Table 2.

Phage therapy in different infectious diseases.

Disease type	Reference	Year	Location	Disease	Object (n)	Study type	Host	Outcome
Skin and soft tissue infections	Weber Dabrowska et al. [35]	2000	Poland	Pyogenic infections of burns	Human (49)	Single arm study	Staphylococcus aureus, Escherichia coli, Klebsiella, Proteus, and Pseudomonas	86% full recovery while 14% marked improvement.
	Markoishvili et al. [43]	2002	United States	Poorly vascularized and venous stasis ulcers	Human (96)	Single arm study	Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Streptococcus, and Proteus	The wounds/ulcers healed completely in 67 (70%) out of 96 patients. In 22 cases in which microbiologic data were available, healing was associated with the concomitant elimination of, or a reduction in, specific pathogenic bacteria in the ulcers.
	Rhoads et al. [44]	2009	United States	Venous leg ulcers	Human (42)	RCT	Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli	No adverse events. No significant difference of healing compared to antibiotic control.
	Morozova et al. [45]	2018	Russian	Infected diabetic foot ulcers	Human (2)	Case report	Staphylococcus, Enterococcus, and Pseudomonas aeruginosa	Wound continues to improve, while MRSA infection is not detected.
	Fish et al. [46]	2018	United States	Infected diabetic toe ulcers	Human (6)	Case report	Staphylococcus aureus	No adverse effects, tissue breakdown, or recurrence of infection were seen
	Kifelew et al. [47]	2020	Australia	Diabetic wound infections	Balb/c mice (48)	Animal experiment	Staphylococcus aureus	In phage-treated mice, wound healing was seen as similar to vancomycin treatment. No mortality was recorded associated with infections, and postmortem examinations did not show any evident pathological lesions other than the skin wounds. No adverse effects related to the application of phages were observed.
	Kumari et al. [48]	2011	India	Burn wound infection	Balb/c mice (30)	Animal experiment	Klebsiella pneumoniae	Significant reduction in mortality and more effective than silver nitrate and gentamicin.
	Yin et al. [49]	2017	China	Wound infection	Balb/c mice (36)	Animal experiment	Acinetobacter baumannii	Wound sizes in animals receiving locally applied phage were significantly smaller, drier, and cleaner than in mice receiving either systemically administered phage or no treatment. Infected mice receiving no treatment succumbed rapidly. In contrast, all mice treated with phage or polymyxin B survived the entire 7 days of the observation period.
	Totte et al. [50]	2017	Netherlands	Acne vulgaris and eczema	Human (3)	Case report	Staphylococcus aureus	Reduction and prevention of clinical symptoms and does not interfere with the commensal skin microbes and is also not expected to induce bacterial resistance.
Oral infection	Castillo-Ruiz et al. [51]	2011	Chile	Periodontitis	17 clinical samples were obtained from saliva and wastewater from dental chair drainages (NA)	In vitro	Aggregatibacter actinomycetemcomitans	Kill 99% of the bacteria within a biofilm.
	Guo et al. [52]	2015	United States	Dental caries	20 bacterial species, including multiple oral Streptococcus (NA)	In vitro	Streptococcus	Potent in killing Streptococcus mutans and Streptococcus salivarius.
	Tinoco et al. [53]	2017	Brazil	Dentin infection	Enterococcus faecalis V583 (vancomycin resistant strain) or Enterococcus faecalis JH2-2 (fusidic acid and rifampin resistant, vancomycin sensitive strain) (NA)	In vitro	Enterococcus faecalis	The recovered Enterococcus faecalis titer was reduced by 18% for the Enterococcus faecalis JH2-2 infected models and by 99% for the Enterococcus faecalis V583 infected models.
	Xu et al. [54]	2018	China	Dental caries	Sprague Dawley rats (36)	Animal experiment	Streptococcus	Streptococcus mutans and Streptococcus sobrinus biofilms are significantly decreased after treatment with ClyR for 5 min. Furthermore, continuous administration of ClyR for 40 days significantly reduced the severity of caries in rat models infected with a single or a mixed bacteria of Streptococcus mutans and Streptococcus sobrinus.
	Li et al. [55]	2018	China	Endodontic infection	Caries-free single-rooted teeth selected from orthodontic extraction (NA)	Ex vivo dental model	Enterococcus faecalis	ClyR degrades Enterococcus faecalis biofilm with high efficacy in a dose-dependent manner.
Gastrointestinal infections	Ott et al. [37]	2016	Germany	Diarrhea	Human (5)	Case report	Clostridium difficile	Sufficient to restore normal stool habits and eliminate symptoms.
	Bruttin and Brussow [56]	2005	Switzerland	Healthy volunteers to measure the bioavailability of oral phage for diarrheal diseases	Human (15)	Single arm study	Escherichia coli	Safe
	Sarker et al. [57]	2016	Bangladesh	Diarrhea	Human (120)	RCT	Escherichia coli	No adverse events. Fecal coliphage was increased in treated over control children, but the titers did not show substantial intestinal phage replication but no amelioration in quantitative diarrhea parameter by phage therapy.
	Vahedi et al. [58]	2018	Iran	Diarrhea	Balb/c mice (48)	Animal experiment	Enteropathogenic Escherichia coli	Able to control the infection.
	Jaiswal et al. [59]	2013	India	Diarrhea	New Zealand white rabbits (6)	Animal experiment	Vibrio cholerae	Lowered the shedding of bacteria significantly
	Nale et al. [60]	2016	United Kingdom	Diarrhea	Hamster (NA)	Animal experiment	Clostridium difficile	Reduced Clostridium difficile colonization at 36 h postinfection.
	Galtier et al. [61]	2016	France	Uropathogenic Escherichia coli infection	Balb/cYJ mice (5)	Animal experiment	Uropathogenic Escherichia coli	Microbiota diversity was much less affected by phages than by antibiotics and efficiently target uropathogenic Escherichia coli strains residing in the gut.
Respiratory infection	Cao et al. [62]	2015	China	Pneumonia	Swiss Webster mice (20)	Animal experiment	Klebsiella pneumoniae	Phage-treated mice exhibited a lower level of Klebsiella pneumoniae burden in the lungs as compared to the untreated control. These mice lost less body weight and exhibited lower levels of inflammatory cytokines in their lungs.
	Alemayehu et al. [63]	2012	Ireland	Pneumonia and cystic fibrosis	Balb/c mice (16)	Animal experiment	Pseudomonas aeruginosa	Effective in killing the pathogen in murine lungs. Pseudomonas was effectively cleared from murine lungs in 6 h.
	Oduor et al. [64]	2016	Kenya	Haematogenous Staphylococcus aureus pneumonia	Balb/c mice (30)	Animal experiment	Staphylococcus aureus	Histology showed that the mice treated with phage did not develop pneumonia. Phage therapy is effective against haematogenous infection.
	Waters et al. [65]	2017	United Kingdom	Chronic lung infections	Balb/c mice (60)	Animal experiment	Pseudomonas aeruginosa	Phage therapy was again highly effective against the established 6 d lung infection, completely clearing bacteria from the lungs of 70% of mice and significantly reducing CFU counts in the other 30% compared with controls.
	Bao et al. [41]	2020	China	Recurrent urinary tract infection	Human (1)	Case report	Klebsiella pneumoniae	The combination of sulfamethoxazole-trimethoprim with the phage cocktail inhibited the emergence of phage resistant mutant in vitro, and the urinary tract infection of the patient was successfully cured by this combination.
Urinary tract infection	Leitner et al. [66]	2021	Switzerland	Infection after transurethral resection of the prostate	Human (113)	RCT	Enterococcus spp., Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus spp., and Streptococcus spp.	The efficacy of the phage group was similar to that the of antibiotic group (bacterial titer decreased significantly), but the adverse reactions were less.
	Kuipers et al. [67]	2019	Netherlands	Recurrent urinary tract infection after posttransplant	Human (1)	Case report	Klebsiella pneumoniae	The infection eventually evolved into epididymitis which was successfully treated with meropenem and phages.
	Rostkowska et al. [68]	2021	Poland	Chronic urinary tract infection after kidney transplantation (caused by polycystic kidney disease)	Human (1)	Case report	Klebsiella pneumoniae	Fully recovered following a nephrectomy of his own left kidney.
Eye infection	Fukuda et al. [69]	2012	Japan	Keratitis	C57BL/6 mice (NA)	Animal experiment	Pseudomonas aeruginosa	Significantly improved disease outcome and preserved the structural integrity and transparency of the infected cornea. Suppression of neutrophil infiltration and greatly enhanced bacterial clearance in the infected cornea.
	Furusawa et al. [70]	2016	Japan	Keratitis	C57BL/7 mice (NA)	Animal experiment	Pseudomonas aeruginosa	A great reduction of bacterial proliferation was shown in phage therapy for mouse models of Pseudomonas aeruginosa keratitis (suppressed bacterial multiplication to 0.004%).
Ear infection	Wright et al. [71]	2009	United Kingdom	Chronic otitis	Human (24)	RCT	Pseudomonas aeruginosa	No adverse events. Phage-treated group Pseudomonas aeruginosa counts were significantly lower only in the phage-treated group.
	Hawkins et al. [72]	2010	United Kingdom	Otitis	Dogs (13)	Animal experiment	Pseudomonas aeruginosa	48 h after treatment, the clinical score and Pseudomonas aeruginosa count of all ears had fallen.
Nasal infection	Ooi et al. [73]	2019	Australia	Chronic rhinosinusitis	Human (9)	Single arm study	Staphylococcus aureus	Preliminary efficacy results indicated favorable outcomes across all cohorts, with 2 of 9 patients showing clinical and microbiological evidence of eradication of infection.
Sepsis/Bacteremia	Schneider et al. [74]	2018	Hungary	Sepsis	Balb/c mice (36)	Animal experiment	Escherichia coli	Phage particles administered 10 and 60 min following the bacterial challenge elicited 100% and 95% survival, respectively. But no mice could be rescued if phage administration occurred 3 hours postinfection.
	Pouillot et al. [75]	2012	France	Sepsis and meningitis	Sprague Dawley rat pups (50)	Animal experiment	Escherichia coli	When phages were given at 7 h and 24 h after bacterial injection, the survival rates of rats were 100% and 50%, respectively
Novel coronavirus pneumonia	Li et al. [76]	2020	United States	SARS-CoV-2 infection	BALB/c mice (55); Hamster (10)	Animal experiment	SARS-CoV-2	Potently neutralized mouse-adapted SARS-CoV-2 in wild-type mice at a dose as low as 2 mg/kg and exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection

Note. NA, not applicable; RCT, randomized controlled trial.