First case of echinocandin resistance caused by fks1 mutation found in Aspergillus

Submitted by BethBradshaw on 7 November 2017

Triazole antifungals are the first-line treatment for invasive aspergillosis (IA) and chronic pulmonary aspergillosis (CPA) but resistance to them is rising, primarily through mutations in the fungal cyp51A gene. Echinocandin antifungals such as micafungin work through a different mechanism and have been used a second-line drug for IA, and resistance is so far much rarer.

Previously, a research group managed to engineer a strain of Aspergillus fumigatus in the lab that was resistant to micafungin by changing a single letter in the DNA of the fks1 gene. This mutation has been linked to problems with antifungal resistance in the opportunistic yeast Candida but it had never been seen ‘in the wild’ in Aspergillus.

A recent paper reports the first known case of this gene mutation occurring in a fungal ball (aspergilloma) removed from a CPA patient. The isolate was almost completely resistant to echinocandins – more than 10,000,000 times as much micafungin or caspofungin was required to inhibit this strain than other clinical isolates removed from the same fungal ball. However, under normal lab conditions it appeared sickly: it grew slowly on agar plates, and appeared white instead of green because of poor sporulation.

This work neatly illustrates the challenges of choosing the right drug for a patient who may be carrying different strains (or even species) of Aspergillus with different levels of resistance to each drug. Unfortunately in this case the patient had previously failed therapy with azoles (itraconazole and voriconazole) and amphotericin B, and eventually had to discontinue micafungin treatment due to developing haemoptysis.

Read the paper here: Jiménez-Ortigosa et al (2017)