Table 1.
Animal models for the development of S. aureus phage therapy.
| Type of infection | Bacterial strain | Inoculum dose and route of infection | Phage/Cocktail | Phage dose, route of administration, and schedule | Follow-up period | Combination therapy | Results | References |
|---|---|---|---|---|---|---|---|---|
| Mice, rats and rabbits | ||||||||
| Systemic infections | ||||||||
| Abscess and systemic infections (mice) | S. aureus A170 (MRSA) | Injection of 106 to 109 CFU subcutaneously or intravenously | MSa phage | Injection of 106 to 109 PFU subcutaneously or intravenously, concurrently or 4 days later | 20 days | – | Prevent abscess development, reduce mortality and bacterial clearance in blood | (Capparelli et al., 2007) |
| Bacteremia (mice) | S. aureus RCS21 (MSSA) | Injection of 2.108 CFU intraperitoneally | GRCS phage | Injection of 2. 109 PFU intraperitoneally after 30 min of bacterial challenge | 8 days | – | Full protection from lethal bacteremia | (Sunagar et al., 2010) |
| Lung-derived septicemia (mice) | S. aureus SA27 | Injection of 6,4.108 CFU intranasally | S13’ phage | Injection of 1010 PFU intraperitoneally 6 hours postinfection | 14 days | – | Significantly higher survival rates | (Takemura-Uchiyama et al., 2014) |
| Systemic infection (mice) | MRSA | Injection of 108 CFU intravenously | S. aureus-specific lytic phage isolated from sewage and wastewater from Nairobi County, Kenya | Injection of 108 CFU intravenously 24 or 72 hours post-infection | 10 days | Clindamycin (8 mg/kg) intravenously | Treatment with phage was more effective than with clindamycin or combination treatment | (Oduor et al., 2016) |
| Skin and soft tissue infections | ||||||||
| Diabetic foot infection (mice) | S. aureus ATCC 43300 (MRSA) | Injection of 106 CFU into hindpaw | MR-10 phage | Injection of 108 PFU into hindpaw 30 min postinfection | 12 days | Linezolid (25 mg/kg) orally | Combined bacteriophage + linezolid therapy was more effective in controlling hindpaw infection in diabetic mice versus antibiotic or phage alone | (Chhibber et al., 2013) |
| Diabetic foot infection (mice) | S. aureus Hocil17 (MSSA) | Injection of 107 CFU into hindpaw | PP1493, PP1815 and PP1957 phages | Injection of 107 or 108 PFU into hindpaw 30 min postinfection | 4 days | Linezolid (25 mg/kg) intraperitoneally | The bacteriophage assembly was more active than linezolid, which failed to resolve the infection. No antibacterial synergistic effect in combined phage + linezolid | (Albac et al., 2020) |
| Diabetic wound infection (mice) | S. aureus NSA1385 (MSSA) | Topical application of 108 CFU on the wound | PN1815 and PN1957 phages | Topical application of 105 PFU on the wound 48 hours postinfection | 7 or 14 days | Amoxicillin-clavulanic acid (60 mg/day) orally for 5 days | Compared to treatment with systemic amoxicillin-clavulanic acid, bacteriophages had superior clinical and microbiological impact | (Huon et al., 2020) |
| Diabetic wound infection (mice) | S. aureus 63–2498 (MRSA) | Topical application of 6,7 log10 CFU on the wound | AB-SA01 phage cocktail (J-Sa36, Sa83, and Sa87) | Topical application of 7,9 log10 PFU 3, 5 and 7 days postinfection | 10 days | – | Bacterial load reduction and wound closure | (Kifelew et al., 2020) |
| Skin and soft tissue infections (rats) | S. aureus ATCC 43300 (MRSA) | Injection of 107 or 109 CFU intramuscularly | MR-5 and MR-10 phages | Injection of 108 or 1010 PFU intramuscularly 30 min or 12 hours postinfection | 18 days | – | 100% survival rate | (Chhibber et al., 2017) |
| Abscess infection (rabbits) | S. aureus 2698 | Subcutaneous injection of 8.107 CFU | LS2a phage | Subcutaneous injection of 2.109 PFU simultaneously | 4 to 6 days | – | Rabbit abscesses healed completely | (Wills et al., 2005) |
| Bone and joint infections | ||||||||
| Joint infection (mice) | S. aureus ATCC 43300 (MRSA) | Injection of 106 CFU into the joint | MR-5 phage mixed with biopolymer | Injection of 109 PFU into the joint followed by the infection | 20 days | Linezolid mixed with biopolymer | Combined phage coating and antibiotics was effective against orthopedic implant infections | (Kaur et al., 2016) |
| Implant-related osteomyelitis (rats) | MRSA | Injection of 5.105 CFU through the skin | Sb-1 phage | Injection of 107 PFU per day through the skin for 3 consecutive days after confirmation of infection (i.e 14 days) | 14 days | Teicoplanin (20 mg/kg/day) intraperitoneally for 14 days | Only bacteriophage in combination with antibiotic therapy significantly reduced bacterial load and prevented biofilm formation | (Yilmaz et al., 2013) |
| Periprosthetic joint infection (rats) | S. aureus ORI16_C02N (MSSA) | Implantation of implant pre-seeded with 1,2.106 CFU into rat femur | StaPh_1, StaPh_3, StaPh_4, StaPh_11 and StaPh_16 phages | Injection of 1,3.108 PFU intraperitoneally on day 21, 22, and 23 postinfection | 7 days | Vancomycin (50 mg/kg) from day 21 to 27 postinfection every 12h | Treatment of infection with both vancomycin and phage significantly reduced bacterial load, while treatment with phage or vancomycin alone only caused a small reduction | (Morris et al., 2019a) |
| Osteomyelitis (rabbits) | MRSA | Intramedullary injection of 5.106 CFU | A cocktail of seven different phages (SA-BHU1, SA-BHU2, SA-BHU8, SA BHU15 and SA-BHU21, SA-BHU37, SA-BHU47) was injected intralesionally in the infected soft tissues | Injection of 2.1012 PFU intraperitoneally 3 weeks postinfection with 4 doses at the interval 48h, or 6 weeks postinfection | 1-4 weeks | – | Rabbits improved clinically. S. aureus was eradicated from acute and chronic osteomyelitis | (Abedon, 2016; Kishor et al., 2016) |
| Heart and pulmonary infections | ||||||||
| Lung infection (mice) | S. aureus Xen29 (MRSA) | Administration of 3.108 CFU intranasally | AB-SA01 phage cocktail (J-Sa36, Sa83, and Sa87) | 5.108 PFU per phage intranasally at 2 and 6 hours postinfection | 24 hours | – | Reduced lung bacterial burden | (Lehman et al., 2019) |
| Ventilator-associated pneumonia (rats) | S. aureus AW7 (MRSA) | Instillation of 6-8.109 CFU via endotracheal tube | 2003, 2002, 3A, and K phages | Injection of 2-3.109 PFU intravenously at 2, 12, 24, 48 and 72 hours postinfection | 96 hours | Teicoplanin (3 mg/kg) intravenously at 2, 12, 24, 48 and 72 hours postinfection | Significantly improved survival rates compared to absolute mortality in controls, with reduced bacterial load and better histopathological outcomes | (Prazak et al., 2019) |
| Endovascular infection (rats) | S. aureus Laus102 (MSSA) | Injection of 1,3.105 CFU intravenously | vB_SauH_2002 and 66 phages | Injection of 8,2.1010 PFU intravenously 6 hours postinfection | 24 hours | Flucloxacillin (2 g every 12 hour for 24 hours) intravenously | Phage treatment accelerated bacterial load clearance at infection sites (cardiac vegetations, blood, spleen, liver, and kidneys) | (Save et al., 2022) |
| Ventilator-associated pneumonia (rats) | S. aureus AW7 (MRSA) | Instillation of 1010 CFU via endotracheal tube | 2003, 2002, 3A, and K nebulized phages | Administration of 2.1010 PFU directly into the lungs at 2, 12, 24, 48 and 72 hours postinfection | 96 hours | Daptomycin (6 mg/kg) intravenously at 2, 12, 24, 48 and 72 hours postinfection | The combination of daptomycin and nebulized phages had saved 55% of the animals, but was not much superior to nebulized phages alone (50%) | (Valente et al., 2021) |
| Ventilator-associated pneumonia (rats) | S. aureus AW7 (MRSA) | Instillation of 1010CFU via endotracheal tube | 2003, 2002, 3A, and K phages | Administration of 1,5.1010 PFU by inhalative treatment, intravenous treatment or a combination of both at 12, 34, 48 and 72 hours postinfection | 96 hours | Linezolid (10 mg/kg) intravenously twice daily at 2, 12, 24, 48 and 72 hours postinfection | Aerophages and intravenous phages in combination saved 91% of rats from severe MRSA pneumonia in comparison to monotherapy or combination of aerophages and linezolid | (Prazak et al., 2022) |
| Nematode | ||||||||
| S. aureus 80wphwpl | Fed for 1 day by S. aureus lawn | phiAGO1.3 phage | Immerged in 109 PFU for 1 hours | 120 hours | – | Better survival rate | (Glowacka-Rutkowska et al., 2019) | |
| Silkworm larva | ||||||||
| S. aureus SA27 and SA14 | Inoculation of 107-108 CFU | S25-3 and S13 phages injected into the hemolymph | Injection of phage at MOI 1, 0,1, 0,01 or 0,0001 into the haemolymph 10 min, 6, 12, or 24 hours postinfection | 3 days | – | No adverse effects in the silkworm larvae and life-prolonging effects | (Takemura-Uchiyama et al., 2013) | |
MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus.