Antibiotics improve survival and alter the inflammatory profile in a murine model of sepsis from Pseudomonas aeruginosa pneumonia.
Differing antibiotic regimens can influence both survival and the inflammatory state in sepsis. We investigated whether the addition and/or type of antimicrobial agent could effect mortality in a murine model of Pseudomonas aeruginosa pneumonia-induced sepsis and if antibiotics altered systemic levels of cytokines. FVB/N mice were subjected to intratracheal injection of pathogenic bacteria and were given gentamicin, imipenem, or 0.9% NaCl 2 h after surgery, which continued every 12 h for a total of six doses. Survival at 7 days (n = 24 in each group) was 100% for mice given gentamicin, 88% for mice given imipenem, and 8% for sham mice treated with 0.9% NaCl (P < 0.0001). Systemic interleukin (IL) 6 levels were assayed 6 h postoperatively on all mice to see if they were predictive of outcome. Plasma IL-6 levels above 3,600 pg/mL were associated with a 100% mortality, levels under 1,200 pg/mL were associated with a 100% survival, and levels between 1,200 and 3,600 pg/mL had no utility in predicting mortality. In a separate experiment, mice were sacrificed at 3, 6, 12 or 24 h after instillation of P. aeruginosa and were assayed for levels of TNF-alpha, IL-6, IL-10, and IL-12. Significant alterations in the proinflammatory cytokines TNF-alpha and IL-6 were present at all time points except 3 h between mice treated with antibiotics and sham controls. In contrast, statistically significant differences in the anti-inflammatory cytokine IL-10 were present between the groups only at 6 h, and levels of IL-12 were similar at all time points. These results indicate that both gentamicin and imipenem increase survival at least 10-fold in a model of pneumonia-induced monomicrobial sepsis, and this is predominantly associated with a down-regulation of proinflammatory cytokines.
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Craig M
CM
Coopersmith
Daniel M
DM
Amiot
Paul E
PE
Stromberg
W Michael
WM
Dunne
Christopher G
CG
Davis
Dale F
DF
Osborne
Kareem D
KD
Husain
Isaiah R
IR
Turnbull
Irene E
IE
Karl
Richard S
RS
Hotchkiss
Timothy G
TG
Buchman
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005839:Gentamicins / Q000627:therapeutic use; D015378:Imipenem / Q000627:therapeutic use; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008815:Mice, Inbred Strains; D018410:Pneumonia, Bacterial / Q000097:blood / Q000150:complications*; D011552:Pseudomonas Infections / Q000097:blood / Q000150:complications*; D011550:Pseudomonas aeruginosa; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D016019:Survival Analysis; D013997:Time Factors
D000900:Anti-Bacterial Agents; D015415:Biomarkers; D016207:Cytokines; D005839:Gentamicins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D015378:Imipenem