Treatment of severe Mycobacterium avium complex pulmonary disease with a adjunctive amikacin and clofazimine versus standard regimen alone, a retrospective study

Abstract

Mycobacterium avium complex (MAC) bacteria, i.e. Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium chimaera and related species, can cause severe pulmonary disease (MAC-PD), especially in patients with chronic pulmonary diseases, like COPD and bronchiectasis [1, 2].Treatment of MAC-PD is difficult due to its long duration, frequent adverse events and comorbidities of the host. Reported cure rates vary by disease manifestation, with poorest cure rates in fibrocavitary disease [3]. The currently recommended treatment for MAC-PD is a combination of a rifamycin (R), ethambutol (E) and a macrolide (M), preferably azithromycin [4]. In severe disease, amikacin (A) can be added to improve treatment outcome, but there is no direct evidence to support its role [4].Clofazimine (C), an old anti-leprosy drug, may add efficacy to MAC-PD treatment regimens. In vitro, clofazimine shows synergy with amikacin and macrolides against MAC [5,6]. In retrospective studies, the outcomes of treatment regimens in which clofazimine replaces rifamycin are similar to those of the recommended REM regimen [7][8][9].In our nontuberculous mycobacterium (NTM) reference clinic, patients with severe MAC-PD have been receiving intensified treatment with the REMAC regimen since 2013. Here, we evaluate its outcome, as compared to a cohort that only received the REM regimen.We conducted a retrospective cohort study of adults (>18 years) with macrolide-susceptible MAC-PD diagnosed according to current guidelines [4], treated from January 2007 until January 2017 in our reference clinic (last check: March 2021). A waiver from the local ethical board has been given for this retrospective study. Patients were classified into two groups: the REM group and the REMAC group. Amikacin was given intravenously at a 15-mg•kg −1 initial dose with therapeutic drug monitoring and clofazimine was dosed at 100 mg once daily. We collected demographic and treatment related data from the electronic medical records. Disease was classified as fibrocavitary or nodular-bronchiectatic and followed up on basis of chest computed tomography reports and a second assessment by two expert pulmonologists (C. Magis-Escurra and W. Hoefsloot). Disease severity and thus indication for REMAC treatment was assessed by the multidisciplinary team (all authors) on the basis of symptoms, immune status, frailty, extent of radiological abnormalities and microbiology (i.e. sputum smear status and quantitative culture).Patients who received either amikacin or clofazimine, or who used amikacin for <2 weeks were excluded from the analysis. Primary outcome measurements were time until sputum culture conversion and cure rates. Outcomes were defined using the NTM-NET definitions [10], except that microbiological cure and culture conversion were defined by two, rather than three, consecutive negative cultures.

The role of amikacin in the treatment of nontuberculous mycobacterial disease

“…The most frequent and likely amikacinrelated adverse events reported were hearing loss (mean 7%, range 0-37%), tinnitus (mean: 6%, range 0-42%) and nephrotoxicity (mean: 2%, range 0-7%). The lowest rates of toxicity were recorded in a study that mostly applied thrice weekly dosing of amikacin [100]; studies using daily doses of 15 mg/ kg reported the highest frequencies of adverse events [78,83].…”

“…There are no direct comparisons of streptomycin versus amikacin. The clinical efficacy of amikacin has been shown only in one small retrospective study comparing rifampicin-ethambutol-macrolide regimens with similar regimens to which amikacin and clofazimine were added, showing similar outcomes (80% cure rate with 3 drugs, 90% with 5 drugs) despite more severe disease in the 5-drug cohort [83]. The clinical efficacy of amikacin was mainly studied in non-comparative studies in the context of macrolide-resistant MAC-PD [84,85].…”

“…Its benefits are mostly in the short term, i.e. faster and more frequent culture conversion [1,82,83], but its impact on long-term treatment outcomes are less obvious and require further studies. Previous guidelines have also recommended amikacin inhalation in the continuation phase of M. abscessus treatment, in CF and non-CF patients [97,101].…”

European Respiratory Society International Congress, Madrid, 2019: nontuberculous mycobacterial pulmonary disease highlights

“…Another study presented at ERS 2019 explored the combination of amikacin and clofazimine on MAC infection [ 49 ]. In this study, patients were treated with either rifampicin/ethambutol/macrolide (n=25) or rifampicin/ethambutol/macrolide plus amikacin/clofazimine (n=19).…”