Aspergillus terreus and amphotericin B resistance: correlation of in vivo and in vitro – susceptible versus resistant strains in a hematogenic mouse-model

Ref ID: 19373

Author:

C. Hortnagl,1 G. Blum,2 C. Speth,2 G. Rambach,2 H. Dietrich3
and C. Lass-Florl2

Author address:

1Medical University Innsbruck, Austria; 2Department of Hygiene
and Social Medicine, Innsbruck Medical University, Austria and
3Central Laboratory Animal Facility, Innsbruck, Austria

Full conference title:

6th Trends in Medical Mycology 2013

Date: 11 October 2014

Abstract:

Objective Amphotericin B (AMB) is one of the most commonly used
antimycotics to treat fungal infections in humans. It is active against
most pathogenic fungi and used to be the antas in therapy for critically
ill patients with invasive mould infections (IMI) and invasive aspergil-
losis (IA). IMI and IA have become increasingly common among
immunocompromised or immunosuppressed patients including solid-
organ or haematopoietic stem-cell transplant recipients and individu-
als who are on immunosuppressive drug regimens. The majority of IA
is caused by Aspergillus fumigatus followed by Aspergillus terreus (A. ter-
reus) and Aspergillus flavus (A. flavus). In particular, A. terreus, a wide-
spread soil saprophyte and producer of several secondary metabolites,
is a common cause of infection at the UniversityHospital of Innsbruck
(UHI), Austria. In vivo and in vitro data indicate that AMB resistance
and emergence of resistance during AMB therapy is rare but almost all
A. terreus isolates are intrinsically resistant to AMB, and a high mortal-
ity rate is associated with this particular mould. It is unclear whether
low AMB-MICs (< 0.20 lg/ml) reflect clinical response and thus corre- late with the in vivo situation; no data are available on strains with AMB-MIC < 0.20 lg/ml. For this study we compared AMB resistant A. terreus strains (ATR; AMB-MIC  4 lg/ml) and a rare A. terreus vari- ant showing enhanced susceptibility (ATS; AMB-MIC 0.20 lg/ml) in response to AMB in vivo. ATS and ATR were susceptible to other anti- fungal agents (e. g. azoles). Methods Inbred BALB/c mice were intravenously (i.v.) injected with 200 mg of cyclophosphamide/kg of body weight on day 3 and every 5th day to produce prolonged immunosuppression. All the mice were inoculated with ATR or ATS on day 0 by intravenous injection of 1 9 106 conidia (100 ll of a 107-conidia/ml stock solution in 0.9% NaCl) into the tail vein. Mice were intraperitoneally treated with 5 mg/kg Amphotericin B deoxycholate and 4 mg/kg Voriconazole (VORI). Organ fungal load (cfu) was checked via fungal plate count. Results ATS infection per se killed 50% of the mice by day 3 and was significantly more lethal than ATR (P < 0.05). At day 18, all mice infected with the ATS strain died, whereas 17% of the animals infected with ATR who received no treatment survived. AMB treat- ment improved survival in ATS infection up to 75%, while this was not the case with ATR infection (P < 0.05). Survival outcome of ATS infected mice with AMB treatment was comparable with VORI therapy. VORI therapy in ATR infected mice significantly enhanced survival compared to AMB. Survival was independent of fungal organ load and showed significant differences between the AMB and VORI groups. Conclusion Our in vivo murine model of disseminated aspergillosis showed that ATS was highly virulent, indicating that loss of fungal fitness is not associated with the appearance of AMB susceptibility. AMB therapy enhanced survival outcome of ATS infected mice. AMB and VORI treatment rescued ATR infected mice, yet independent of the fungal organ load.

Abstract Number: p004

Conference Year: 2013

Link to conference website: NULL

New link: NULL

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