Ceftriaxone pharmacokinetics in interleukin-10-treated murine pneumococcal pneumonia

Abstract

Objectives: Anti-inflammatory therapy with interleukin-10 (IL-10) was previously reported to reduce pulmonary inflammation and to prevent septicaemia in murine pneumococcal pneumonia treated with ceftriaxone. In the present report, we investigated the influence of pulmonary infection and IL-10 administration on the pharmacokinetics of ceftriaxone. Methods: CD1 mice were infected with 107 cfu of Streptococcus pneumoniae. Treatments (intraperitoneal) with IL-10 (1 μg per mouse), ceftriaxone (20 mg/kg) or the combination of IL-10 + ceftriaxone were initiated 18h after infection. Groups of mice were sacrificed at several time points from 5min to 24h after initiation of therapy. Ceftriaxone was quantified in blood and lungs using a microbiological assay. Additional groups of mice received a second dose of IL-10 at 36h post-infection. Survival rates were recorded over 14 days. Results: The clearance of ceftriaxone was significantly reduced in infected mice compared with that in non-infected animals (P < 0.01), whereas AUC, mean residence time, t1/2 and AUClung/AUCserum were significantly enhanced (P < 0.01, 0.01, 0.05, 0.05). Co-administration of IL-10 with ceftriaxone in infected animals further retained ceftriaxone in the bloodstream and reduced its volume of distribution at steady state and the ratio of AUClung/AUCserum. IL-10 alone did not modify significantly the pharmacokinetics of ceftriaxone in blood and lungs of non-infected animals. Conclusions: The results suggest that pulmonary infection, and therapy with IL-10, both affect the pharmacokinetics of ceftriaxone. Indeed, administration of IL-10 + ceftriaxone improved the survival rate of mice (P < 0.001 compared with therapy with ceftriaxone alone). IL-10 should be considered as an adjunctive therapy to antibiotics against severe infections. © The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.