Analysis of adverse drug events in pulmonary Mycobacterium avium complex disease using spontaneous reporting system

Abstract

Background In Japan, Mycobacterium avium complex lung disease (MAC-LD) is the most common in nontuberculous mycobacterial lung disease. Patients often experience adverse events, resulting in the discontinuation of treatment, which causes treatment failure. The JADER (Japanese Adverse Drug Event Report) database is a database of adverse events that allows us to collect real-world data on adverse events. We can collect large-scale data cost-effectively and detect signals of potential adverse events such as reporting odds ratio (ROR) by using spontaneous reporting systems. In this study, we aimed to elucidate the adverse events of clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) using the JADER database. Methods We included cases of MAC-LD between April 2004 and June 2017. We investigated sex, age, and medications that may have caused the adverse events, outcomes, and time of onset. We calculated the safety signal index as the ROR. Time-to-event analysis was performed using the Weibull distribution. Results The total number of adverse events of CAM, EB, and RFP was 2780, with 806 patients. In the overall adverse events, hematologic and lymphatic disorders were the most common adverse events, with 17.3%, followed by eye disorders (16.6%), and hepatobiliary disorders (14.0%). The outcomes were as follows: recovery, 40.0%; remission, 27.1%; non-recovery, 11.2%; and death, 7.1%. Regarding the most common onset time of CAM, EB, and RFP was within 120 days at 40%, 181–300 days at 43.6%, and within 120 days at 88.5%. For CAM, the RORs of infections and infestations, hepatobiliary system disorders, and immune system disorders were 4.13 (95% confidence interval [CI], 2.3–7.44), 2.61 (95% CI, 1.39–4.91), and 2.38 (95% CI, 1.04–5.44). For EB, the ROR of eye disorders was 215.79 (95% CI, 132.62–351.12). For RFP, the RORs of renal and urinary tract disorders and investigations were 7.03 (95% CI, 3.35–14.77) and 6.99 (95% CI, 3.22–15.18). The β value of EB was 2.07 (95% CI, 1.48–2.76), which was classified as a wear-out failure type. Conclusions For MAC-LD, the adverse event which has the highest ROR is infections and infestations in CAM, eye disorders in EB, renal and urinary tract disorders in RFP. Adverse events of EB occur after 180 days, whereas the adverse events of CAM and RFP occur early in the course of treatment.

Variables associated with antibiotic treatment tolerance in patients with Mycobacterium avium complex pulmonary disease

“…ADRs including gastrointestinal symptoms, loss of visual acuity, loss of auditory acuity and leukopenia have been frequently described in association with guideline-based treatment and can complicate therapy [ 7 , 10 ]. Prior studies have found that cytopenias and hepatotoxicity are some of the more common ADR’s and that while some may present early in a patient’s treatment course, others, like reactions to ethambutol, may present many months into treatment [ 11 , 12 ]. Identifying which patients are more likely to suffer from ADRs is not well described.…”

Targeted and efficient delivery of rifampicin to macrophages involved in non-tuberculous mycobacterial infection via mannosylated solid lipid nanoparticles

“…Treatment is also oen discontinued due to long treatment periods, slow progress, and side effects associated with oral and parenteral administration of the drug, such as gastrointestinal distress, skin rashes, renal failure, and liver toxicity. 1,9,10 Among other challenges, the rise of drug resistance in the treatment of mycobacteria is one of the major obstacles to curing this disease. 11,12 Therefore, strategies to deliver existing drugs more efficiently are needed to shorten treatment duration, reduce drug resistance, and improve patient adherence.…”