Linezolid dosing as part of three-drug regimen for drug-resistant TB
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In February, the CDC released provisional guidance for the use of pretomanid as part of the bedaquiline, pretomanid and linezolid (BPaL) regimen to treat drug-resistant tuberculosis.
The guidance gives considerations for administration, precautions and adverse events, and microbiological monitoring. It recommends the use of BPaL in adults with pulmonary extensively drug resistant (XDR), pre-XDR or treatment-intolerant/nonresponsive multidrug-resistant (MDR) TB, administered by direct observation for 26 weeks (or 39 weeks for those with a delayed response within the first 8 weeks).
The FDA-approved doses for BPaL, as outlined by the CDC, are pretomanid 200 mg daily for 26 weeks; bedaquiline 400 mg daily for 2 weeks, followed by 200 mg three times weekly for 24 weeks; and linezolid 1,200 mg daily with dose adjustments to 600 mg daily and further reduction to 300 mg daily or interruption of dosing as necessary for linezolid-adverse reactions of myelosuppression, peripheral neuropathy and optic neuropathy.
The guidance suggests that initiating with a reduced dose of linezolid 600 mg daily might be considered by some expert clinicians. Adverse effects of this regimen must be monitored closely, especially for hepatotoxicity, peripheral and optic neuropathy, myelosuppression, lactic acidosis, QT prolongation and pancreatitis. The 26-week regimen significantly shortens the length of treatment compared with prior treatments for XDR- or pre-XDR TB, which traditionally consisted of four to seven drugs for 15 to 24 months.
Introducing linezolid dosing changes to BPaL
In August 2019, the FDA approved pretomanid to use in combination with bedaquiline and linezolid (BPaL) to treat drug-resistant TB. Pretomanid is a nitroimidazooxazine that blocks cell wall production in actively replicating Mycobacterium tuberculosis (MTB) and kills nonreplicating MTB by nitric oxide release.
The BPaL regimen was studied in the open-label, single-group Nix-TB trial among people with XDR- and MDR-TB that was not responsive to treatment or for which a second-line regimen was discontinued because of side effects. The regimen consisted of bedaquiline 400 mg once daily for 2 weeks, followed by 200 mg three times weekly for 24 weeks; plus pretomanid 200 mg daily for 26 weeks; and linezolid at a dose of 1,200 mg daily for up to 26 weeks, with adjustments for toxicities when necessary. The linezolid dose initially was 600 mg twice daily (44 patients) but was changed to 1,200 mg daily (65 patients) during the study to evaluate if a single daily dose would have less exposure and toxicity.
The primary endpoint was the incidence of unfavorable outcome, which was treatment failure (bacteriological or clinical) or relapse during the 6-month follow-up from the end of treatment. Among 109 enrolled patients, 11 patients (10%) experienced an unfavorable outcome, including seven deaths, two relapses during follow-up, one loss to follow-up and one withdrawn consent. The other 98 patients (90%; 95% CI, 83%-95%) had a favorable outcome. Outcomes were similar when stratified according to TB type, with a favorable outcome in 89% (63/71) of XDR and 92% (35/38) of MDR patients, and results were consistent regardless of HIV status and linezolid dosing scheme.
Safety and adverse-event endpoints included all-cause mortality and the incidence of adverse events during the treatment period, defined as the start of treatment through 14 days after the end of treatment. All patients had at least one adverse event, and 17% had a serious adverse event, with 57% qualifying as grade 3 or higher. Adverse events due to linezolid were very common, with peripheral neuropathy reported in 81% of patients. The majority reported mild to moderate peripheral neuropathy, and the median time to no or mild neuropathy for those with moderate to severe neuropathy was 3 months. The time to first dose reduction or interruption of linezolid for neuropathy was generally after 3 months of treatment. Myelosuppression occurred in 48% of patients, and 37% of the study population experienced anemia with the onset of myelosuppression. This was most common during the first 2 months of treatment. The rates and times to onset of neuropathy or myelosuppression were similar irrespective of which dosing scheme of linezolid was used. A dose reduction or interruption of linezolid was very common, with 34% completing without any interruption — although the dose may have been reduced — and only 15% receiving no interruption or reduction.
Alternative linezolid dosing in BPaL
Following the Nix-TB trial, the ZeNix trial was initiated to evaluate varying doses of linezolid along with bedaquiline (200 mg daily for 8 weeks, followed by 100 mg daily for 18 weeks) and pretomanid (200 mg daily) among highly resistant TB.
Researchers randomly assigned 181 patients in a double-blinded format to linezolid 1,200 mg for 6 months (1,200L6M), 1,200 mg for 2 months (1,200L2M), 600 mg for 6 months (600L6M), or 600 mg for 2 months (600L2M). Similar to Nix-TB trial, there was a high rate of success. The 1,200L6M group had the highest rates of peripheral neuropathy and myelosuppression and need for dose modification. The data suggest that reduced doses and/or durations of linezolid have similar efficacy and improved safety (Table).
The BPaL regimen was initiated in an individual patient case in the United States for pulmonary XDR-TB. However, the linezolid dose was initiated at 600 mg daily because of the toxicities seen in the Nix-TB trial with 1,200 mg daily. Therapeutic drug monitoring of linezolid was performed with the goal of maintaining the linezolid peak between 12 and 26 µg/mL and trough less than 2 µg/mL to reduce toxicity. An 18-hour post-dose level a few weeks into therapy was 7.62 µg/mL. To maintain the peak but lower the trough, the dose was reduced to 600 mg every Monday, Wednesday and Friday. The follow-up trough was calculated at less than 2 µg/mL, and the patient completed 182 doses of BPaL over 26 weeks without treatment interruption. The only reported adverse effect was mild nausea, and there were no notable changes in laboratory values. The patient remained well 9 months after completion of treatment.
Further real-world experience with BPaL in the U.S. was described at IDWeek in 2021 for those who received therapy from August 2019 through May 2020. During this period, 17 patients received BPaL. The resistance pattern was MDR (eight patients), pre-XDR (eight patients), and unreported (one patient). A side effect was reported in 11 (65%) patients, with peripheral neuropathy being most common (five patients), followed by depression (four), vestibular changes (three) and vision changes (three). Sixteen (94%) patients received less than the initial approved dose of 1,200 mg linezolid daily, and 15 (88%) underwent therapeutic drug monitoring of linezolid exposure. At 12 months after BPaL initiation, all patients completed treatment without recurrence or death, indicating good outcomes may be achievable with lower linezolid doses.
The BPaL regimen significantly reduces the number of drugs needed and duration of treatment for drug-resistant — especially XDR — TB with high clinical treatment success. Reduced doses of linezolid from the original study of the BPaL regimen have shown reduced rates of neuropathy, myelosuppression and therapy interruption while maintaining similar rates of success. It appears reasonable to consider lower linezolid doses as part of the BPaL regimen, along with therapeutic drug monitoring of linezolid.
- References:
- CDC. Provisional CDC guidance for the use of pretomanid as part of a regimen [bedaquiline, pretomanid, and linezolid (BPaL)] to treat drug-resistant tuberculosis disease. https://www.cdc.gov/tb/topic/drtb/bpal/default.htm.
- Conradie F, et al. Abstract LB02. Presented at: International AIDS Society Conference on HIV Science; July 18-21, 2021 (virtual meeting).
- Conradie F, et al. N Engl J Med. 2020; doi:10.1056/NEJMoa1901814.
- Goswami N, et al. Open Forum Infect Dis. 2021;doi:10.1093/ofid/ofab466.1592.
- Haley C, et al. Emerg Infect Dis. 2021; doi: 10.3201/eid2701.203766.
- For more information:
- Kelly M. Percival, PharmD, BCPS AQ-ID, is a clinical pharmacy specialist in infectious diseases at University of Iowa Hospitals & Clinics. Percival can be reached at kelly-percival@uiowa.edu.
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