Bactericidal antibiotics temporarily increase inflammation and worsen acute kidney injury in experimental sepsis*

Abstract

Objective To explore the relationships between bactericidal antimicrobial treatment of sepsis, inflammatory response, severity of AKI, and outcomes. Design Controlled laboratory experiment. Setting University laboratory. Interventions Sepsis was induced by cecal ligation and puncture (CLP) in 52 rats and was treated with either bactericidal antibiotics (ampicillin/sulbactam) or placebo (saline). Serial blood specimens were obtained after CLP for serum creatinine, interleukin (IL)-6, and neutrophil gelatinase-associated lipocalin (NGAL) concentrations. RIFLE criteria were used to assess severity of AKI. All animals were observed for survival up to one week. In a separate experiment, 6 healthy animals were given antibiotics and renal function was assessed. Another 12 animals were sacrificed 2 days after laparotomy for kidney histology. Measurements and Main Results Survival in the placebo group was 50% compared to 81.8% in the antibiotic group (P <0.05). Most animals (93%) without antibiotics developed AKI, of which 39% exhibited greater than a 3-fold rise in serum creatinine (RIFLE-F). Furthermore survival decreased as AKI severity increased. Surprisingly, all antibiotic-treated animals developed AKI, of which 68.6% reached RIFLE-F. However, renal dysfunction was less persistent in these animals. Patterns of plasma IL-6 were similar to creatinine with higher concentrations seen earlier in antibiotic-treated animals but with faster resolution. IL-6 concentration at 24 hrs was independently associated with the development of RIFLE-F. Histological findings were consistent with functional parameters showing that antibiotics worsened AKI. Conclusion In polymicrobial sepsis bactericidal antibiotics resulted in more inflammation and more severe AKI. However, resolution of inflammation and AKI was faster with antibiotics and correlated best with survival. These results suggest that transient worsening of renal function may be an expected consequence of sepsis therapy. These findings also question the value of peak severity of AKI as a primary endpoint and suggest that resolution of AKI may be more appropriate.

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

“…Ampicillin/sulbactam treatment of CLP rats temporarily increases inflammation, as indicated by elevated serum interleukin-6 concentration (44). Ampicillin/sulbactam also exacerbates the CLP-induced acute liver and kidney dysfunction, as shown by increased serum levels of alanine aminotransferase and creatinine, respectively (44). These findings suggest that a need exists for adjuvant therapies that prevent the inflammatory and injurious effects of bactericidal antibiotics in sepsis.…”

“…CLP is the most clinically relevant model of septic peritonitis, because of inflammatory responses to both the polymicrobial infections induced by cecal puncture and the ischemic tissue injury resulting from cecal ligation (8). Ampicillin/sulbactam treatment of CLP rats temporarily increases inflammation, as indicated by elevated serum interleukin-6 concentration (44). Ampicillin/sulbactam also exacerbates the CLP-induced acute liver and kidney dysfunction, as shown by increased serum levels of alanine aminotransferase and creatinine, respectively (44).…”

Antioxidant protection of statins in acute kidney injury induced by sepsis

“…By this criterion, the AKI can be classified into three stages: the AKIN stage 1, in which is observed the increase of 0.3 mg/dl, or of one to two times the baseline serum creatinine value, or urine output less than 0.5 ml/kg/h for 6 hours; AKIN stage 2, where there is an increase of two to three times the baseline serum creatinine value, and urine output less than 0.5 mL/kg/h for 12 hours; the AKIN stage 3, which represents an increase of more than three times the baseline serum creatinine value, or urine output less than 0.3 mL/ kg/h for 24 hours (8) . The survival rate was analyzed by the adaptation of the Kaplan-Meier curve (19) .…”

Efeito renoprotetor da estatina em modelo experimental de lesão renal aguda induzida por sepse

“…Foi realizada a análise da taxa de sobrevivência dos animais dos diversos grupos por meio de uma adaptação da curva de sobrevida de Kaplan-Meier (43) . Os dados apresentam médias ± desvio padrão.…”

“…Na clínica, a classificada AKIN-3 inclui todos os pacientes mais graves, em terapia de substituição renal (7) . (43) .…”