Table 2.
Alternative strategies against ESKAPE pathogens.
| Target ESKAPE | Model used | Agent used and dosage details | Route of administration | In vivo efficacy: log reduction of pathogen; % survival of host | Other advantages | References |
|---|---|---|---|---|---|---|
| ANTIBIOTICS IN COMBINATION | ||||||
| Ef | Galleria mellonella larvae infection model | Rifampin (0.5–2) μg/ml+Tigecycline (0.03 μg/ml)/Vancomycin (64, 128 μg/ml)/Linezolid (2 μg/ml) | Injection into hemocoel | 20–73% survival | – | Skinner et al., 2017 |
| S | Retrospective study 2011–2017 | Fosfomycin+Daptomycin/Oxacillin/Vancomycin | – | Successful treatment in 81% patients | – | Coronado-Álvarez et al., 2018 |
| S | Wistar mouse | Rifampin (20 mg/kg) + Flucloxacillin (200 mg/kg)/ Moxifloxacin (10 mg/mg) | Intraperitoneal (IP) | 4 log decrease with both combinations | Antibiofilm | Greimel et al., 2017 |
| S | Wistar rats | Gentamicin (8, 50 mg/kg) + 4- (Benzylamino) cyclohexyl 2-hydroxycinnamate (16, 64 mg/kg) | – | 4 log reduction; 100% survival | Antibiofilm | Balamurugan et al., 2015 |
| K | Murine complicated urinary tract infection model | Meropenem (400 mg/kg) + Nacubactam (150 mg/kg) | – | >3 log reduction in isolates resistant to meropenem-nacubactam | – | Monogue et al., 2018a |
| A | Murine Thigh and Lung Infection Models | Colistin + Tazobactam/Avibactam | IP | No effect | – | Monogue et al., 2018b |
| P | Murine thigh infection model | Imipenem (4 or 5 g/day with a 1-g loading dose)+ Tobramycin (7 mg/kg) | – | ≥2.5 or ≥1.50 log reduction | – | Yadav et al., 2017 |
| P | Murine infection model | Colistin (2.5–5 mg/kg) + Rifampicin (10 mg/kg) | Subcutaneous | ~5 log reduction | – | Cai et al., 2018 |
| E | G.mellonella infection model | Colistin (2.5 mg/kg) + Imipenem (15 mg/kg) | Injection into hemocoel | 80–90% survival | – | Yang et al., 2018a |
| PHAGE THERAPY | ||||||
| Ef | Murine bacteraemia model | Phage ENB6 and C3 (A2 morphotype group), of 3 × 108 PFU | IP | Single dose: 50% survival; Multiple doses: 100% survival | Immunocompatible | Biswas et al., 2002 |
| S | 65-year-old woman with Corneal abscess | SATA-8505 (ATCC PTA-9476) | Topical (eye drops and nasal spray) and intravenous (IV) | Eradication of pathogen and stabilization of ocular signs | - | Fadlallah et al., 2015 |
| S | Case series (six human subjects suffering from diabetic foot ulcer) | Commercial staphylococcal phage Sb-1; (0.05–0.4 ml of 107-108 PFU/ml) | Topical | – | Wound healing within 7 weeks | Fish et al., 2016 |
| S | Rabbit osteomyelitis model | Cocktail of phages (SA-BHU1, 2, 8, 15, 21, 37 and 47); 15 μl of 5 × 1012 PFU/ml of each | Intramuscular (IM) | 100% survival | Viruses with stable genomic structure | Kishor et al., 2016 |
| S | Murine bacteraemia model | Phage SLPW Podoviridae; 0.2 mL of 1 × 109 PFU | IP | ~100% decrease in bacterial count; up to 80% survival | Stable up to 45°C, pH 6- 10; Immunocompatible | Wang et al., 2016 |
| S | Murine wound infection model | MR 5 and MR 10, Myoviridae; free phage 109 PFU/50 μl and its liposomal formulation | Topical | Up to 3 log reduction on day 10 | Wound healing within 7 days | Chhibber et al., 2018 |
| K | Murine burn wound infection model | Five phages KØ1 to 5 (107 PFU/ml) in equal proportion as a cocktail or loaded in liposomes | IP | >4 log reduction; 100% survival | Enhanced wound healing | Chadha et al., 2017 |
| A | Case study 77-year-old man with post-operative infection | Five phages active against 104 A. baumannii from the NMRC's phage-Biolog system 2.14 × 107 PFU/mL | Intravenous (IV) | No effect | – | LaVergne et al., 2018 |
| A | Murine wound infection model | Cocktail of AB-Army 1 and AB-Navy 1 to 4 (~4 × 109 PFU) | Topical, IP or loaded on TegadermTM bandage | 3 log tested in vitro; ND | Antibiofilm; Reduction in wound bio-burden and size (loss of capsule production in phage infected Acinetobacter) | Regeimbal et al., 2016 |
| A | Murine wound infection model | Acinetobacter phage- Siphoviridae; (400 μl of 3 × 109 PFU/ml) | Topical | 100% clearance of infection in 8 days | Reduction in wound bio-burden but no difference in time required for wound healing | Shivaswamy et al., 2015 |
| A | G.mellonella infection model | Phage WCHABP1 and WCHABP12 Myoviridae; 104 PFU/larva | Injection into hemocoel | 75% survival | No integrase and repressor genes were identified in both bacteriophages | Zhou et al., 2018 |
| A | Case study (68 year old patient with infected diabetic patient) | Cocktails of AB Phage ΦPC (AB-Navy1, 4, 71, 97, and AbTP3Φ1); ~109 PFU/dose | Percutaneous catheter, IV | Clearance of infection | – | Schooley et al., 2017 |
| P | Murine infected model | Phage PEV20, Podoviridae; Inhalable powder 2 × 107 PFU/mg | Intranasal and intratracheal | 5 log reduction | Non-toxic | Chang et al., 2018 |
| P | Case study (2-year-old boy with a history of DiGeorge syndrome) | Cocktail from US Navy library of bacteriophages 3.5 × 105 every 6 h. six doses total and resumed after 11 days | IV | Blood cultures negative After phage treatment | - | Duplessis et al., 2018 |
| P | Case study (61 year old male patient with acute septicaemia and large necrotic pressure sores) | Phage BFC1 50 μl IV infusion every 6 h for 10 days; Wounds irrigation- 50 ml BFC1 every 8 h for 10 days | IV infusion and Topical | Clearance of septicaemia immediately after therapy; pressure sores remained infected with several bacterial species, including P. aeruginosa | No adverse effects | Jennes et al., 2017 |
| P | G.mellonella infection model | Phage KTN4; MOI100 | Injection into hemocoel | 4–7 log reduction; 100% survival | Antibiofilm; Stable up to 40–70°C | Danis-Wlodarczyk et al., 2016 |
| E & P | Case series (9 UTI patients) | Pyophage | Pyophage instillation by suprapubic catheter | bacterial titers decreased after bacteriophage treatment in six out of nine patients (67%). | No bacteriophage-associated adverse events detected | Ujmajuridze et al., 2018 |
| S, A, & P | Murine sepsis model | Phage against A. baumanni, P. aeruginosa, and S. aureus | IP | 100% reduction in A and P; 100% survival | – | Soothill, 1992; Lin et al., 2017 |
| K & E | G. mellonella infection model | Cocktail of Escherichia phage ECP311, Klebsiella phage KPP235, and Enterobacter phage ELP140 | – | 100% reduction after 5 doses; 90% survival | – | Manohar et al., 2018 |
| SILVER NANOPARTICLES | ||||||
| S | Infected Daniorerio-Zebrafish model | Sunlight mediated AgNP synthesized using plantextract (HWP AgNP) (10–40 nm) | – | >1 log reduction | Antibiofilm; Non-toxic | Lotha et al., 2018 |
| S | Murine wound infection model | Chitosan-coated AgNPs (10–30 nm) (50 μg/g·bw) | Topical | – | Wound healing within 14 days; Non-toxic | Peng et al., 2017 |
| S | Rabbit flexor tendon rupture model | Core-shell nanofibrous membranes with embedded AgNPs in PEG/poly (caprolactone) shell and hyaluronic acid/ibuprofen in the core | AgNP Coated implant | – | Antibacterial activity; Prevention of peritendinous adhesion after tendon surgery; Non-toxic | Shalumon et al., 2018 |
| S | Murine model | Wound dressing containing nanosilver nanohydrogels (nSnH) along with Aloe vera | Topical | – | Antibacterial; Wound healing within 16 days; Non-toxic | Anjum et al., 2016 |
| S | Murine wound infection model | Sodium carboxymethylcellulose hydrogel loaded with PEG-coated-AgNPs (19.2 ± 3.6 nm) (500 μg AgNPs/g of hydrogel) | Topical | 97.30% reduction; 100% survival | Wound healing within 10 days | Mekkawy et al., 2017 |
| S | Murine model | Mesoporous silica nanoparticles coated with AgNPs (Ag-MSNs) | Topical | – | Antibacterial; Wound healing within 5 weeks; Anti-inflammatory | Dong et al., 2016 |
| S | Rabbit flexor tendon model | AgNPs embedded in electrospun hyaluronic acid (HA)/polycaprolactone (PCL) nanofibrous membranes (NFMs) | AgNP Coated implant | – | Antibacterial; Prevention of peritendinous adhesion after tendon surgery | Chen et al., 2015 |
| S & P | Murine wound infection model | AgNPs (20 nm)/chitosan composite dressing (0.5 mM) | Topical | – | Wound healing within 8 days; Non-toxic | Liang et al., 2016 |
| S & P | G. mellonella model | Electrochemically synthesized AgNPs (8–10 nm) (6.8 and 3.4 mg/mL) | Injected into hemocoel | – | Antibiofilm; Non-toxic | Pompilio et al., 2018 |
| S & P | Murine model | Bilayer composite of Chitosan-AgNPs (5–50 nm) (CS-AgG) on CSGB (Bletilla striata polysaccharide) both linked with genipin | Topical | – | Antibacterial; Wound healing; Non toxic | Ding et al., 2017 |
| S & P | Murine model | NanoAg (< 50 nm) wound dressings; 100 μL of 1 mg/mL | Topical | – | Antibacterial; Antibiofilm; Biocompatible | Radulescu et al., 2016 |
| S & P | Murine model | Collagen nanofiber mats containing AgNPs (25–55 nm) | Topical | – | Antibacterial; Wound healing within 14 weeks; No hypersensitive; Anti-inflammatory | Rath et al., 2016 |
| S & P | Gottingen minipigs femur model | Nanocomposite coating formed by polysaccharide 1-deoxylactit-1-yl chitosan (Chitlac) and AgNPs on methacrylate thermosets | AgNP Coated implant | – | Antibiofilm; Anti-inflammatory; Non-toxic | Marsich et al., 2013 |
| ANTIMICROBIAL PEPTIDE (AMP) | ||||||
| A | Murine infection model | Chex1-Arg20 amide; 2 and 5 mg/kg | IM | >2 log reduction; >50% survival | Anti-inflammatory | Ostorhazi et al., 2018 |
| A | Murine wound infection model | K11, a hybrid peptide of melittin, cecropin A1, and magainin 2 | Topical | ~100% pathogen clearance; 100% survival | Wound healing (21 days) | Rishi et al., 2018 |
| P | Murine infection model | Feleucin-K3 analogs; 5 mg/kg | IP | ~ 1 log reduction | Stable; Low toxicity; Antibiofilm | Xie et al., 2018 |
| S | G. mellonella infection model | PT-13, Plant derived crude extract; 64 μM | Injection into hemocoel | 60% survival | – | Al Akeel et al., 2018 |
| P | G. mellonella infection model | SP-E, a proline-rich pig saliva derived peptide; 6.1 μmol/kg | Injection into hemocoel | ~50% survival | Non-toxic | Ciociola et al., 2018 |
| S & A | S. aureus murine sepsis model, A. baumannii infected murine lung model | D-150–177C, peptide modified by attaching C-terminal Cysteine; 5 and 10 mg/kg | IP | 70% survival | Non-toxic | Chen et al., 2018 |
| S & A | Murine skin infection model | SAAP-148, a LL-37 human cathelicidin inspired peptide used to prepare ointment; 0.125 to 0.5% (w/w) | Topical | 87% and complete clearance of S. aureus and A. baumannii, respectively After a single treatment with 2% (w/w) SAAP-148 ointment | Antibiofilm; Kills persister cells; Reducing bioburden and wound healing; Non-toxic | de Breij et al., 2018 |
| P | Murine lung infection model | Esc (1–21)-1c, frog skin derived AMP; 0.1 mg/kg | Intra-tracheal injection | 2 log reduction | Anti-inflammatory | Chen et al., 2017 |
| ANTIMICROBIAL LIGHT THERAPY | ||||||
| S | Murine burn infection model | Laser light-50 J/cm2; PS-PS- sinoporphyrin sodium (DVDMS)- 2, 5, and 10 μM, 75 min | Topical | 4 log reduction at 5 μM of DVDMS with 50 J/cm2 light | DVDMS promoted wound healing after burn infections | Mai et al., 2017 |
| S | Murine ulcer infection model | Laser light-LED 410 nm, 50 J/cm2; PS-5-ALA; 200 mg/kg | Topical | 2 log reduction | – | Morimoto et al., 2014 |
| S | Murine infection model | Light: 660 nm- 45 J/cm2- 10 min exposure; household light- 7.5 J/cm2- 10 min exposure; PS pentalysine-β-carbonylphthalocyanine Zinc (ZnPc(Lys)5)- 5 μl at 1 mM | Topical | 44.3% clearance of infection at 7.5 J/cm2 | Improved wound healing | Ullah et al., 2018 |
| A | Murine burn infection model | Light- LED 415 nm 72–360 J/cm2 | Topical | 3 log reduction | Antibiofilm | Wang et al., 2017 |
| P | Murine skin abrasion model | Light- 415 nm, 48 J/cm2 | Topical | 5 log reduction | – | Amin et al., 2016 |
Ef, Enterococcus faecium; S, Staphylococcus aureus; K, Klebsiella pneumonia; A, Acinetobacter baumannii; P, Pseudomonas aeruginosa; and E, Enterobacter spp.