Meeting the challenges of NTM-PD from the perspective of the organism and the disease process: innovations in drug development and delivery

Abstract

Non-tuberculous mycobacterial pulmonary disease (NTM-PD) poses a substantial patient, healthcare, and economic burden. Managing NTM-PD remains challenging, and factors contributing to this include morphological, species, and patient characteristics as well as the treatment itself. This narrative review focusses on the challenges of NTM-PD from the perspective of the organism and the disease process. Morphological characteristics of non-tuberculous mycobacteria (NTM), antimicrobial resistance mechanisms, and an ability to evade host defences reduce NTM susceptibility to many antibiotics. Resistance to antibiotics, particularly macrolides, is of concern, and is associated with high mortality rates in patients with NTM-PD. New therapies are desperately needed to overcome these hurdles and improve treatment outcomes in NTM-PD. Amikacin liposome inhalation suspension (ALIS) is the first therapy specifically developed to treat refractory NTM-PD caused by Mycobacterium avium complex (MAC) and is approved in the US, EU and Japan. It provides targeted delivery to the lung and effective penetration of macrophages and biofilms and has demonstrated efficacy in treating refractory MAC pulmonary disease (MAC-PD) in the Phase III CONVERT study. Several other therapies are currently being developed including vaccination, bacteriophage therapy, and optimising host defences. Newly developed antibiotics have shown potential activity against NTM-PD and include benzimidazole, delamanid, and pretomanid. Antibiotics commonly used to treat other infections have also been repurposed for NTM-PD, including clofazimine and bedaquiline. Data from larger-scale studies are needed to determine the potential of many of these therapies for treating NTM-PD.

Evaluation of mycobacteria infection prevalence and optimization of the identification process in North Sardinia, Italy

“…For the NTM, the most common resistances detected in our study are linezolid and fluoroquinolone (ciprofloxacin and moxifloxacin). Linezolid resistance was usually induced by 23S rRNA gene mutation, while fluoroquinolone resistance was induced by DNA gyrase or topoisomerase mutation ( 35 , 36 ). The AST results of NTM are grim too.…”

Omadacycline, Eravacycline, and Tigecycline Express Anti-Mycobacterium abscessus Activity In Vitro

“…Usually, the regimen is composed of an oral macrolide, intravenous amikacin, and ≥1 additional antibiotics, e.g., tigecycline (TGC), imipenem, or cefoxitin administered intravenously ( 10 ). While treatment with TGC has achieved certain success, adverse effects such as nausea and vomiting, and the requirement for intravenous administration limit its use ( 11 , 12 ). The development of new therapies that utilize antibiotics that exhibit comparable or better anti- M. abscessus activity, improved bioavailability, and fewer adverse side effects are urgently needed.…”

Clinical characteristics of patients with non-tuberculous mycobacterial pulmonary disease: a seven-year follow-up study conducted in a certain tertiary hospital in Beijing

“…The prevalence of NTM-PD is increasing worldwide, with recent reports estimating a prevalence of 2.3-6.5 per 100,000 in Europe ( Prevots and Marras, 2015 ; Ringshausen et al., 2016 ; van der Laan et al., 2022 ). In Japan, prevalence rates were even higher at an estimated 33-65 cases per 100,000, and in the United States, incidence rates were 3.1 per 100,000 in 2008, increasing to 4.7 per 100,000 in 2015 ( Morimoto et al., 2014 ; Winthrop et al., 2020 ; Schildkraut et al., 2021 ).…”