A New Model of Drug-Disease Interaction in Rabbits

Background: Drug-infection interaction should be considered in drug prescribing, particularly if potentiated by co-occuring drug-drug interactions. The effects of Candida and e-coli infections separately, and fluconazole administration were tested on cyclosporine blood level in rabbits. Methods: Three study designs were carried out, crossover single-dose-fluconazole-cyclosporine study testing fluconazole-cyclosporine interaction, multi-dose candida-fluconazole-cyclosporine and multi-dose escherichia coli-cyclosporine study designs involving each rabbit acting as its control; cyclosporine was given daily in both studies. Candida and e-coli infections were inoculated on day 5. In the Multi-Candida-Fluc-CyA, fluconazole-cyclosporine interaction was also considered, and fluconazole was administered daily from day 9-18. In all three studies, Cyclosporine trough levels and serum creatinine were measured by CMIA and enzymatic assay respectively, pre, during, post-infection and after fluconazole administration in the Candida study. Results: Both infections resulted in significant rise in cyclosporine trough level (p = 0.018) and (p = 0.005) in fungal and bacterial studies, respectively. The median rise in CyA level reached 52% (range 9-426%) in the Candida infection and reached 60 ± 47.5% (mean) with the e-coli infection. Fluconazole also increased mean cyclosporine trough levels in the single-dose study by 70.3 ± 45.3 and the concomitant rise in the multi-dose study reached 76% (median, range 22-665%). Conclusions: Cyclosporine trough levels increased during Candida and e-coli infections and also during fluconazole administration in the single and multi-dose studies. Fluconazole exerted an additive effect to the Candida inhibitory effect. Type of infection and inoculum size affected CyA levels differently. Monitoring cyclosporine level during episodes of infection as well as in therapy regimen involving interacting drugs is advisable.