Efficacy of posaconazole and amphotericin B in experimental invasive pulmonary aspergillosis in dexamethasone immunosuppressed rats.
OBJECTIVE
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 10(6) 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 log(10) 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 log(10) 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.
Ullmann
Andrew J
AJ
3rd Medical Department, Johannes Gutenberg University, Mainz, Germany. ullmann@uni-mainz.de
Krammes
Erik
E
Sommer
Sita
S
Buschmann
Ines
I
Jahn-Muehl
Bernhard
B
Cacciapuoti
Anthony
A
Schmitt
Heinz-Josef
HJ
D000666:Amphotericin B / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000188:drug therapy* / Q000276:immunology; D001232:Aspergillus fumigatus / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D025141:Drug Resistance, Fungal; D004359:Drug Therapy, Combination; D016867:Immunocompromised Host; D008297:Male; D008826:Microbial Sensitivity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use*
D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole; D003907:Dexamethasone; D000666:Amphotericin B