Animal Models in the Evaluation of the Effectiveness of Phage Therapy for Infections Caused by Gram-Negative Bacteria from the ESKAPE Group and the Reliability of Its Use in Humans

Abstract

The authors emphasize how extremely important it is to highlight the role played by animal models in an attempt to determine possible phage interactions with the organism into which it was introduced as well as to determine the safety and effectiveness of phage therapy in vivo taking into account the individual conditions of a given organism and its physiology. Animal models in which phages are used make it possible, among other things, to evaluate the effective therapeutic dose and to choose the possible route of phage administration depending on the type of infection developed. These results cannot be applied in detail to the human body, but the knowledge gained from animal experiments is invaluable and very helpful. We would like to highlight how useful animal models may be for the possible effectiveness evaluation of phage therapy in the case of infections caused by gram-negative bacteria from the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species) group of pathogens. In this review, we focus specifically on the data from the last few years.

Mycobacteriophage–antibiotic therapy promotes enhanced clearance of drug-resistant Mycobacterium abscessus

“…Numerous animal models have recently been developed for the evaluation of phage therapy for infections caused by the ESKAPE group of pathogens (consisting of notable drug-resistant pathogens, such as Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter baumannii, P. aeruginosa and Enterobacter spp.) (Ciesĺik et al, 2021). These include Galleria mellonella, Drosophila melanogaster and various mouse models of sepsis/ peritonitis/pneumonia/urinary tract infection or eye infection.…”

A Phage Foundry Framework to Systematically Develop Viral Countermeasures to Combat Antibiotic-Resistant Bacterial Pathogens

“…Specific selection criteria for choosing a most suitable infection model system should be established that includes the model's complexity, relevance, handling, and operational costs ( Alivisatos et al., 2015 ; Blaser et al., 2016 ; Douglas, 2018 , 2019 ; Chevrette et al., 2019 ). A number of model systems such as Caenorhabditis elegans , Galleria mellonella, Drosophila melanogaster , zebrafish and mouse models, organoids, and organs-on-chip for in vivo studies ( Bulitta et al., 2019 ; Brix et al., 2020 ; Aguilar et al., 2021 ; Cieślik et al., 2021 ; Penziner et al., 2021 ), whereas Fabricated Ecosystems (EcoFAB and EcoPODs) for intensive field-scale monitoring of phage-target pathogen-host interactions are brought on-board ( Buttimer et al., 2017 ; Koskella and Taylor, 2018 ; Zengler et al., 2019 ). These model systems are useful to quantitatively assess efficacy of phages, phage cocktails and phage-antibiotic, pesticide, biocides, ionophores, or metal combinations.…”

Recurrent Urinary Tract Infection: A Mystery in Search of Better Model Systems

“…DBA/1 are susceptible to immune mediated nephritis (Xie et al, 2004) Infected with E. coli 1677 (O6, type 1), DBA/1 and DBA/2 strains could resolve the initially high level of infection in bladder and kidney (Hopkins et al, 1998) DBA/2 lack surface expression of CD94/ NKG2A on NK cells known to be expressed on most fetal NK cells (Vance et al, 2002) DBA/1 mice were infected with Pseudomonas aeruginosa for phage therapy applications and found there was more enhanced killing of intracellular bacteria (reviewed in (Ciesĺik et al, 2021) BALB/c Naturally resistant to prolonged UTI (Bishop et al, 2007) 8-and 12-weeks post infection with S. faecalis GK (ATCC 23241), BALB/c mice had a significantly lower incidence of infected kidneys compared with SWR mice (Guze et al, 1985) Used in cancer research and when older can develop renal tumors in males (Noronha, 1977) Infected with E. coli 1677 (O6, type 1), BALB/c mice had highest bacterial presence in the bladder and second highest in the kidneys after 24 hours. After 14 days, infection decreased in both bladder and kidney (Hopkins et al, 1998) Infected with E. coli CI5 to determine the efficacy of Forskolin as a treatment for UTI (increases cAMP-driven exocytosis).…”