Post-antifungal effect of amphotericin B and voriconazole against Aspergillus fumigatus analysed by an automated method based on fungal CO2 production: dependence on exposure time and drug concentration.
The post-antifungal effect (PAFE) of amphotericin B and voriconazole, either alone or in combination, on Aspergillus fumigatus was studied using an automated system based on fungal CO2 production.


METHODS
Conidia of A. fumigatus were exposed to concentrations of 1-10 x MIC of amphotericin B and 1-40 x MIC of voriconazole for 1, 2 and 4 h. After a washing step, exposed and control conidia were inoculated into Pedi-BacT culture bottles. CO2 production was automatically monitored until the bottles signalled positive. The difference in time span for positive signals in drug-exposed and control bottles was used to calculate PAFE.


RESULTS
There was a linear relationship between inoculum size and time to positive signal (r2=0.99). The precision of duplicate analyses was 1.5%. Longer exposure times increased the amphotericin B-induced PAFE (P<0.001), whereas concentrations above the MIC did not. Voriconazole after 4 h of exposure induced a short dose-independent PAFE. The combination with amphotericin B did not prolong the PAFE over that caused by amphotericin B alone.


CONCLUSIONS
This automated method can be used for determination of PAFE. In contrast to Candida spp., in which amphotericin B-induced PAFE is mainly related to the area under the curve, the effect on A. fumigatus was more dependent on the exposure time. This implies that pharmacodynamic data obtained from Candida experiments cannot be directly extrapolated to Aspergillus.
Department of Clinical Microbiology L202, Karolinska University Hospital, S-171 76 Stockholm, Sweden. Erja.Chryssanthou@kus.se
Erja
E
Chryssanthou
Jan
J
Sjölin
D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects*; D002245:Carbon Dioxide / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D065819:Voriconazole
D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D002245:Carbon Dioxide; D000666:Amphotericin B; D065819:Voriconazole