Phage Therapy: a Potential Alternative in the Treatment of Multi-Drug Resistant Bacterial Infections

Journal of Microbiology & Experimentation

Phage Therapy: A Potential Alternative in the Treatment of Multi-Drug Resistant Bacterial Infections

Abstract Review Article

The development of antibiotic-resistant in bacteria has enhanced the scope of Volume 5 Issue 7 - 2017 developing alternative approaches to conventional drugs. Bacteriophage therapy is

live phages in counteracting lethal infectious and life threatening diseases caused by Gramone such positive approach and Gram that can negative be used bacteria as an alternativehas been reported. to antibiotics. Bacteriophage The significance therapy ofis 1Department of Microbiology, Federal University of Agriculture, Nigeria infections as phages are used topically, orally or systemically in studies reviewed. 2 Thea significant success alternativerates found to in antibiotics these studies in the were current 80-95% era of multidrugwith few gastrointestinal resistant bacterial or Federal University of Oye-Ekiti, Ekiti State, Nigeria

*Corresponding author: against Escherichia coli, Acinetobacter spp., Pseudomonas spp and Staphylococcus aureusallergic. US side studies effects. dealt British with studies improving also the verified bioavailability significant of effectiveness phage. Problems of phages faced Adebayo OS, Department of in these studies have also been discussed. Conclusively, phage therapy may prove as Email:Microbiology, Federal University of Agriculture, Abeokuta, an important alternative to antibiotics for combating multidrug resistant pathogens. Ogun State, P.M.B: 2240, Nigeria, Tel: +2347030303230; Received: September 21, 2017 | Published: November 15, Keywords: 2017 Bacteriophage; Infectious disease; Drug resistance

Introduction The lysogenic cycle on the other hand involves replication of phage nucleic acid together with the host genes for numerous Phages are viruses that infect the bacteria and causes bacterial generations without major metabolic consequences for the cell cell lysis [1]. They are “programmed” to terminate one or a few [6]. This is known as a latent mode of infection which occurs at a kinds of different strains of bacteria. Phages are widespread in very low frequency. The phage genes in this state may occasionally nature and can appear naturally in food and in the human body return to lytic cycle, leading to release of phages particles. This phenomenon is known as lysogeny and phages that can develop bacteria which have built up resistance over time to antibiotics both lytically and lysogenically are regarded as temperate phages (for example in the intestines). Phages can efficiently destroy and which causes life-threatening infections [1,2]. Phage therapy [6]. was introduced by Felix d’Herelle, who co discovered phages Phage Therapy timearound of 1920its discovery, [3]. These phage findings therapy occurred was aboutbeing 20considered years prior as Phage therapy combats bacterial infections of humans (or ato potential practical applicationtreatment technique of penicillin, against the first bacterial antibiotic. infectious At the animals) with the goal of reducing bacterial load. Findings diseases. Phage therapy was used to treat and prevent infectious shows that appropriate administration can be used to treat bacterial diseases in the former Soviet Union and Eastern Europe lethal infectious diseases caused by Escherichia coli, Vibro and was abandoned by the West in the 1940s with antibiotic era cholerae, Staphylococcus aureus and Salmonella spp. [7]. Phages springing up. can be delivered topically, orally, directly into body tissues, or

Bacteriophages are regarded as one of the possible alternatives terms of delivery. Phage - infected bacteria may be employed as a to antibiotics in animal therapy, prophylaxis and reduction of meanssystemically. of delivering A second phages means to intracellular in which therapiespathogens differ[8]. Finally, is in bacterial loads in food products of animal origin. Trials with the normal ability of lytic phages to destroy infected bacteria bacteriophages and farm animals have been proven to be may be exploited, as is generally the case with phage therapy, or successful and thereby used to destroy food borne pathogen such alternatively phages may also be engineered to deliver non-phage as Escherichia coli [4], Salmonella [4] and Campylobacter [5]. genes coding for antibacterial agents [9]. Life Cycles of Phages The success of phage therapy is a function of elementary

Phages possess a developmental cycle inside the host bacteria a phage that can infect a bacterium, and the effectiveness relies which can be lytic or lysogenic [6]. The lytic cycle covers a series onprinciples the extent of phage-bacterialof phage bacterial infection. infection. One Secondly, must first if treatmentrecognize of events that occur between attachment of phage particle to a is initiated during early stages of infections it may be essential to bacterial cell and its subsequent release of new daughter phage compensate, by using a larger phage dosage, due to the inability of too-few bacteria to successfully expand phage population to host cell, penetration of phage nucleic acid, transcription and [10]. The advent of antibiotic -resistance bacteria has grown translation,particles. It assemblyconsists of and five exit. stages, namely; adsorption of phage

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into a major problem for clinician over the last 2-3 decades. In US Studies United State, antibiotic resistance bacteria infect approximately 2 million people each year of which at least 23,000 people has been Merrill et al. [24] discovered a system to overcome this documented to die annually [11]. In recent times, bacteria such sequestration of phage in the reticulo endothelial system. He as Acinetobacter baumannii, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococus faecium, Klebsiella pneumonia have re grown in a mutant E. coli strain repeatedly ten times. This serial injected λ phage into mice and isolated the phage. This phage was developed multi-drug resistance and cause major healthcare disaster in ICUs [12,13]. mutation in major phage head protein that enabled it to evade the reticulocycling of endothelial phage proved system effective [24]. in selecting λ with an amino acid The development of severe infectious diseases resistant to antibiotics has been an issue of serious concern and this in turn has Phage Therapy in Animals led to the discovery of alternative approaches that could replace Bacteriophages are broadly used for the treatment of infections these conventional antibiotics. Steady decline in the discovery of caused by Escherichia coli and Salmonella in chickens, calves, pigs new class of antibiotics, has enhanced the scope of bacteriophage and lambs. Smith and Huggins [25] experimentally proved that, as an alternative to conventional antimicrobial drugs. Therefore, bacteriophage can be employed as therapeutic agent to combat mice due to septicemia caused by E.coli which cannot be treated infections caused by multi-drug resistance bacteria [14,15]. witha single multiple dose of doses phage ofR isantibiotics. effective in They averting consequently the mortality used in Clinical Studies of Phages in Human Patients bacteriophages for the treatment of infections caused by entero toxigenic E.coli in neonatal lambs, calves and pigs [25]. Vintage In human, a number of infectious diseases such as septicemia, research on the therapeutic ability of phages were conducted wound infections, skin infection, osteomyelitis, urinary tract infections and middle ear infections were effectively treated (Salmonella enterica subspecies enterica serovar Gallinarum) and with phage therapy [16]. In the US, phages were commonly used laboratoryby Felix d’Herelle, studies whoon dysentery carried out in rabbitsfield studies (Shigella on fowldysenteriae typhoid) for preparation of human and animal vaccine. In phage therapy, [3]. Successive animal studies have revealed that phage therapy phages were used in the form of liquid suspension, tablets, creams rinses, aerosols [17,18]. Phages therapy trials have been carried S dysenteriae phage injected out in some countries and it is discussed below. intraperitoneallyis effective in animal in mice systems. showed René in Dubosthe blood et al. stream [26] at (and Harvard even crossedUniversity the (USA) brain-blood showed barrier) that anti- but were rapidly cleared by the Polish Studies reticuloendothetial system (particularly the spleen). Slopek et al. [19] reported cases of the treatment of staphylococcal infected patients of which 151 cases were of Advantages of Phage Therapy over Antibiotics mixed infection including Staphylococcus. Positive results were obtained in 75% of infected ulcerated varicose vein cases and antibiotics can be framed in terms of phage properties. 100% in gastrointestinal infection, pericarditis and furunculosis Advantages of phage therapy over the use of chemical due to Staphylococcus Bactericidal agents more than 60 years of age and in patients with mixed infections. Bacteria that have been successfully infected by obligate lytic . Response rates were lower for patients Interestingly, parallel administration of antibiotics diminished the phages are unable to regain their viability. In contrast, certain effectiveness of phage therapy from 95.2% to 84.9%. antibiotics such as tetracycline are bacteriostatic, and result in Weber et al. [20] evaluated the extent to which orally bacterial resistance [27]. administered anti staphylococcal and anti-pseudomonal phage Auto “dosing” were penetrated into the serum or urine of 56 patients with suppurative bacterial infection. By the tenth day of treatment, it Phages during bacterial-lysing process have the capability of was established that 84% serum samples and 35% urine samples contained phage indicating a high bio-availability [21]. though with constraint such as dependence on relatively high increasing in numbers specifically where the hosts are located, British Studies the phages themselves backs the establishment of the phage dose bacterial densities [28]. This is known as Auto “dosing” because [28]. Acinetobacter, Pseudomonas and staphylococcal infection in miceSoothill and the [22] research verified reported the ability limited of phagesuse of phage in experimental therapy in Minimal disruption of normal flora staphylococcal infections. Soothill then shifted attention to the problematic cases of cutaneous infection due to burns among infect few strains of bacterial species to more than one relatively patients with graft failure leading to bacterial infection. The closelyDue related to their bacterial host specificity- genus. However, This ranges numerous from theconventional ability to study was experimented in guinea pigs and split skin grafts were antibiotics, which have broader spectrums of activity, are taken and full thickness defects were created [23]. Prior to re predisposed to induce infections, such as antibiotic associated implantation of graft, wound bed was infected with Pseudomonas Clostridium difficile colitis or Candida albicans yeast infections. The preference towards developing only broader spectrum antibiotics, however, may be changing [29]. strain with its respective phage. After five days, Grafts were accepted and they vascularized [23].

Citation: 10.15406/jmen.2017.05.00173 Adebayo OS, Gabriel- Ajobiewe R, Taiwo MO, Kayode JS (2017) Phage Therapy: A Potential Alternative in the Treatment of Multi-Drug Resistant Bacterial Infections. J Microbiol Exp 5(7): 00173. DOI: Phage Therapy: A Potential Alternative in the Treatment of Multi-Drug Resistant Copyright: 3/4 Bacterial Infections ©2017 Adebayo et al.

Rapid discovery Conclusion Phages acting against many pathogenic bacteria are found It’s quite obvious from the above study that the use of in sewage and other waste materials that contain high bacterial bacteriophages to control bacterial infections shows therapeutic promise. The worldwide increase of pathogenic bacteria resistant and may differ based on the number of phage types affecting them to antibiotics makes it imperative to exploit alternative strategies [30].concentrations. Unlike antibiotics, However, which the host can bacteria be toxic, are phages difficult that to displayculture to combat this threat. The therapeutic use of bacteriophages - little or no toxicity can be isolated against most target bacteria. perhaps in combination with antibiotics – may turn out to be a valuable approach. However, it is also quite clear that the safe and Biofilm clearance controlled use of phage therapy will require detailed information

system, both in vitro and in vivo. The in vivo susceptibility of antibiotics when compare to planktonic bacteria. Phages however bacterialon the properties pathogens and to bacteriophagesbehavior of the isspecific poorly phage–bacteriumunderstood. Biofilms are complex in nature and can resist a wide range of Phages, as antibacterial agents, have a number of properties have a proven ability to clear at least some biofilms, possibly that make them alternatives to chemical antibiotics while most exopolymer-degradingdue to their ability to infiltrate depolymerases their way [31]. into biofilms by lysing or perhaps all concerns associated with phage therapy should a bacterial layer at a time, or owing to the display of biofilm be manageable through a combination of proper phage selection, Narrower potential for inducing resistance effective formulation, and greater clinician understanding of and familiarity with product application. Use of antibiotics along with The narrow host range demonstrated by most phages restricts more likely to inhibit phage effectiveness than to enhance it and mechanisms. There are contrasts with the large fraction of combinationphages has been may tried result with in limitedproblem/resistant benefit because genes. antibiotics Hence it are is bacteriathe number that ofcan bacterialbe affected types by most for specific conventional phage-resistance antibiotics concluded that phage therapy alone is more effective. [27]. This implies that when patients are infected with multiple bacteria, in this situation bacteriophage therapy will not effective. They are used for typing of clinical bacterial strains for in situ Shortcomings of Phage Therapy bacterialIn medicine detection in recent through times, labeled phages phages, find many (Listeria), applications. phage display system for vaccines, control of food pathogens and for drug Not all phages make good therapeutics and gene delivery using defective phage with targeted receptor. Good therapeutic phages should possess a high potential to Phage therapy for eliminating multidrug resistant bacteria is reach and kill the bacteria in combination with a low potential gaining importance. Nevertheless, more studies are still required to otherwise negatively modify the environments to which they before phages can be considered a real approach for therapy of are applied. The usage of temperate phages as therapeutics is bacterial infections. The usage of phages for therapeutic purposes challenging owing to a combination of display of super infection immunity [32], which then converts phage-sensitive bacteria into environment [33]. insensitive ones, and the encoding of bacterial virulence factors, has need of specific phages for the pathogenic strains of a precise including bacteria toxins. Acknowledgment In order to avoid temperate or toxin-carrying phages, the None. phages displaying poor lysing potential against target bacteria Conflict of Interest are excluded. Such low “virulence” can be due to poor adsorption properties, low potential to evade bacterial defenses, or poor replication characteristics. Ideally, phages should also parade low potential to exchange bacterial genes between bacteria [30]. ReferencesThere is no conflict of interest. 1. The problem of narrow host range Bacteriophage therapy rescues mice bacteremic from a clinical isolateBiswas of B, vancomycin- Adhya S, Washart resistant P, EnterococcusPaul B, Carlton faecium RM,. Infect et al. Immun (2002) No antimicrobials displaying selective toxicity will have effect 70(1): 204-210. on all possible microbial targets. Usually the narrowness of phage host ranges- a few strains, a few species, or much rarer, a few 2. Wang J, Hu B, Hu J, Xu M, Yan Q, et al. (2006) Use of bacteriophage in the treatment of experimental animal bacteremia from imipenem- genera of bacteria, will at the lowest place limits on presumptive resistant Pseudomonas aeruginosa. Int J Mol Med 17(2): 309-317. treatment, i.e., treatment courses that begin earlier to the 3. Summers WC (2001) Bacteriophage therapy. 55: 437-451. Annual Rev Microbiol beidentification employed ofin thecombination pathogen’s with susceptibility other antibacterial to antibacterial agents, 4. includingsuch as to other specific phages phages (so-called [32]. phage However, cocktails), as phages the lytic can range often Colibacillosis in of phage products can often be much broader than the range of broilerHuff WE, chickens. Huff GR, Poult Rath Sci NC, 85(8): Donoghue 1373-1377. AM (2006) Evaluation of the activity of individual phage types [32]. influence of bacteriophage titer on the treatment of 5.

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