Phage Therapy for Nontuberculous Mycobacteria: Challenges and Opportunities

Abstract

Non-tuberculous mycobacterium (NTM) infections are often clinically challenging, with lengthy antibiotic regimens that fail to resolve the infections with few good outcomes remaining. Mycobacteriophages-viruses that infect Mycobacterium hosts-show promise as therapeutic agents for NTM infections and have been used in 20 compassionate use cases. Favorable outcomes were observed in many but not all cases, although the phages show exceptional safety profiles and no evidence of phage resistance was observed, even when only a single phage was administered. Phage-specific antibodies are commonly present following intravenous administration and are often neutralizing for the phage in vitro. However, phage neutralization does not consistently correlate with poor treatment outcomes and may not be a therapeutic limitation in all patients, even when immunocompetent. Currently, the therapeutic potential of phages is substantially limited by the great variation in phage susceptibility and a relatively small repertoire of therapeutically useful phages. As many as 45% of clinical isolates can have a smooth colony morphotype, and phages that both efficiently infect and kill these strains have yet to be described. In contrast, * 75% of rough strains are susceptible to and killed by one or more phages and therapeutic options can be considered on a compassionate use basis. Although therapies must currently be personalized, elucidating the determinants of phage host specificity, expanding the useful phage repertoire, and identifying the key determinants of clinical outcomes will reveal their full therapeutic potential.

Biophysical Breakthroughs Projected for the Phage Therapy of Bacterial Disease

“…The following quotations make this point from the perspective of active phage therapy trials. "Currently, the therapeutic potential of phages is substantially limited by the great variation in phage susceptibility and a relatively small repertoire of therapeutically useful phages" [80]. "Although several scientific organizations/societies recognized that phage therapy could be of key value in modern wound care, specific aspects are critical for a burn surgeon and might represent pitfalls discouraging phage therapy adoption in burn wound management; in particular, the unavailability of consensual therapeutic guidelines/regulatory policies and the lack of laboratorial support that might be predictive of its efficacy" [13].…”

Sequence analysis of Discoknowium, an A5 mycobacteriophage

“…A growing body of research has documented the importance of bacteriophages in the mammalian microbiome, not only for understanding microbial dynamics but also for therapeutic applications ( 1 – 4 ). We therefore employed a rat fecal sample to isolate phages that infect Mycobacterium smegmatis , from a genus with pathogenic members that are increasingly developing antibiotic resistance ( 5 – 8 ).…”

Mycobacteriophages in diagnosis and alternative treatment of mycobacterial infections

“…Limited case reports about phage therapy against mycobacterial infection are currently available ( Table 2 ) ( Allué-Guardia et al, 2021 ; Hatfull, 2023 ). However, the idea of using mycobacteriophages to treat patients has long been discovered.…”