Use of linezolid to replace kanamycin in the shorter MDR-TB regimen in case of hearing loss: experience in Niger.

Aims and objectives: The standardized short treatment regimen (STR) is implemented in Niger to treat multidrug-resistant tuberculosis (MDR-TB) since 2008 with excellent outcomes. However, ototoxicity secondary to injectable is a concern and data on modified oral STR are limited. The aim of this study is to test if linezolid can replace the injectable. Both drugs have a similar mechanism of action and the use of linezolid in replacement of SLI may preserve bedaquiline as core-drug in a salvage regimen to treat possible failures and relapses. Linezolid is used only in the intensive phase to reduce the risk of peripheral neuropathy and optic neuritis. Methods: A prospective longitudinal study was conducted on a modified STR replacing kanamycin with linezolid (600 mg/d) in case of hearing loss (grade 1) at baseline or during treatment. WHO definitions were used for outcomes and adverse events were assessed according to French National Agency for Research on AIDS. Audiometry was performed bimonthly from 2016 to 2017 and monthly from 2018 onwards. Results: A total of 173 patients were treated with the STR for pulmonary MDR-TB from 2016 to June 2018. Among them, 22 (12.7%) had a modified STR, switching from kanamycin to linezolid during treatment (14) or starting with linezolid (8) because of hearing loss. Fourteen (63.6%) were males, 2 (9.1%) were HIV positive, the median age was 37.5 years (range 21-71) and the median BMI was 16.5 kg/m2 (range 13-24.2). No patients had strains resistant to fluoroquinolones and/or injectables. The median time from treatment start to switch kanamycin to linezolid was 2 months (range 0-3) and the median duration of treatment with linezolid was 2 months (range 1-5). All patients had smear and culture conversion with a median and range of 1 month (1-6) and 2 months (2-4) respectively. Nineteen patients (86.4%) were cured and 3 died of respiratory failure (2) and severe immunosuppression (1). Eighteen patients were assessed for follow-up 6 months and 12 were assessed 12 months after cure. All remained smear and culture negative. Severe adverse events were anaemia in 5 cases (22.7%) with a median onset of 1 month (range 1-3) and thrombocytopenia in 1 case (4.5%). Linezolid was temporarily discontinued and these patients received blood transfusions. The drug was reintroduced at reduced dosage (300 mg) with no further problems. Seven patients (31.8%) had a reversible mild to moderate peripheral neuropathy which was reversible at the end of treatment. No patients had optic neuritis. From 2016 onwards no serious hearing loss secondary to SLI use was detected nationwide in Niger. Conclusions: A modified STR with linezolid may achieve high cure rates with manageable adverse events.