Drug-resistant tuberculosis treatment

Dosing of linezolid. The linezolid dosage used in the Nix-TB study was 1200 mg per day. Initially, 
all study participants received 600 mg of linezolid BID, because that was the approved dose used to 
treat bacterial infections for up to 28 days at the time the study commenced. However, in May 2018, 
the protocol was changed to dosing of 1200 mg QD. According to the protocol, dose reduction to 
600 mg daily, and further to 300 mg daily or temporary cessation of linezolid, was permitted for up 
to 35 consecutive days for any known linezolid adverse reactions of myelosuppression, peripheral 
neuropathy and optic neuropathy. If toxicity prohibited further treatment with linezolid, patients 
could remain on bedaquiline and pretomanid, provided that they had received the 1200 mg per day 
dose for at least the first 4 consecutive weeks, were sputum smear negative, and were responding to 
treatment based on clinical monitoring and follow-up. Missed doses of linezolid were not made up 
during the Nix-TB study, and dose modifications for bedaquiline and pretomanid were not allowed. 
Overall, 18 patients (17.3%) in the Nix-TB study completed a full course of linezolid at the 1200 mg 
dose, 38 (36.5%) completed with a 600 mg dose, 16 (15.4%) completed with a 300 mg dose and 32 
(30.7%) stopped linezolid early due to an adverse event. The experience of the Nix-TB study suggests 
that it may be necessary to modify the dose of linezolid during treatment based on adverse events, 
highlighting the importance of close monitoring and patient follow-up, and aDSM. Additional studies 
such as the ZeNix study (TB Alliance) are underway to assess the optimal dosing and duration of 
linezolid for the treatment of drug-resistant TB; however, the results of these studies are not yet 
available for review. 
To date, the BPaL regimen has been studied as a standardized course of treatment. Modification of the 
regimen through early discontinuation or replacement of any of the component medicines may result 
in poor treatment outcomes. The pretomanid product label recommends that if either bedaquiline 
or pretomanid tablets are discontinued, the entire BPaL regimen should also be discontinued. If 
linezolid is permanently discontinued during the initial 4 consecutive weeks of treatment, bedaquiline 
and pretomanid should also be discontinued. If linezolid is discontinued after the initial 4 weeks 
of consecutive treatment, clinicians should continue administering bedaquiline and pretomanid, 
consistent with the Nix-TB study protocol. In the Nix-TB study, it was necessary for patients to 
complete 6 months of the regimen (i.e. 26 weeks of prescribed doses) within 8 months; for those 
in whom treatment was extended, it was necessary for patients to complete 9 months of treatment 
(i.e. 39 weeks of prescribed doses) within 12 months. Patients who remained culture positive or who 
reverted to being culture positive between months 4 and 6, and whose clinical condition suggested 
they may have ongoing TB infection, had their treatment extended to a total of 9
months.