Lower Linezolid Doses Effective Against Highly Resistant TB

Various doses of the potent antibacterial linezolid (Zyvox) appeared to have similar effectiveness in clearing pulmonary tuberculosis (TB) infection in patients who have developed multidrug resistance to the infection, researchers reported.

In a four-arm study that compared linezolid doses of 600 and 1,200 mg given for either 2 or 6 months — along with standard doses of bedaquiline (Sirturo) and pretomanid — relapse-free status at 6 months was achieved by 84-93% of the patients diagnosed with highly drug-resistant TB, said Francesca Conradie, MBChB, of the University of Witwatersrand in Johannesburg.

“The ZeNix trial confirms the high relapse-free cure rate for the bedaquiline-pretomanid-linezolid regimen in highly resistant tuberculosis and suggests that reduced doses and/or shorter durations of linezolid than 1,200 mg for 6 months have similar efficacy and improved safety,” she said at a press conference at the virtual International AIDS Society Conference on HIV Science.

The late-breaker study was a follow-up to the team’s Nix-TB trial, which showed the three-drug therapy to be effective — “89% durable cure at 24 months” — in treating highly resistant TB in Africa, but was accompanied by a high rate of linezolid-related adverse events (AEs). The new study was an attempt to see if reducing the dosing of linezolid could reduce AEs and yet maintain effectiveness against the disease, Conradie explained.

She and her colleagues recruited 181 participants from South Africa, Russia, Georgia, and Moldova, who had been diagnosed with highly resistant TB. Patients were treated for 6 months with bedaquiline (200 mg daily for 8 weeks followed by 100 mg daily for 18 weeks); pretomanid (200 mg daily); and were randomized, dose-blinded, to daily linezolid starting at 1,200 mg for 6 months, 1,200 mg for 2 months, 600 mg for 6 months, or 600 mg for 2 months.

Clinical, laboratory, and sputum liquid culture evaluations were performed at baseline, weekly for 8 weeks, and then every 2 to 4 weeks through the end of treatment, monthly for 3 months, and at the primary endpoint of 6 months after completion of treatment.

Relapse-free rates after 1 year for the various doses of linezolid were as follows, the researchers reported:

• 1,200 mg daily for 6 months, 93%

• 1,200 mg daily for 2 months, 89%

• 600 mg daily for 6 months, 91%

• 600 mg daily for 2 months, 84%

Rates of peripheral neuropathy and myelosuppression, the main AEs related to linezolid, were as follows:

• 1,200 mg daily for 6 months, 38% and 29%, respectively

• 1,200 mg daily for 2 months, 24% and 15%

• 600 mg daily for 6 months, 24% and 13%

• 600 mg daily for 2 months, 13% and 16%

In addition, four patients experienced optic neuropathy that reversed, all in the arm receiving 1,200 mg linezolid for 6 months. Patients receiving lower doses or a shorter duration of treatment with linezolid were less likely to require linezolid dose modifications, Conradie and co-authors reported.

A co-moderator of the press conference, Hendrik Streeck, MD, director of the Institut of Virology and Institute for HIV Research at the University Bonn in Germany, called the new dosing findings “exciting results which could change treatment guidelines for highly drug-resistant tuberculosis, with real benefits for the patients.”

He also noted: “This month, we will mark 100 years since the BCG [bacille Calmette-Guerin] vaccine for tuberculosis was first administered. This vaccine has saved many lives — but unfortunately, it has very limited effectiveness and it is still the only tuberculosis vaccine we have. This anniversary is a reminder of the urgent need for improved prevention and treatment options, including for highly drug-resistant TB.”