Background: Posaconazole (POS) is an extended-spectrum triazole, recommended for prophylaxis against invasive aspergillosis (IA). We investigated the efficacy of POS in preventing IA due to azole-resistant A. fumigatus isolates. Methods: Four clinical A.fumigatus isolates were studied in a neutropenic murine model of pulmonary infection: three genetically identical isolates harboring A9T and F219I point mutations in the cyp51A gene with an POS MIC of 0.063, 0.05 and ≥ 16 mg/L, resp. Isolate 4 was genetically different with a POS MIC of 0.5 mg/L and harbored a TR34/L98H resistance mechanism. Groups of 11 female CD-1 mice were rendered neutropenic by injection of cyclophosphamide on days -4, -1 and +4. Mice were treated daily from day -2 to 7 days post challenge with 4, 8, 16 and 32 mg/kg oral POS once daily. Mice were infected through instillation of fungal inocula in the nares at day 0 and 2 h after therapy. In addition, POS concentrations in blood were assayed in a separate pharmacokinetic study at 8 predefined time points post challenge by a validated HPLC method. Results: Survival at day 10 post challenge was significantly better for POS treated mice than that of controls. A dose-response relationship was observed for each isolate. The maximum effect (100% survival) was reached at a dose of 16 mg/kg for the isolates with MIC 8804; 0.5 mg/L, independent of corresponding genotype. Yet, in the isolate with the MIC ≥ 16 mg/L maximum effect was lower (less than 70 %) compared to other isolates, even with the highest dose (32 mg/kg). The Hill equation with a variable slope fitted the relationship between the area under the plasma concentration-time curve (AUC) and 10- days survival well, with a 50% effective AUC of 79.17, 69.50 and 182 (h.mg/L), resp. for three genetically identical isolates with low, intermediate and high MIC (R2= 0.99, 0.98 and 0.95, resp.) and 70.45 mg/kg for the isolate with different genotype and intermediate susceptibility to POS (R2= 0.96). Conclusions: POS prophylaxis was effective in A. fumigatus with POS MICs 8804; 0.5 mg/L, independent of the genotypes and azoleresistance mechanisms. POS was less effective against the isolate with a MIC of >16 mg/L, indicating the potential for breakthrough IA.
Full conference title:
53rd Interscience Conference on Antimicrobial Agents and Chemotherapy
- ICAAC, 53rd (2013)