Linezolid for treatment of chronic extensively drug-resistant tuberculosis

Myungsun Lee, Jongseok Lee, Matthew W. Carroll, Hongjo Choi, Seonyeong Min, Taeksun Song, Laura E. Via, Lisa C. Goldfeder, Eunhwa Kang, Boyoung Jin, Hyeeun Park, Hyunkyung Kwak, Hyunchul Kim, Han Seung Jeon, Ina Jeong, Joon Sung Joh, Ray Y. Chen, Kenneth N. Olivier, Pamela A. Shaw, Dean FollmannSun Dae Song, Jong Koo Lee, Dukhyoung Lee, Cheon Tae Kim, Veronique Dartois, Seung Kyu Park, Sang Nae Cho, Clifton E. Barry

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Abstract

BACKGROUND: Linezolid has antimycobacterial activity in vitro and is increasingly used for patients with highly drug-resistant tuberculosis. METHODS: We enrolled 41 patients who had sputum-culture-positive extensively drug-resistant (XDR) tuberculosis and who had not had a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their background regimen. The primary end point was the time to sputum-culture conversion on solid medium, with data censored 4 months after study entry. After confirmed sputum-smear conversion or 4 months (whichever came first), patients underwent a second randomization to continued linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 months, with careful toxicity monitoring. RESULTS: By 4 months, 15 of the 19 patients (79%) in the immediate-start group and 7 of the 20 (35%) in the delayed-start group had culture conversion (P = 0.001). Most patients (34 of 39 [87%]) had a negative sputum culture within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant adverse events that were possibly or probably related to linezolid, including 3 patients who discontinued therapy. Patients who received 300 mg per day after the second randomization had fewer adverse events than those who continued taking 600 mg per day. Thirteen patients completed therapy and have not had a relapse. Four cases of acquired resistance to linezolid have been observed. CONCLUSIONS: Linezolid is effective at achieving culture conversion among patients with treatment-refractory XDR pulmonary tuberculosis, but patients must be monitored carefully for adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and the Ministry of Health and Welfare, South Korea; ClinicalTrials.gov number, NCT00727844.)

Original languageEnglish
Pages (from-to)1508-1518
Number of pages11
JournalNew England Journal of Medicine
Volume367
Issue number16
DOIs
Publication statusPublished - 2012 Oct 18

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Linezolid
Extensively Drug-Resistant Tuberculosis
Sputum
Therapeutics
Random Allocation
National Institute of Allergy and Infectious Diseases (U.S.)

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Lee, M., Lee, J., Carroll, M. W., Choi, H., Min, S., Song, T., ... Barry, C. E. (2012). Linezolid for treatment of chronic extensively drug-resistant tuberculosis. New England Journal of Medicine, 367(16), 1508-1518. https://doi.org/10.1056/NEJMoa1201964
Lee, Myungsun ; Lee, Jongseok ; Carroll, Matthew W. ; Choi, Hongjo ; Min, Seonyeong ; Song, Taeksun ; Via, Laura E. ; Goldfeder, Lisa C. ; Kang, Eunhwa ; Jin, Boyoung ; Park, Hyeeun ; Kwak, Hyunkyung ; Kim, Hyunchul ; Jeon, Han Seung ; Jeong, Ina ; Joh, Joon Sung ; Chen, Ray Y. ; Olivier, Kenneth N. ; Shaw, Pamela A. ; Follmann, Dean ; Song, Sun Dae ; Lee, Jong Koo ; Lee, Dukhyoung ; Kim, Cheon Tae ; Dartois, Veronique ; Park, Seung Kyu ; Cho, Sang Nae ; Barry, Clifton E. / Linezolid for treatment of chronic extensively drug-resistant tuberculosis. In: New England Journal of Medicine. 2012 ; Vol. 367, No. 16. pp. 1508-1518.
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abstract = "BACKGROUND: Linezolid has antimycobacterial activity in vitro and is increasingly used for patients with highly drug-resistant tuberculosis. METHODS: We enrolled 41 patients who had sputum-culture-positive extensively drug-resistant (XDR) tuberculosis and who had not had a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their background regimen. The primary end point was the time to sputum-culture conversion on solid medium, with data censored 4 months after study entry. After confirmed sputum-smear conversion or 4 months (whichever came first), patients underwent a second randomization to continued linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 months, with careful toxicity monitoring. RESULTS: By 4 months, 15 of the 19 patients (79{\%}) in the immediate-start group and 7 of the 20 (35{\%}) in the delayed-start group had culture conversion (P = 0.001). Most patients (34 of 39 [87{\%}]) had a negative sputum culture within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82{\%}) had clinically significant adverse events that were possibly or probably related to linezolid, including 3 patients who discontinued therapy. Patients who received 300 mg per day after the second randomization had fewer adverse events than those who continued taking 600 mg per day. Thirteen patients completed therapy and have not had a relapse. Four cases of acquired resistance to linezolid have been observed. CONCLUSIONS: Linezolid is effective at achieving culture conversion among patients with treatment-refractory XDR pulmonary tuberculosis, but patients must be monitored carefully for adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and the Ministry of Health and Welfare, South Korea; ClinicalTrials.gov number, NCT00727844.)",
author = "Myungsun Lee and Jongseok Lee and Carroll, {Matthew W.} and Hongjo Choi and Seonyeong Min and Taeksun Song and Via, {Laura E.} and Goldfeder, {Lisa C.} and Eunhwa Kang and Boyoung Jin and Hyeeun Park and Hyunkyung Kwak and Hyunchul Kim and Jeon, {Han Seung} and Ina Jeong and Joh, {Joon Sung} and Chen, {Ray Y.} and Olivier, {Kenneth N.} and Shaw, {Pamela A.} and Dean Follmann and Song, {Sun Dae} and Lee, {Jong Koo} and Dukhyoung Lee and Kim, {Cheon Tae} and Veronique Dartois and Park, {Seung Kyu} and Cho, {Sang Nae} and Barry, {Clifton E.}",
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Lee, M, Lee, J, Carroll, MW, Choi, H, Min, S, Song, T, Via, LE, Goldfeder, LC, Kang, E, Jin, B, Park, H, Kwak, H, Kim, H, Jeon, HS, Jeong, I, Joh, JS, Chen, RY, Olivier, KN, Shaw, PA, Follmann, D, Song, SD, Lee, JK, Lee, D, Kim, CT, Dartois, V, Park, SK, Cho, SN & Barry, CE 2012, 'Linezolid for treatment of chronic extensively drug-resistant tuberculosis', New England Journal of Medicine, vol. 367, no. 16, pp. 1508-1518. https://doi.org/10.1056/NEJMoa1201964

Linezolid for treatment of chronic extensively drug-resistant tuberculosis. / Lee, Myungsun; Lee, Jongseok; Carroll, Matthew W.; Choi, Hongjo; Min, Seonyeong; Song, Taeksun; Via, Laura E.; Goldfeder, Lisa C.; Kang, Eunhwa; Jin, Boyoung; Park, Hyeeun; Kwak, Hyunkyung; Kim, Hyunchul; Jeon, Han Seung; Jeong, Ina; Joh, Joon Sung; Chen, Ray Y.; Olivier, Kenneth N.; Shaw, Pamela A.; Follmann, Dean; Song, Sun Dae; Lee, Jong Koo; Lee, Dukhyoung; Kim, Cheon Tae; Dartois, Veronique; Park, Seung Kyu; Cho, Sang Nae; Barry, Clifton E.

In: New England Journal of Medicine, Vol. 367, No. 16, 18.10.2012, p. 1508-1518.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Linezolid for treatment of chronic extensively drug-resistant tuberculosis

AU - Lee, Myungsun

AU - Lee, Jongseok

AU - Carroll, Matthew W.

AU - Choi, Hongjo

AU - Min, Seonyeong

AU - Song, Taeksun

AU - Via, Laura E.

AU - Goldfeder, Lisa C.

AU - Kang, Eunhwa

AU - Jin, Boyoung

AU - Park, Hyeeun

AU - Kwak, Hyunkyung

AU - Kim, Hyunchul

AU - Jeon, Han Seung

AU - Jeong, Ina

AU - Joh, Joon Sung

AU - Chen, Ray Y.

AU - Olivier, Kenneth N.

AU - Shaw, Pamela A.

AU - Follmann, Dean

AU - Song, Sun Dae

AU - Lee, Jong Koo

AU - Lee, Dukhyoung

AU - Kim, Cheon Tae

AU - Dartois, Veronique

AU - Park, Seung Kyu

AU - Cho, Sang Nae

AU - Barry, Clifton E.

PY - 2012/10/18

Y1 - 2012/10/18

N2 - BACKGROUND: Linezolid has antimycobacterial activity in vitro and is increasingly used for patients with highly drug-resistant tuberculosis. METHODS: We enrolled 41 patients who had sputum-culture-positive extensively drug-resistant (XDR) tuberculosis and who had not had a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their background regimen. The primary end point was the time to sputum-culture conversion on solid medium, with data censored 4 months after study entry. After confirmed sputum-smear conversion or 4 months (whichever came first), patients underwent a second randomization to continued linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 months, with careful toxicity monitoring. RESULTS: By 4 months, 15 of the 19 patients (79%) in the immediate-start group and 7 of the 20 (35%) in the delayed-start group had culture conversion (P = 0.001). Most patients (34 of 39 [87%]) had a negative sputum culture within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant adverse events that were possibly or probably related to linezolid, including 3 patients who discontinued therapy. Patients who received 300 mg per day after the second randomization had fewer adverse events than those who continued taking 600 mg per day. Thirteen patients completed therapy and have not had a relapse. Four cases of acquired resistance to linezolid have been observed. CONCLUSIONS: Linezolid is effective at achieving culture conversion among patients with treatment-refractory XDR pulmonary tuberculosis, but patients must be monitored carefully for adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and the Ministry of Health and Welfare, South Korea; ClinicalTrials.gov number, NCT00727844.)

AB - BACKGROUND: Linezolid has antimycobacterial activity in vitro and is increasingly used for patients with highly drug-resistant tuberculosis. METHODS: We enrolled 41 patients who had sputum-culture-positive extensively drug-resistant (XDR) tuberculosis and who had not had a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their background regimen. The primary end point was the time to sputum-culture conversion on solid medium, with data censored 4 months after study entry. After confirmed sputum-smear conversion or 4 months (whichever came first), patients underwent a second randomization to continued linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 months, with careful toxicity monitoring. RESULTS: By 4 months, 15 of the 19 patients (79%) in the immediate-start group and 7 of the 20 (35%) in the delayed-start group had culture conversion (P = 0.001). Most patients (34 of 39 [87%]) had a negative sputum culture within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant adverse events that were possibly or probably related to linezolid, including 3 patients who discontinued therapy. Patients who received 300 mg per day after the second randomization had fewer adverse events than those who continued taking 600 mg per day. Thirteen patients completed therapy and have not had a relapse. Four cases of acquired resistance to linezolid have been observed. CONCLUSIONS: Linezolid is effective at achieving culture conversion among patients with treatment-refractory XDR pulmonary tuberculosis, but patients must be monitored carefully for adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and the Ministry of Health and Welfare, South Korea; ClinicalTrials.gov number, NCT00727844.)

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