Addition of 17-(allylamino)-17-demethoxygeldanamycin to a suboptimal caspofungin treatment regimen in neutropenic rats with invasive pulmonary aspergillosis delays the time to death but does not enhance the overall therapeutic efficacy.

Jeannine M Refos,Wendy W J Van De Sande,Marian T Ten Kate,Henri A Verbrugh,Irma A J M Bakker-Woudenberg,Alieke G Vonk,Kimberly Eadie

doi:10.1371/journal.pone.0180961

Abstract

Caspofungin (CAS) which is used as salvage therapy in patients with invasive pulmonary aspergillosis (IPA) inhibits the 1,3-β-D-glucan synthesis in Aspergillus fumigatus. Inhibiting 1,3-β-D-glucan synthesis induces a stress response and in an invertebrate model it was demonstrated that inhibiting this response with geldamycin enhanced the therapeutic efficacy of CAS. Since geldamycin itself is toxic to mammalians, the therapeutic efficacy of combining geldamycin with CAS was not studied in rodent models. Therefore in this study we investigated if the geldamycin derivate 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) was able to enhance the therapeutic efficacy of CAS in vitro and in our IPA model in transiently neutropenic rats. In vitro we confirmed the earlier demonstrated synergy between 17-AAG and CAS in ten A. fumigatus isolates. In vivo we treated A. fumigatus infected neutropenic rats with a sub-optimal dose of 0.75 mg/kg/day CAS and 1 mg/kg/day 17-AAG for ten days. Survival was monitored for 21 days after fungal inoculation. It appeared that the addition 17-AAG delayed death but did not improve overall survival of rats with IPA. Increasing the doses of 17-AAG was not possible due to hepatic toxicity. This study underlines the need to develop less toxic and more fungal specific geldamycin derivatives and the need to test such drugs not only in invertebrate models but also in mammalian models.

Highlights

Invasive pulmonary aspergillosis (IPA), mainly caused by the fungus Aspergillus fumigatus, is a difficult to treat, life-threatening fungal infection observed in severely immunocompromised patients
Within the G. mellonella model, combination of CAS and geldanamycin resulted in significantly improved survival of larvae infected with a lethal dose of A. fumigatus compared to mono-therapy treated larvae [14]
We investigated if combining CAS with geldamycin derivative 17-AAG would enhance the therapeutic efficacy of CAS in our well known animal model of unilateral invasive pulmonary aspergillosis in neutropenic rats [16,17,18,19,20,21,22,23]

Summary

Introduction

Invasive pulmonary aspergillosis (IPA), mainly caused by the fungus Aspergillus fumigatus, is a difficult to treat, life-threatening fungal infection observed in severely immunocompromised patients. Inhibition of 1,3-β-D-glucan synthesis by the echinocandins causes loss of cell wall integrity and induces an acute stress response [7], in which the chaperone molecule heat shock protein 90 (Hsp90) plays a key role [8,9,10]. Within the G. mellonella model, combination of CAS and geldanamycin resulted in significantly improved survival of larvae infected with a lethal dose of A. fumigatus compared to mono-therapy treated larvae [14]. We investigated if combining CAS with geldamycin derivative 17-AAG would enhance the therapeutic efficacy of CAS in our well known animal model of unilateral invasive pulmonary aspergillosis in neutropenic rats [16,17,18,19,20,21,22,23]

Materials and methods

Results

Discussion