Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata

Abstract

Candida glabrata has thoroughly adapted to successfully colonize human mucosal membranes and survive in vivo pressures prior to and during antifungal treatment. Out of all the medically relevant Candida species, C. glabrata has emerged as a leading cause of azole, echinocandin, and multidrug (MDR: azole + echinocandin) adaptive resistance. Neither mechanism of resistance is intrinsic to C. glabrata, since stable genetic resistance depends on mutation of drug target genes, FKS1 and FKS2 (echinocandin resistance), and a transcription factor, PDR1, which controls expression of major drug transporters, such as CDR1 (azole resistance). However, another hallmark of C. glabrata is the ability to withstand drug pressure both in vitro and in vivo prior to stable ‘genetic escape’. Additionally, these resistance events can arise within individual patients, which underscores the importance of understanding how this fungus is adapting to its environment and to drug exposure in vivo. Here, we explore the evolution of echinocandin resistance as a multistep model that includes general cell stress, drug adaptation (tolerance), and genetic escape. The extensive genetic diversity reported in C. glabrata will be highlighted.

Antifungal drug susceptibility, molecular basis of resistance to echinocandins and molecular epidemiology of fluconazole resistance among clinical Candida glabrata isolates in Kuwait

“…In the United States, the rate of resistance of C. glabrata to echinocandins has been increasing steadily and ~9% of fluconazole-resistant bloodstream isolates were also resistant to echinocandins 14,22,30,39 . Emergence of resistance to echinocandins in C. glabrata and increasing reports of multidrug resistance to azoles, echinocandins and amphotericin B is a worrisome development as it severely limits the choice of antifungal drugs for the treatment of invasive C. glabrata infections 13,14,20,30,31 . In this context, multidrug resistance detection in only one C. glabrata isolate in Kuwait is encouraging, however, continued surveillance studies are needed to provide accurate estimates of trends in antifungal resistance and their impact on treatment outcome.…”

“…has also appeared in recent years with the highest rate occurring among C. glabrata and breakthrough invasive C. glabrata infections have been reported in patients on micafungin therapy [14][15][16][21][22][23][24] . Resistance to polyenes is also being reported with increasing frequency in clinical C. glabrata isolates [25][26][27][28][29] and a multidrug-resistant phenotype (resistant to azoles and echinocandins) occurring in ICU and non-ICU settings has also been described in recent years 30,31 .…”

Major challenges and perspectives in the diagnostics and treatment of dermatophyte infections

“…4) (Cowen 2008;Martinez-Rossi et al 2018). Exposure of dermatophytes to an antifungal drug, damage to their cell wall, disturbances in the osmolarity of the environment and appearance of reactive oxygen forms are stimuli that can be activators of signalling pathways aimed at counteracting the effects of sudden cellular stress (Hayes et al 2014;Healey and Perlin 2018). Most of the well-known molecular mechanisms underlying the tolerance and resistance to antifungal substances have been explained for pathogenic fungi of the genera Candida, Cryptococcus and Aspergillus, while the issue is very poorly understood in the case of dermatophytes.…”

Candida tropicalis is the most prevalent yeast species causing candidemia in Algeria: the urgent need for antifungal stewardship and infection control measures

“…Historically, C. albicans is known to be the most prevalent cause of candidemia, but the changing landscape of candidemia epidemiology showed that the prevalence of non-albicans Candida (NAC) species is increasing [4] and in some cases surpassing that of C. albicans [5]. Unfortunately, some of the NAC species, such as C. glabrata [6] and Pichia kudriavzveii [7], intrinsically have higher minimum inhibitory concentration (MIC) values toward azoles, and C. glabrata rapidly acquires resistance to echinocandins [6], the frontline antifungal recommended for the treatment of candidemia [8]. Presently, numerous studies in different countries reported the emergence of C. parapsilosis [9] and C. tropicalis [10] blood isolates resistant to fluconazole, the frontline antifungal drug used to treat candidemia in developing countries [5,11].…”