subject><subject>Linezolid - therapeutic use</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Nitroimidazoles</subject><subject>Oxazolidinones - administration & dosage</subject><subject>Oxazolidinones - adverse effects</subject><subject>Oxazolidinones - therapeutic use</subject><subject>Treatment Outcome</subject><subject>Tuberculosis, Multidrug-Resistant - 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Given linezolid's toxicity profile, prudence suggests reconsidering its dose and duration. We determined the effectiveness and safety of structured dose reduction of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant (pre-XDR) or treatment-intolerant/nonresponsive multidrug-resistant (MDRTI/NR) pulmonary tuberculosis.
Adults with pre-XDR or MDRTI/NR pulmonary tuberculosis were enrolled in a multicenter, parallel-group, randomized clinical trial in India. Patients were randomized to 26 weeks of bedaquiline, pretomanid, and daily linezolid, at 600 mg for 26 weeks (arm 1); 600 mg for 9 weeks followed by 300 mg for 17 weeks (arm 2); or 600 mg for 13 weeks followed by 300 mg for 13 weeks (arm 3). Study end points included sustained cure, bacteriological failure, toxicity, and death.
Of 403 patients enrolled, 255 (63%) were <30 years old, 273 (68%) had prior tuberculosis episodes, and 238 (59%) were malnourished. At the end of treatment, after excluding those with negative baseline cultures, cure was seen in 120 (93%), 117 (94%), and 115 (93%) in arms 1, 2, and 3 respectively. Myelosuppression seen in 85 patients each in arms 1 and 2 and 77 patients in arm 3, not significantly different. Peripheral neuropathy was noticed in 66 patients (30, 17, and 19 in arms 1, 2, and 3) at 10-26 weeks (P = .02). The linezolid dose was reduced because of toxicity in 13, 2, and 4 patients in arms 1, 2, and 3, respectively.
In adults with pre-XDR or MDRTI/NR pulmonary tuberculosis, structured linezolid dose reduction to 300 mg/d is as effective as the standard 600-mg dose but with fewer cases of peripheral neuropathy when given with bedaquiline and pretomanid.
Clinical Trial Registry of India (CTRI/2021/03/032189).</abstract><cop>United States</cop><pmid>39194339</pmid><doi>10.1093/cid/ciae388</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-1324-4595</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1058-4838 |
| ispartof | Clinical infectious diseases, 2024-12, Vol.79 (6), p.1375-1385 |
| issn | 1058-4838 1537-6591 1537-6591 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_3097855885 |
| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current) |
| subjects | Adolescent Adult Antitubercular Agents - administration & dosage Antitubercular Agents - adverse effects Antitubercular Agents - therapeutic use Diarylquinolines - administration & dosage Diarylquinolines - adverse effects Diarylquinolines - therapeutic use Drug Therapy, Combination Female Humans India Linezolid - administration & dosage Linezolid - adverse effects Linezolid - therapeutic use Male Middle Aged Nitroimidazoles Oxazolidinones - administration & dosage Oxazolidinones - adverse effects Oxazolidinones - therapeutic use Treatment Outcome Tuberculosis, Multidrug-Resistant - drug therapy Tuberculosis, Pulmonary - drug therapy Young Adult |
| title | Effectiveness and Safety of Varying Doses of Linezolid With Bedaquiline and Pretomanid in Treatment of Drug-Resistant Pulmonary Tuberculosis: Open-Label, Randomized Clinical Trial |
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