How Phages Overcome the Challenges of Drug Resistant Bacteria in Clinical Infections

Figures & data

Table 1 Advantages and Disadvantages of Using Phage Therapy in the Treatment of Bacteria

Advantage	Disadvantage
Active against gram-positive and gram-negative	Bacteria are able to develop resistance against phages
Rapid isolation and lower development costs	When the target organism is not present the phages will not replicate
Relatively free of side-effects	Phages may carry antibiotic-resistance genes or bacterial virulence factors
Widely used in food preservation	Phages are perceived by the immune system as invaders and can be rapidly removed
Disrupt bacterial biofilms, MDR, and XDR	There are no clear official guidelines
Phage therapy can affect the immune system with functions such as decrease in mean C reactive protein values and leukocyte counts	Phage rapidly can lyse bacteria that may lead to the release of endotoxins and super antigens and induce an inflammatory cascade leading to multiple organ failure
Reduces the damage caused to the normal microbial community	The genome of the majority of phages has been unraveled and the function of many of these genes is still unknown.
Avoids the potential overgrowth of the secondary pathogen	It is difficult to extrapolate from in vitro phage growth data to in vivo prospect
Rapidly distribute throughout the body	The phage specificity for bacterial host causing needs to exact host bacterium be identified
Absence of cross-resistance to antibiotics	lytic phages should be used exclusively
Recognizing different cell surface receptors Cocktail of phages has some advantages, such as the higher impact on targeted bacteria	Diagnosing an infectious agent in clinical microbiology laboratories is very time-consuming for using specific bacteriophage solution for patient
	Phage treatment is not covered by public health insurance
	Phages are not accepted as pharmaceutical drugs

Figure 1 A schematic representation of a bacterial cell, with the different cellular processes that are influenced by phage or phage proteins. 1; CRISPR 2; RNA Polymerase 3; Metabolism Pathway 4; Peptidoglycan 5; Flagella 6; pili 7; DNA 8; Ribosomes 9; RNA degrade 10; Sec Secretion System.

Table 2 Summary of Major Experimental Studies with Phage Therapy

Name and Reference	Published Time	Country	Subjects	Type of Phage for Treatment	Type of Resistance Bacteria	Outcomes
Rashel et al^Citation95	2007	Japan	Mice	ϕMR11	MDR S. aureus	Effectively eradicated MRSA into the nares of mice
Latz et al^Citation96	2017	Germany	In vitro	SL1, SL2, and SL4	MDR P. aeruginosa	Greatest anti-biofilm and planktonic cells activity was observed
Golkar et al^Citation97	2013	USA	Mice	PS5	MDR P. aeruginosa	Deep wound infection and chronic infection treated the each of the infections by respective dermal application of phages
Wang et al^Citation98	2006	China	Mice	ØA392	Imipenem-resistant P. aeruginosa	Protection from death occurred only in animals inoculated with bacteria-specific virulent phage strains
Pouillot et al^Citation100	2012	France	Rat	EC200^PP	MDR E. coli O25:H4-ST131	In the sepsis model and meningitis model phage rescued animals
Jun et al^Citation99	2014	Korea	Mice	pVp-1	MDR V. parahaemolyticus	Phage-treated mice displayed protection from a V. parahaemolyticus infection and survived lethal oral and intraperitoneal bacterial challenges
Wills et al^Citation101	2005	United Kingdom	Rabbit	LS2a	Drug-resistant S. aureus	Phage prevented abscess formation in rabbits when it was injected simultaneously with S. aureus
Kwiatek et al^Citation102	2015	Poland	In vitro	WP1, WP2, WP3, WP4, and WP5	MDR and XDR P. aeruginosa	Bacteriophages WP3, WP2 and WP5 exhibited the highest lytic activity against P. aeruginosa strains
Shen et al^Citation45	2012	Taiwan	In vitro and human cells culture	φkm18p	XDR A. baumannii	Phage φkm18p improved human lung epithelial cells survival rates when they were incubated with A. baumannii
Mapes et al^Citation17	2016	USA	In vitro	ϕKMV, ϕPA2, ϕPaer4, and ϕE2005	MDR and XDR P. aeruginosa	Phages were able to lyse MDR P. aeruginosa and prevent biofilm formation
Larché et al^Citation104	2012	France	In vitro	FrNa3 and FrNa9	XDR and MDR P. aeruginosa	Bacteriophages were found to lyse 42 of the 44 analyzed strains
Shokri et al^Citation105	2017	Iran	In vitro	Psu1 and Psu2	MDR, XDR, and PDR P. aeruginosa	Cocktails of phages had extended host range activity against all MDR, XDR, and PDR strains
Yin et al^Citation18	2017	China	Mice and human cells culture	Abp1	PDR A. baumannii	Abp1 can rescue HeLa cells from A. baumannii infection
Bai et al^Citation106	2018	China	In vitro	vB_AbaM_IME200	PDR A. bsaumannii	Phage had strong lytic activity against PDR A. baumannii
Wright et al^Citation75	2009	UK	Human	Biophage-PA	Antibiotic resistant P. aeruginosa in chronic otitis	P. aeruginosa counts were significantly lower only in the phage treated group and clinical indicators improved for the phage treated group relative to the placebo group.
Rhoads et al^Citation74	2009	USA	Human	WPP-201	Three common bacterial wound pathogens including S. aureus, P. aeruginosa and E. coli	No significant difference (p>0.05) was determined between the test and control groups for frequency of adverse events, rate of healing, or frequency of healing.
Jennes et al^Citation72	2017	Belgium	Human	BFC1	MDR P. aeruginosa septicaemia	Not only blood cultures turned negative, CRP levels dropped and the fever disappeared but also kidney function recovered after a few day.
Chan et al^Citation71	2018	USA	Human	OMKO1	Drug-resistant P. aeruginosa	A single application of phage OMKO1 and ceftazidime, the infection appeared to resolve with no signs of recurrence.
Schooley et al^Citation68	2017	USA	Human	AB-Navy1, AB-Navy4, AB-Navy71, AB-Navy97, AbTP3Ф1, AC4, C1P12, C2P21, C2P24	MDR A. baumannii infection	This clinical study showed that systemic administration of the bacteriophage therapy through intravenous administration was cured A. baumannii infection in anatomic sites.
Ooi et al^Citation69	2019	Australia	Human	AB-SA01	MDR S. aureus infections	Results showed that treatment was well performed, no adverse effects were observed
Letkiewic^Citation73	2009	Poland	Human	PT	Chronic E. faecalis Prostatitis	Phage eliminated infection, and improved patients with lack of early disease recurrence.

Table 3 A Summary of the Anti-Phage Mechanisms of Bacteria

Anti-Phage Mechanism	Mode of Action
Restriction-modification (R-M)	Cleaving phage DNA
CRISPR	Degradation of the injected phage DNA
Genetic mutation	Disturbance in receptors for phage adsorption
RNases	Interfere with phage adsorption
Super infection exclusion (Sie) systems	Prevent the entry of phage DNA into bacterial cytoplasm
BREX defense system	Block phage DNA replication
Quorum sensing defense	Alternate between different phage protection mechanisms depending on population cell density
Abortive infection (Abi) systems	Blocking phage multiplication and cause premature bacterial cell death upon phage infection
DISARM	Restricts incoming phage DNA
Phage-inducible chromosomal islands (PICIs)	Interfere with the reproduction of phages
PICI-like element	The activity is not yet known

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