In vivo efficacy of liposomal amphotericin B against clinical Aspergillus fumigatus isolates in two different immunosuppressed models of invasive aspergillosis

Seyedmojtaba (Amir) Seyedmousavi


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.



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European Congress of Clinical Microbiology and Infectious Diseases
    • ECCMID 26th (2016)