Rebekah M Dedrick1, Bailey E Smith1, Madison Cristinziano1, Krista G Freeman1, Deborah Jacobs-Sera1, Yvonne Belessis2, A Whitney Brown3, Keira A Cohen4, Rebecca M Davidson5, David van Duin6, Andrew Gainey7, Cristina Berastegui Garcia8, C R Robert George9, Ghady Haidar10, Winnie Ip11, Jonathan Iredell12, Ameneh Khatami13, Jessica S Little14, Kirsi Malmivaara15, Brendan J McMullan12, David E Michalik16, Andrea Moscatelli17, Jerry A Nick18, Maria G Tupayachi Ortiz19, Hari M Polenakovik20, Paul D Robinson21, Mikael Skurnik22, Daniel A Solomon14, James Soothill15, Helen Spencer23, Peter Wark24, Austen Worth11, Robert T Schooley25, Constance A Benson25, Graham F Hatfull1. 1. Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. 2. School of Women's and Children's Health, University of New South Wales, Sydney, Australia; Dept. of Respiratory Medicine, Sydney Children's Hospital, Sydney, Australia. 3. Inova Fairfax Hospital, Falls Church, VA, USA. 4. Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. 5. Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA. 6. Division of Infectious Diseases, University of North Carolina, Chapel Hill, NC, USA. 7. Department of Pharmacy, Division of Pediatric Infectious Diseases, Prisma Health Children's Hospital - Midlands, Columbia, South Carolina, USA. 8. Department of Respiratory Disease, Hospital Universitari Vall d'Hebron, Barcelona, Spain. 9. NSW Health Pathology Microbiology John Hunter Hospital, New Lambton, NSW, Australia. 10. Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, USA. 11. Department of Pediatric Immunology, Great Ormond Street Hospital, London, UK. 12. Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Randwick, NSW Australia. 13. Department of Infectious Diseases & Microbiology, The Children's Hospital at Westmead, Westmead, Australia; Discipline of Child and Adolescent Health, University of Syndey, Australia. 14. Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA. 15. Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK. 16. Miller Children's and Women's Hospital, Division of Pediatric Infectious Diseases, Long Beach, CA, USA. 17. Neonatal and Pediatric Intensive Care Unit, Instituto Giannina Gaslini, Genoa, Italy. 18. Department of Medicine, National Jewish Health, Denver, CO, 80206, USA. 19. Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136, USA. 20. Internal Medicine Department, Dayton Children's Hospital, Wright State University, Boonshoft School of Medicine, Dayton, OH, USA. 21. Dept of Respiratory Medicine, The Children's Hospital at Westmead, Westmead, NSW, Australia. 22. Department of Bacteriology and Immunology, Human Microbiome Research Program, University of Helsinki, and Division of Clinical Microbiology, Helsinki University Hospital, 00290 Helsinki, Finland. 23. Respiratory Medicine and Cardiothoracic Transplantation, Great Ormond Street Hospital, London, UK. 24. Immune Health Program, Hunter Medical Research Institute, University of Newcastle, Australia. 25. Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California at San Diego, San Diego, California 92103, USA.
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.
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.
Authors: Victoria J Frost; Jada E Fogle; Ryan N Harris; Brooke Jewell; Kaylee E Mills; Jessica E Morgan; Precious T Thompson; Emi Umemoto; Kristi M Westover Journal: Microbiol Resour Announc Date: 2022-09-26
Authors: Qingquan Chen; Tejas Dharmaraj; Pamela C Cai; Elizabeth B Burgener; Naomi L Haddock; Andy J Spakowitz; Paul L Bollyky Journal: Pharmaceutics Date: 2022-07-07 Impact factor: 6.525