Differential effects of antibiotics in combination with G-CSF on survival and polymorphonuclear granulocyte cell functions in septic rats.
BACKGROUND
In addition to their antimicrobial activity, antibiotics modulate cellular host defence. Granulocyte-colony stimulating factor (G-CSF) is also a well known immunomodulator; however little is known about the interactions of G-CSF with antibiotics. We investigated in septic rats the effects of two antibiotic combinations with G-CSF.


METHODS
In two clinic modelling randomised trials (CMRTs), male Wistar rats were anesthetized, given antibiotic prophylaxis, had a laparotomy with peritoneal contamination and infection (PCI), and were randomly assigned (n = 18 rats/group) to: 1) PCI only; 2) PCI+antibiotic; and, 3) PCI+antibiotic+G-CSF prophylaxis (20 mug/kg, three times). This sequence was conducted first with 10 mg/kg coamoxiclav, and then with ceftriaxone/metronidazole (Cef/met, 10/3 mg/kg). In additional animals, the blood cell count, migration and superoxide production of PMNs, systemic TNF-alpha and liver cytokine mRNA expression levels were determined.


RESULTS
Only the combination coamoxiclav plus G-CSF improved the survival rate (82 vs. 44%, p < 0.001). Improved survival with this combination was accompanied by normalised antimicrobial PMN migratory activity and superoxide production, along with normalised systemic TNF-alpha levels and a reduced expression of TNF-alpha and IL-1 in the liver.


CONCLUSIONS
There are substantial differences in the interaction of antibiotics with G-CSF. Therefore, the selection of the antibiotic for combination with G-CSF in sepsis treatment should be guided not only by the bacteria to be eliminated, but also by the effects on antimicrobial functions of PMNs and the cytokine response.
Bauhofer
Artur
A
Institute of Theoretical Surgery, Philipps-University Marburg, Baldingerstrasse, 35033 Marburg, Germany. a-bauhofer@web.de
Huttel
Markus
M
Lorenz
Wilfried
W
Sessler
Daniel I
DI
Torossian
Alexander
A
D019980:Amoxicillin-Potassium Clavulanate Combination / Q000008:administration & dosage; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D019072:Antibiotic Prophylaxis; D002443:Ceftriaxone / Q000008:administration & dosage; D002633:Chemotaxis; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005243:Feces / Q000382:microbiology; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D006098:Granulocytes / Q000502:physiology*; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007375:Interleukin-1 / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008297:Male; D008795:Metronidazole / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D018805:Sepsis / Q000276:immunology* / Q000517:prevention & control*; D013481:Superoxides / Q000032:analysis / Q000378:metabolism; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood
D000900:Anti-Bacterial Agents; D016207:Cytokines; D007375:Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D008795:Metronidazole; D016179:Granulocyte Colony-Stimulating Factor; D019980:Amoxicillin-Potassium Clavulanate Combination; D002443:Ceftriaxone