Evolutionary trends in antifungal resistance: a meta-analysis

Abstract

The present paper includes a meta-analysis of literature data on 318 species of fungi belonging to 34 orders in their response to 8 antifungal agents (amphotericin B, caspofungin, fluconazole, itraconazole, ketoconazole, posaconazole, terbinafine, and voriconazole). Main trends of MIC results at the ordinal level were visualized. European Committee on Antimicrobial Susceptibility Testing and Clinical & Laboratory Standards Institute (CLSI) clinical breakpoints were used as the staff gauge to evaluate MIC values ranging from resistance to susceptibility, which were subsequently compared with a phylogenetic tree of the fungal kingdom. Several orders (Hypocreales, Microascales, and Mucorales) invariably showed resistance. Also the basidiomycetous orders Agaricales, Polyporales, Sporidiales, Tremellales, and Trichosporonales showed relatively high degrees of azole multi-resistance, while elsewhere in the fungal kingdom, including orders with numerous pathogenic and opportunistic species, that is, Onygenales, Chaetothyiales, Sordariales, and Malasseziales, in general were susceptible to azoles. In most cases, resistance vs susceptibility was consistently associated with phylogenetic distance, members of the same order showing similar behavior.

Importance: A kingdom-wide the largest set of published wild-type antifungal data comparison were analyzed. Trends in resistance in taxonomic groups (monophyletic clades) can be compared with the phylogeny of the fungal kingdom, eventual relationships between fungus-drug interaction and evolution can be described.

Keywords: antifungals; breakpoint; phylogeny; resistance.

Fig 1

Flow chart of data collection and visualization.

Fig 2

Box–whisker plot of GM values of the 15 ordinal groups of the fungi kingdom listed in Table 2. Eight antifungal agents are shown with colored labels, arranged at the X1-axis, in order of appearance: allylamine (TBF), polyene (AMB), echinocandin (CAS), long-tailed azoles (KTZ, PCZ, and ITZ), and short-tailed azoles (VCZ and FCZ).

Fig 3

Parallel coordinate plot GM and MIC values of Hypocreales, Microascales, Mucorales, Saccharomycetales, and Malasseziales. MIC and GM values are plotted separately per antifungal and per species (generic names listed), with GM at the left and MIC at the right. Antifungal drugs arranged at left Y-axis, from top to bottom: short-tailed azoles (FCZ and VCZ), long-tailed azoles (ITZ, PCZ, and KTZ), echinocandins (CAS), and polyenes (AMB and TBF). Eight colors were used to distinguish the antifungals. As FCZ is applied in yeasts but not in filamentous fungi, only the orders Agaricales, Polyporales, Saccharomycetales, Sporidiales, Tremellales, and Trichosporonales show the FCZ color. Right Y-axis displays the genera; the lines connected with the antifungal via the central axis are summarized values of individual species. Left and right columns are connected for each species. Accordingly, each line represents the summary of a species taken from the Atlas of Clinical Fungi.

Fig 4

Two methods CBP were compared in the orders Eurotiales and the Saccharomycetales as an example. EUCAST CBP displayed at the top, CLSI CBP at the bottom. Fig. 4A is the heatmap result, Fig. 4B is the traffic light result.

Fig 5

Maximum likelihood tree of the fungal kingdom combined with antifungal data in traffic light format. Thirty-four clinically relevant orders and 11 non-clinical orders are included. Red bars display >50% resistance, green bars >50% susceptible; yellow = intermediate.