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

Rebekah M Dedrick; Bailey E Smith; Madison Cristinziano; Krista G Freeman; Deborah Jacobs-Sera; Yvonne Belessis; A Whitney Brown; Keira A Cohen; Rebecca M Davidson; David van Duin; Andrew Gainey; Cristina Berastegui Garcia; C R Robert George; Ghady Haidar; Winnie Ip; Jonathan Iredell; Ameneh Khatami; Jessica S Little; Kirsi Malmivaara; Brendan J McMullan; David E Michalik; Andrea Moscatelli; Jerry A Nick; Maria G Tupayachi Ortiz; Hari M Polenakovik; Paul D Robinson; Mikael Skurnik; Daniel A Solomon; James Soothill; Helen Spencer; Peter Wark; Austen Worth; Robert T Schooley; Constance A Benson; Graham F Hatfull

doi:10.1093/cid/ciac453

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

Clin Infect Dis. 2023 Jan 6;76(1):103-112. doi: 10.1093/cid/ciac453.

Authors

Rebekah M Dedrick¹, Bailey E Smith¹, Madison Cristinziano¹, Krista G Freeman¹, Deborah Jacobs-Sera¹, Yvonne Belessis^{2

3}, A Whitney Brown⁴, Keira A Cohen⁵, Rebecca M Davidson⁶, David van Duin⁷, Andrew Gainey⁸, Cristina Berastegui Garcia⁹, C R Robert George¹⁰, Ghady Haidar¹¹, Winnie Ip¹², Jonathan Iredell¹³, Ameneh Khatami^{14

15}, Jessica S Little¹⁶, Kirsi Malmivaara¹⁷, Brendan J McMullan¹³, David E Michalik¹⁸, Andrea Moscatelli¹⁹, Jerry A Nick²⁰, Maria G Tupayachi Ortiz²¹, Hari M Polenakovik²², Paul D Robinson²³, Mikael Skurnik^{24

25}, Daniel A Solomon¹⁶, James Soothill¹⁷, Helen Spencer²⁶, Peter Wark²⁷, Austen Worth¹², Robert T Schooley²⁸, Constance A Benson²⁸, Graham F Hatfull¹

Affiliations

¹ Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
² School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia.
³ Department of Respiratory Medicine, Sydney Children's Hospital, Sydney, New South Wales, Australia.
⁴ Inova Fairfax Hospital, Falls Church, Virginia, USA.
⁵ Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁶ Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA.
⁷ Division of Infectious Diseases, University of North Carolina, Chapel Hill, North Carolina, USA.
⁸ Department of Pharmacy, Division of Pediatric Infectious Diseases, Prisma Health Children's Hospital-Midlands, Columbia, South Carolina, USA.
⁹ Department of Respiratory Disease, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
¹⁰ New South Wales Health Pathology Microbiology, John Hunter Hospital, New Lambton, New South Wales, Australia.
¹¹ Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
¹² Department of Pediatric Immunology, Great Ormond Street Hospital, London, United Kingdom.
¹³ Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Randwick, New South Wales, Australia.
¹⁴ Department of Infectious Diseases and Microbiology, Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁵ Discipline of Child and Adolescent Health, University of Syndey, Sydney, New South Wales, Australia.
¹⁶ Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹⁷ Great Ormond Street Hospital, London, United Kingdom.
¹⁸ Miller Children's and Women's Hospital, Division of Pediatric Infectious Diseases, Long Beach, California, USA.
¹⁹ Neonatal and Pediatric Intensive Care Unit, Instituto Giannina Gaslini, Genoa, Italy.
²⁰ Department of Medicine, National Jewish Health, Denver, Colorado, USA.
²¹ Department of Medicine, Division of Pulmonary and Critical Care Medicine, Miller School of Medicine, University of Miami, Miami, Florida, USA.
²² Internal Medicine Department, Dayton Children's Hospital, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA.
²³ Department of Respiratory Medicine, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
²⁴ Department of Bacteriology and Immunology, Human Microbiome Research Program, University of Helsinki, Helsinki, Finland.
²⁵ Division of Clinical Microbiology, Helsinki University Hospital, Helsinki, Finland.
²⁶ Respiratory Medicine and Cardiothoracic Transplantation, Great Ormond Street Hospital, London, United Kingdom.
²⁷ Immune Health Program, Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia.
²⁸ Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, San Diego, San Diego, California, USA.

Abstract

Background: Nontuberculous Mycobacterium 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 8 patients, potentially contributing to lack of treatment response in 4 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.

Keywords: mycobacteriophage; nontuberculous mycobacteria; phage therapy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / therapeutic use
Bacteriophages*
Compassionate Use Trials
Cystic Fibrosis* / microbiology
Humans
Mycobacterium Infections, Nontuberculous* / microbiology
Mycobacterium*
Phage Therapy*
Pharmaceutical Preparations

Substances

Pharmaceutical Preparations
Anti-Bacterial Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding