TLR4 inhibition impairs bacterial clearance in a therapeutic setting in murine abdominal sepsis

Objective and design

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 × 10⁴–2 × 10⁶ 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 × 10⁴ 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 × 10⁵ 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.