Linezolid is by far the most toxic drug in the BPaLM and BPaL regimens; it requires significant monitoring and at times a mitigation strategy to reduce adverse effects. Although it is preferred to continue linezolid at the full dose for the entire duration, the dose of linezolid can be reduced to 300 mg or discontinued (and restarted when possible) if there is significant toxicity. In general, action should be taken in the following manner for the common toxicities associated with linezolid:
- for optic neuritis diagnosed at any grade, permanent discontinuation of linezolid is indicated;
- for peripheral neuropathy Grade 2, reduce the dose of linezolid to 300 mg per day with a possible drug holiday for 1–2 weeks before dose reduction;
- for peripheral neuropathy Grade 3 or 4, in most cases permanent suspension of linezolid will be needed; in some cases, after a 1–2-week drug holiday and reversion to Grade 2, the linezolid can be restarted and tolerated, provided it does not revert back to a Grade 3 or 4 (caution is warranted with this approach because patients can be left with a severe painful and disabling permanent peripheral neuropathy); and
- myelosuppression (even of Grade 3 or 4) is often reversible with a short 1-to-2-week drug holiday followed by reducing the dose of linezolid to 300 mg per day; severe anaemia may need to be treated with transfusions or erythropoietin.
The adverse events were noted more frequently in regimens using high-dose linezolid (1200 mg/daily). In the ZeNix study, 18.6% (8/43) participants in the study arm using linezolid 1200 mg daily for up to 26 weeks experienced a Grade 3 or more adverse event compared with 14.0% (6/43) participants in the intervention arm using 600 mg of linezolid for 26 weeks, and 19.6% (20/102) of participants in the BPaL arm using linezolid 600 mg or 300 mg in the TB-PRACTECAL trial (1). The most common adverse events resulting in dose modifications or early interruption of linezolid in the Nix-TB study were peripheral neuropathy and myelosuppression. Although optic neuritis was infrequent, it is an important adverse event that can result in the early interruption of linezolid. In comparison, in the ZeNix and TB-PRACTECAL trials, more than 90% of participants were able to complete more than 75% of the maximal intended dose and duration of linezolid. Peripheral neuropathy and myelosuppression were noted in both trials, but were often not severe and they improved with dose reductions or cessation of linezolid. A toxicodynamic modelling study using Nix-TB data showed lower percentages of patients with severe peripheral neuropathy (median, 5% versus 19%) and severe anaemia (1% versus 15%) in patients using 600 mg compared with 1200 mg linezolid daily (23).