Affiliation:
1. Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, the Netherlands
2. Centre of Expertise in Mycology, Radboudumc/CWZ, Nijmegen, the Netherlands
3. Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, the Netherlands
4. Invasive Fungi Research Center, Mazandaran University of Medical Sciences, Sari, Iran
Abstract
ABSTRACT
Using an immunocompetent murine model of invasive aspergillosis (IA), we previously reported that the efficacy of liposomal amphotericin B (L-AmB) (Ambisome) is not hampered by the presence of azole resistance mutations in
Aspergillus fumigatus
(S. Seyedmousavi, W. J. G. Melchers, J. W. Mouton, and P. E. Verweij, Antimicrob Agents Chemother 57:1866–1871, 2013,
https://doi.org/10.1128/AAC.02226-12
). We here investigated the role of immune suppression, i.e., neutropenia and steroid treatment, in L-AmB efficacy in mice infected with wild-type (WT)
A. fumigatus
and with azole-resistant
A. fumigatus
harboring a TR
34
/L98H mutation in the
cyp-51A
gene. Survival of treated animals at day 14 in both immunosuppressed models was significantly better than that of nontreated controls. A dose-response relationship was observed that was independent of the azole-resistant mechanism and the immunosuppression method used. In the neutropenic model, 100% survival was reached at an L-AmB dose of 16 mg/kg of body weight for the WT strain and the TR
34
/L98H isolate. In the steroid-treated group, 90.9% survival and 100% survival were achieved for the WT isolate and the TR
34
/L98H isolate with an L-AmB dose of 16 mg/kg, respectively. The 50% effective dose (ED
50
) was 1.40 mg/kg (95% confidence interval [CI], 0.66 to 3.00 mg/kg) for the WT isolate and 1.92 mg/kg (95% CI, 0.60 to 6.17 mg/kg) for the TR
34
/L98H isolate in the neutropenic model and was 2.40 mg/kg (95% CI, 1.93 to 2.97 mg/kg) for the WT isolate and 2.56 mg/kg (95% CI, 1.43 to 4.56 mg/kg) for the TR
34
/L98H isolate in the steroid-treated group. Overall, there were no significant differences between the two different immunosuppressed conditions in the efficacy of L-AmB against the wild-type and azole-resistant isolates (
P
> 0.9). However, the required L-AmB exposure was significantly higher than that seen in the immunocompetent model.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
6 articles.
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