A 15 year-old girl with cystic fibrosis (Phe508del homozygous, FEV1 29%) infected with antibiotic-resistant Mycobaterium abscessus subspecies massiliense underwent double lung transplant. Severe post-surgery side effects necessitated discontinuation of i.v. antibiotics. Within 1 week M. abscessus was cultured from sputum, and granulomatous skin lesions were evident at the surgical incision and on the girl’s forearm. The patient was diagnosed with disseminated mycobacterial infection and discharged 7 months after surgery with a palliative care plan that included a novel antimicrobial therapy.
During this time the patient’s M. abscessus (designated GD01) was used to identify therapeutic phages from a collection of >10,000 phages. Three promising phages were identified – Muddy, ZoeJ and BPs. Recombineering of ZoeJ and a lytic derivative of BPs (BPsΔ33HTH) to remove a repressor gene and mutate portal gene 3, respectively, enhanced their lytic activity against GD01. No bacterial survival in vitro was observed using the engineered three-phage cocktail (Muddy-ZoeJΔ45-BPsΔHTH-HRM10). Topical therapy to the sternum wound was initiated followed by i.v. therapy (10^9 plaque forming units per dose of each phage, every 12h for 32 weeks). After 1 month the sterum wound had improved and 6 months later the patient continued to improve clinically. M. abscessus was detectable in the slowly-resolving skin nodules up to month 5, but was not isolated from serum or sputum at any point after initiation of phage therapy.
###Comment
Dedrick et al report the first therapeutic use of bacteriophages for human mycobacterial infection. In addition, this is the first time engineered phages have been administered to a human and shown a clinical improvement. Drug resistant mycobacterium and non-tuberculous mycobacterium (NTM, including M. abscessus) are difficult to manage clinically and when present prior to surgery can result in substantial post-surgery morbidity and mortality. This report demonstrates that i.v. phage treatment was well tolerated and associated with sternal wound closure, improved liver function and substantial resolution of infected skin nodules. Unfortunately, the phages identified here do not kill other M. abscessus clinical isolates efficiently and therefore this is not a generalizable treatment. However, the Science Alliance Phage Hunters Advancing Genomics and Evolutional Science (SEA-PHAGES) program from which these phages were identified may hold the cure for other NTM-infected patients.