1380. Safety of Repurposed Drugs for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: An Analysis of Adverse Events Reported in the Literature

Abstract

Background. Multi and extensively drug-resistant (MDR and XDR) tuberculosis (TB) remains a treatment challenge due to drug adverse events (AEs) and long regimens. Our aim was to identify AEs which resulted from repurposing drugs for MDR and XDR-TB. Methods. A PubMed search for case reports of repurposed drugs for MDR and XDR-TB from January 1, 2014 to October 23, 2018 identified 130 patients (78 MDR, 52 XDR) in 91 articles. There were 31 extrapulmonary, 81 pulmonary TB cases, and 18 with both. Drugs were regarded as repurposed if they were either not approved for TB by the FDA, or they were approved for TB but were used in novel populations, novel combinations, or nonstandard doses. Drug labels were reviewed for AEs. Results. Linezolid (n = 65) and moxifloxacin (n = 48) were the most commonly repurposed drugs. The following were also frequently used: clofazimine (n = 47), levofloxacin (n = 45), amikacin (n = 43), amoxicillin-clavulanate (n = 40), kanamycin (n = 36), carbapenems (n = 22), and clarithromycin (n = 17). Of the drugs that are approved for TB, the following were repurposed in a novel population, dose, or combination: cycloserine (n = 20), bedaquiline (n = 13), capreomycin (n = 4), ethambutol (n = 3), and isoniazid (n = 3). Treatments were discontinued due to AEs in 41 patients. There were no discontinuations for amoxicillin-clavulanate and levofloxacin. Extended drug exposure is a unique treatment feature for MDR and XDR-TB, which often requires ∼2 years of treatment. Approximately 87% of treatment discontinuations due to AEs occurred after >1 month of exposure. AEs leading to treatment discontinuation after > 6 months of drug exposure were seen in 15 cases, of which 12 were due to linezolid and cycloserine. Peripheral and optic neuropathy was the most common AE reported (linezolid n = 12, cycloserine n = 1). Most AEs were labeled events. Conclusion. Several antimicrobials are being repurposed to treat MDR and XDR-TB. There were no AEs reported after prolonged use that was not described in drug labels. Physicians should review information in labeling if prescribing drugs in this manner. There is a need for comparative safety data for repurposed drugs assessed through clinical trials.