Abstract
Four sequential Aspergillus fumigatus isolates from a patient with chronic granulomatous disease (CGD) eventually failing azole-echinocandin combination therapy were investigated. The first two isolates (1 and 2) were susceptible to antifungal azoles, but increased itraconazole, voriconazole and posaconazole MICs were found for the last two isolates (3 and 4). Microsatellite typing showed that the 4 isolates were isogenic, suggesting that resistance had been acquired during azole treatment of the patient. An immunocompromised mouse model confirmed that the in vitro resistance corresponded with treatment failure. Mice challenged with the resistant isolate 4 failed to respond to posaconazole therapy, while those infected by susceptible isolate 2 responded. Posaconazole-anidulafungin combination therapy was effective in mice challenged with isolate 4. No mutations were found in the Cyp51A gene of the four isolates. However, expression experiments of the Cyp51A showed that the expression was increased in the resistant isolates, compared to the azole-susceptible isolates. The microscopic morphology of the four isolates was similar, but a clear alteration in radial growth and a significantly reduced growth rate of the resistant isolates on solid and in broth medium was observed compared to isolates 1 and 2 and to unrelated wild-type controls. In the mouse model the virulence of isolates 3 and 4 was reduced compared to the susceptible ones and to wild-type controls. For the first time, the acquisition of azole resistance despite azole-echinocandin combination therapy is described in a CGD patient and the resistance demonstrated to be directly associated with significant change of virulence.
Highlights
Aspergillus fumigatus is the Aspergillus species involved in the vast majority of invasive infections
In contrast to A. terreus, which is intrinsically resistant to amphotericin B, and certain newly described species like A. lentulus, which are resistant to multiple antifungal drugs, A. fumigatus is normally susceptible to all three antifungal drug classes licensed for the treatment of invasive aspergillosis [1]
The posaconazole resistance in isolate 4 was not absolute, as significant kidney burden reduction was observed at the early time point day 4 and mortality was delayed in posaconazole treated animals (Mantel-Cox analysis P 0.0002) and as a tendency was seen towards better efficacy in the combination group than in the anidulafungin mono-therapy group
Summary
Aspergillus fumigatus is the Aspergillus species involved in the vast majority of invasive infections. Clinical failures involving A. fumigatus isolates with acquired triazole resistance are being increasingly reported over the recent years [2,3,4,5,6,7]. The fungus may become resistant through exposure of the patient to azoles, which has been reported most frequently in patients with aspergilloma. It has been suggested that the mode of reproduction of the fungus is important for the phenotypic expression of azole resistance [8]. In patients with aspergilloma or other cavitary lesions, the fungus reproduces by asexual sporulation which facilitates transfer of resistance genes to spores and subsequent offspring [8]. Patients with cavitary lesions may be at increased risk of harbouring resistant fungus
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