title: TLR4 inhibition impairs bacterial clearance in a therapeutic setting in murine abdominal sepsis.
abstract: OBJECTIVE
  To investigate the therapeutic effect of E5564 (a clinically used TLR4 inhibitor) in murine abdominal sepsis elicited by intraperitoneal infection with a highly virulent Escherichia coli in the context of concurrent antibiotic therapy.
  
  
  METHODS
  Mice were infected with different doses (~2 × 10(4)-2 × 10(6) CFU) of E. coli O18:K1 and treated after 8 h with ceftriaxone 20 mg/kg i.p. combined with either E5564 10 mg/kg i.v. or vehicle. For survival studies this treatment was repeated every 12 h. Bacterial loads and inflammatory parameters were determined after 20 h in peritoneal lavage fluid, blood, liver and lung tissue. Plasma creatinin, AST, ALT and LDH were determined to assess organ injury.
  
  
  RESULTS
  E5564 impaired bacterial clearance under the antibiotic regime after infection with a low dose E. coli (1.7 × 10(4) CFU) while renal function was slightly preserved. No differences were observed in bacterial load and organ damage after infection with a tenfold higher (1.7 × 10(5) E. coli) bacterial dose. While treatment with E5564 slightly attenuated inflammatory markers provoked by the sublethal doses of 104-105 E. coli under the antibiotic regime, it did not affect lethality evoked by infection with 1.7 × 106 E. coli.
  
  
  CONCLUSIONS
  The impact of TLR4 inhibition during abdominal sepsis by virulent E. coli bacteria is only beneficial at low infection grade at cost of bactericidal activity.
authors.affiliation: Center of Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, m.h.vanlieshout@amc.nl.
authors.forename: Miriam H P
authors.initials: MH
authors.lastname: van Lieshout
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.forename: Cornelis
authors.initials: C
authors.lastname: van't Veer
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001202:Ascitic Fluid / Q000382:microbiology; D058491:Bacterial Load; D002443:Ceftriaxone / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004926:Escherichia coli / Q000302:isolation & purification; D004927:Escherichia coli Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D005260:Female; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008099:Liver / Q000382:microbiology; D008168:Lung / Q000382:microbiology; D008810:Mice, Inbred C57BL; D010533:Peritoneal Lavage; D010538:Peritonitis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D016207:Cytokines; C404742:E5564; D008050:Lipid A; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D002443:Ceftriaxone