title: Lysis-deficient bacteriophage therapy decreases endotoxin and inflammatory mediator release and improves survival in a murine peritonitis model.
abstract: BACKGROUND
  Lysis-deficient (LyD) bacteriophages (phages) kill bacteria without endotoxin (Et) release. This may minimize systemic cytokine responses and limit inflammation in bacterial sepsis. We determined the effects of t amber A3 T4 LyD and virulent wild-type (WT) phages on mouse bacterial peritonitis.
  
  
  METHODS
  Balb/c mice were injected with B40sul Escherichia coli, treated intraperitoneally with LyD, WT, or a beta-lactam antibiotic [latamoxef sodium (LMOX)], and followed for survival. We measured Et release, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, as well as bacterial counts and peritoneal exudative cells (PECs) in peritoneal lavage fluid at 6 and 12 hours after infection.
  
  
  RESULTS
  LyD mice showed significantly greater survival compared with other groups. Et levels were significantly lower in the LyD mice at 6 and 12 hours after infection. TNF-alpha and IL-6 levels were lower in LyD mice compared with control (untreated) mice at 12 hours. Compared with controls, bacteria counts in peritoneal lavage fluid were lower in all treatment groups (LyD, WT, or LMOX) at 6 and 12 hours. PEC counts were highest in LyD mice at 6 hours but significantly lower than that in WT phage- and LMOX-treated mice at 12 hours.
  
  
  CONCLUSIONS
  LyD phage therapy significantly improves survival and attenuates the systemic effects of bacterial sepsis by minimizing Et release and pro-inflammatory mediators in murine bacterial peritonitis. Further studies may find phage therapy useful in treating peritonitis and multidrug-resistant bacterial infections.
authors.affiliation: Department of Surgery, Weill Medical College of Cornell University, New York, USA.
authors.forename: Takeaki
authors.initials: T
authors.lastname: Matsuda
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Freeman
authors.forename: David W
authors.initials: DW
authors.lastname: Hilbert
authors.forename: Michael
authors.initials: M
authors.lastname: Duff
authors.forename: Michele
authors.initials: M
authors.lastname: Fuortes
authors.forename: Philip P
authors.initials: PP
authors.lastname: Stapleton
authors.forename: John M
authors.initials: JM
authors.lastname: Daly
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001202:Ascitic Fluid / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D001435:Bacteriophages; D001691:Biological Therapy / Q000379:methods*; D015169:Colony Count, Microbial; D004731:Endotoxins / Q000037:antagonists & inhibitors*; D004926:Escherichia coli / Q000302:isolation & purification; D004927:Escherichia coli Infections / Q000382:microbiology; D005260:Female; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D009070:Moxalactam / Q000627:therapeutic use; D010538:Peritonitis / Q000378:metabolism* / Q000382:microbiology / Q000628:therapy*; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D000093242:Interleukin-6 Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D004731:Endotoxins; D018836:Inflammation Mediators; D009070:Moxalactam; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors