JAC Advance Access published online on June 10, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn224
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Original research |
Does pre-exposure of Aspergillus fumigatus to voriconazole or posaconazole in vitro affect its virulence and the in vivo activity of subsequent posaconazole or voriconazole, respectively? A study in a fly model of aspergillosis
1 Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA 2 University of Houston College of Pharmacy, Houston, TX, USA
Received 25 March 2008; returned 28 April 2008; revised 8 May 2008; accepted 12 May 2008
* Correspondence address. Department of Infectious Diseases, Infection Control and Employee Health, Unit 402, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel: +1-713-792-6237; Fax: +1-713-745-6839; E-mail: dkontoyi{at}mdanderson.org
Objectives: Voriconazole and posaconazole are effective as both prophylaxis and treatment for invasive aspergillosis (IA) in immunocompromised patients. Hence, it is important to determine whether Aspergillus pre-exposure to voriconazole or posaconazole diminishes subsequent posaconazole or voriconazole activity, respectively.
Methods: We used Aspergillus fumigatus (AF) 293 conidia with or without prior exposure to voriconazole or posaconazole [three serial passages on plates containing regular yeast extract-glucose (YAG) media, YAG+0.0625 mg/L voriconazole or YAG+0.025 mg/L posaconazole]. Toll-deficient Drosophila melanogaster flies were infected by injection, and 8 day survival was monitored. Following infection, flies were fed either regular food, food containing 1000 mg/L voriconazole (posaconazole-exposed conidia) or 1000 mg/L posaconazole (voriconazole-exposed conidia). Voriconazole and posaconazole concentrations in flies were confirmed by HPLC.
Results: AF inoculation resulted in 71% mortality 8 days post-infection (median survival 4 days). Prior conidial exposure to voriconazole or posaconazole did not affect mortality (73%, P = 0.8 for voriconazole pre-exposed and 76%, P = 0.49 for posaconazole pre-exposed). Voriconazole treatment post-infection had a protective effect, reducing mortality to 42% (P = 0.0002), while prior conidial exposure to posaconazole did not alter the protective effect of voriconazole (34% 8 day mortality, P = 0.35). Likewise, posaconazole treatment post-infection reduced mortality to 36%, while prior conidial exposure to voriconazole did not alter the protective effect of posaconazole (39% mortality, P = 0.92). Median fly homogenate concentrations of voriconazole and posaconazole were 0.44 and 2.05 mg/L, respectively.
Conclusions: Prior exposure of AF to voriconazole or posaconazole did not affect the virulence of AF nor the subsequent activity of the alternate triazole in a Drosophila model of IA.
Key Words: fungal infections , triazoles , Drosophila melanogaster
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