Table 1.
Animal models of human phage therapy with treatment delays exceeding 24 ha.
| Organism(s) treated | Delay before treatmentb | Challenge | Consequence | Treatment | Resultsc | References |
|---|---|---|---|---|---|---|
| Escherichia coli | 168 h | Force-fed axenic mice with 5 × 107 CFU | Intestinal colonization | 105 PFU/ml in drinking water | ~108 CFU/ml reduced to ~104 CFU/ml in feces | Chibani-Chennoufi et al., 2004 |
| Escherichia coli O157:H7 | 48 h | Force-fed mice with 109 CFU | Intestinal colonization | Force fed 108 PFU, 1 dose, or 1010 PFU, 1 dose or “daily” | < 103 vs. < 102 CFU/g in feces for control (etc.) vs. “daily” treatment, around day 8 | Tanji et al., 2005 |
| Mycobacterium avium | 168 h | IV 3 × 107 CFU to mice | Continuing replication | IV 8 × 109 PFU or 4 × 107 phage-infected M. smegmatis in 100 μl, 1 or 2 doses | ~0.5-log fewer CFU in spleen for phage-infected M. smegmatis, day 14, no reduction for phage only | Danelishvili et al., 2006 |
| Staphylococcus aureus | 96 h | Subcutaneous 108 or 109 CFU/mouse | Abscess development | Subcutaneous 109 PFUd in 200 μl, 1 or 4 doses | ~108 vs. ~106 or ~104 CFU per abscess for control vs. treatments | Capparelli et al., 2007 |
| Staphylococcus aureus | 240 h | IV 5 × 106 CFU to mice | Non-lethal systemic infection | 109 PFU in 200 μle | ~104 CFU vs. 0 in various organs, day 20 | Capparelli et al., 2007 |
| Pseudomonas aeruginosa | 96, 240 hf | 108 CFU/ml in mouse drinking waterg | Gut-derived septicemia | 1010 PFU in 100 μl orally administered | 0, 10, and 66.7% 20-day survival for no, 240, and 96-h treatments | Watanabe et al., 2007 |
| Salmonella enterica | 48, 336 h | IV 106 or 105 CFU, respectively, to mice | Sublethal systemic infection | IV 107 PFU in 100 μl | ~104 CFU reduced to 0 in various organs | Capparelli et al., 2010 |
| Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus | 96 h | Mouse wounds injected with 100 μl of organisms of one type | Infected wound (diabetes mellitus model) | 108–109 PFU presumably topical following one or more debridements, >10 doses | ~105 vs. ~102 CFU/swab, day 8, control vs. treatment (S. aureus)h | Mendes et al., 2013 |
| Mycobacterium ulcerans | 792 h | Subcutaneous 3 × 105 CFU into mouse footpad | Footpad swelling with continuing replication | Subcutaneous 108 PFU into mouse footpad | ~3 × 105 vs. ~3 × 103 CFU/footpad, day 68, control vs. treatment | Trigo et al., 2013 |
| Staphylococcus aureus (MRSA) | 96 h | Intranasal 106 CFU/mouse | Nare potentially transient colonization | Intranasal 50 μl of 107 PFU/ml, 2 doses | ~105.5 vs. ~101 CFU/g, day 11, control vs. treatment | Chhibber et al., 2014 |
| Staphylococcus aureus | 168 h | Sinus inoculation of sheep | Sinusitis model | Sinus inoculation of 100 ml of 2 × 108 PFU/ml, 5 doses | ~80% reduction in biofilm biomass, control vs. treatment | Drilling et al., 2014 |
| Acinetobacter baumannii (multi-drug resistant) | 48 h | 108 CFU inoculated into wound of diabetic rats | Abscess development | 400 μl of 3 × 109/ml PFU sprayed onto debrided wound | ~109 vs. 0 CFU, day 8, control vs. treatment | Shivaswamy et al., 2015 |
| Klebsiella pneumoniae | 48, 72 h | Intranasal 104 CFU/mouse | Lobar pneumonia | IP, liposome-entrapped phagesi | ~105 vs. ~103 vs. 0 CFU, day 5, control vs. 72-h delay vs. 48-h delayj | Singla et al., 2015 |
| Staphylococcus aureus (MRSA) | 504, 1008 hk | Intramedullary injection of rabbits with uncertain number (≤ 5 × 106) CFU | Chronic osteomyelitis | Intralesional injection of 5 × 1011 PFU, 4 doses | Cure of infection versus (for 504 h delay) lack of cure w/o treatment | Kishor et al., 2016 |
CFU, Colony-Forming Units; IP, Intraperitoneal; IV, Intravenous; MRSA, Methicillin-Resistant or Multi-drug Resistant Staphylococcus aureus; PFU, Plaque-Forming Units.
Time between initial exposure to bacteria and initial exposure to phages. Shown per study are only those delays of longer than 24 h.
Day indicated is post initial bacterial challenge.
It is difficult to tell whether the phage administration was or was not made directly to the abscess.
Phages were presumably delivered intravenously, though this is not explicitly stated.
Phage additions were either 48- to 96-h prior to (96-h treatment) or 48- to 96-h post (240-h treatment) the cyclophosphamide-mediated induction of septicemia.
This was followed days later by cyclophosphamide IP injection to induce septicemia.
P. aeruginosa saw similar drops without phage treatment though sooner with phage treatment; A. baumanni also saw substantial drops with phage treatment when assaying for colony counts using selective media; mostly analogous though not identical and also more variable results were seen for S. aureus and P. aeruginosa with an otherwise equivalent pig model.
Both free and liposome-entrapped phages were administered in this study representing concentrations of 109 and 107 PFU/ml and multiplicities of infection of 1 and 0.01, respectively.
No difference in results was observed between control and 48-h delay in phage treatment w/o liposome entrapment. Note that 5-days post bacterial challenge is 3 and 2 days post 48 and 72-h phage treatment, respectively. The 72-h treatment also was reduced to zero CFU 7 days post bacterial challenge while the no-treatment control was reduced to 103 CFU/ml at 7 days.
3 and 6 weeks, respectively, though the 3-week treatment may in fact have actually begun on day 16.