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      Growing Trend of Fighting Infections in Aquaculture Environment—Opportunities and Challenges of Phage Therapy

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          Abstract

          Phage therapy, a promising alternative to antimicrobial treatment of bacterial diseases, is getting more and more popular, especially due to the rising awareness of antibiotic resistance and restrictions in antibiotics’ use. During recent years, we observed a growing trend of bacteriophages’ application in aquaculture, which in each year reports high losses due to bacterial diseases. This review provides an update of the status of bacteriophage therapy for the treatment and prevention of infections in the aquatic environment. As it is still mostly in the scientific stage, there are a few constraints that may prevent effective therapy. Therefore, specific characteristics of bacteriophages, that can act in favor or against their successful use in treatment, were described. We underlined aspects that need to be considered: specificity of phages, bacterial resistance, safety, immune response of the host organism, formulation, administration and stability of phage preparations as well as bacteriophages’ influence on the environment. The biggest challenge to overcome is finding the right balance between the desired and problematic characteristics of bacteriophages. Finally, regulatory approval challenges may be encountered by bacteriophage manufacturers. Even though there are still some technical constraints connected with the global use of bacteriophage therapy, it was concluded that it can be successfully applied in aquaculture.

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          Most cited references95

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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.

          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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            Global trends in antimicrobial resistance in animals in low- and middle-income countries

            The global scale-up in demand for animal protein is the most notable dietary trend of our time. Antimicrobial consumption in animals is threefold that of humans and has enabled large-scale animal protein production. The consequences for the development of antimicrobial resistance in animals have received comparatively less attention than in humans. We analyzed 901 point prevalence surveys of pathogens in developing countries to map resistance in animals. China and India represented the largest hotspots of resistance, with new hotspots emerging in Brazil and Kenya. From 2000 to 2018, the proportion of antimicrobials showing resistance above 50% increased from 0.15 to 0.41 in chickens and from 0.13 to 0.34 in pigs. Escalating resistance in animals is anticipated to have important consequences for animal health and, eventually, for human health.
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              Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa

              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
                Antibiotics (Basel)
                Antibiotics (Basel)
                antibiotics
                Antibiotics
                MDPI
                2079-6382
                04 June 2020
                June 2020
                : 9
                : 6
                : 301
                Affiliations
                [1 ]Proteon Pharmaceuticals, 90-364 Lodz, Poland; jkazimierczak@ 123456proteonpharma.com (J.K.); psowinska@ 123456proteonpharma.com (P.M.S.); ewojcik@ 123456proteonpharma.com (E.A.W.); jdastych@ 123456proteonpharma.com (J.D.)
                [2 ]Department of Microbiology and Clinical Immunology, Faculty of Veterinary Medicine, University of Warmia and Mazury, 10-719 Olsztyn, Poland; siwicki@ 123456uwm.edu.pl
                Author notes
                Author information
                https://orcid.org/0000-0003-1102-9389
                Article
                antibiotics-09-00301
                10.3390/antibiotics9060301
                7345527
                32512805
                9f1a2873-66e7-47af-b640-0e95667adb03
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 April 2020
                : 03 June 2020
                Categories
                Review

                phage therapy,aquaculture,antibiotic resistance,phage,pathogenic bacteria

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