INTRODUCTION

Bacteriophages are one of the most proficient substi-tutes for antibiotics against bacterial infections [1]. Phag-es are existing in every environment where bacteria ex-ist, and there is at least one type of phage, more than one in most cases, to infect every strain of bacteria [2]. Before the development of antibiotics, bacteriophages were the choice of treatment against bacterial infections such as diarrhoea [3]. But soon after the starter of antibi-otics, the use of bacteriophages in therapy was almost abandoned. [4]. The misuse and mismanagement of anti-biotics led to the progress of antibiotic-resistant bacteria which is one of the most troublesome healthcare prob-lems. In the post-antibiotic era, it becomes obligatory to combat antibiotic-resistant bacterial infections using alternate therapies as antimicrobial compounds are inef-fective. Phage therapy receives renewed curiosity among phage researchers, and vital and practical studies on bacteriophages increased intensely, newly also to-gether with clinical trials [3]. The investigation of bacte-riophages for clinical or biotechnological purposes add-ed increasing attention after the 2000s, pparticularly the isolation of virulent bacteriophages for the treatment of bacterial infections, and the research of phage banks for personalized phage delivery [4]. However, bacteriophag-es and their proteins have a crowd of applications in different fields, for clinical use, therapeutic phages are required to be characterized in much detail. Virulent phages undergo a lytic cycle that differs from that of the temperate phage which by a lysogenic cycle. During this cycle, the phage genome integrates into the host genome, which can present a benefit to the host as some prophages encourage host behaviour or virulence by encoding virulence factors such as poisons or antimicro-bic resistance genes. [5,6,7]. Phages suitable for therapeu-tic purposes are usually lytic, where the produced phage progeny is released by lysis (the devastation of the bac-terial cell envelope) after their replication inside the host bacterium [8]. With this specific quality, virulent phages can be used to slaughter the pathogenic bacteria present inside the human system, and more often phages are specific to specific bacteria. This review mainly empha-sizes the phages in medicine for the treatment of bacte-rial diseases.

Antibiotic Resistance and Phage Therapy

Antibiotic resistance amid the pathogenic bacteria has made a universal emergency, instigating the quest for an alternate cure.

Bacteriophages were discovered over a century ago and are evidenced to be an effective alternative at the time of antibiotic medication catastrophe [9]. According to WHO’s (2020) report the percentage of resistance to ciprofloxacin, an antibiotic that is used to treat urinary tract infections, diverse from 8.4 per cent to 92.9 per cent for Escherichia coli and from 4.1percentage to 79.4 percentage for Klebsiella pneumoniae in countries reporting to the global antimicrobial resistance and use surveillance system, in some countries, carbapenem antibiotics does not work in more than half of the pa-tients administered for K. pneumoniae infections due to resistance and the resistance to fluoroquinolone antibi-otics in E. coli, which is used for the treatment of uri-nary tract infections, is widespread. There are several countries in many parts of the world where this treat-ment is now unsuccessful for more than half of the pa-tients. Colistin is the only last choice treatment for le-thal infections caused by carbapenem-resistant Entero-bacteriaceae which are E. coli, Klebsiella. Bacteria tolerant to colistin have also been detected in some countries and regions, triggering infections for which there is no active antibiotic treatment at present. The bacteria Staphylococcus aureus is a chunk of our skin flora and is also a communal cause of infections both in the public and in healthcare facilities. People with methicillin-resistant Staphylococcus aureus infections are 64% more likely to die than persons with drug-sensitive infections. Phage therapy practices are active-ly taking place in various Eastern European countries with effort work in Georgia and Poland being the most conversed. Several efforts have been made to investi-gate records of their development, testing, and applica-tions; though, it is not vibrant what section of the appli-cable info is reachable due to soviet-era practices, mili-tary concerns, and language fences. phages into magis-tral provisions for human use has been legalized since 2018 [10]. Thus, it’s the correct time to switch to Phages which appear to be better therapeutic agents as they have numerous advantages over traditional antibiotics [11,12,13]..

Table.1 Recent advances of phage therapy in human medicine

The above research in Table 1 was carried out on hu-mans. P.aeruginosa prosthesis knee infection was treat-ed with PP1450, PP1777, and PP1792 phages where the patient got cured [14]. Pyophages and intestine phages were used against the Enterococcus faecalis infected total hip arthroplasty where the patient also got cured [15].

The patient who had also been ill with debilitating plas-tic anemia for more than 2 years, was recovering after receiving adjuvant bacteriophage therapy (PM448 phage), and also the recalcitrant Staphylococcus epider-midis prosthetic knee Infection was also cured [16]. Pyophage cocktail (Georgian pharmaceutical product registration number R-022600) was used against the urinary tract infections in patients undergoing tran-surethral resection of the prostate which resulted in the normalization of urine culture, measured by a quantita-tive microbiological urine test [17]. Cocktail of phages isolated from the hospital sewage, river Ganga, ponds, and sewer of the municipal corporation against chronic nonhealing wounds s due to infection by AMR Esche-richia coli (37.5%) followed by Pseudomonas aerugino-sa (31.2%) and Staphylococcus aureus (31.2%), while Klebsiella pneumoniae (12.5%), Proteus species (6.2%), Citrobacter freundii (4.1%), Morganella mor-ganii (2.1%), and Acinetobacter baumannii (2.1%) where a total of 5 to 7 applications were made till the wound became free from infecting bacteria. The success rate of therapy was found to be 81.2% was obtained, of which 90.5% (19 out of 21) patients were nondiabetic and 74.1% (20 out of 27) diabetic patients. The wounds diseased with Klebsiella pneumoniae had relatively de-layed healing [18]. Three lytic phages of cocktail APC 1.1, JWDelta, and JWT against the pan drug-resistant Achromobacter xylosoxidans due to the cocktail of phages treatment, the bacteria became favourable both susceptible to the applied phage cocktails [19]. Coli A11/58c, Kl 53N/1920, EF1/1679L, Ps1N/734, Coli 77/850 phage against the chronic urinary and urogenital MDR bacterial infection caused by E.coli, K.variicola, K.pneumoniae, P.aeruginosa there was a significant reduction in the bacterial load was observed [20]. A trend in the biofilm biomass reduction was distinguished after 22 hours of exposure to KpJH46Φ2 in the limb-threatening prosthetic knee Klebsiella pneumoni-ae infection [21]. Ab_SZ3 with z tigecycline and poly-myxin treatment led to clearance of the carbapenem-resistant Acinetobacter baumannii lung Infection in the patient [22]. After treatment of AbW4878ø1 phage along with sulfamethoxazole/trimethoprim and tigecycline for a total of 35 days the health of the patient became good and discharged [23]. Phage M1 along with meropenem and colistin, followed by ceftazidime/avibactam was highly effective against the patient’s K. pneumoni-ae strain in vitro, in 7-day mature biofilms and suspen-sion [24].

Recent advances of phage therapy in veterinary medicine

Phages have also been effectively used for veteri-nary applications either to direct address infectious dis-eases in animals or for satisfying facts when about hu-man clinical trials [25]. It is too significant to reveal that animal phage therapy trials do not have a similar degree of strict obstacles as human trials and are plausible to put a key pattern for phage therapy in the clinical set-ting. The earliest use of phages in veterinary medicine was conducted by D‟Herelle in 1919, who showed their efficacy in averting and treating fowl typhoid (S. galli-narum) in six experimentally disease-ridden chickens [26].

Table 2. Recent advances of phage therapy in rats

The above research in table 2 was carried out on the rats. A mischief of rats was infected with MDR A. baumannii and dared with bacteriophages. There was a substantial fall in disease, the phase of colonization, and injury shrinkage were noted in the phage dared group when related to the antibiotic-treated unre-strained diabetic rats also the control group. Swabs which were procured on day 2 exposed Gram-negative bacilli with more grade four neutrophils and MDR A. baumannii. The reduction in the inflammatory cells was detected on day four and six where the phages were administered after 48 hours, the bacterial load amplified on day 4, and got reduced on day six. On day 8 no bacteria were detected. Consequent swabs also did not disclose the existence of any bacteria or inflammatory cells, and no growth for MDR A. bau-mannii[27]. Phages PaAH2ΦP, PaBAP5Φ2, and PaΦ13 provided a significant survival benefit over the sub-efficacious dose of meropenem [28]. ZCKP8 phage exhibited the high therapeutic efficacy in vivo on the rat as it can treat full-thickness wounds disease-ridden with a K. pneumoniae clinical isolate, which was re-sistant to the multiple antibiotics [29]. Continued phage therapy for 28 days against Klebsiella pneumoni-ae XDR strain was found to be safe concerning animal haematology histopathology, body weight, feed in-take, and behavioural parameters biochemistry [30]. The phage cocktail of equal 4 genetically unique phages called 2003, 2002, 3A, and phage K enhanced the animal survival and reduced MRSA burdens in tissues [31].

Table 3. Recent advances in phage therapy in mouse

The Kp_Pokalde_002 phage against carbapenem-resistant Klebsiella Pneumoniae there was a substantial drop of bacterial load (3-7 log10 CFU/ ml) in the blood and lung was observed in the treatment group [32]. phiEF7H, phiEF14H1 and phiEF19G phages lysed broad-range E. faecalis, including strains derived from endophthalmitis and mice got cured [33]. Lytic bacteri-ophages extracted from hospital sewage were collected from the third pond of sewage in Ghanem Hospital of Mashhad city and filtered by a membrane filter where the prepared ointment effectively prevented and treat the post-burn infections with no allergic reactions caused by an opportunistic pathogen, Pseudomonas aeruginosa which became complex due to its innate and attained resistance in mice [34]. They did not alter the intestinal microbiota of healthy mice and reduced mi-crobiota perturbations induced by Salmonella [35]. The Phage vB_PaeS-PAJD – 1 protected the mice from mastitis infection by MDR P. aeruginosa [36]. Virulent bacteriophage vB PaeP-SaPL on 24 h post-inoculation single dose of a treated group the Multidrug-resistant Pseudomonas aeruginosa PA-1 showed survival of 100 % (27 out of 27 mice) [37]. One purified phage filtrate which was obtained among the sewage samples with an average plaque size of 0.816 mm treatment demonstrat-ed was more efficient against the test antibiotic ciprof-loxacin as it selectively eradicated the Wild-type Sal-monella enterica serovar Typhimurium infection [38].

The cocktail of phage Pharr (P1), a 40.6-kb podophage, and ϕKpNIH-2 (P2), a 49.4-kb Sipho phage, proved the extreme increase in survival against MDR Klebsiella pneumoniae ST258 [39]. The mice inoculated with MDR Cutibacterium infection developed the inflammatory nodules After TCUCAP1 phage injection, the nodule size reduced which also decreased the manifestation of inflammatory marker IL-1β and apoptotic marker caspase-3 days [40]. S. aureus phage SaGU1 and S. epi-dermidis SE-4 possessed a sufficient efficacy against atopic dermatitis and that with the combinational use of probiotics and phages was effective in the treatment of S. aureus-associated atopic dermatitis [41]. Bacterio-phage strain KPP10 had a protective effect against pneumonia caused by P. aeruginosa D4. Furthermore, the administration of phage at delayed time points of post infections and the survival rate in pneumonic mice got well improved [42]. Lytic Phage SHWT1 tolerated the pH and the temperatures and was able to effectively inhibit the growth of bacteria and biofilm caused by prevalent Salmonella serovars. Furthermore, phage SHWT1 exhibited lytic activity against the intracellu-lar Salmonella also [43]. vB_PaeP_PA01EW effectively lysed the Pseudomonas aeruginosa causing pneumonia in eight-week-old BALB/c mice with a large surge of release after a short incubation time [44].

Table 4. Recent advances in phage therapy in other veterinary

Cocktail of phage PP1450, PP1777, PP1902, PP1792 & PP179 is used to treat Pneumonia caused by Pseudomonas aeruginosa during mechanical ventilation the piglet got cured [45]. Phage XC31The survival was 83%, exhibited higher photosynthetic ability and robust antioxidant capaci-ty of Pyropia haitanensis to cope with the Yellow spot dis-ease conchocelis (Vibrio mediterranei 117-T6) [46]. (Φ 16-izsam) and 39 (Φ 7-izsam) phage reduced Campylobac-ter counts [47]. After the Injection of the 20vB_AsM_ZHF phage, they abridged the 24 mortalities in turbot challenged by A.salmonicida subsp. Masoucida [48]. Three phages B_EcoM_SYGD1, vB_EcoP_SYGE1, and vB_EcoM_SYGMH1 showed promised effect as antimi-crobial agents especially when used as the cocktail to sig-nificantly reduce the number of bacteria, somatic cells, and inflammatory aspects lower the signs of mastitis by AMR Escherichia coli and accomplishes a similar effect as anti-biotic treatment [49]. Cocktail of three Staphylococcus phag-es fPfSau02, fPfSau03, and fPfSau04 against MRSA There was no reduction in the MRSA levels in the sampled healthy carrier pigs [50]. The IME-AB2 phage reduced 90% bacterial count was achieved after the 4-hour treatment in the pigskin model [51]. K. pneumoniae infected Zebrafish were treated with phages alone was found to be 77.7% and also the combination of streptomycin showed a substantial 97.2% decline in CFU/ml [52]. vB_ZEFP phage is evidenced to be effective when used in a mixture with hypochlorite allowing for the use of dual therapies the phage has poten-tial for effectiveness in the prevention of infection after root canal treatments [53]. The Single dose of EP1 cleared the Enterotoxigenic Escherichia coli infection while anoth-er phage EP2 was unable to eliminate the bacterial patho-gen in Galleria mellonella. A phage cocktail consisting of EP1 together with EP2 protected the larvae from bacterial infection with a 100% larval survival rate. The phage-antibiotic synergy, a combination of phage with cefotaxime was done where there observed a 100% survival rate within 72 hrs., while there was no significant survival was ob-served in the control group [54].

Table 5. Comparison of bacteriophages and antibiotics