Refractory Pseudomonas aeruginosa infections treated with phage PASA16: A compassionate use case series.

Humans Bacteriophages Pseudomonas Infections / drug therapy Compassionate Use Trials Pseudomonas Phages Anti-Bacterial Agents / therapeutic use
Pseudomonas aeruginosa Translation to patients bacteriophage therapy bone and joint infections clinical phage microbiology persistant infections phage therapy resistant infections

Journal

Med (New York, N.Y.)
ISSN: 2666-6340
Titre abrégé: Med
Pays: United States
ID NLM: 101769215

Informations de publication

Date de publication:
08 09 2023
Historique:
received: 09 05 2023
revised: 23 06 2023
accepted: 11 07 2023
medline: 11 9 2023
pubmed: 11 8 2023
entrez: 10 8 2023
Statut: ppublish

Résumé

A growing number of compassionate phage therapy cases were reported in the last decade, with a limited number of clinical trials conducted and few unsuccessful clinical trials reported. There is only a little evidence on the role of phages in refractory infections. Our objective here was to present the largest compassionate-use single-organism/phage case series in 16 patients with non-resolving Pseudomonas aeruginosa infections. We summarized clinical phage microbiology susceptibility data, administration protocol, clinical data, and outcomes of all cases treated with PASA16 phage. In all intravenous phage administrations, PASA16 phage was manufactured and provided pro bono by Adaptive Phage Therapeutics. PASA16 was administered intravenously, locally to infection site, or by topical use to 16 patients, with data available for 15 patients, mainly with osteoarticular and foreign-device-associated infections. A few minor side effects were noted, including elevated liver function enzymes and a transient reduction in white blood cell count. Good clinical outcome was documented in 13 out of 15 patients (86.6%). Two clinical failures were reported. The minimum therapy duration was 8 days with a once- to twice-daily regimen. PASA16 with antibiotics was found to be relatively successful in patients for whom traditional treatment approaches have failed previously. Such pre-phase-1 cohorts can outline potential clinical protocols and facilitate the design of future trials. The study was funded in part by The Israeli Science Foundation IPMP (ISF_1349/20), Rosetrees Trust (A2232), United States-Israel Binational Science Foundation (2017123), and the Milgrom Family Support Program.

Sections du résumé

BACKGROUND
A growing number of compassionate phage therapy cases were reported in the last decade, with a limited number of clinical trials conducted and few unsuccessful clinical trials reported. There is only a little evidence on the role of phages in refractory infections. Our objective here was to present the largest compassionate-use single-organism/phage case series in 16 patients with non-resolving Pseudomonas aeruginosa infections.
METHODS
We summarized clinical phage microbiology susceptibility data, administration protocol, clinical data, and outcomes of all cases treated with PASA16 phage. In all intravenous phage administrations, PASA16 phage was manufactured and provided pro bono by Adaptive Phage Therapeutics. PASA16 was administered intravenously, locally to infection site, or by topical use to 16 patients, with data available for 15 patients, mainly with osteoarticular and foreign-device-associated infections.
FINDINGS
A few minor side effects were noted, including elevated liver function enzymes and a transient reduction in white blood cell count. Good clinical outcome was documented in 13 out of 15 patients (86.6%). Two clinical failures were reported. The minimum therapy duration was 8 days with a once- to twice-daily regimen.
CONCLUSIONS
PASA16 with antibiotics was found to be relatively successful in patients for whom traditional treatment approaches have failed previously. Such pre-phase-1 cohorts can outline potential clinical protocols and facilitate the design of future trials.
FUNDING
The study was funded in part by The Israeli Science Foundation IPMP (ISF_1349/20), Rosetrees Trust (A2232), United States-Israel Binational Science Foundation (2017123), and the Milgrom Family Support Program.

Identifiants

DOI: 10.1016/j.medj.2023.07.002 PMID: 37562400
pubmed: 37562400
pii: S2666-6340(23)00225-8
doi: 10.1016/j.medj.2023.07.002
pii:
doi:

Substances chimiques

Anti-Bacterial Agents 0

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

600-611.e4

Subventions

Organisme : NIAMS NIH HHS
ID : R01 AR082167
Pays : United States

Informations de copyright

Copyright © 2023 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests R.N.P. has been a scientific consultant for BiomX and has participated and served as a PI and on Data Safety Monitoring Boards for a clinical trial by Technophage. N.B. is currently an employee of Pfizer, Israel. M.J.B., J.R.F., B.H., R.H., and S.B. were or are APT (manufacturer of the i.v. PASA16 formulation) employees. K.L.U. is a recipient of NIH grant NIAMS R01 AR082167; he also declares consulting fees from APT not related to the cases described here. R.H. is a recipient of MTEC Foundation Fund MTEC #2019-432. R.H., J.F., and B.H. declare owning stocks or stock options at APT. J.R.F. declares a contract with the United States Defense Health Agency (DHA) to support advancing phage therapy. R.M.L.H. serves on the Takeda advisory board. M.M. was a consultant for Karius, Inc. and Cidara Therapeutics. J.R.I. has been a scientific consultant for Vectura Fertin Pharma. R.C.Y.L., S.L., and A.K. are recipients of the Australia Medical Research Future Fund, Frontiers Stage 1 RFRHPI000017, 2021–2022. R.C.Y.L. and S.L. are recipients of the Australian National Health and Medical Research Council grant Gnt1197534. A.K. is a recipient of the Australian National Health and Medical Research Council grant GNT2008024 and has participated on DSMB for the FluBub Study. R.C.Y.L. had participated on DSMB for Phage Australia as a part of the leadership team, as a chair on the Genomics Scientific Advisory Committee, and as a committee member on the Biobanking Scientific Advisory Committee. S.L. serves as an organizer in Phage Bite, Phage Directory, and as a committee member on Australia Society for Microbiology, Special Interest Group, Phage. P.N.B. received funding from the Royal Australasian College of Physicians for a Cottrell Research Establishment Fellowship. R.B.-A. is a recipient of Israeli Science Foundation grant 442/18, Ministry of Science and Technology grant 88555, and National Health and Medical Research Council (NHMRC) Ideas grant APP2002520. He also received honoraria from Gilead Sciences, Inc. and Teva Pharmaceuticals and has participated on DSMB for Merck and Pfizer.

Auteurs

Hadil Onallah (H)

Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel; The Israeli Phage Therapy Center (IPTC) of Hadassah Medical Center and the Hebrew University, Jerusalem 9112102, Israel.

Ronen Hazan (R)

The Israeli Phage Therapy Center (IPTC) of Hadassah Medical Center and the Hebrew University, Jerusalem 9112102, Israel; Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.

Ran Nir-Paz (R)

Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel; The Israeli Phage Therapy Center (IPTC) of Hadassah Medical Center and the Hebrew University, Jerusalem 9112102, Israel; Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center (HHUMC), Jerusalem 9112000, Israel. Electronic address: ran.nir-paz@mail.huji.ac.il.

Michael J Brownstein (MJ)

Adaptive Phage Therapeutics, Gaithersburg, MD 20878, USA.

Joseph R Fackler (JR)

Adaptive Phage Therapeutics, Gaithersburg, MD 20878, USA.

Bri'Anna Horne (B)

Adaptive Phage Therapeutics, Gaithersburg, MD 20878, USA.

Robert Hopkins (R)

Adaptive Phage Therapeutics, Gaithersburg, MD 20878, USA.

Subhendu Basu (S)

Adaptive Phage Therapeutics, Gaithersburg, MD 20878, USA.

Ortal Yerushalmy (O)

The Israeli Phage Therapy Center (IPTC) of Hadassah Medical Center and the Hebrew University, Jerusalem 9112102, Israel; Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.

Sivan Alkalay-Oren (S)

The Israeli Phage Therapy Center (IPTC) of Hadassah Medical Center and the Hebrew University, Jerusalem 9112102, Israel; Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.

Ron Braunstein (R)

The Israeli Phage Therapy Center (IPTC) of Hadassah Medical Center and the Hebrew University, Jerusalem 9112102, Israel; Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.

Amit Rimon (A)

The Israeli Phage Therapy Center (IPTC) of Hadassah Medical Center and the Hebrew University, Jerusalem 9112102, Israel; Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.

Daniel Gelman (D)

The Israeli Phage Therapy Center (IPTC) of Hadassah Medical Center and the Hebrew University, Jerusalem 9112102, Israel; Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel; Department of Military Medicine, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.

Leron Khalifa (L)

The Israeli Phage Therapy Center (IPTC) of Hadassah Medical Center and the Hebrew University, Jerusalem 9112102, Israel; Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.

Karen Adler (K)

The Israeli Phage Therapy Center (IPTC) of Hadassah Medical Center and the Hebrew University, Jerusalem 9112102, Israel; Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.

Mohanad Abdalrhman (M)

The Israeli Phage Therapy Center (IPTC) of Hadassah Medical Center and the Hebrew University, Jerusalem 9112102, Israel; Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center (HHUMC), Jerusalem 9112000, Israel.

Shira Gelman (S)

The Israeli Phage Therapy Center (IPTC) of Hadassah Medical Center and the Hebrew University, Jerusalem 9112102, Israel; Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel; Department of Military Medicine, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.

Eyal Katvan (E)

The Martin (Szusz) Department of Land of Israel Studies and Archaeology, Bar Ilan University, Ramat-Gan 52900, Israel; Peres Academic Center, Rehovot 7610202, Israel.

Shunit Coppenhagen-Glazer (S)

The Israeli Phage Therapy Center (IPTC) of Hadassah Medical Center and the Hebrew University, Jerusalem 9112102, Israel; Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.

Allon Moses (A)

Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center (HHUMC), Jerusalem 9112000, Israel.

Yonatan Oster (Y)

Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel; Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center (HHUMC), Jerusalem 9112000, Israel.

Michal Dekel (M)

Infectious Diseases Unit, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6423906, Israel.

Ronen Ben-Ami (R)

Infectious Diseases Unit, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6423906, Israel.

Amal Khoury (A)

Infectious Diseases Unit, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6423906, Israel.

Daniel J Kedar (DJ)

Department of Plastic and Reconstructive Surgery, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6423906, Israel.

Suzy E Meijer (SE)

Department of Plastic and Reconstructive Surgery, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6423906, Israel.

Itay Ashkenazi (I)

Division of Orthopedic Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel.

Nancy Bishouty (N)

Pharmacy Department, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel.

Dafna Yahav (D)

Infectious Disease Unit, Rabin Medical Center, Petah Tikva 49100, Israel.

Eran Shostak (E)

Pediatric Cardiac Intensive Care Unit, Schneider Children's Medical Center, Petah Tikva 4920235, Israel.

Gilat Livni (G)

Pediatric Infectious Diseases Unit, Schneider Children's Medical Center, Petah Tikva 4920235, Israel.

Mical Paul (M)

Rambam Health Care Campus and Faculty of Medicine, The Technion - Israel Institute of Technology, Haifa 3109601, Israel.

Menachem Gross (M)

Department of Otolaryngology-Head and Neck Surgery, Hadassah-Hebrew University Medical Center, Jerusalem 9112000, Israel.

Matityahou Ormianer (M)

Department of Otolaryngology-Head and Neck Surgery, Hadassah-Hebrew University Medical Center, Jerusalem 9112000, Israel.

Saima Aslam (S)

Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA 92093, USA; Center for Innovative Phage Applications and Therapeutics, University of California, San Diego, La Jolla, CA 92093, USA.

Michele Ritter (M)

Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA 92093, USA.

Kenneth L Urish (KL)

Bone and Joint Center, Magee Hospital, Department of Orthopedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.

Ricardo M La Hoz (RM)

Division of Infectious Disease and Geographic Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Ameneh Khatami (A)

Department of Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.

Philip N Britton (PN)

Department of Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.

Ruby C Y Lin (RCY)

Centre for Infectious Diseases and Microbiology, Westmead Institute for Medical Research, Westmead, NSW 2145, Australia.

Jonathan R Iredell (JR)

Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Centre for Infectious Diseases and Microbiology, Westmead Institute for Medical Research, Westmead, NSW 2145, Australia.

Aleksandra Petrovic-Fabijan (A)

Centre for Infectious Diseases and Microbiology, Westmead Institute for Medical Research, Westmead, NSW 2145, Australia.

Stephanie Lynch (S)

Centre for Infectious Diseases and Microbiology, Westmead Institute for Medical Research, Westmead, NSW 2145, Australia.

Pranita D Tamma (PD)

Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Alexandra Yamshchikov (A)

Infectious Diseases Unit, Rochester Regional Health, Rochester, NY 14617, USA; Infectious Diseases Unit, University of Rochester Medical Center, Rochester, NY 14617, USA.

Emil Lesho (E)

Infectious Diseases Unit, Rochester Regional Health, Rochester, NY 14617, USA.

Megan Morales (M)

Division of Infectious Diseases, Virginia Commonwealth University, Richmond, VA 23284, USA.

Alissa Werzen (A)

Division of Infectious Diseases, Jefferson Medicine, Philadelphia, PA 19107, USA.

Kapil Saharia (K)

University of Maryland School of Medicine, Baltimore, MD 21201, USA.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Refractory Pseudomonas aeruginosa infections...
questionsmedicales.fr › Virus › Bactériophages › Refractory Pseudomonas aeruginosa infections...
questionsmedicales.fr › Infection › Infections bactériennes et mycoses › Infections bactériennes › Infections bactériennes à Gram négatif › Infections à Pseudomonas › Refractory Pseudomonas aeruginosa infections...
questionsmedicales.fr › Techniques d'investigation › Essais cliniques à usage compassionnel › Refractory Pseudomonas aeruginosa infections...
questionsmedicales.fr › Virus › Bactériophages › Phages de Pseudomonas › Refractory Pseudomonas aeruginosa infections...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antibactériens › Refractory Pseudomonas aeruginosa infections...