Enhancement of the therapeutic effect of cephalosporins in experimental endocarditis by altering their pharmacokinetics with diclofenac

Abstract

We studied the effect of a nonsteroidal anti-inflammatory drug, diclofenac, in rabbits on the kinetics of three cephalosporins: cefotiam, cefmenoxime and ceftriaxone, and compared the antibacterial effect of these antibiotics, given alone or with diclofenac, in experimental endocarditis. Diclofenac significantly increased (P less than .05) the area under the curve in tissue-cage fluid of ceftriaxone and cefotiam-treated animals, and the terminal half-life of ceftriaxone in their sera (3.45 +/- 0.4 vs. 2.8 +/- 0.5 hr). Diclofenac reduced urinary excretion of cefotiam only. Cefmenoxime pharmacokinetics remained unchanged by diclofenac. The alteration of ceftriaxone kinetics appeared to be due to nonrenal mechanisms and could suggest reduction of biliary excretion. In Escherichia coli endocarditis, diclofenac enhanced the concentration (P less than .05) of cefotiam (23 +/- 16 vs. 8.9 +/- 5 micrograms/g) and ceftriaxone (13.2 +/- 3 vs. 8.5 +/- 4 micrograms/g) in infected vegetations, but not that of cefmenoxime. The antibacterial effect of ceftriaxone increased with diclofenac (5.5 +/- 1 vs. 7.2 +/- 1 log10 colony forming unit/g of vegetation). In vitro, neither protein binding to rabbit serum proteins nor intrinsic activity on the E. coli strain of each antibiotic was modified by diclofenac. These results suggest that anti-inflammatory drugs could increase antibiotic efficacy by altering their pharmacokinetics. The renal and nonrenal site of interaction may be involved for drugs belonging to the same class. Results obtained in tissue-cage fluid were predictive of the interference at the infected site.