Mechanisms of Resistance, Insights From Case Reports, and Future Prospects in Mycobacteriophage Therapy

Evolution of drug-resistant mycobacterial infections warrants renewed efforts in identifying more efficient preventive and control strategies as well as alternative treatment options. Interest in phage therapy is regaining significant traction, especially in cases of failed conventional therapy. However, phage therapy faces challenges, including the identification of a suitable therapeutic phage, phage delivery, phage resistance, and host immunity. This article reviews existing clinical literature on the therapeutic use of mycobacteriophages as adjuncts to antibiotics in the treatment of drug-resistant mycobacterial infections and discusses such aspects as mycobacterial phage resistance, coevolutionary phage training, and impact of host immunity, as well as the benefits and limitations of phage therapy. To date, at least 27 patients received mycobacteriophage therapy, where M. abscessus accounts for 82.1% of all cases in contrast to M. chelonae (7.1%), M. avium complex (3.6%), and BCG (3.6%). Mycobacteriophages used were either wild-type or derivatives of BPs, D29, Fionnbharth, Fred313, Itos, Muddy, or ZoeJ. Evolution of phage resistance is rare, and the impact of host immunity varies between patients, with most treatment outcomes having little to do with immune responses. However, identification of a suitable therapeutic mycobacteriophage remains a pressing challenge, especially for infections involving the smooth morphotype of M. abscessus. Only about 10 mycobacteriophages made it to clinical use, including wild-type, host range mutants and engineered derivatives, which warrants the expansion of this narrow arsenal of therapeutic mycobacteriophages by building novel candidates or expanding the host ranges of existing ones. The outcomes recorded in these case reports represent a significant achievement. However, the results remain exploratory due to sample size limitations and therefore warrant larger, methodologically rigorous, controlled trials in the future.