An Invisible Threat: Mutation-Mediated Resistance to Triazole Drugs in Aspergillus
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EPIDEMIOLOGICAL ASPECTS OF FUNGAL INFECTIONS (T CHILLER AND J BADDLEY, SECTION EDITORS)
An Invisible Threat: Mutation-Mediated Resistance to Triazole Drugs in Aspergillus Cau D. Pham & Shawn R. Lockhart
Published online: 16 September 2012 # Springer Science+Business Media, LLC (outside the USA) 2012
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. Keywords Aspergillus . Aspergillus fumigatus . Triazole . Cyp51a . Voriconazole . Itraconazole . Posaconazole . Resistance
Introduction Aspergillus is a large genus of ubiquitous environmental molds that includes the major clinically relevant species A. fumigatus, A. flavus, A. niger, and A. terreus [1•, 2]. Conidia of these species are found in both indoor and outdoor environments [3, 4]. Consequently, chronic exposure to Aspergillus conidia is an unavoidable consequence of breathing. Aspergillosis is a spectrum of disease resulting from the inhalation of airborne conidia by susceptible hosts. Once inhaled, disease development and progression depends on the immune status of the host. Clinical disease ranges from allergic bronchopulmonary aspergillosis C. D. Pham : S. R. Lockhart (*) Mycotic Diseases Branch, Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30333, USA e-mail: [email protected]
(ABPA) to chronic pulmonary aspergillosis (CPA) and finally to invasive aspergillosis (IA). Invasive aspergillosis is an important contributor to longer hospital stays and increased morbidity and mortality in susceptible populations [5–8]. Advances in the antifungal arsenal and novel tools for early detection of infection may have improved the outcome in patients with IA. However, favorable prognosis for CPA and IA still remains unacceptably low with the overall mortality rates around 42 % and 75 %, respectively [9•, 10•, 11]. Unfavorable outcome is attributed to host factors as well as failure to respond to antifungal treatment. Antifungal treatment failure can be a consequence of bioavailability, which is poor for many antifungal agents, and to some degree, to the development by Aspergillus spp. of mechanisms that confer resistance [12, 13•, 14•, 15]. This review gives a description of susceptible populations, a history of emergence of antifungal resistance in aspergilli worldwide, and an overview of advances made in understanding the mechanisms underlying resistance to antifungal agents.
Populations at Risk Individuals with c
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