Dependence of Positive Effects of Granulocyte Colony‐stimulating Factor on the Antibiotic Regimen: Evaluation in Rats with Polymicrobial Peritonitis

Abstract

We tested the hypothesis that the ability of granulocyte colony-stimulating factor (G-CSF) to prevent death from fecal peritonitis is influenced by the composition of the antibiotic regimen with which it is administered. We used a rodent model of polymicrobial peritoneal contamination and infection and the concept of clinical modeling randomized trials (CMRTs), which includes the conditions of randomized, clinical trials and complex clinical interventions (e.g., anesthesia, volume substitution, antibiotics, surgery, postoperative analgesia). With the peritonitis model we obtained a mortality dose-response curve that was sensitive to antibiotic prophylaxis. G-CSF was most efficacious when it was administered both prophylactically and after the onset of peritonitis. Cefuroxime/metronidazole, ofloxacin/metronidazole, and amoxicillin/clavulanate improved survival in combination with G-CSF best, whereas cefotaxime or ceftriaxone with and without metronidazole did not. G-CSF administration was associated with improved polymorphonuclear neutrophil phagocytosis and enhanced bacterial clearance. Pro-inflammatory cytokine release (tumor necrosis factor-a, interleukin-6, macrophage inflammatory protein-2) was decreased in plasma and in the peritoneal fluid. Their expression was lowered in various organs on the protein and mRNA level. The results were used to design a clinical trial to test the ability of G-CSF to prevent serious infections in patients with colorectal cancer surgery. In this trial G-CSF application and antibiotic prophylaxis were performed with the most effective scheduling and combinations (cefuroxime/metronidazole and ofloxacin/metronidazole) as defined here.

Individual behavioral differences in recovery from abdominal sepsis in rats

“…As demonstrated previously [25] and in trial 1, sepsis led to a high mortality rate which could be substantially reduced by prophylactic treatments, especially when using antibiotics plus G-CSF. Previously, with this combination, antimicrobial cellular functions (polymorphonuclear cells migration to bacteria, phagocytosis and oxygen radical formation) were improved and hyper-inflammation (TNF-a, IL-6 and IL-8) was reduced [28]. Here, however, the lower number of animals dying in the G-CSF group was not significantly different from standard treatment with antibiotics (trial 1), or untreated sepsis (trial 2).…”

Effects of Granulocyte-Colony Stimulating Factor on the Polymorphonuclear Leukocyte Activity and the Course of Sepsis in Rats with Experimental Peritonitis

“…G-CSF has been shown to improve the host immunity by increasing the number and ameliorating functions of such granulocytes. 2,3,4,9 The present study aims to evaluate the effects of G-CSF on the phagocytic and chemotactic function of neutrophils in the presence of serious intra-abdominal infection, and during the course of sepsis.…”

“…The benefi cial effects of G-CSF have been reported in previous neutropenic and non-neutropenic animal models, and the results showed that G-CSF plays an important role in severe infections by stimulating the neutrophil function with the local and systemic cytokine response. [2][3][4][5] Sepsis has an impact on tissue perfusion and cellular oxygenation. The imbalance between oxygen delivery and consumption secondary to septic changes induces tissue hypoxia and metabolic acidosis, which can be objectively evaluated by measuring the plasma lactate concentrations.…”

Sickness behavior of rats with abdominal sepsis can be improved by antibiotic and G-CSF prophylaxis in clinic modeling randomized trials

“…In addition, with this combination antimicrobial cellular functions (PMN migration to bacteria, phagocytosis and oxygen radical formation) were improved and hyper-inflammation (TNF-a, IL-6 and IL-8) was reduced [10].…”

“…To obtain this goal in rats, we used the concept of clinic modeling randomized trials (CMRTs) [9,10], which includes conditions of randomized clinical trials and items modeling clinical complexity (e. g. antibiotic prophylaxis, anesthesia, surgery, polymicrobial infection, pain management). As in randomized clinical trials in CMRTs not all single interventions can be assessed.…”