Preclinical Assessment of Bacteriophage Therapy against Experimental <i>Acinetobacter baumannii</i> Lung Infection
Sandra-Maria Wienhold,
Markus C. Brack,
Geraldine Nouailles,
Gopinath Krishnamoorthy,
Imke H. E. Korf,
Claudius Seitz,
Sarah Wienecke,
Kristina Dietert,
Corinne Gurtner,
Olivia Kershaw,
Achim D. Gruber,
Anton Ross,
Holger Ziehr,
Manfred Rohde,
Jens Neudecker,
Jasmin Lienau,
Norbert Suttorp,
Stefan Hippenstiel,
Andreas C. Hocke,
Christine Rohde,
Martin Witzenrath
Affiliations
Sandra-Maria Wienhold
Division of Pulmonary Inflammation, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany
Markus C. Brack
Division of Pulmonary Inflammation, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany
Geraldine Nouailles
Division of Pulmonary Inflammation, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany
Gopinath Krishnamoorthy
Division of Pulmonary Inflammation, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany
Imke H. E. Korf
Department of Microorganisms, Leibniz Institute DSMZGerman Collection of Microorganisms and Cell Cultures, 38124 Braunschweig, Germany
Claudius Seitz
Department of Pharmaceutical Biotechnology, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), 38124 Braunschweig, Germany
Sarah Wienecke
Department of Pharmaceutical Biotechnology, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), 38124 Braunschweig, Germany
Kristina Dietert
Department of Veterinary Pathology, Freie Universität Berlin, 14163 Berlin, Germany
Corinne Gurtner
Department of Veterinary Pathology, Freie Universität Berlin, 14163 Berlin, Germany
Olivia Kershaw
Department of Veterinary Pathology, Freie Universität Berlin, 14163 Berlin, Germany
Achim D. Gruber
Department of Veterinary Pathology, Freie Universität Berlin, 14163 Berlin, Germany
Anton Ross
Department of Pharmaceutical Biotechnology, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), 38124 Braunschweig, Germany
Holger Ziehr
Department of Pharmaceutical Biotechnology, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), 38124 Braunschweig, Germany
Manfred Rohde
Central Facility for Microscopy, Helmholtz-Centre for Infection Research (HZI), 38124 Braunschweig, Germany
Jens Neudecker
Department of General, Visceral, Vascular and Thoracic Surgery, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany
Jasmin Lienau
Division of Pulmonary Inflammation, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany
Norbert Suttorp
Department of Infectious Diseases and Respiratory Medicine, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany
Stefan Hippenstiel
Department of Infectious Diseases and Respiratory Medicine, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany
Andreas C. Hocke
Division of Pulmonary Inflammation, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany
Christine Rohde
Department of Microorganisms, Leibniz Institute DSMZGerman Collection of Microorganisms and Cell Cultures, 38124 Braunschweig, Germany
Martin Witzenrath
Division of Pulmonary Inflammation, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany
Respiratory infections caused by multidrug-resistant Acinetobacter baumannii are difficult to treat and associated with high mortality among critically ill hospitalized patients. Bacteriophages (phages) eliminate pathogens with high host specificity and efficacy. However, the lack of appropriate preclinical experimental models hampers the progress of clinical development of phages as therapeutic agents. Therefore, we tested the efficacy of a purified lytic phage, vB_AbaM_Acibel004, against multidrug-resistant A. baumannii clinical isolate RUH 2037 infection in immunocompetent mice and a human lung tissue model. Sham- and A. baumannii-infected mice received a single-dose of phage or buffer via intratracheal aerosolization. Group-specific differences in bacterial burden, immune and clinical responses were compared. Phage-treated mice not only recovered faster from infection-associated hypothermia but also had lower pulmonary bacterial burden, lower lung permeability, and cytokine release. Histopathological examination revealed less inflammation with unaffected inflammatory cellular recruitment. No phage-specific adverse events were noted. Additionally, the bactericidal effect of the purified phage on A. baumannii was confirmed after single-dose treatment in an ex vivo human lung infection model. Taken together, our data suggest that the investigated phage has significant potential to treat multidrug-resistant A. baumannii infections and further support the development of appropriate methods for preclinical evaluation of antibacterial efficacy of phages.
