The importance of antibiotics in animal models of sepsis

Objective

Our group developed an ovine model of Pseudomonas aeruginosa sepsis associated with acute lung injury (ALI) [1]. The aim of this study was to modify this model by the administration of Ceftazidime (Cef) to simulate a more clinically relevant situation. In addition we studied the effects of recombinant human activated protein C (rhAPC), as well as an combined treatment of rhAPC and Cef. This modification could be the basis for future studies investigating new treatment strategies in sepsis.

Methods

Thirty sheep (35–40 kg) were operatively prepared for chronic study. After 7 days of recovery, sheep were randomly allocated either to sham, control, Cef, rhAPC, or Cef + rhAPC groups (n = 6 each). After a tracheostomy, ALI was produced and P. aeruginosa were instilled into the lungs, following an established protocol [1]. The sham group received the vehicle. The sheep were studied for 24 hours in the awake state and were ventilated with 100% oxygen. The PaO₂/FiO₂ ratio was determined at baseline (BL) and every 3 hours. Ceftazidime (3 g) was administered intravenously 1 and 13 hours post injury. rhAPC was given as a continuous infusion (24 μg/kg/hour), starting 1 hour post injury. The animals were resuscitated with Ringer's lactate solution to maintain filling pressures and hematocrit. Statistical analysis: two-way analysis of variance and Student–Newman–Keuls post hoc comparisons. Data are expressed as mean ± standard error of the mean. Significance P < 0.05.

Results

The PaO₂/FiO₂ ratio remained stable in sham (BL: 518.3 ± 12.7 vs 12 hours: 507.3 ± 18.8) animals. The control group showed a significant decrease in PaO₂/FiO₂ ratio (BL: 496.8 ± 21 vs 12 hours: 83.5 ± 9.8). The Cef group also showed a fall in PaO₂/FiO₂ ratio (BL: 524 ± 11.4 vs 12 hours: 173 ± 47), as well as the rhAPC (541.3 ± 12.2 vs 12 hours: 150.7 ± 28.6) group. In both groups there was a significant improvement of the PaO₂/FiO₂ ratio compared with the control group. The PaO₂/FiO₂ ratio of the Cef + rhAPC group (525.4 ± 9.9 vs 12 hours: 335.8 ± 25.8) was significantly higher than all other injured groups.

Conclusion

Since the application of Cef + rhAPC after ALI associated with bacterial challenge improved pulmonary function more than Cef or rhAPC alone, it underlines the importance of antibiotic treatments for further studies in animal models of sepsis.