단일 3차 의료기관 실제자료 분석과 의약품부작용보고시스템(KAERS)을 활용한 nontuberculous mycobacteria (NTM) 감염 환자에서 약물치료의 유효성 및 안전성 평가

Abstract

The incidence of nontuberculous mycobacteria pulmonary disease (NTM-PD) has been increasing worldwide. However, treatment options for NTM-PD have been limited by multidrug-resistant nature of these organisms and toxicities of antibiotics. Due to the lack of clinical studies related to NTM-PD treatment in Korea, the objectives of this study were to evaluate the efficacy of NTM-PD medication treatments and to identify the risk factors for adverse events (AEs) as well as the characteristics. Patients diagnosed with NTM-PD and treated at a tertiary-care hospital from January 2017 to December 2021 were enrolled in Part I study. The data of part I study were retrospectively collected from electronic medical records (EMRs). Patterns of treatment medications for NTM-PD were analyzed. The efficacy of medication treatments for NTM-PD was evaluated through microbiology results including culture conversion and improvement in clinical symptoms. The occurrence of AEs and potential drug-drug interactions were also evaluated for the safety of NTM-PD treatment. In addition, we used the Korea Adverse Event Reporting System database (KAERS DB) from 2017 to 2021 to evaluate clinical characteristics of various AEs and serious adverse events (SAEs) in medication treatments for NTM-PD patients in Part II study. Among the 972 patients diagnosed with NTM-PD during the part I study period, 747 patients were finally clinically diagnosed with NTM-PD, of which 273 patients initiated medication treatments. The most common causative organism for NTM-PD was M. intracellulare in 66.3%, M. avium in 10.9%, M. abscessus in 7.1%, and M. massiliens. As a result of the macrolides susceptibility test, most of MAC showed sensitivity, but 83.3% of M. abscessus had inducible resistance. Macrolides (clarithromycin and azithromycin), ethambutol and rifampin were mainly used for MAC-PD treatments, and intravenous aminoglycosides or beta-lactams were prescribed to 85% for M. abscessus. Approximately 43% of patients discontinued the NTM-PD treatment due to AEs or follow-up loss. Of the 197 patients who maintained the treatment for more than 12 months, 74 out of 96 who were able to confirm the microbiological results succeeded in "culture conversion," and 89 of the remaining 101 showed "clinical cure." SAEs occurred in about 30% of patients, and 16% and 11% of patients led to discontinuation of the suspicious drug and whole treatment, respectively. Serious potential drug-drug interactions were significantly increased with extra-pulmonary malignancy, diabetes, dyslipidemia, cardiovascular disease, immunosuppressant use, longer treatment duration and with AEs (odds ratio>1, p<0.05 for all). According to the analyses of 2017-2021 KAERS DB in Part II study, 1,034 AEs were reported for NTM-PD treatment, and the most common causative agents of AEs were ethambutol (19.1%), followed by rifampin (17.2%), azithromycin (12.6%), moxifloxacin (7.0%), clarithromycin (6.0%), levofloxacin (5.1%), amikacin (4.7%), cefoxitin (3.9%), imipenem (3.1%), linezolid (2.1%), ciprofloxacin (0.8%). SAEs were approximately 5% of the total AEs and the most frequently reported drugs for SAEs were rifampin, ethambutol, clarithromycin, and levofloxacin in order. MAC-PD was the main causative organism in NTM-PD, followed by M. abscessus. Compared to MAC-PD, a higher treatment failure rate was observed in infections caused by M. abscessus. AEs during NTM-PD treatments were the major causes of treatment discontinuation. Also, patients with NTM-PD treatments presented with a considerable number of important drug-drug interactions. Therefore, careful monitoring of AEs and drug-drug interactions is required for safe medication treatments in patients with NTM-PD. Further related studies are needed to confirm this study.