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Linezolid-for-Ethambutol Pulmonary TB Therapy Fails to Outperform Existing Treatment Options

Linezolid failed to outperform existing treatments in a new study of patients with pulmonary tuberculosis (TB), but investigators say the antibiotic may still have a role to play in shortening the course of treatment.

Typically, patients with drug-resistant pulmonary TB are given an intensive 2-month course of isoniazid, rifampicin, pyrazinamide, and ethambutol, after which pyrazinamide and ethambutol are dropped while the other 2 drugs are continued for 4 more months.

“Although this regimen is highly effective, the long duration of treatment increases the likelihood of adverse events (AEs) while decreasing patients' adherence to anti-tuberculosis drugs,” wrote Jung-Kyu Lee, MD, of Seoul Metropolitan Government–Seoul National University Boramae Medical Center, first author of the new research published in The Lancet Infectious Diseases.

In fact, 16.8% of people on the 6-month course of treatment were non-adherent in a clinical-setting study. In the real world setting, one study found non-adherence was 3 times that—48%.
In search of a better treatment, Lee and a team of South Korean colleagues decided to investigate what would happen if doctors replaced ethambutol with a shorter course of linezolid. Linezolid has already been shown to be highly effective at combating multidrug-resistant TB (MDR-TB).

“On the basis of its impressive effects among patients with MDR-TB, we [hypothesized] that linezolid could increase the proportion of 2-month negative culture conversion of sputum in patients with drug-susceptible pulmonary tuberculosis,” Lee and colleagues wrote.

Between 2014 and 2017, the investigators recruited 429 patients, 428 of whom were then assigned to 1 of 3 groups. The control group received the current standard care, with the 4-drug combination for the first 2 months followed by 4 more months of just isoniazid and rifampicin. A second group received all of the drugs except ethambutol, but also received linezolid for the first 2 weeks of therapy. A third group received the same treatment as the second group, except they were prescribed linezolid for 4 weeks.

The patients were treated at one of 4 South Korean hospitals; they were all between the ages of 20 and 80.

A total of 401 patients were included in the study’s modified intent-to-treat analysis. Most of those excluded from the analysis (18) were excluded due to non-adherence to the protocol. In that analysis, the 2-week linezolid group outperformed the control group in achieving the primary endpoint of negative cultures at 8 weeks (82% versus 77%). The 4-week linezolid group performed roughly the same as the control group (76%).

Only 325 patients were included in the per-protocol study. The investigators said the biggest reason for exclusion from that analysis was lack of information about patient outcomes.

In that analysis, both the 2-week linezolid group (96%) and the 4-week linezolid group (90%) out-performed the control group (82%) at 8 weeks.

Lee and colleagues said the differences in culture conversion between the two analyses were most likely due to differences in attrition rates among the groups. And while the 2-week course of linezolid seemed to be more effective than the other 2 regimens, the authors noted that it did not match the performance of other new treatment regimens that are slightly shorter but achieved 97%-99% culture conversion rates.

However, linezolid showed a positive safety profile, and the drug seemed to work in many patients. Thus, investigators say additional research is warranted to see where linezolid might fit into TB protocols.

“Given that linezolid-including regimens yielded higher proportions of culture conversion at 8 weeks, as well as at earlier time points, linezolid could be considered for new shorter regimens for drug-susceptible tuberculosis,” Lee and colleagues wrote. “Various combinations, including linezolid and other existing or newly developed anti-tuberculosis drugs, could be tested in the future.”
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