In vitro evaluation of voriconazole in combination with antifungals

M. Ghannoum, N. Isham, M. Hossain, and D. Sheehan

Author address: 

Center for Medical Mycology/Mycology Reference Laboratory, Department of Dermatology, University Hospitals of Cleveland and Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 441065028, 2Pjizer Pharmaceuticals Group, Nk: NY 1001


Background: The search for safe, effective treatment of invasive fungal infections has yielded novel antifungals, including the triazole voriconazole (Pfizer), liposomal preparations of amphotericin such as Abelcet (Liposome), the echinocandin micafungin (FK) (Fujisawa) and the pneumocandin caspofungin (MK) (Merck). These new antifungals are active against pathogenic fungi, yet less toxic than amphotericin B. In this study, the effects of combining voriconazole (VOR) with amphotericin B (AM), Abelcet (AB), 5fluorocytosine (5FC), fluconazole (FLU), FK463, and MK0991 were investigated. Methods: The checkerboard combination test method was used to determine the synergistic, additive, indifferent, or antagonistic interactions effect on minimum inhibitory concentration (MIC) values. Two antifungal agents are serially diluted in a desired medium to produce 11 concentrations of the drugs under investigation. The range is chosen to include achievable serum levels of the drugs. The two antifungals are then combined into wells of a microtiter plate so that the concentration of one drug increases as that of the other also increases. Two rows consisting of serial dilutions of each individual drug are included for comparison. Yeast isolates tested include 3 strains each of Candida albicans, Candida glabrata, Candida krusei, Candida parapsibsis, Candida tropicalis, and Cryptococcus neoformans. Both fluconazole- susceptible and resistant strains were included. Results: All of the isolates tested were susceptible to VOR, AB, and AM. All Candida species were susceptible to MK and FK, while all Cryptococcus strains were resistant to these two antifungals. Susceptibility to 5-FC and FLU varied. Our data shows that VOR/MK combinations were 33% additive and 67% indifferent. VOR/FK combinations were 11% synergistic, 11% additive, and 78% indifferent. VOR/FLU combinations were 39% additive and 61% indifferent. VORAB combinations were 22% additive and 72% indifferent.VOR/ AM combinations were 22% additive and 78% indifferent. Finally, VOR/S-FC combinations were 11% additive and 89% indifferent. Importantly, no antagonism was noted. Conclusion: Overall, 25.9% of all VOR combinations against these yeast isolates were either additive or synergistic, while 74.1% were indifferent, indicating minimal lowering of the individual MIC’s. Interactions were strain specific, suggesting that it is necessary to test combinations with each isolate. This study points to the need for expanded combination testing of VOR. Correlation with clinical outcome remains to be determined.

abstract No: 


Full conference title: 

12th International Symposium on Infections in the Immunocompromised Host
    • ISIIH 12th