Background: The management of invasive aspergillosis (IA) has become more complicated due to the emergence of acquired azole resistance in Aspergillus fumigatus, which is associated withtreatment failure and a mortality rate of up to 88%. Using an immunocompetent murine model of IA, we previously reported (AAC, 2013, 57, 4, 1866–1871) that the efficacy of liposomal amphotericin B (L-AmB) in azole-resistant IA was comparable to that in wild type infection, indicating that the efficacy of L-AmB is not hampered by the presence of azole resistance mutations. As IA commonly affects patients who are neutropenic or receive corticosteroids, we investigated the efficacy of L-AmB in these two immunosuppressed conditions.
Material/methods: Two clinical A. fumigatusisolates obtained from patients with proven IA werestudied in neutropenic and steroid immunosuppressed murine models of infection, separately: a wild type (WT) isolate without mutations in the cyp51A gene and an azole-resistant isolates harboring a 34-bp tandem repeat mutation in the promoter region of the cyp51A gene in combination withsubstitutions at codon L98 [TR34/L98H]. Female CD-1 mice were infected intravenously (iv) 24 h priorto the start of therapy. Groups of 11 mice were treated iv at days 1, 2, and 5 post challenge withincreasing 4-fold doses of L-AmB ranging from 0.004 to 16 mg/kg/day and observed for 14 days. In neutropenic groups, mice were rendered immunosuppressed by injection of 150 mg/kg cyclophosphamide intraperitoneally on days -4 and -1 and +4. For steroid immunosuppression, cortisone acetate (100 mg/kg/d) was administered 3 days before and 5 days after infection,subcutaneously.
Results: Survival at day 14 in both immunosuppressed models was significantly better than that of controls. A dose-response relationship was observed independent of the azole-resistant mechanisms and immunosuppression used. In neutropenic model, the maximum effect (100% survival) was reached at a L-AmB dose of 16 mg/kg for the WT and the TR34/L98H isolate. In the steroid immunosuppression groups, 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 immunosuppression groups. There were no significant differences in efficacy of L-AmB against wild type and azole-resistant isolates between the 2 immunocompromized conditions (P > 0.05).
Conclusions: The results of these experiments indicate that L-AmB was able to prolong survival in vivo independent of the azole-resistance mechanisms and type of immunosuppression used.
Full conference title:
- ECCMID 26th (2016)