Comparative Antifungal Activity of the Echinocandin FK463 against Disseminated Candidiasis and Invasive Pulmonary Aspergillosis in Persistently Neutropenic Rabbits.
In vitro studies demonstrate that FK463 (FK) has broad-spectrum activity against Candida and Aspergillus species. Little is known about its comparative antifungal activity in persistently neutropenic hosts. Therapeutic efficacy of FK against experimental disseminated candidiasis (DC) and invasive pulmonary aspergillosis (IPA) was studied in persistently neutropenic rabbits. Candidiasis: Treatment was started 24h after IV inoculation of 1x103 Candida albicans (CA) blastoconidia. Study groups: untreated controls (UC), FK at 0.25(FK0.25), 0.5(FK0.5), 1(FK1), or amphotericin B 1(AmB) mg/kg IV. Rabbits treated with FK0.5, FK1, and AmB showed significant dosage-dependent tissue clearance of CA in liver, spleen, kidney, and brain (p<0.001), lung (p<0.01), vena cava (p<0.05) in comparison to that of UC. Rabbits treated with FK0.25 had a significant reduction of CA in all tissues but vena cava and lung. In vitro time-kill assays demonstrated concentration-dependent fungicidal activity that correlated with in vivo results. Aspergillosis: Treatment was started 24h after endotracheal inoculation of 1.5x108 Aspergillus fumigatus (AF). Study groups: UC, FK0.5, FK1, FK2, AmB, or liposomal amphotericin B at 5(LAMB) mg/kg IV. In comparison to the significant FK dosage-dependent reduction in CFU/g of CA in DC, FK-treated rabbits with IPA had no reduction in CFU/g of AF. As therapeutic controls, AmB and LAMB significantly reduced CA and AF in tissues (p<0.01). Despite the absence of reduction of AF in lungs, there was significant improvement in survival and reduction of pulmonary infarcts (p<0.05) in FK-treated rabbits. Conclusions: FK463 demonstrated concentration and dosage-dependent clearance of CA in DC but not of AF in IPA in persistently neutropenic rabbits.
Full conference title:
Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy