Combination Therapy of Advanced Invasive Pulmonary Aspergillosis in Transiently Neutropenic Rats Using Human Pharmacokinetic Equivalent Doses of Voriconazole and Anidulafungin

Abstract

At present, voriconazole (VOR) is the drug of first choice for treating invasive pulmonary aspergillosis (IPA).However, particularly in advanced stages of disease and in the severely immunocompromised host, the mortality remains substantial. The combination of VOR with an echinocandin may improve the therapeutic outcome. We investigate here whether combining VOR and anidulafungin (ANI) in advanced IPA in transiently neutropenic rats results in a higher therapeutic efficacy. Since VOR is metabolized more rapidly in rodents than in humans, dosage adjustment for VOR is necessary to obtain an area under the plasma concentrationtime curve (AUC) in rodents that is equivalent to that of humans. In this study, the pharmacokinetics of VOR and ANI in rats were elucidated, and dosage schedules were applied that produced AUCs similar to those of humans. The developed dose schedules were well tolerated by the rats, without effects on renal and hepatic functions. VOR showed excellent efficacy in early IPA (100% rat survival). In advanced IPA, VOR was less efficacious (50% rat survival), whereas a significant decrease in galactomannan concentrations in lungs and sera was found in surviving rats. ANI administered in advanced IPA resulted in 22% rat survival, and the serum concentrations of fungal galactomannan were slightly but not significantly decreased. The addition of ANI to VOR did not result in significantly increased therapeutic efficacy in advanced IPA, resulting in 67% rat survival and a significant decrease in galactomannan concentration in serum. In conclusion, VOR monotherapy is therapeutically effective in the treatment of advanced-stage IPA and superior to the use of ANI. Combining both agents does not significantly improve the therapeutic outcome.Invasive pulmonary aspergillosis (IPA) continues to be a major problem in immunocompromised patients (18). Since voriconazole (VOR) was shown to be superior to amphotericin B (AMB) in a large randomized trial, it became the drug of choice for the treatment of IPA (22, 44). More recently, another class of antifungal agents, the echinocandins, has been used to salvage patients with refractory IPA (44). Echinocandins target 1,3-␤-D-glucan synthesis of most pathogenic fungi. Caspofungin (CAS) was the first drug of this class, and more recently anidulafungin (ANI) has become available. However, despite these new treatment options for IPA, the mortality remains substantial, with mortality rates of 25 to 35% 12 weeks after diagnosis (21, 22). Combination therapy might reduce mortality rates further. From clinical observational studies, it appeared that in 57 to 68% of the favorable results were obtained in patients when combination therapy with VOR and CAS was applied (27,37). In neither of these studies, however, was the combination therapy compared to VOR monotherapy in a randomized fashion.In this respect, preclinical research in animal models of IPA is important for investigating the potency of antifungal agents in combination. In our laboratory, we developed a model of uni...

Pharmacodynamics of Anidulafungin against Clinical Aspergillus fumigatus Isolates in a Nonneutropenic Murine Model of Disseminated Aspergillosis

“…In humans, the AUC after a standard dose is slightly over 100 mg · h/liter (28,29). Andes et al found that a fAUC 0-24 /MEC value of 100 was required to result in a static effect in a Candida infection model (27).…”

Impact of In Vivo Triazole and Echinocandin Combination Therapy for Invasive Pulmonary Aspergillosis: Enhanced Efficacy against Cyp51 Mutant Isolates

“…The posaconazole static dose for this combination was reduced by almost 13-fold compared to that for monotherapy, which is both highly statistically significant and, one might expect, clinically important (P Յ 0.001). Previous in vivo studies have demonstrated similar enhanced effects with voriconazole and each of the three licensed echinocandins (52)(53)(54)(55)(56)(57), although this is the first to utilize posaconazole and to examine the results from a pharmacodynamic perspective.…”

In Vitro Activity and In Vivo Efficacy of Anidulafungin in Murine Infections by Aspergillus flavus

“…In contrast, the good results obtained with the therapy were not accompanied by a decrease in galactomannan serum levels. This fact was also observed in disseminated and pulmonary murine infections by A. fumigatus (1,10,14,15). It has been suggested that due to their fungistatic activity, the echinocandins are not able to reduce galactomannan levels in serum, since this phenomenon was not observed in the treatment of aspergillosis with fungicidal drugs, like azoles (1).…”