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

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: Dhammika.L@chula.ac.th.
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: Anthony.Kicic@telethonkids.org.au.
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: Tanittha.C@chula.ac.th.
³³ School of Integrative Medicine, Mae Fah Luang University, Chiang Rai, Thailand; Mae Fah Luang University Hospital, Chiang Rai, Thailand. Electronic address: parichart.hon@mfu.ac.th.
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: abeshu@icloud.com.

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

Free article

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

Aye Mya Sithu Shein et al. Biomed Pharmacother. 2023.

Free article

. 2023 Oct 28:168:115793.

doi: 10.1016/j.biopha.2023.115793. Online ahead of print.

Authors

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: Dhammika.L@chula.ac.th.
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: Anthony.Kicic@telethonkids.org.au.
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: Tanittha.C@chula.ac.th.
³³ School of Integrative Medicine, Mae Fah Luang University, Chiang Rai, Thailand; Mae Fah Luang University Hospital, Chiang Rai, Thailand. Electronic address: parichart.hon@mfu.ac.th.
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: abeshu@icloud.com.

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.

PubMed Disclaimer

Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

LinkOut - more resources

Full Text Sources
- ClinicalKey
- Elsevier Science

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources