Novel intranasal phage-CaEDTA-ceftazidime/avibactam triple combination therapy demonstrates remarkable efficacy in treating Pseudomonas aeruginosa lung infection

Aye Mya Sithu Shein; Dhammika Leshan Wannigama; Cameron Hurst; Peter N Monk; Mohan Amarasiri; Vishnu Nayak Badavath; Phatthranit Phattharapornjaroen; William Graham Fox Ditcham; Puey Ounjai; Thammakorn Saethang; Naphat Chantaravisoot; Wanwara Thuptimdang; Sirirat Luk-In; Sumanee Nilgate; Ubolrat Rirerm; Chanikan Tanasatitchai; Naris Kueakulpattana; Matchima Laowansiri; Tingting Liao; Rosalyn Kupwiwat; Rojrit Rojanathanes; Natharin Ngamwongsatit; Arsa Thammahong; Hitoshi Ishikawa; Daniel Pletzer; Asada Leelahavanichkul; Naveen Kumar Devanga Ragupathi; Pattama Wapeesittipan; S M Ali Hosseini Rad; Talerngsak Kanjanabuch; Robin James Storer; Kazuhiko Miyanaga; Longzhu Cui; Hiroshi Hamamoto; Paul G Higgins; Anthony Kicic; Tanittha Chatsuwan; Parichart Hongsing; Shuichi Abe

doi:10.1016/j.biopha.2023.115793

Novel intranasal phage-CaEDTA-ceftazidime/avibactam triple combination therapy demonstrates remarkable efficacy in treating Pseudomonas aeruginosa lung infection

Biomed Pharmacother. 2023 Oct 28:168:115793. doi: 10.1016/j.biopha.2023.115793. Online ahead of print.

Authors

Aye Mya Sithu Shein¹, Dhammika Leshan Wannigama², Cameron Hurst³, Peter N Monk⁴, Mohan Amarasiri⁵, Vishnu Nayak Badavath⁶, Phatthranit Phattharapornjaroen⁷, William Graham Fox Ditcham⁸, Puey Ounjai⁹, Thammakorn Saethang¹⁰, Naphat Chantaravisoot¹¹, Wanwara Thuptimdang¹², Sirirat Luk-In¹³, Sumanee Nilgate¹, Ubolrat Rirerm¹, Chanikan Tanasatitchai¹⁴, Naris Kueakulpattana¹, Matchima Laowansiri¹, Tingting Liao¹⁵, Rosalyn Kupwiwat¹⁶, Rojrit Rojanathanes¹⁷, Natharin Ngamwongsatit¹⁸, Arsa Thammahong¹⁹, Hitoshi Ishikawa²⁰, Daniel Pletzer²¹, Asada Leelahavanichkul²², Naveen Kumar Devanga Ragupathi²³, Pattama Wapeesittipan²⁴, S M Ali Hosseini Rad²⁵, Talerngsak Kanjanabuch²⁶, Robin James Storer²⁷, Kazuhiko Miyanaga²⁸, Longzhu Cui²⁸, Hiroshi Hamamoto²⁹, Paul G Higgins³⁰, Anthony Kicic³¹, Tanittha Chatsuwan³², Parichart Hongsing³³, Shuichi Abe³⁴

Affiliations

¹ Department of Microbiology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; Center of Excellence in Antimicrobial Resistance and Stewardship Research, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
² Department of Microbiology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; Center of Excellence in Antimicrobial Resistance and Stewardship Research, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan; School of Medicine, Faculty of Health and Medical Sciences, The University of Western Australia, Nedlands, Western Australia, Australia; Biofilms and Antimicrobial Resistance Consortium of ODA receiving countries, The University of Sheffield, Sheffield, United Kingdom; Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan; Yamagata Prefectural University of Health Sciences, Kamiyanagi, Yamagata 990-2212, Japan. Electronic address: [email protected].
³ Molly Wardaguga Research Centre, Charles Darwin University, Queensland, Australia.
⁴ Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield Medical School, United Kingdom.
⁵ Laboratory of Environmental Hygiene, Department of Health Science, School of Allied Health Sciences, Kitasato University, Kitasato, Sagamihara-Minami, Kanagawa 252-0373, Japan.
⁶ School of Pharmacy & Technology Management, SVKM's Narsee Monjee Institute of Management Studies (NMIMS), Hyderabad 509301, India.
⁷ Department of Emergency Medicine, Center of Excellence, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Institute of Clinical Sciences, Department of Surgery, Sahlgrenska Academy, Gothenburg University, 40530 Gothenburg, Sweden.
⁸ School of Medicine, Faculty of Health and Medical Sciences, The University of Western Australia, Nedlands, Western Australia, Australia.
⁹ Department of Biology, Faculty of Science, Mahidol University, Bangkok, Thailand.
¹⁰ Department of Computer Science, Faculty of Science, Kasetsart University, Bangkok, Thailand.
¹¹ Center of Excellence in Systems Biology, Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
¹² Institute of Biomedical Engineering, Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand.
¹³ Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
¹⁴ Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan.
¹⁵ Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Center of Excellence for Microcirculation, Faculty of Medicine, Chulalongkorn University, Thailand.
¹⁶ Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan; Department of Dermatology. Faculty of Medicine Siriraj Hospital. Mahidol University, Bangkok, Thailand.
¹⁷ Center of Excellence in Materials and Bio-Interfaces, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
¹⁸ Department of Clinical Sciences and Public Health, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom, Thailand.
¹⁹ Center of Excellence in Antimicrobial Resistance and Stewardship Research, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan.
²⁰ Yamagata Prefectural University of Health Sciences, Kamiyanagi, Yamagata 990-2212, Japan.
²¹ Department of Microbiology and Immunology, University of Otago, 720 Cumberland St., 9054 Dunedin, New Zealand.
²² Center of Excellence in Antimicrobial Resistance and Stewardship Research, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Translational Research in Inflammation and Immunology Research Unit (TRIRU), Department of Microbiology, Chulalongkorn University, Bangkok, Thailand.
²³ Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan; Department of Chemical and Biological Engineering, The University of Sheffield, Sheffield, United Kingdom; Department of Clinical Microbiology, Christian Medical College, Vellore, India.
²⁴ Department of Clinical Science, University of Bergen, Bergen, Norway.
²⁵ Department of Microbiology and Immunology, University of Otago, Dunedin 9010, Otago, New Zealand; Center of Excellence in Immunology and Immune-Mediated Diseases, Chulalongkorn University, Bangkok 10330, Thailand.
²⁶ Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Center of Excellence in Kidney Metabolic Disorders, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Dialysis Policy and Practice Program (DiP3), School of Global Health, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Peritoneal Dialysis Excellence Center, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
²⁷ Office of Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
²⁸ Division of Bacteriology, School of Medicine, Jichi Medical University, Tochigi, Japan.
²⁹ Department of Infectious Diseases, Faculty of Medicine Yamagata University, Yamagata, Japan.
³⁰ Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; German Centre for Infection Research, Partner site Bonn-Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50935 Cologne, Germany.
³¹ Telethon Kids Institute, University of Western Australia, Nedlands 6009, Western Australia, Australia; Centre for Cell Therapy and Regenerative Medicine, Medical School, The University of Western Australia, Nedlands 6009, Western Australia, Australia; Department of Respiratory and Sleep Medicine, Perth Children's Hospital, Nedlands 6009, Western Australia, Australia; School of Public Health, Curtin University, Bentley 6102, Western Australia, Australia. Electronic address: [email protected].
³² Department of Microbiology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; Center of Excellence in Antimicrobial Resistance and Stewardship Research, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Electronic address: [email protected].
³³ School of Integrative Medicine, Mae Fah Luang University, Chiang Rai, Thailand; Mae Fah Luang University Hospital, Chiang Rai, Thailand. Electronic address: [email protected].
³⁴ Biofilms and Antimicrobial Resistance Consortium of ODA receiving countries, The University of Sheffield, Sheffield, United Kingdom; Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan. Electronic address: [email protected].

PMID: 39491417
DOI: 10.1016/j.biopha.2023.115793

Abstract

Given the rise of multidrug-resistant (MDR) Pseudomonas aeruginosa infections, alternative treatments are needed. Anti-pseudomonal phage therapy shows promise, but its clinical application is limited due to the development of resistance and a lack of biofilm penetration. Recently, adjuvants like CaEDTA have shown the ability to enhance the effectiveness of combined antimicrobial agents. Here, we tested a phage-adjuvant combination and demonstrated the effectiveness of intranasally inhaled phage (KKP10) + CaEDTA in addition to ceftazidime/avibactam (CZA) for chronic P. aeruginosa lung infections. The results emphasize that intranasal inhalation of phage along with CaEDTA can successfully re-sensitize MDR P. aeruginosa to CZA in a triple combination treatment. This promising approach shows potential as a therapy for chronic respiratory tract infections.

Keywords: Antibiotic resistance; CaEDTA; Combination therapy; Infection; Intranasal; Lung; Phage; Pseudomonas aeruginosa.