COMBINATION THERAPY WITH AMPHOTERICIN-B AND FLUCONAZOLE AGAINST INVASIVE CANDIDIASIS IN NEUTROPENIC-MOUSE AND INFECTIVE-ENDOCARDITIS RABBITMODELS

Although there are an increasing number of new antifungal agents avail able, the morbidity and mortality due to invasive mycoses remain high, The high rates of polyene toxicities and the development of azole res istance have raised the issue of using antifungal agents of these clas ses in combination, despite theoretical concerns regarding antagonism between such agents. This study,vas designed to evaluate the in vivo e fficacy of combined therapy with amphotericin B and fluconazole agains t Candida albicans, Two distinct animal models were used in this study : a neutropenic-mouse model of hematogenously disseminated candidiasis and the infective-endocarditis rabbit model, Treatment efficacy was a ssessed by determining reductions in mortality as well as decreases in tissue fungal densities, In the neutropenic-mouse model, amphotericin B, as well as combination therapy, significantly prolonged survival c ompared to untreated controls (P < 10(-5) and P = 0.001, respectively) , The fungal densities in the kidneys of neutropenic mice were signifi cantly reduced with either amphotericin B monotherapy or amphotericin B-fluconazole combined therapy compared to those of controls (P < 10(- 6)), Fluconazole monotherapy also reduced fungal densities in the kidn eys; however, this decrease was not statistically significant (P = 0.1 7), In contrast, treatment with either fluconazole alone or combined w ith amphotericin B (but not amphotericin B monotherapy) significantly decreased fungal densities in the brain (P = 0.025), In the rabbit end ocarditis model, amphotericin B monotherapy or combined therapy signif icantly decreased fungal densities in cardiac vegetations (P < 0.01 ve rsus the controls). Although no significant antagonism was seen when f luconazole was given in combination with amphotericin B, combination t herapy did not augment the antifungal activity of amphotericin B.