Table 2.
A compilation of case studies (2017–2022) that have conducted safety monitoring on phage therapy against MDR bacteria.
| Studies | Phage/s | Against | Phage Distribution | Normal Imaging/Lab Assessment (e.g., X-rays, Liver Function) | Presence of Abnormal (Increase or Decrease) of | Phage-Related Adverse Events (Physiological Effects) | ||
|---|---|---|---|---|---|---|---|---|
| Phage/s (Administration Route) | Endotoxin within Acceptable Range | Cell Infiltration/Cytokine Production | Antibodies Production | |||||
| Eskenazi et al., 2022 [118] |
Phage vB_KpnM_M1 (M1) (Local) |
Fracture-related pandrug-resistant Klebsiella pneumoniae infection | Yes | Neutralizing antibodies are triggered | None | |||
| Lebeaux et al., 2021 [7] |
APC 2.1 cocktail (Inhalation) | Yes, 30 mL of APC 2.1 was diluted tenfold from stock (5 × 109 pfu/mL, 1760 EU/mL endotoxin level) | Pandrug-resistant Achromobacter xylosoxidans in lung transplanted cystic fibrosis infection | Initial persisting airway colonization with no adverse effects | ||||
| Johri et al., 2021 [119] |
Pyo, Intesti, and Staphylococcal phage (Oral, intrarectal, and urethral instillations) |
Methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus haemolyticus, Enterococcus faecalis, and Streptococcus mitis in chronic bacterial prostatitis | Yes | None | None | None | ||
| Wu et al., 2021 [33] |
ɸAb124 (Inhalation) |
Carbapenem- resistant A. baumannii (CRAB) secondary to COVID-19 infection | Yes | Present (Atypical cytokine storm, dramatic increase of IL6 and IL8 during initiation) |
Transient fever | |||
| Ramirez-Sanchez et al., 2021 [120] |
AB-SA01 cocktail and SaGR51ø1 phage (IV and IA) |
Yes, <250 EU/mL (<5 EU/kg per dose) and <1 EU/mL, respectively | Persistent methicillin- sensitive S. aureus (MSSA) in prosthetic joint infection | Yes | None | Neutralizing antibodies are triggered | Liver function tests, renal function, and complete cell blood count remained stable |
|
| Khatami et al., 2021 [115] |
PASA16 (IV) |
Yes, 170 EU/mL. | MDR P. aeruginosa | Detected in blood during initiation (Day 2 and 5) | Yes | Present (CRP peaked) |
Present (Increased serum IgG) |
Transient fever and transient increase in pain at the infected site (heel) |
| Ferry et al., 2020 [5] |
PP1493, PP1815, and PP1957 phage cocktail (Local) |
Orosthetic knee infection (PKI) Methicillin- susceptible S. aureus |
Present (Mild synovitis) | Mild discharge of synovial fluid and mild synovial inflammation without adverse effects or superinfection | ||||
| Bao et al., 2020 [117] |
Cocktail III composed of Kp152, Kp154, Kp155, Kp164, Kp6377, and HD001 (Local) |
Extensively drug-resistant Klebsiella pneumoniae in UTI | None | |||||
| Rostkowska et al., 2020 [121] |
Phage therapy (Intrarectal) |
MDR ESBL- producing Klebsiella pneumoniae in UTI | Yes | None | Yes | |||
| Doub et al., 2020 [10] |
S. aureus phage, SaGR51Φ1 (Intraarticular/Intravenous) |
Yes, <1 EU/mL |
Chronic methicillin-resistant S. aureus prosthetic joint infection | Yes | Present (Transaminitis) | Transient transaminitis | ||
| Rubalskii et al., 2020 [32] |
Various phage cocktails (Local, Oral, Inhalation) |
MDR/especially recalcitrant S. aureus, Enterococcus faecium, P. aeruginosa, K. pneumoniae, and E. coli in cardiothoracic surgery infection | Yes | Present | None | |||
| Aslam et al., 2020 [116] |
Patient 8 SDSU1 cocktail, SDSU2 cocktail, and PAK_P1 single phage (IV) |
Yes, 4.3 EU per dose. Diluted. | MDR and antibiotic-recalcitrant P. aeruginosa | Transient fever, wheezing, and shortness of breath | ||||
| Gainey et al., 2020 [87] |
Ax2CJ45ϕ2 (Intravenous) |
Pan-drug resistance Achromobacter spp. In cystic fibrosis | Yes | No infusion site reactions, anaphylaxis, elevated liver enzymes, increased serum creatinine, electrolyte abnormalities, seizures, abnormal vitals, and gastro- intestinal disturbances |
||||
| Corbellino et al., 2020 [122] |
vB_KpnM_GF (Oral and Intrarectal) |
MDR Carbapenemase-Producing Klebsiella pneumoniae | Yes | Normal clinical examinations, complete blood count, the serum C-reactive protein levels, and the concentrations of liver enzymes and serum electrolytes. No adverse effects | ||||
| Aslam et al., 2019 [31] |
Various phage cocktails and single phage (Intravenous/Inhalation) |
Yes, between 0.2 EU/mL and 7300 EU/mL | MDR infections caused by P. aeruginosa and Burkholderia dolosa in lung transplant | Yes | Present | None | ||
| Nir-Paz et al., 2019 [123] |
ɸAbKT21phi3; MK278859; and ɸKpKT21phi1; MK278861 (Intravenous) |
Yes, 35 EU/mL for ɸKpKT21phi1 and 5 EU/mL for ɸAbKT21phi3 | Extensively drug-resistant A. baumannii and MDR K. pneumoniae in bone infection | Not detected in blood, stool, urine, or saliva after 8 months | Yes | None | None | |
| Tkhilaishvili et al., 2019 [124] |
Phage (Local) |
MDR P. aeruginosa in Periprosthetic Joint Infection | None | |||||
| Onsea et al., 2019 [114] |
BFC 1 and Pro phage cocktails (Local) |
Yes. | MDR S. epidermidis, MDR P. aeruginosa, S. aureus, Sagalactiae, and E. faecalis in musculoskeletal infections | Yes | None | None | No severe systemic side effects or immune reactions The systemic inflammatory markers (CRP and WBC count) decreased to normal levels after one month, and no antibodies were produced against the administered phages |
|
| Maddocks et al., 2019 [125] |
AB-PA01 (Inhalation, IV) |
MDR P. aeruginosa in ventilator-associated pneumonia and empyema | None |
|||||
| Law et al., 2019 [126] |
AB-PA01 (IV) |
MDR P. aeruginosa in cystic fibrosis | Yes | No adverse events noted clinically or on laboratory monitoring (liver function tests, complete blood counts, electrolytes) |
||||
| Dedrick et al., 2019 [9] |
Three phage cocktail—Muddy, BPs33ΔHTH-HRM10, and ZoeJΔ45 (IV) |
Undetectable levels of endotoxin | MDR Mycobacterium abscessus | Detected in serum after 1 day of treatment Detected in feces 4 and 6 days post-treatment Detected in wound swabs at 3 and 5 days post-treatment Undetected in saliva, although a high phage titer was observed on Day 9 after treatment initiation |
Yes | Present | Transient sweats and flushing for the first 2 days of therapy, but continued therapy without event | |
| Kuipers et al., 2019 [127] |
Anti-Klebsiella pneumoniae phages (Oral/intravesical) |
No exact details of endotoxin concentration | MDR-ESBL-producing K. pneumoniae in chronic UTI | None | ||||
| Aslam et al., 2019 [128] |
AB-SA01 cocktail (IV) |
MSSA in left ventricular assist device infection | No adverse clinical or laboratory events | |||||
| Ferry et al., 2018 [129] |
Staphylococcal phage Sb-1 (Local) |
Yes, <1–5 (EU)/mL for 1010 pfu/mL | XDR P. aeruginosa in complex bone and joint infection | |||||
| Duplessis et al., 2018 [130] |
Phage cocktail (IV) |
Yes, <5 EU/kg per hour Diluted to meet standard. |
MDR P. aeruginosa in bacteremia | None | ||||
| LaVergne et al., 2018 [11] |
Phage (IV) |
Yes, <5 EU/kg per hour Diluted to meet standard. |
MDR A. baumannii in craniectomy site infection | Detected in blood during initial administration |
Yes | Transient hypotension | ||
| Ferry et al., 2018 [131] |
Phage cocktail (Local) |
MDR P. aeruginosa and methicillin- susceptible S. aureus in Prosthetic-Joint Infection | None | |||||
| Ujmajuridze et al., 2018 [78] |
Adapted Pyo phage (Intravesical) |
MDR uropathogens (S. aureus, E. coli, Streptococcus spp., P. aeruginosa, and Proteus mirabilis) in UTI | Transient fever and chills | |||||
| Schooley et al., 2017 [30] |
ΦPC, ΦIV, and ΦIVB (IV and Intracavitary) |
Yes, 2.4 × 103 endotoxin units (EU)/mL, 5.89 × 103 EU/mL, and 1.64 × 103 EU/mL, respectively. Diluted to meet standard. |
MDR A. baumannii in infection | No detectable phage titer in plasma samples after 6 h following initial injection | Yes | None | ||
| Zhvania et al., 2017 [132] |
Sb1, Pyo, and Fersis phages (Local) |
Antibiotic-resistant chronic S. aureus in skin infection | Yes | None | ||||
| Jennes et al., 2017 [133] |
BFC1 cocktail (IV) |
MDR P. aeruginosa in acute kidney injury | Yes | None | No unexpected adverse events, clinical abnormalities, or changes in laboratory tests | |||
Gray columns indicate that the respective aspects were not reported in the study. MDR: Multidrug resistant; MRSA: Methicillin resistant S. aureus; CRAB: Carbapenem-resistant A. baumannii; MSSA: Persistent methicillin-sensitive S. aureus; PKI: Orosthetic knee infection; UTI: Urinary tract infection; CRP: C-reactive protein; WBC: white blood cells.