JAC Advance Access published online on September 12, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm328
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Efficacy of posaconazole and amphotericin B in experimental invasive pulmonary aspergillosis in dexamethasone immunosuppressed rats
1 3rd Medical Department, Johannes Gutenberg University, Mainz, Germany 2 Horst Schmidt Klinik, Wiesbaden, Germany 3 Schering-Plough Research Institute, Kenilworth, NJ, USA 4 Paediatric Department, Johannes Gutenberg University, Mainz, Germany
Received 8 May 2007; returned 27 June 2007; revised 6 July 2007; accepted 25 July 2007
* Corresponding author. Tel / Fax: +49-6131-17-6564; E-mail: ullmann{at}uni-mainz.de
Objectives: Invasive pulmonary aspergillosis is associated with high mortality. To assess new antifungal therapy options, animal models have to be developed to assess, in an appropriate setting, the activity of new drugs.
Methods: Male albino CD rats (125–150 g) were fed with a protein-free diet and received dexamethasone thrice weekly subcutaneously during the whole experiment. After 2 weeks, an inoculum of 106 conidia of Aspergillus fumigatus (H11-20) was injected intratracheally. Antifungal treatment was initiated and continued for a total of 7 days. Animals were grouped in numbers of 10. One group of animals served as untreated control, whereas the others were treated with amphotericin B intraperitoneally (2 and 4 mg/kg) and posaconazole via gavage (2, 4, 10 and 20 mg/kg). Survival and log10 cfu/g of the lungs were the endpoints. The strain H11-20 was tested for susceptibility in vitro to amphotericin B and posaconazole, respectively. Fungal burden of the lungs was expressed as log10 cfu/g. Survival analysis was performed by the Kaplan–Meier method. Differences in fungal burden were assessed by the Mann–Whitney test.
Results: All untreated animals died within a week. Amphotericin B and posaconazole at 2 mg/kg demonstrated survival benefits over control (P = 0.01 and P = 0.04). Dosages of 4 mg/kg were superior to 2 mg/kg for amphotericin B (P = 0.02) and posaconazole (P < 0.05), respectively. No further survival benefits were demonstrated beyond dosages of 10 mg/kg. Rats treated with 20 mg/kg posaconazole, however, had a lower fungal burden than all the other treatment groups (P = 0.0002).
Conclusions: Posaconazole and amphotericin B are effective in a dosage-dependent manner in this pulmonary aspergillosis model in immunocompromised rats.
Key Words: animal models , Aspergillus fumigatus , azoles , polyenes