Phage treatment of an aortic graft infected with  Pseudomonas aeruginosa

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Abstract

Management of prosthetic vascular graft infections caused by Pseudomonas aeruginosa can be a significant challenge to clinicians. These infections often do not resolve with antibiotic therapy alone due to antibiotic resistance/tolerance by bacteria, poor ability of antibiotics to permeate/reduce biofilms and/or other factors. Bacteriophage OMKO1 binding to efflux pump proteins in P. aeruginosa was consistent with an evolutionary trade-off: wildtype bacteria were killed by phage whereas evolution of phage-resistance led to increased antibiotic sensitivity. However, phage clinical-use has not been demonstrated. Here, we present a case report detailing therapeutic application of phage OMKO1 to treat a chronic P. aeruginosa infection of an aortic Dacron graft with associated aorto-cutaneous fistula. Following a single application of phage OMKO1 and ceftazidime, the infection appeared to resolve with no signs of recurrence.

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Aminoglycoside antibiotics induce bacterial biofilm formation.

Lucas Hoffman, David D'Argenio, Michael MacCoss … (2005)

Biofilms are adherent aggregates of bacterial cells that form on biotic and abiotic surfaces, including human tissues. Biofilms resist antibiotic treatment and contribute to bacterial persistence in chronic infections. Hence, the elucidation of the mechanisms by which biofilms are formed may assist in the treatment of chronic infections, such as Pseudomonas aeruginosa in the airways of patients with cystic fibrosis. Here we show that subinhibitory concentrations of aminoglycoside antibiotics induce biofilm formation in P. aeruginosa and Escherichia coli. In P. aeruginosa, a gene, which we designated aminoglycoside response regulator (arr), was essential for this induction and contributed to biofilm-specific aminoglycoside resistance. The arr gene is predicted to encode an inner-membrane phosphodiesterase whose substrate is cyclic di-guanosine monophosphate (c-di-GMP)-a bacterial second messenger that regulates cell surface adhesiveness. We found that membranes from arr mutants had diminished c-di-GMP phosphodiesterase activity, and P. aeruginosa cells with a mutation changing a predicted catalytic residue of Arr were defective in their biofilm response to tobramycin. Furthermore, tobramycin-inducible biofilm formation was inhibited by exogenous GTP, which is known to inhibit c-di-GMP phosphodiesterase activity. Our results demonstrate that biofilm formation can be a specific, defensive reaction to the presence of antibiotics, and indicate that the molecular basis of this response includes alterations in the level of c-di-GMP.

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A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy.

A Wright, C H Hawkins, E E Anggård … (2009)

To evaluate the efficacy and safety of a therapeutic bacteriophage preparation (Biophage-PA) targeting antibiotic-resistant Pseudomonas aeruginosa in chronic otitis. Randomised, double-blind, placebo-controlled Phase I/II clinical trial approved by UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Central Office for Research Ethics Committees (COREC) ethical review process. A single specialist university hospital. 24 patients with chronic otitis with a duration of several years (2-58). Each patient had, at the time of entry to the trial, an ear infection because of an antibiotic-resistant P. aeruginosa strain sensitive to one or more of the six phages present in Biophage-PA. Participants were randomised in two groups of 12 treated with either a single dose of Biophage-PA or placebo and followed up at 7, 21 and 42 days after treatment by the same otologist. Ears were thoroughly cleaned on each occasion and clinical and microbiological indicators measured. Physician assessed erythema/inflammation, ulceration/granulation/polyps, discharge quantity, discharge type and odour using a Visual Analogue Scale (VAS). Patients reported discomfort, itchiness, wetness and smell also using a VAS. Bacterial levels of P. aeruginosa and phage counts from swabs were measured initially and at follow-up. At each visit patients were asked about side effects using a structured form. Digital otoscopic images were obtained on days 0 and 42 for illustrative purposes only. Relative to day 0, pooled patient- and physician-reported clinical indicators improved for the phage treated group relative to the placebo group. Variation from baseline levels was statistically significant for combined data from all clinic days only for the phage treated group. Variation from baseline levels was statistically significant for the majority of the patient assessed clinical indicators only for the phage treated group. P. aeruginosa counts were significantly lower only in the phage treated group. No treatment related adverse event was reported. The first controlled clinical trial of a therapeutic bacteriophage preparation showed efficacy and safety in chronic otitis because of chemo-resistant P. aeruginosa.

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Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa

Benjamin Chan, Mark Sistrom, John Wertz … (2016)

Increasing prevalence and severity of multi-drug-resistant (MDR) bacterial infections has necessitated novel antibacterial strategies. Ideally, new approaches would target bacterial pathogens while exerting selection for reduced pathogenesis when these bacteria inevitably evolve resistance to therapeutic intervention. As an example of such a management strategy, we isolated a lytic bacteriophage, OMKO1, (family Myoviridae) of Pseudomonas aeruginosa that utilizes the outer membrane porin M (OprM) of the multidrug efflux systems MexAB and MexXY as a receptor-binding site. Results show that phage selection produces an evolutionary trade-off in MDR P. aeruginosa, whereby the evolution of bacterial resistance to phage attack changes the efflux pump mechanism, causing increased sensitivity to drugs from several antibiotic classes. Although modern phage therapy is still in its infancy, we conclude that phages, such as OMKO1, represent a new approach to phage therapy where bacteriophages exert selection for MDR bacteria to become increasingly sensitive to traditional antibiotics. This approach, using phages as targeted antibacterials, could extend the lifetime of our current antibiotics and potentially reduce the incidence of antibiotic resistant infections.

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Author and article information

Journal

Journal ID (nlm-ta): Evol Med Public Health

Journal ID (iso-abbrev): Evol Med Public Health

Journal ID (publisher-id): emph

Title: Evolution, Medicine, and Public Health

Publisher: Oxford University Press

ISSN (Electronic): 2050-6201

Publication date Collection: 2018

Publication date (Electronic): 08 March 2018

Publication date PMC-release: 08 March 2018

Volume: 2018

Issue: 1

Pages: 60-66

Affiliations

[1 ]Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA

[2 ]Program in Microbiology, Yale School of Medicine, New Haven, CT, USA

[3 ]Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale School of Medicine, New Haven, CT, USA

[4 ]Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, USA

[5 ]Section of Cardiac Surgery, Department of Surgery, Yale School of Medicine, New Haven, CT, USA

Author notes

Corresponding author. Section of Plastic and Reconstructive Surgery, Yale University School of Medicine, P.O. Box 208062, New Haven, CT 06520-8062, USA. Tel: +203-785-7313; Fax: +203-785-5714; E-mail: deepak.narayan@ 123456yale.edu

Article

Publisher ID: eoy005

DOI: 10.1093/emph/eoy005

PMC ID: 5842392

PubMed ID: 29588855

SO-VID: 2244ad12-6078-4d5d-b1d3-7f4da7f5d973

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 29 September 2017

Date accepted : 28 January 2018

Page count

Pages: 7

Funding

Funded by: National Institutes of Health 10.13039/100000002

Award ID: #R01-HD028016

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Phage treatment of an aortic graft infected with Pseudomonas aeruginosa

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