In vivo efficacy of liposomal amphotericin B against wild type and azole-resistant Aspergillus fumigatus isolates in two different immunosuppressed models of invasive aspergillosis [PublishAheadOfPrint]

Using an immunocompetent murine model of invasive aspergillosis (IA), we previously reported (AAC, 2013, 57, 4, 1866–1871) that the efficacy of liposomal amphotericin B (L-AmB) is not hampered by the presence of azole resistance mutations in Aspergillus fumigatus. We here investigated the role of immune suppression, i.e. neutropenic and steroid-treated, on L-AmB efficacy in mice infected with a wild type (WT) and azole-resistant Aspergillus fumigatus harboring TR₃₄/L98H mutation in cyp-51A gene.

Survival of treated animals at day 14 in both immunosuppressed models was significantly better than that of non-treated controls. A dose-response relationship was observed independent of the azole-resistant mechanism and immunosuppression used. In the neutropenic model, 100% survival was reached at a L-AmB dose of 16 mg/kg for the WT and the TR₃₄/L98H isolate. In the steroid-treated group, 90.9 % and 100% survival was achieved for the WT and TR₃₄/L98H isolate with a L-AmB dose of 16 mg/kg, respectively. In the neutropenic model, the 50% effective dose (ED₅₀) was 1.40 (95% CI, 0.66 to 3.00 mg/kg) for the WT isolate and 1.92 (95% CI, 0.60 to 6.17 mg/kg) for the TR₃₄/L98H isolate, and 2.40 (95% CI, 1.93 to 2.97 mg/kg) for the WT isolate and 2.56 (95% CI, 1.43 to 4.56 mg/kg) for the TR₃₄/L98H isolate in the steroid-treated group.

Overall, there were no significant differences in efficacy of L-AmB against wild type and azole-resistant isolates between the two different immunosuppressed conditions (P > 0.9). However, the required L-AmB exposure was significantly higher than immunocompetent model.

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