Novel therapies for treatment of resistant and refractory nontuberculous mycobacterial infections in patients with cystic fibrosis

Abstract

Respiratory infections caused by non‐tuberculous mycobacteria (NTM) are a major cause of morbidity for patients living with cystic fibrosis (CF), as NTM pulmonary disease (NTM‐PD) is challenging to both diagnose and eradicate. Despite the lengthy courses of the established regimens recommended by the Cystic Fibrosis Foundation (CFF) and European Cystic Fibrosis Society (ECFS) consensus guidelines, only about 50% to 60% of patients achieve culture conversion, and treatment regimens are often complicated by antibiotic resistance and toxicities. Since publication of the CFF/ECFS guidelines, several new or alternative antibiotic regimens have been described for patients with CF who have NTM‐PD. These regimens offer new options for patients who do not clear NTM with standard therapies or cannot utilize the usual regimens due to toxicities or drug‐drug interactions.

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

“…Although less active against NTM compared with M. tuberculosis , bedaquiline has demonstrated in vitro bacteriostatic activity against MAC and M. abscessus . However, a real-world case series with a limited number of patients (n = 10) suggested that although it was able to improve symptoms and decrease bacterial load, sustained culture conversion after 6 months of treatment was not observed [ 96 ]. A Phase II/III trial to evaluate the efficacy and safety of treatment regimens containing bedaquiline in patients with refractory MAC-PD is currently underway (trial registration: NCT04630145).…”

“…One example is tedizolid, an oxazolidinone typically used to treat acute bacterial skin and skin structure infections (ABSSSI), which has demonstrated efficacy in a macrophage model and in a case study of an immunocompromised patient with M. abscessus infection. Omadacycline, also more commonly used for ABSSSI, has similarly demonstrated significant in vitro activity against M. abscessus , but clinical data are currently limited to case series [ 96 , 97 ].…”

“…Bacteriophage therapy provides another potential novel approach to treat NTM-PD [ 96 , 98 ], which uses viruses that infect and neutralise infecting bacteria. Although clinical data are currently lacking, a case report of a patient with disseminated M. abscessus infection where pulmonary disease predominated demonstrated clearance of infection after receiving treatment with multiple phages [ 98 ].…”

“…Another candidate in development is granulocyte–macrophage colony stimulating factor (GM-CSF), which contributes to macrophage activation. Inhalation of GM-CSF may have the potential to enhance the host defence mechanism against M. abscessus [ 96 ]. A study to explore its utility in M. abscessus infection (ENCORE) was terminated in 2021 because of COVID-19 limitations and another (OPTIMA) was completed in 2020, with initial results demonstrating that in patients with severe disease, inhaled GM-CSF did not significantly improve culture conversion rates, although a slight reduction in bacterial load was observed (trial registration: NCT03597347; NCT03421743) [ 101 ].…”

The host-directed therapeutic imatinib mesylate accelerates immune responses to Mycobacterium marinum infection and limits pathology associated with granulomas

“…Importantly, Mtb strains resistant to some or all available antibiotics have emerged [ 5 , 6 ], including stains resistant to newly developed antibiotics such as bedaquiline, delamanid, and pretomanid [ 7 , 8 ], highlighting the need for novel treatment strategies for TB. Similarly, antibiotic resistance is of significant concern in infections caused by nontuberculous mycobacteria [ 9 , 10 ].…”