Therapeutic intratracheal application of a lytic phage against Acinetobacter baumannii lung infection in mice

SM Wienhold; M Brack; G Nouailles; C Seitz; A Ross; H Ziehr; C Gurtner; K Dietert; AD Gruber; M Rohde; N Suttorp; C Rohde; M Witzenrath

doi:10.1055/s-0037-1615315

Pneumologie, Inhaltsverzeichnis

Pneumologie 2018; 72(03): 226-227
DOI: 10.1055/s-0037-1615315

Infektionen

Georg Thieme Verlag KG Stuttgart · New York

Therapeutic intratracheal application of a lytic phage against Acinetobacter baumannii lung infection in mice

SM Wienhold

¹Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Infectious Diseases and Pulmonary Medicine, Berlin

,

M Brack

¹Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Infectious Diseases and Pulmonary Medicine, Berlin

,

G Nouailles

¹Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Infectious Diseases and Pulmonary Medicine, Berlin

,

C Seitz

²Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Dept. of Pharmaceutical Biotechnology, Braunschweig, Germany

,

A Ross

²Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Dept. of Pharmaceutical Biotechnology, Braunschweig, Germany

,

H Ziehr

²Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Dept. of Pharmaceutical Biotechnology, Braunschweig, Germany

,

C Gurtner

³Freie Universität Berlin, Department of Veterinary Pathology, Berlin, Germany

,

K Dietert

³Freie Universität Berlin, Department of Veterinary Pathology, Berlin, Germany

,

AD Gruber

³Freie Universität Berlin, Department of Veterinary Pathology, Berlin, Germany

,

M Rohde

⁴Helmholtz Centre for Infection Research, Braunschweig, Germany

,

N Suttorp

¹Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Infectious Diseases and Pulmonary Medicine, Berlin

,

C Rohde

⁵Leibniz Institute DSMZ – German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany

,

M Witzenrath

¹Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Infectious Diseases and Pulmonary Medicine, Berlin

› Institutsangaben

Abstract

Volltext

*presenting author

Introduction:

Chronic lung diseases are frequently complicated by lung and airway infections. The rise of new resistance mechanisms is alarming, and MDR bacteria, including Acinetobacter baumannii, are spreading globally. Rediscovery of phage-therapy could be a solution to overcome this problem. High specificity of bacteriophages and their effectivity in lysis make phages attractive as antibiotics are failing more and more. However, phages need to be properly chosen and characterized according to quality standards, and preparations must be highly purified.

Objectives:

This preclinical study aimed at determining the efficacy, safety and tolerability of a novel phage preparation in anticipation of a future clinical trial applying aerosolized lytic phages against A. baumannii.

Methods:

The specific phage Acibel004 [1], a myovirus, was produced as high-titer suspension subjected to final processing including highly efficient depletion of endotoxins by chromatography. Mice were transnasally infected with a MDR A. baumannii strain [2]. 12h p.i. mice were treated intratracheally with phage or solvent. At defined time points clinical parameters were measured, bacterial burdens in different organs determined and cell-influx analyzed. Lung permeability and cytokine release were measured and histological analyses performed. Furthermore, presence of vital phages was determined.

Results:

Phage application in uninfected mice did not cause measurable immune responses. In A. baumannii infected mice, phage therapy enhanced recovery from infection-associated hypothermia and improved clinical outcome. Bacterial loads in lungs and BALF of the phage-treated group were significantly reduced by 48h p.i.. Cellular recruitment to the lung and blood was unaffected by phage treatment, while lung permeability and cytokine production were significantly reduced. Hematoxylin and eosin stained lung slides of phage treated mice showed less spreading of bacteria to periphery. Phages were detected in BALF, lungs and plasma of treated mice. No adverse effects of phage therapy were observed.

Conclusion:

For the first time a highly purified phage preparation against A. baumannii was used successfully in vivo. The current preclinical data further support the concept of developing a phage-based therapy against pulmonary A. baumannii infections in patients.

Acknowledgments:

Phage vB_AbaM_Acibel004 was kindly provided by M. Merabishvili, PhD. Acinetobacter baumannii RUH2037 was kindly provided by Dr. A. de Vos.

[1] Merabishvili M, et al. Characterization of newly isolated lytic bacteriophages active against Acinetobacter baumannii. PLoS One. 2014 Aug 11;9(8):e104853.

[2] Knapp S, et al. Differential roles of CD14 and toll-like receptors 4 and 2 in murine Acinetobacter pneumonia. Am J Respir Crit Care Med. 2006 Jan 1;173(1):122 – 9.