Linezolid for drug-sensitive tuberculosis

Lancet Infect Dis. 2019 Jan;19(1):46-55

Contributed by Dr Kiran Kumar, Dr Abi Manesh

The long duration of treatment for tuberculosis is cumbersome and translates to poor compliance. Multiple attempts in the past to shorten treatment using fluoroquinolones (RIFAQUIN, OFLOTUB, and REMoxTB trials) have been disappointing. Importantly fluoroquinolones have better culture conversions at 8 weeks but later relapses were the predominant problem. Drugs with better sterilization capacity could potentially help in this regard. Linezolid, an oxazolidinone, substantially improves treatment outcomes of multidrug-resistant tuberculosis and extensively drugresistant tuberculosis. The authors looked at whether, if linezolid substituted ethambutol, the rate of sputum culture conversion at 8 weeks of treatment in patients with drug-susceptible tuberculosis would improve.

The authors performed a phase 2, multicentre, randomised, open-label trial for patients with pulmonary tuberculosis at three centers in South Korea. Adult patients with a positive sputum test for pulmonary tuberculosis, but without resistance to rifampicin by Gene Xpert, were randomly assigned at a 1:1:1 ratio into three groups. The control group received ethambutol (2 months) with isoniazid, rifampicin, and pyrazinamide. The second group used linezolid (600 mg/day) for 2 weeks and the third group for 4 weeks, instead of ethambutol for 2 months. In the modified intentionto- treat analyses, negative cultures in liquid media at 8 weeks of treatment were observed in 103 (76·9%) of 134 control patients, 111 (82·2%) of 135 in the linezolid 2 weeks group, and 100 (75·8%) of 132 in the linezolid 4 weeks groups. The difference from the control group was 5.4% (95% CI -4·3 to 15·0, p=0·28) for the linezolid 2 weeks group and -1·1% (-11·3 to 9·1, p=0·83) for the linezolid 4 weeks group.

The authors concluded that linezolid substitution did not result in better culture conversions at 8 weeks. One reason may be reduced linezolid levels after the first two weeks due to hepatic enzyme induction by rirampicin. The treatment of drug sensitive TB remains the same for the last almost 5 decades despite many trials, millions of dollars and enthusiastic efforts.