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Breakthrough invasive mold infections (IMIs) that occur during posaconazole or voriconazole prophylaxis are rare complications for which epidemiological data are lacking. This retrospective analysis comparing 24 microbiologically documented breakthrough with 66 nonbreakthrough IMIs shows a shift towards non-Aspergillus molds with a significantly increased proportion of rare multidrug-resistant molds.

Objectives Invasive mould infections are associated with a high mortality rate and the emergence of MDR moulds is of particular concern. Calcineurin and its chaperone, the heat shock protein 90 (Hsp90), represent an important pathway for fungal virulence that can be targeted at different levels. We investigated the antifungal activity of compounds directly or indirectly targeting the Hsp90-calcineurin axis against different mould species. Methods The in vitro antifungal activity of the anticalcineurin drug FK506 (tacrolimus), the Hsp90 inhibitor geldanamycin, the lysine deacetylase inhibitor trichostatin A and the Hsp70 inhibitor pifithrin-μ was assessed by the standard broth dilution method against 62 clinical isolates of Aspergillus spp. and non-Aspergillus moulds (Mucoromycotina, Fusarium spp., Scedosporium spp., Purpureocillium/Paecilomyces spp. and Scopulariopsis spp.) Results FK506 had variable antifungal activity against different Aspergillus spp. and was particularly active against Mucor spp. Geldanamycin had moderate antifungal activity against Fusarium spp. and Paecilomyces variotii. Importantly, trichostatin A had good activity against the triazole-resistant Aspergillus ustus and the amphotericin B-resistant Aspergillus terreus as well as the MDR Scedosporium prolificans. Moreover, trichostatin A exhibited synergistic interactions with caspofungin against A. ustus and with geldanamycin against Rhizopus spp. for which none of the other agents showed activity. Pifithrin-μ exhibited little antifungal activity. Conclusions Targeting the Hsp90-calcineurin axis at different levels resulted in distinct patterns of susceptibility among different fungal species. Lysine deacetylase inhibition may represent a promising novel antifungal strategy against emerging resistant moulds.

The first case of postoperative endophthalmitis after cataract surgery caused by Aspergillus ustus, a species that has only rarely been implicated in human disease, is described. Six weeks after cataract surgery, a 67-year-old medically controlled diabetic patient presented with uveitis, mild ciliary injection and ocular discomfort. Anterior chamber paracentesis, vitreous tap and finally complete vitrectomy with removal of the capsular bag including the intraocular lens were performed and several sets of culture yielded A. ustus. Despite vigorous systemic (itraconazole and caspofungin) and intravitreal (amphotericin B and caspofungin) antifungal therapy, the endophthalmitis did not improve. The painful eye with marked inflammation was finally enucleated. In vitro susceptibility testing of the isolate showed that it appeared resistant to amphotericin B, caspofungin, itraconazole, voriconazole, and posaconazole, and susceptible to terbinafine.

Aspergillus ustus is a soil residing fungus that rarely has been implicated in human infections. A 72-year-old man who had undergone surgery for mitral valve replacement and triple coronary artery bypass developed progressive pneumonia with A. ustus . The infection had spread to other organs and finally was diagnosed at postmortem examination.

A new enzyme responsible for the oxidation of d-glutamic acid was obtained from the mycelium of Aspergillus ustus strain f isolated from the soil. Many properties of this enzyme in the state of dried cell or crude extract were studied. The enzyme preparation strongly oxidizes d-glutamic and d-aspartic acids but does not affect any other dl-amino acids at all. A new micro-determination method for d-glutamic acid has been devised by means of this enzyme.

It is confirmed by a new method for the determination of d-glutamic acid, that Aerobacter strain A rapidly metabolizes d-glutamic acid, while it only shows feeble metabolic activity towards l-glutamic acid when it is grown on a dl-glutamate-K2HPO4 medium. A specific d-glutamic oxidase is demonstrated in the cell-free extracts of Aerobacter strain A. This enzyme seems to be different from d-glutamic-aspartic oxidase obtained from Aspergillus ustus by the authors, since the former has no activity towards d-aspartic acid.