Personalized bacteriophage therapy outcomes for 100 consecutive cases: a multicentre, multinational, retrospective observational study
Jean‐Paul PirnayEuropean Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Non-traditional Antibacterial Therapy (ESGNTA), Basel, Switzerland. [email protected]Sarah DjebaraCenter for Infectious Diseases, Queen Astrid Military Hospital, Brussels, BelgiumGriet SteursLaboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Brussels, BelgiumJohann GriselainLaboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Brussels, BelgiumChristel CochezLaboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Brussels, BelgiumSteven De SoirLaboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Brussels, BelgiumTéa GlontiLaboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Brussels, BelgiumAn SpiessensCenter for Infectious Diseases, Queen Astrid Military Hospital, Brussels, BelgiumEmily Vanden BergheCenter for Infectious Diseases, Queen Astrid Military Hospital, Brussels, BelgiumSabrina I. GreenLaboratory of Gene Technology, Department of Biosystems, KU Leuven, Leuven, BelgiumJeroen WagemansLaboratory of Gene Technology, Department of Biosystems, KU Leuven, Leuven, BelgiumCédric LoodLaboratory of Gene Technology, Department of Biosystems, KU Leuven, Leuven, BelgiumEddie SchrevensDepartment of Biosystems, KU Leuven, Leuven, BelgiumНіна ЧанішвіліEliava Institute of Bacteriophages, Microbiology and Virology, Tbilisi, GeorgiaMzia KutateladzeEliava Institute of Bacteriophages, Microbiology and Virology, Tbilisi, GeorgiaMathieu de JodeBacterial Diseases, Sciensano, Brussels, BelgiumPieter‐Jan CeyssensBacterial Diseases, Sciensano, Brussels, BelgiumJean‐Pierre DrayeLaboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Brussels, BelgiumGilbert VerbekenLaboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Brussels, BelgiumDaniël De VosLaboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Brussels, BelgiumThomas RoseLaboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Brussels, BelgiumJolien OnseaDepartment of Trauma Surgery, University Hospitals Leuven; Department of Development and Regeneration, KU Leuven, Leuven, BelgiumBrieuc Van NieuwenhuyseBacteriophage Therapy ProvidersCenter for Infectious Diseases, Queen Astrid Military Hospital, Brussels, BelgiumKim Win PangCenter for Infectious Diseases, Queen Astrid Military Hospital, Brussels, BelgiumWillem‐Jan MetsemakersDepartment of Trauma Surgery, University Hospitals Leuven; Department of Development and Regeneration, KU Leuven, Leuven, BelgiumDimitri Van der LindenPediatric Infectious Diseases, Pediatric Department, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain-UCLouvain, Brussels, BelgiumOlga ChatzisUCLouvainAnaïs EskenaziClinic of Infectious Diseases, Erasme Hospital, Brussels, BelgiumÁngel L. LópezHNO-Zentrum Simmering, Vienna, AustriaAdrien De VoeghtDepartment of Medicine, Division of Hematology, Centre Hospitalier Universitaire de Liège, University of Liège, Liège, BelgiumAnne‐Françoise RousseauDepartment of Intensive Care and Burn Center, University Hospital, University of Liège, Liège, BelgiumAnne TilmanneFaculté de Médecine, Université Libre de Bruxelles, Brussels, BelgiumDaphné VensDivision of Pediatric Infectious Diseases and Infection Prevention and Control, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles (ULB), Brussels, BelgiumJ. GérainDepartment of Internal Medicine, Delta Hospital (CHIREC), Brussels, BelgiumBrice LayeuxDelta Hospital (CHIREC), Brussels, BelgiumErika VliegheDepartment of General Internal Medicine, Infectious Diseases and Tropical Medicine, University Hospital Antwerp, Edegem, BelgiumIngrid BaarDepartment of Critical Care Medicine, University Hospital Antwerp, University of Antwerp, Edegem, BelgiumSabrina H. van IersselDepartment of Critical Care Medicine, University Hospital Antwerp, University of Antwerp, Edegem, BelgiumJohan Van LaethemDepartment of Internal Medicine and Infectious Diseases, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, Brussels, BelgiumJulien GuiotPneumology Department, CHU Liège, Domaine Universitaire du Sart-Tilman, Liège, BelgiumSophie De RoockQueen Astrid Military Hospital, Brussels, BelgiumSerge JennesQueen Astrid Military Hospital, Brussels, BelgiumSaartje UyttebroekDepartment of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven; Experimental Otorhinolaryngology, Rhinology Research, Department of Neurosciences, KU Leuven, Leuven, BelgiumLaura Van GervenDepartment of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven; Experimental Otorhinolaryngology, Rhinology Research, Department of Neurosciences, KU Leuven, Leuven, BelgiumPeter W. HellingsDepartment of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven; Experimental Otorhinolaryngology, Rhinology Research, Department of Neurosciences, KU Leuven, Leuven, BelgiumLieven DupontDepartment of Pneumology, University Hospitals Leuven; Respiratory Diseases and Thoracic Surgery, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, BelgiumYves DebaveyeDepartment of Intensive Care Medicine, University Hospitals Leuven; Department of Cellular and Molecular Medicine, KU Leuven, Leuven, BelgiumDavid DevolderPharmacy Department, University Hospitals Leuven, Leuven, BelgiumIsabel SprietPharmacy Department, University Hospitals Leuven; Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, BelgiumPaul De MunterDepartment of General Internal Medicine, University Hospitals Leuven; Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, BelgiumMelissa DepypereDepartment of Laboratory Medicine, University Hospitals Leuven; Laboratory of Clinical Bacteriology and Mycology, KU Leuven, Leuven, BelgiumMichiel VanfleterenSt-Jozefskliniek Izegem, Izegem, BelgiumOlivier CornuDepartment of Orthopaedic Surgery, University Hospital Saint Luc, Brussels, BelgiumStijn VerhulstDepartment of Pediatrics, Antwerp University Hospital, Edegem, BelgiumTine BoiyDepartment of Pediatrics, Antwerp University Hospital, Edegem, BelgiumStoffel LamoteDepartment of Intensive Care Medicine, AZ Groeninge, Kortrijk, BelgiumThibaut Van ZeleDepartment of Otorhinolaryngology, UZ Ghent University Hospital, Ghent, BelgiumGrégoire WieërsService de Médecine Interne Générale, Clinique Saint Pierre, Ottignies, BelgiumCécile CourtinService de Dermatologie, Cliniques Saint-Pierre, Ottignies, BelgiumDavid LebeauxService de Microbiologie, Unité Mobile d’Infectiologie, AP-HP, Hôpital Européen Georges Pompidou, Paris, FranceJacques SartreLaboratoire de biologie médicale, Centre Hospitalier de Valence, Valence, FranceTristan FerryCentre de Référence des Infections Ostéo-Articulaires Complexes de Lyon (CRIOAc Lyon), Hospices Civils de France, Lyon, FranceFrédéric LaurentInstitut des agents Infectieux - Hospices Civils de Lyon, Centre International de Recherche en Infectiologie, Lyon, FranceKevin PaulUniversity Children’s Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyMariagrazia Di LucaDepartment of Biology, University of Pisa, Pisa, ItalyStefan GottschlichPraxis Cordes and Gottschlich and Heß and Scherl, Rendsburg, GermanyTamta TkhilaishviliDepartment of Cardiothoracic and Vascular Surgery, Charité German Heart Center, Berlin, GermanyNovella CestaPhD Course in Microbiology, Immunology, Infectious Diseases, and Transplants (MIMIT), University of Rome Tor Vergata, Rome, ItalyKārlis RācenisDepartment of Biology and Microbiology, Riga Stradins University, Riga, LatviaTelma BarbosaDepartment of Pediatrics, Maternal Child Center of the North (CMIN), University Hospital Center of Porto (CHUP), Porto, PortugalLuis Eduardo López-CortésEnfermedades Infecciosas y Microbiología Clínica, Hospital Universitario Virgen Macarena, Sevilla, SpainMaría TomásTranslational and Multidisciplinary Microbiology Group (MicroTM) - Institute of Biomedical Research A Coruña, Microbiology Department of Hospital of A Coruña (CHUAC), University of A Coruña (UDC), A Coruña, SpainMartin HübnerDepartment of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, SwitzerlandTruong‐Thanh PhamDivision of Infectious Diseases, Department of Medicine, Geneva University Hospitals, Geneva, SwitzerlandPaul NagtegaalDepartment of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, Rotterdam, the NetherlandsJaap ten OeverDepartment of Internal Medicine and Radboud Centre for Infectious Diseases, Radboud University Medical Center, Nijmegen, the NetherlandsJohannes M. A. DanielsDepartment of Pulmonary Medicine, Amsterdam UMC Locatie VUmc, Amsterdam, the NetherlandsM.C. LoubertMeander Medisch Centrum, Amersfoort, the NetherlandsGhariani IhebClinique Saint Augustin, Tunis, TunisiaJoshua D. JonesEdinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh, UKLesley HallDiabetes and Endocrinology, Queen Elizabeth University Hospital, Glasgow, UKMatthew J. YoungDiabetes Foot Clinic, Royal Infirmary, Edinburgh, UKBacteriophage DonorsEliava Institute of Bacteriophages, Microbiology and Virology, Tbilisi, GeorgiaNana BalarjishviliEliava Institute of Bacteriophages, Microbiology and Virology, Tbilisi, GeorgiaMarina TediashviliEliava Institute of Bacteriophages, Microbiology and Virology, Tbilisi, GeorgiaYigang TongCollege of Life Science and Technology, Beijing University of Chemical Technology, Beijing, ChinaChristine H. RohdeLeibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures GmbH, Braunschweig, GermanyJohannes WittmannLeibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures GmbH, Braunschweig, GermanyRonen HazanIsraeli Phage Therapy Center (IPTC) of Hadassah Medical Center and the Hebrew University, Jerusalem, IsraelRan Nir‐PazEuropean Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Non-traditional Antibacterial Therapy (ESGNTA), Basel, SwitzerlandJoana AzeredoDepartment of Biological Engineering, University of Minho, Braga, PortugalВ. Н. КрыловMechnikov Research Institute of Vaccines and Sera, Moscow, RussiaDavid R. CameronDepartment of Intensive Care Medicine, Bern University Hospital, University of Bern, Bern, SwitzerlandMelissa PittonDepartment of Intensive Care Medicine, Bern University Hospital, University of Bern, Bern, SwitzerlandYok‐Ai QueUniversity Hospital of BernGrégory ReschLaboratory of Bacteriophages, Lausanne University Hospital, Lausanne, SwitzerlandShawna McCallinDepartment of Neuro-Urology, Balgrist University Hospital, University of Zürich, Zürich, SwitzerlandMatthew DunneDepartment of Neuro-Urology, Balgrist University Hospital, University of Zürich, Zürich, SwitzerlandSamuel KilcherInstitute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland
2024en
ABI
Аннотация
In contrast to the many reports of successful real-world cases of personalized bacteriophage therapy (BT), randomized controlled trials of non-personalized bacteriophage products have not produced the expected results. Here we present the outcomes of a retrospective observational analysis of the first 100 consecutive cases of personalized BT of difficult-to-treat infections facilitated by a Belgian consortium in 35 hospitals, 29 cities and 12 countries during the period from 1 January 2008 to 30 April 2022. We assessed how often personalized BT produced a positive clinical outcome (general efficacy) and performed a regression analysis to identify functional relationships. The most common indications were lower respiratory tract, skin and soft tissue, and bone infections, and involved combinations of 26 bacteriophages and 6 defined bacteriophage cocktails, individually selected and sometimes pre-adapted to target the causative bacterial pathogens. Clinical improvement and eradication of the targeted bacteria were reported for 77.2% and 61.3% of infections, respectively. In our dataset of 100 cases, eradication was 70% less probable when no concomitant antibiotics were used (odds ratio = 0.3; 95% confidence interval = 0.127-0.749). In vivo selection of bacteriophage resistance and in vitro bacteriophage-antibiotic synergy were documented in 43.8% (7/16 patients) and 90% (9/10) of evaluated patients, respectively. We observed a combination of antibiotic re-sensitization and reduced virulence in bacteriophage-resistant bacterial isolates that emerged during BT. Bacteriophage immune neutralization was observed in 38.5% (5/13) of screened patients. Fifteen adverse events were reported, including seven non-serious adverse drug reactions suspected to be linked to BT. While our analysis is limited by the uncontrolled nature of these data, it indicates that BT can be effective in combination with antibiotics and can inform the design of future controlled clinical trials. BT100 study, ClinicalTrials.gov registration: NCT05498363 .
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