Comparison of azoles against aspergilli in vitro and in an experimental model of pulmonary aspergillosis.
Current treatment modalities for bronchopulmonary aspergillosis are not very satisfying. We determined the in vitro activity of recently available azoles against Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger. Subsequently, these agents were evaluated in an animal model of bronchopulmonary aspergillosis using A. fumigatus as test organism. In vitro, detectable activity was only found for itraconazole (all minimal inhibitory concentrations, MICs, less than or equal to 3.2 micrograms/ml). The MICs for SCH39304 were greater than or equal to 12.8 micrograms/ml and greater than or equal to 25.6 micrograms/ml for ketoconazole and fluconazole. In vivo, amphotericin B was the most active agent tested, and SCH39304 was the most active azole in terms of survival and reduction in lung weight, followed by itraconazole. Ketoconazole and fluconazole did not improve survival nor reduce the lung weight of infected animals. We conclude, (1) that in vitro activity of azoles against aspergilli does not always correlate with in vivo activity; (2) that in vivo, SCH39304 was the most active azole tested, followed by itraconazole; (3) that for those agents for which data about effectiveness in human pulmonary aspergillosis are available (amphotericin B, ketoconazole, itraconazole) antifungal activity in our model corresponds to activity as seen in human beings, and (4) that SCH39304 and itraconazole are rational choices for clinical trials in human pulmonary aspergillosis.
Schmitt
H J
HJ
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, N.Y.
Edwards
F
F
Andrade
J
J
Niki
Y
Y
Armstrong
D
D
D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy*; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000188:drug therapy*; D001230:Aspergillus / Q000187:drug effects*; D001231:Aspergillus flavus / Q000187:drug effects; D001232:Aspergillus fumigatus / Q000187:drug effects; D004195:Disease Models, Animal; D017964:Itraconazole; D007654:Ketoconazole / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014230:Triazoles / Q000494:pharmacology*
D000935:Antifungal Agents; D014230:Triazoles; C056513:Sch 39304; D017964:Itraconazole; D000666:Amphotericin B; D007654:Ketoconazole