Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis.

Area of Science:

• Infectious Diseases
• Pharmacology
• Clinical Medicine

Background:

• Highly drug-resistant tuberculosis (TB) poses a significant treatment challenge.
• The bedaquiline-pretomanid-linezolid regimen demonstrates high efficacy but is associated with significant adverse events, particularly at higher linezolid doses.
• Optimal dosing and duration of linezolid in combination regimens for drug-resistant TB require further investigation to balance efficacy and safety.

Purpose of the Study:

• To evaluate the efficacy and safety of different doses and durations of linezolid when combined with bedaquiline and pretomanid for treating extensively drug-resistant (XDR) or pre-XDR tuberculosis.
• To determine the optimal linezolid dose and treatment duration that minimizes toxicity while maintaining high treatment success rates.

Main Methods:

• A randomized clinical trial involving participants with XDR, pre-XDR, or treatment-failure rifampin-resistant TB.
• Participants received bedaquiline (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks) and pretomanid (200 mg daily for 26 weeks) combined with linezolid at varying doses (1200 mg or 600 mg daily) and durations (9 or 26 weeks).
• Primary endpoint was the incidence of unfavorable outcomes (treatment failure or relapse) at 26 weeks post-treatment; safety assessments included adverse events like peripheral neuropathy, myelosuppression, and optic neuropathy.

Main Results:

• Favorable outcomes ranged from 84% to 93% across the four treatment arms.
• The group receiving 1200 mg of linezolid daily for 26 weeks experienced high rates of peripheral neuropathy (38%) and myelosuppression (22%), with 51% requiring dose modification.
• The regimen with 600 mg of linezolid daily for 26 weeks showed a favorable outcome rate of 91% with significantly lower rates of peripheral neuropathy (13%), myelosuppression (7%), and dose modification (13%).

Conclusions:

• The bedaquiline-pretomanid-linezolid regimen is highly effective for drug-resistant tuberculosis, with favorable outcome rates between 84-93%.
• A daily dose of 600 mg of linezolid for 26 weeks, in combination with bedaquiline and pretomanid, presents a superior risk-benefit profile.
• This optimized regimen significantly reduces adverse events and linezolid dose modifications while maintaining high efficacy, making it a preferred option for treating challenging TB cases.