Linezolid for treatment of chronic extensively drug-resistant tuberculosis.
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.).
International Tuberculosis Research Center, Changwon, South Korea.
Myungsun
M
Lee
Jongseok
J
Lee
Matthew W
MW
Carroll
Hongjo
H
Choi
Seonyeong
S
Min
Taeksun
T
Song
Laura E
LE
Via
Lisa C
LC
Goldfeder
Eunhwa
E
Kang
Boyoung
B
Jin
Hyeeun
H
Park
Hyunkyung
H
Kwak
Hyunchul
H
Kim
Han-Seung
HS
Jeon
Ina
I
Jeong
Joon Sung
JS
Joh
Ray Y
RY
Chen
Kenneth N
KN
Olivier
Pamela A
PA
Shaw
Dean
D
Follmann
Sun Dae
SD
Song
Jong-Koo
JK
Lee
Dukhyoung
D
Lee
Cheon Tae
CT
Kim
Veronique
V
Dartois
Seung-Kyu
SK
Park
Sang-Nae
SN
Cho
Clifton E
CE
Barry
D000081:Acetamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000302:isolation & purification; D023303:Oxazolidinones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013183:Sputum / Q000382:microbiology; D055815:Young Adult
D000081:Acetamides; D000995:Antitubercular Agents; D023303:Oxazolidinones; D000069349:Linezolid