Effects of antibiotics on intestinal microcirculation, cytokine release and in-vitro vascular reactivity in septic rats

Background

Antibiotic treatment represents a key component of therapy for severe sepsis. Apart from the sensibility of the causing microorganisms, when choosing antimicrobial agents in septic conditions possible effects of antibiotics on the microcirculation, inflammatory mediators and vascular (hypo)reactivity should be taken into account.

Objectives

The aim of this study was to evaluate the effects of metronidazole (MET), imipenem (IMI), tobramycin (TOB) and vancomycin (VAN) on the intestinal microcirculation in septic rats using intravital microscopy (IVM), on the release of the cytokines TNF-α, IL-1β, IL-6 and IL-10, and on the in-vitro reactivity of the rat aorta.

Methods

We induced sepsis in the animals (Lewis rats) using the Colon Ascendens Stent Peritonitis (CASP) model. MET (10 mg/kg), IMI (20 mg/kg), TOB (25 mg/kg) and VAN (70 mg/KG) were given intravenously 16 hours following sepsis induction. Intravital microscopic examination was performed 2 hours later. Cytokine release was estimated at the end of the experiments. Direct effects of the antibiotics on vascular tonus were studied in normal rat aortal rings in-vitro precontracted either with phenylephrine (PE) (5 × 10^–8M) or 20/40 mM KCl.

Results

In the CASP model we observed a reduced functional capillary density in the muscular and mucosal layers of the intestine and an increased number of temporary and firmly adhering leukocytes in submucosal venules. Acute treatment with MET attenuated this response. TNF-α release in untreated CASP animals was twice as high as compared with MET-treated animals. In vitro, higher concentrations (up to 10^-4M) of some antibiotics produced moderate relaxation: TOB 47% (PE), VAN 44% (PE), MET 48% (20 mM KCl).

Conclusion

Antibiotics may exert, in addition to their antimicrobial action, effects on the microcirculation, and potentially could influence vascular (hypo)reactivity in septic conditions.