The effect of 17-(allylamino)-17-demethoxygeldanamycin in combination with caspofungin therapy in an invasive pulmonary Aspergillosis rat model

Ref ID: 19431

Author:

J. M. Refos,1 A. G. Vonk,2 M. Ten Kate,2 K. Eadie,2
H. A. Verbrugh,2 I. A. J. M. Bakker-Woudenberg2 and
W. W. J. van de Sande2

Author address:

1Erasmus MC, Rotterdam, the Netherlands and 2Department of
Medical Microbiology & Infectious Diseases, Rotterdam, the
Netherlands

Full conference title:

6th Trends in Medical Mycology 2013

Date: 11 October 2014

Abstract:

Introduction Invasive pulmonary aspergillosis (IPA) is a life-threat-
ening fungal infection in immunocompromised patients, mostly
caused by Aspergillus fumigatus. Despite new treatment options for
IPA, therapy continues to be a major problem due to toxicity and
emerging resistance against the first choice antifungal drug vorico-
nazole. The echinocandin caspofungin (CAS) is used as salvage ther-
apy. This drug has a different mode of action compared to the azoles
and inhibits the biosynthesis of 1,3 b-glucan. The synthesis of 1,3 b-
glucan is also influenced by the stress response of the fungus. One of
the key players in this stress response is heat shock protein 90
(Hsp90) which is able to upregulate 1,3 b-glucan synthesis. 17-(ally-
lamino)-17-demethoxygeldanamycin (17-AAG) is an Hsp90 inhibitor
and enhances the therapeutic efficacy of CAS in an in vivo systemic
aspergillosis model in the moth Galleria mellonella. However, no data
are available for mammal models of IPA. To determine if combina-
tion therapy also shows a promising beneficial effect in IPA in mam-
mals, we investigated if 17-AAG could improve the in vivo efficacy of
CAS in IPA in transiently neutropenic rats.
Methods For 10 A. fumigatus strains, an XTT-based checkerboard
titration was performed to assess in vitro synergy between CAS and
17-AAG. Subsequently, the therapeutic efficacy of 17-AAG in combi-
nation with CAS was studied in transiently neutropenic female RP
rats with IPA. A left-sided pulmonary infection was established via
intubation and administration of A. fumigatus conidia into the left
lung lobe. Subgroups of rats were treated intraperitoneally according
to the following 3 regimens: 17-AAG 1 mg/kg/day, 17-AAG 5 mg/
kg/day or 17-AAG 20 mg/kg/day with or without the CAS dosage of
0.75 mg/kg/day which has suboptimal efficacy when administered
as mono-therapy. Treatment duration was 10 days and started 16 h
after infection. One group of control animals received CAS mono-
therapy and the other group control animals received vehicle.
Results In vitro activity, 17-AAG did not show an antifungal effect
(MIC>128 lg/ml), but a synergistic interaction was observed when
combining 17-AAG with CAS (FICI = 0.5).
In vivo efficacy, treatment with 1 mg/kg 17-AAG as mono-therapy
was well tolerated, however did not show any efficacy in rats with
IPA. Addition of 17-AAG to sub-optimal CAS therapy did not result
in significantly increased therapeutic efficacy, 33% rat survival was
obtained which was also observed after CAS mono-therapy. Increased
dosages of 17-AAG at 5 mg/kg or 20 mg/kg in combination with
CAS were not tolerated and resulted in renal and hepatic
dysfunctions.
Conclusion Whereas synergistic activity between 17-AAG and CAS
towards A. fumigatus in vitro is demonstrated, a synergistic effect of
17-AAG at the maximum tolerated dosage and CAS in IPA in neu-
tropenic rats is not observed. Although combining 17-AAG with CAS
proved to be beneficial in a moth model with systemic aspergillosis,
this combination of drugs is not successful in a clinically-relevant
animal model of IPA in immunocompromised rats.

Abstract Number: p257

Conference Year: 2013

Link to conference website: NULL

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