Table 1.

Principal in vivo studies investigating the relation between phage therapy and phage resistance.

	Bacterium	Model	Phage Type	Treatment Outcome	Resistant Found in after Treatment?	Impact of Resistance on Virulence	Receptor	Ref.
Intestinal colonization	Campylobacter jejuni	Chicken intestinal colonization	CP8 and CP34	Bacterial decrease between 0.5 and 5 log10 CFU/g of caecal contents compared to untreated controls over a 5-day period post-administration.	Yes, at a freq. of 4%	Less infective at low dose. Rapid phenotypic reversion when reintroduced in chicken.	ND	[11,12]
	Campylobacter jejuni	Chicken intestinal colonization	phiCcoIBB35, phiCcoIBB37, and phiCcoIBB12	Phage cocktail decreases the titre of C. jejuni in faeces by approximately 2 log10 CFU/g when administered orally.	Yes, at a freq. of 13%	Not less infective. No phenotypic reversion when reintroduced in chicken.	ND	[13]
	Escherichia coli	Calf, piglet, lamb Ta diarrhoea	B44/1, B44/2, B44/3, P433/1, and P433/2	Protected calves against a potentially lethal infection, cured diarrhoea in piglets, improved the course of disease in lambs.	Most calves that did not respond to phage treatment had a high number of phage-resistant variants. No phage-resistant mutants were isolated from lambs.	Decreased virulence	Capsular polysaccharides	[14]
	Escherichia coli	Calf diarrhoea	B41/1	Rapid reduction of bacterial titres to numbers that are harmless.	Yes	Reduced virulence	Capsular polysaccharides	[15]
	Escherichia coli	Sheep, mouse, steer intestinal colonization	KH1 and SH1	Oral phage treatment did not decrease intestinal E. coli in sheep. Decreased the number of E. coli CFU in cattle. Phage therapy cleared the bacteria in a mouse model of intestinal E. coli O157 carriage.	No	-	ND	[16]
	Escherichia coli	Mouse intestinal colonization	T4 phage, oral	ND	Phage resistant bacterial strains dominated gut after 92 days.	ND	ND	[17]
	Escherichia coli	Mouse intestinal colonization	cocktail made of phages CLB_P1, CLB_P2, and CLB_P3	No bacterial level change in the faeces after treatment.	No	-	ND	[18]
	Enterococcus faecalis	Gnotobiotic mouse intestinal colonization	φ VPE25	Threefold drop in E. faecalis total intestinal load after 24 h of VPE25 treatment.	Phage resistant variant replaced WT during treatment.	Resistant variants can colonize intestine.	Integral membrane protein PIPEF	[19]
	Salmonella enterica	Chicken intestinal colonization	cocktail of phages, EP2, MUT3, M4, and YP	Significant difference between phage-treated and untreated groups.	Yes	ND	ND	[20]
	Salmonella enterica	Chicken intestinal colonization	φ10, φ25, and φ151	Phages reduced caecal colonization.	Phage-resistance occurred at a frequency commensurate with the titre of phage being administered.	Colonization levels of resistant variants in the ceca did not differ from the controls. Reversion observed after infection.	ND	[21]
	Vibrio cholerae	Infant mouse and rabbit cholera model	ICP1, ICP2, and ICP3	Oral administration of phages up to 24 h before V. cholerae challenge reduced colonization of the intestinal tract and prevented cholera-like diarrhoea.	Yes	Variants can colonize intestine.	O-Antigen	[22]
Meningitis	Escherichia coli	Mouse meningitis	phage R	One dose of phage was at least equivalent to multiple doses of antibiotics, whether administered intramuscularly or intrathecally.	Yes	Supposably reduced virulence as described in [14].	Capsular polysaccharides	[23]
Endocarditis	Pseudomonas aeruginosa	Rat infective endocarditis	cocktail made of phages 12 bacteriophages	3 log reduction or valve sterilisation when combined with antibiotics.	No	Reduced virulence	LPS and pilus	[24]
Sepsis	Escherichia coli	Rat neonatal sepsis	phage EC200PP	Phage administered 7 h postinfection rescued 100% of the animals and 50% after 24 h.	Phage resistant variant were found when phage treatment was delayed for 24 h.	Avirulence	ND	[25]
	Klebsiella pneumoniae	Mouse liver abscess and bacteraemia	Phage φNK5	Intraperitoneal and intragastric administration of phage 30 min after infection protected mice from death in a dose-dependent manner. Decreased bacterial burden and liver damage.	No	Reduced virulence	ND	[26]
	Staphylococcus aureus	Experimental cow mastitis	Bacteriophage K	Decreased bacterial load after treatment.	Yes	ND	ND	[27]
	Pseudomonas plecoglossicida	Fish haemorrhagic ascites	PPpW-3 and PPpW-4. Oral	Protective effects of phage treatment with lower and delayed mortality 1 or 24 h after bacterial challenge.	No	Reduced virulence	ND	[28]
	Klebsiella pneumoniae	Mice acute bacteraemia	GH-K1, GH-K2, and GH-K3	Phage cocktail significantly enhanced the protection of bacteremic mice against lethal infection.	ND	Reduced virulence	ND	[29]
	Salmonella enterica Parathyphi B	Mouse sepsis	phage φ1	Phage given concurrently with a lethal dose of bacteria rescued 100% of the animals.	ND	Avirulence	O-Antigen	[30]
pneumonia	Pseudomonas aeruginosa	Mouse acute pneumonia	PAK_P1	Treatment failed to prevent fatality due to subsequent bacterial outgrowth after 24 h in immunocompromised mice. 100% of bacteria recovered from phage-treated at 24 h were resistant.	Yes, in immunocompromised mice	ND	ND	[31]
Phage resistant variants for vaccine production and studying virulence factors	Vibrio cholerae	Infant mouse cholera model	ICP1	ND	ND	Attenuated in vivo.	O-Antigen	[32]
	Vibrio cholerae	Infant mouse cholera model	K139	ND	ND	Significantly reduced in its ability to colonize the mouse small intestine.	Core oligosaccharide	[33]
	Vibrio cholerae	Infant mouse cholera model	phage JA1	ND	ND	Impaired colonization	Capsule/O-antigen	[34]
	Staphylococcus aureus	Mouse vaccination	MSa phage	ND	ND	Avirulence	Teichoic acids	[35]
	Yersinia pestis	Mouse vaccination	L-413C, P2 vir1, φ JA1a, φ A1122, T7, T7Ype, Pokrovskaya, Y, PST, Rh	ND	ND	Atenuated or avirulent.	LPS	[36]
	Flavobacterium columnare	Zebrafish	FCL-1 and FCL-2	ND	ND	Avirulence	ND	[37]
	Bacillus thuringiensis	Cecropia moth	φ42, φ51,and φ64	ND	ND	Decreased virulence	ND	[38]
	Serratia marcescens	Cecropia moth, Drosophila	Phages φJ and φK	ND	ND	Decreased virulence	ND	[39]
	Serratia marcescens	Cecropia moth	Phages φJ	ND	ND	Decreased virulence	ND	[40]