Continuous antibiotic treatment for experimental abdominal sepsis: effects on organ inflammatory cytokine expression and neutrophil sequestration.

Abstract

Tumour necrosis factor (TNF) alpha and interleukin (IL) 1 beta are produced in the lung after peritonitis and may contribute to neutrophil-mediated organ injury. It was hypothesized that, during experimental peritonitis, continuous rather than intermittent antibiotic therapy would reduce lung expression of TNF-alpha and IL-1 beta messenger RNA (mRNA) and neutrophil sequestration. After caecal ligation and puncture, mice received either intermittent or continuous cefoxitin, or continuous metronidazole or aztreonam. Cytokine mRNAs were determined by reverse transcription differential polymerase chain reaction and lung neutrophil content by myeloperoxidase (MPO) assay. Continuous cefoxitin reduced median (interquartile range (i.q.r.)) lung IL-1 beta mRNA expression ((ratio to beta-actin): continuous 0.18 (0.14-0.34), intermittent 0.46 (0.44-0.49), saline 0.43 (0.38-0.53), P < 0.05) and median (i.q.r.) lung MPO content (continuous 22.5 (9.7-40), intermittent 65 (57.5-76), saline 47 (41-64), P < 0.05) compared with intermittent therapy and saline controls. Continuous infusion was also associated with reduced bacteraemia (P < 0.05) but not serum TNF-alpha or endotoxin levels. Both continuous metronidazole and aztreonam reduced lung MPO concentration (P < 0.05) and TNF-alpha and IL-1 beta mRNA expression (P < 0.05) compared with those in saline controls. These effects were dependent on a reduction in the number of susceptible bacteria rather than serum TNF-alpha or endotoxin levels. The stimulus for organ inflammatory cytokine production and neutrophil sequestration during peritonitis is the level of bacteraemia present, which is more effectively controlled with continuous antibiotic therapy.