Molecular mechanisms of acquired antifungal drug resistance in principal fungal pathogens and EUCAST guidance for their laboratory detection and clinical implications

Abstract

The increasing incidence and changing epidemiology of invasive fungal infections continue to present many challenges to their effective management. The repertoire of antifungal drugs available for treatment is still limited although there are new antifungals on the horizon. Successful treatment of invasive mycoses is dependent on a mix of pathogen-, host- and antifungal drug-related factors. Laboratories need to be adept at detection of fungal pathogens in clinical samples in order to effectively guide treatment by identifying isolates with acquired drug resistance. While there are international guidelines on how to conduct in vitro antifungal susceptibility testing, these are not performed as widely as for bacterial pathogens. Furthermore, fungi generally are recovered in cultures more slowly than bacteria, and often cannot be cultured in the laboratory. Therefore, non-culture-based methods, including molecular tests, to detect fungi in clinical specimens are increasingly important in patient management and are becoming more reliable as technology improves. Molecular methods can also be used for detection of target gene mutations or other mechanisms that predict antifungal drug resistance. This review addresses acquired antifungal drug resistance in the principal human fungal pathogens and describes known resistance mechanisms and what in-house and commercial tools are available for their detection. It is emphasized that this approach should be complementary to culture-based susceptibility testing, given the range of mutations, resistance mechanisms and target genes that may be present in clinical isolates, but may not be included in current molecular assays.

The emergence and worldwide spread of the species Trichophyton indotineae causing difficult-to-treat dermatophytosis: A new challenge in the management of dermatophytosis

“…indotineae , and T . rubrum [ 37 ]. Yamada and colleagues introduced the 2 common abovementioned amino acid substitutions into the endogenous SQLE gene of a TRB-sensitive Arthroderma vanbreuseghemii (formerly T .…”

“…The most common substitution in T. indotineae strains reported worldwide is Phe397Leu in 95% of the studies leading to high TRB MICs (range: 1 to >32 mg/L) followed by Leu393Phe (MIC range: 1 to 64 mg/L) and Leu393-Ser (MIC range: 0.5 to 1 mg/L) [3][4][5]7,10,11,[13][14][15][16][17]19,21,22,[25][26][27][28]. Notably, Phe397Leu or Leu393Phe substitutions confer high-level TRB resistance in T. mentagrophytes, T. interdigitale, T. indotineae, and T. rubrum [37]. Yamada and colleagues introduced the 2 common abovementioned amino acid substitutions into the endogenous SQLE gene of a TRB-sensitive Arthroderma vanbreuseghemii (formerly T. mentagrophytes) strain and showed that resistance to TRB in A. vanbreuseghemii transformants was due to the respective point alterations [36].…”

Genomic Data Mining Reveals Abundant Uncharacterized Transporters in Coccidioides immitis and Coccidioides posadasii

“…Notably, ABC transporters have been widely implicated in the development of multidrug resistance (MDR) to antimicrobials or anticancer drugs [ 71 , 72 , 73 ]. MDR conferred by ABC transporters is increasingly concerning in fungal pathogens [ 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ]. Comprehensive phylogenetic analyses of 27 other fungal species from 18 orders of five fungal phyla defined a complex evolutionary history and classification of fungal ABC transporters [ 21 ].…”

Treatment of onychomycosis in an era of antifungal resistance: Role for antifungal stewardship and topical antifungal agents

“…51,53 Such mechanisms of antifungal resistance among dermatophytes, yeasts and non-dermatophyte moulds have been reviewed extensively. 10,46,[53][54][55][56][57][58][59] Briefly, azole antifungals (e.g., itraconazole) deplete ergosterol, an essential regulator of fungal cell membrane integrity. 60 Generally, azole resistance among dermatophytes reflects overexpression of genes that regulate membrane transporters, resulting in increased drug efflux from the cell.…”

“…Trichophyton species is mainly conferred by amino acid substitutions in the squalene epoxidase gene that reduce the binding affinity of terbinafine, although increases in drug degradation and efflux transporter expression have also been reported. 10,[56][57][58] As each antifungal drug class tends to provide only one mechanism of action, the…”