Phage Therapy of Mycobacterium Infections: Compassionate Use of Phages in 20 Patients With Drug-Resistant Mycobacterial Disease

Abstract

Background Non-tuberculous Mycobacterium (NTM) infections, particularly Mycobacterium abscessus, are increasingly common among patients with cystic fibrosis and chronic bronchiectatic lung diseases. Treatment is challenging due to intrinsic antibiotic resistance. Bacteriophage therapy represents a potentially novel approach. Relatively few active lytic phages are available and there is great variation in phage susceptibilities among M. abscessus isolates, requiring personalized phage identification. Methods Mycobacterium isolates from 200 culture-positive patients with symptomatic disease were screened for phage susceptibilities. One or more lytic phages were identified for 55 isolates. Phages were administered intravenously, by aerosolization, or both to 20 patients on a compassionate use basis and patients were monitored for adverse reactions, clinical and microbiologic responses, the emergence of phage resistance, and phage neutralization in serum, sputum, or bronchoalveolar lavage fluid. Results No adverse reactions attributed to therapy were seen in any patient regardless of the pathogen, phages administered, or the route of delivery. Favorable clinical or microbiological responses were observed in 11 patients. Neutralizing antibodies were identified in serum after initiation of phage delivery intravenously in eight patients, potentially contributing to lack of treatment response in four cases but were not consistently associated with unfavorable responses in others. Eleven patients were treated with only a single phage, and no phage resistance was observed in any of these. Conclusions Phage treatment of Mycobacterium infections is challenging due to the limited repertoire of therapeutically useful phages, but favorable clinical outcomes in patients lacking any other treatment options support continued development of adjunctive phage therapy for some mycobacterial infections.

Mycobacteriophages: From Petri dish to patient

“…Screening of over 200 M . abscessus clinical isolates facilitated therapeutic interventions in at least 20 additional compassionate use cases of highly drug resistant Mycobacterium strains [ 115 ]. These revealed a further set of key insights.…”

Mycobacterium abscessus: It’s Complex

“…Recently, compassionate use with phage therapy was included in a pilot study in patients with various mycobacterial infections, untreatable with antibiotics, which showed positive clinical responses in 11 out of 20 patients [ 135 ]. Favorable or partial responses were observed in two patients with M. abscessus subsp.…”

“…massiliense , six patients with M. abscessus subsp. abscessus, one patient with M. chelonae , one patient with Mav complex, and one patient with disseminated BCG [ 135 ]. The development of phage treatments could provide a crucial tool for physicians when no other options are available.…”

Bacteriophage and Bacterial Susceptibility, Resistance, and Tolerance to Antibiotics

“…In addition, over the past 15 years, the interest in using bacteriophage therapy has been re-kindled in laboratories and hospitals. Despite mixed results from phage therapy clinical trials [ 23 , 24 , 25 ], there are multiple instances and case series of successful phage therapy using either conventional or modified phages [ 26 , 27 , 28 , 29 , 30 ]. Phage therapy is generally safe and well-tolerated [ 31 ], although many questions remain regarding the optimal dosages and treatment regimens [ 32 ].…”