An Invisible Threat: Mutation-Mediated Resistance to Triazole Drugs in Aspergillus

Abstract

Aspergillosis has emerged as an important contributor to infection-related morbidity and mortality in susceptible populations. This comes at a time when we are also seeing an increase in the vulnerable populations themselves. At the same time, some parts of the world are reporting an increased incidence of aspergillosis refractory to triazole therapy. Resistance to triazole drugs may have major implications for aspergillosis management since our antifungal armamentarium is limited. This review gives an overview of populations at risk of developing aspergillosis and highlights resistance mechanisms that may contribute to morbidity and mortality in these vulnerable populations.

Passive Surveillance for Azole-ResistantAspergillus fumigatus, United States, 2011–2013

“…A common mechanism that confers resistance to azole drugs is a mutation in the lanosterol 14 α-demethylase gene that encodes the CYP51A protein. This protein is the primary target of azole drugs and sterol demethylation inhibitor (DMI) fungicides ( 9 – 11 ). However, not all cyp51A mutations contribute to azole resistance (some are benign), and not all azole resistance is caused by mutations in the cyp51A gene ( 12 ).…”

“…In the past decade, novel cyp51A promoter duplication mutations, especially the cooperative pair of cyp51A mutations known as TR 34 /L98H, have emerged as a predominant azole-resistance mechanism in A. fumigatus ( 1 , 4 , 6 , 10 , 11 , 13 – 22 ). Isolates harboring the TR 34 /L98H mutation are cross-resistant to multiple azoles ( 4 , 15 , 17 ).…”