The phage therapy as a promising treatment method

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Last updated: October 3, 2019

Thefollowing search criteria were applied: (1) retrospective studies of phagetherapy against pseudomonas aeruginosathat cause infection to the respiratory tract, ear and burn wounds (2) full-textresearch articles with in-vivo studies on either pre-clinical animal models orclinical human models (3) studies considering the effectiveness of phagetherapy by using colonies-forming units (CFU) or phage-forming units (PFU)counts or animal models survival rate as outcome criteria and (4) studies inEnglish. Since the use of phage as therapeutic agent has been proposed in 1917and many studies have been performed after, this systematic review searchcomprise of the time period between January 2007 and December 2017. Selection Criteria Relevantpublications on the efficacy of phage therapy against pseudomonas aeruginosa were identified by searching databases suchas PudMed, Aston Library and ScienceDirect as well as additional sources frombibliographies of several articles. The date of search was 9 December 2017, 19December 2017 and 25 December 2017 respectively. “Bacteriophage” and “pseudomonas aeruginosa” served askeywords.

Search Method Figure 1. Results ofsystematic literature search Materials and Method  Beingone of the leading opportunistic pathogens involved in nosocomial infection, P. aeruginosa has been the focus ofphage application and genotyping studies.

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Recent studies of both in-vitro andin-vivo, as well as in animals and human models have shown phage therapy as apromising treatment method against P.aeruginosa.(Wrigh et al., 2009; Hagenset al., 2006; Rhoads et al., 2009; Hurley et al., 2012) To date, there are a total of 137 phages known to targetPseudomonas species. Of that, 94.

2%of the phage belongs to the Caudoviralesorder that comprises of phages with short and noncontractile tail (Podoviridae); phages with along and contractile tail (Myoviridae),and phages with a long and noncontractile tail (Siphoviridae).Among the Pseudomonas genus phagesthat are sequenced, approximately 60% of them are lytic phages and holdspotential therapeutic function against Pseudomonasspecies. (Ackermann, 2009; Sillankorva and Pires, 2014; Ceyssens and Lavigne, 2010)Bacteriophages were discovered almost a century ago. (Pires et al., 2015) It wasproposed by Félixd’Hérelle, a French-Canadian microbiologist in 1917, regarding the use of phage as antimicrobial agents. (Pires et al., 2015) Following D’Hérelle’s finding, phage therapy was used totreat dysentery in 1919, staphylococcal skin disease in 1921 as well as severalstudies as reported by Thurman B.

R., Schless R. A.  and Stout B. F. (Sulakvelidzeet al., 2001) Therapeutic phages were also actively produced bycommercial laboratory against various bacterial infections includingsuppurating wounds and upper respiratory tract infections. (Pires et al.

, 2015) However, with the introduction of antibiotics, phagetherapy has been superseded in most of the Western world but continue tobe used in Eastern Europe and the former Soviet Republic of Georgia.  (Sulakvelidzeet al., 2001) Antibiotics were seen as the choice of treatment againstbacterial infection as they are cheap and effective. Yet ironically, the use ofantibiotics promotes the emergence of anti-microbial resistance bacteria. (Pires et al.

, 2015) Moreover, with several distinctive advantages ofbacteriophage over antibiotic therapy such as bacterial specificity andeffectiveness against biofilm, a renew interest in phage therapy has arise. (Azeredoand Sutherland, 2008)  Phage therapy involved the use of bacteriophages, inreplacement of antibiotics, to treat bacterial infection. (Abedon,2015) It is one of the potential therapeutic approaches in view to theemergence of multidrug resistance bacteria. (Abedonet al.

, 2011) Bacteriophages, or phages,are viruses that specifically infect and kill bacteria. They are divided intotwo classes based on their life cycle, namely the lytic phage and temperatephage. (Guttman et al., 2004) Lytic phage infects bacteriaby injecting and replicating its genome into the bacterium, followed byinducing host cell lysis. This results in the release of new viral particles tostart another round of infection, for as long as sufficient bacteria host ispresent.

(Harper and Kutter, 2008)  On the other hand, temperate phage, whichundergo the lysogenic cycle, infects bacteria by injecting and integrating itsgenome into the host chromosome. The integrated viral genome, or prophage,replicate with the host cell DNA and unless activated by specific stimuli, willremain latent in the daughter cells. (Harperand Enright, 2011; Little, 2005) For therapeutic purposes, only bacteriophages that are obligatelytic in nature are desired due to their rapid killing of host cell.

(Harper and Enright, 2011) P.aeruginosa also has an ability to produce biofilm, which are slimyextracellular polymeric substance (EPS) matrix,. (Taylor etal.

, 2014)These biofilm have a 10-1000 fold higher resistance againstantimicrobial killing comparing to planktonic bacteria cells. (Hoyle and Costerton, 1991) Biofilms are aggregate of cells that firstadherent irreversibly to a surface through the action of pili and flagella.  EPS matrix is then produced by the cells topromote stronger cell adherence and confers biofilm structure. (O’Tooleand Kolter, 1998; Toutain et al., 2007) This matrix, though allowsnutrients and small molecules to penetrate, act as a barrier for effectiveantimicrobial activity and host immune defence.

(Olson et al., 2002) Itis proposed that this gain of resistant mechanism in P. aeruginosa is the result of adaptive ability by modifying geneexpression and external environment conditions. The high resilient to physicalstress and antibiotic clearance has made P.aeruginosa a major therapeutic concern within healthcare setting,(Taylor etal., 2014) P. aeruginosa biofilm commonly colonizedmedical devices and epithelial cells such as ventilators and open wounds,resulting in infections that are difficult to eradicate using conventionaltherapeutic methods, (Bjarnsholt et al.

, 2009; Boucher et al., 1997, Worlitzschetal., 2002) An example is the colonization of P.

aeruginosa in CF lungs. The formation of biofilm within CF lungsresults in chronic infection that, despite all means of antibiotic therapies,persists for life, (Taylor et al., 2014)  Hence, the development of newantimicrobial agents and strategies are at a growing demand against thesepathogenic bacteria. Currenttreatment against P. aeruginosainfection involved the use of anti-pseudomonal agents such as ?-lactams, aminoglycosides, fluoroquinolonesand more recently, polymyxins.

  (Mesaroset al., 2007).However, the highintrinsic, acquired and adaptive resistance ability displayed by P.

aeruginosa makes its eradication achallenge. (Taylor et al., 2014)  Intrinsic resistance refers to theinnate ability of wild type bacteria to limit its susceptibility toantibiotics. P. aeruginosa possessthis underlying ability due to the low permeability of its outer member. (Giamarellou,2002) As the outer membrane of P aeruginosa is 12-100 fold less permeable than other gram negativebacteria, (Hancock and. Bell, 1998) it serves as a barrier slowing downantibiotic penetration through the water-filled porin channels. Also, theexpression of efflux pump and production of enzymes that inactivate antibioticsynergizes with the slow antibiotics uptake, making P.

aeruginosa Intrinsically more resistance. (Giamarellou,2002) The Multidrugefflux systems such as the MexAB-OprM, MexEF-OprN and MexCD-OprJ conferresistance to ?-lactam, fluoroquinolones and aminoglycoside (Chatterjeeet al., 2016) while inactivating enzymes such as AmpC ?-lactamasedegrade slow flowing antibiotic that are penetrating across the outer membrane.(Tayloret al., 2014) Acquired resistance is the consequence of antibioticexposure resulting in mutation of chromosomal gene or acquiring of antibioticresistance gene. (Pires et al.

, 2015)P. aeruginosa has one of thelargest genome within the prokaryotic world that encodes for large amount ofproteins responsible for its pathogenesis. Intrinsically, 0.

3% of its codinggene possesses antimicrobial function, (Mesaros et al., 2007) With5570 open reading frames, the large genome is also highly flexible in acquiringmobile genetic elements such as plasmids and integrons that confer antibioticability. (Mesaros et al.

, 2007; Taylor et al., 2014).  Adaptive resistance, on the other hand,is dependent on the growth conditions and environmental stimuli to triggercellular regulatory events and this susceptibility are usually revert with theremoval of these triggers, (Fernández et al., 2011) Conditions suchas antibiotic exposure, DNA stress, heat shock and environmental PH has beenreported to induce adaptive resistance.

(Fernández et al., 2011) The ability of P. aeruginosa to thrive in diverseenvironment and resist a range of antibiotics is probably due to its large andcomplex genome as adaptive resistance involved many genes including resistomes,explaining the highversatility and adaptive capacity of the species, (Taylor etal., 2014)Infectionsof P. aeruginosa are difficult totreat as the bacteria possess an arsenal of virulence factor that helps in itspathogenesis and invasion of host cells.

The extracellular virulence factorsinclude proteases which degrades and inhibits complement proteins activation (Chatterjee et al., 2016), Elastase (LasA and LasB),  (Kessler et al., 1997; Grande etal., 2007) exotoxin A which inhibits protein synthesis in eukaryotes, (Stuartand Pollack, 1982) phospholipases that causes erythrocytes hemolysis, (Shortridgeet al., 1992) exoenzymes that promote invasion and chronic infections bydisrupting cytoskeletal structure (Sadiko et al., 2005) whilethe cell-associated factor includes lipopolysaccharide (LPS), flagella, andpili that facilitate P.

aeruginosa colonization, survival and invasion withinhost tissues. (Chemani et al., 2009) P. aeruginosa is capable of causinginfections that are both acute and chronic. One such example is infections tothe respiratory tract. The environment of the respiratory tract allows P. aeruginosa to adapt and grow well,resulting in potential pneumonia or lung infection, especially in those who areimmunocompromised or hospitalised within intensive care units.

(Mesaroset al., 2007) Hospital-acquired pneumonia is the second leading complicationof P. aeruginosa infection. (Torreset al.

, 2010) It is usually ventilator-associated where pneumoniadevelops after more than 48 hours of mechanical ventilation or intubation. (Bielenet al., 2017) Anothersusceptible group are individuals with cystic fibrosis (CF). CFis a heterogeneous recessive genetic disorder due to mutation of the CF transmenbranceregulator (CFTR) gene.

(Knowles and Durie, 2002) Thisgene helps in the regulation of transporting chlorine ions across theepithelia, necessary for the production of mucus that lubricates the airway. Inclassic CF, a loss of function due to mutation to both the CFTR gene leads to airwaydehydration and an impaired mucociliary clearance of bacteria, allowingbacteria to colonize the lungs more readily. (Taylor et al., 2014) P. aeruginosa is also the predominant agents causing acute diffuseotitis externa, commonly known as swimmer’s ear. (Mesaros et al., 2007) Itis characterized by erythema, otalgia and itch as early symptoms and mayprogress to having aural fullness, discharge and conductive hearing loss. (Nuttall,2016) This type of otitis externa is known asswimmer’s ear as swimmers are at a risk that is 5 times greater thannon-swimmers while cases of otalgia are 2.

4 times greater in swimmers thannon-swimmers. (Hoadley and Knight, 1975) Besides the heatand humidity that cause swelling of the skin, moisture from swimming increasesskin maceration of the external auditory canal. This encourages breaching ofthe protective skin barrier, allowing viable pathogenic organism in the marinewaters, such as P. aeruginosa, toemerge and become infective. (Wang et al., 2005) Burn wounds arehighly susceptible to infections especially by P.

aeruginosa where complications such as bacteraemia and septicaemia are oftenserious and life-threatening. (Mesaros et al., 2007) Otherthan maintain body fluid homeostasis and thermoregulation, an intact human skinalso served as a physical barrier against microbial invasion. Following severethermal injury, extensive skin surface of the affected area are breached. (Elsayedet al., 2006) Since P. aeruginosais so commonly found in the environment, burned individual are likely to becolonized with this microorganisms before the burn wounds are heal completely.

(Lyczaket al., 2000)Pseudomonas aeruginosa is a gramnegative bacillus that acts as an opportunistic human pathogen. It isconsidered as one of the nosocomial causative agents and is responsible for the large scale multi-drug resistantinfections. (Pier and Ramphal, 2005) Rarely,P. aeruginosa infects healthyindividual. However, it is capable of infecting all tissue when the physicalbarrier is breached or in individuals whose immune defence is compromised suchas those with cystic fibrosis and cancer. (Morrison and Wenzel, 1984)Hence, this explains why P.

aeruginosais a major concern within healthcare settings and their infections are oftensevere and life-threatening. (Maschmeyer and Braveny, 2000) Eachyear, it is estimated that there are 51,000 cases of hospital acquired P.aeruginosainfections within the United States.

Of that, multidrug-resistant P. aeruginosa strains accounts foraround 13% of the cases, contributing to roughly 400 deaths annually. (Chatterjee et al., 2016)The increased incidence of antimicrobial resistance has beenone of the pressing problems faced by healthcare services worldwide. Bacteriaare gaining resistance to most of the currently availableantimicrobial agents which results in significant increased morbidity, mortality and healthcare costs. (Sulakvelidzeet al., 2001) It is estimated that theseinfections affects 2.5 million people annually and has claimed the lives of atleast 50 000 people across Europe and USA alone.

(Centers for DiseaseControl and Prevention, 2013) The emergence ofmultidrug-resistance bacteria has also raised the concern for nosocomialinfections. It is define as infections acquired during hospital stay and wasabsence at the point of admission, (Ducelet al., 2002) as well as potential occupationalinfections among staff within the facility. (Benenson, 1995) Anincidence survey conducted by the World Health Organization (WHO) across 14countries within Europe, Eastern Mediterranean, South-East Asia and WesternPacific that involved 55 hospitals has shown that an average of 8.

7% ofhospitalized patients acquire nosocomial infection. Thus,  this means that at least 1.4 million peopleworldwide are suffering from complications acquired in hospital at any point oftime. (Tikhomirov, 1987)

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