Elevated minimum inhibitory concentrations to antifungal drugs prevail in 14 rare species of candidemia-causing Saccharomycotina yeasts

Abstract

Antifungal susceptibility profiles of rare Saccharomycotina yeasts remain missing, even though an increase in prevalence of such rare Candida species was reported in candidemia. Majority of these rare yeast species carry intrinsic resistances against at least one antifungal compound. Some species are known to be cross-resistant (against multiple drugs of the same drug class) or even multi-drug resistant (against multiple drugs of different drug classes). We performed antifungal susceptibility testing (AFST) according to EUCAST broth microdilution for 14 rare species (Clavispora lusitaniae, Candida intermedia, Candida auris, Diutina rugosa, Wickerhamiella pararugosa, Yarrowia lipolytica, Pichia norvegensis, Candida nivariensis, Kluyveromyces marxianus, Wickerhamomyces anomalus, Candida palmioleophila, Meyerozyma guilliermondii, Meyerozyma caribbica, and Debaryomyces hansenii) known to cause candidemia. In total, 234 isolates were tested for amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, anidulafungin, micafungin, and caspofungin. Amphothericin B had the broadest efficiency against the 14 tested rare yeast species, while high minimum inhibitory concentrations (MICs) against azole drugs and echinocandins were common. Voriconazole was the most efficient azole drug. Multidrug resistance was observed for the species C. auris and K. marxianus. Multidrug resistant individual isolates were found for Y. lipolytica and M. caribbica. In conclusion, the observed high MIC values of the rare Saccharomycotina species tested limit antifungal treatment options, complicating the management of such infections.

Epidemiology of Candidemia in Kuwait: A Nationwide, Population-Based Study

“…Among other yeast species, L. elongisporus and C. fabianii isolates were susceptible to all four antifungal drugs, while R. minuta and M. capitatus isolates showed non-susceptibility to fluconazole and caspofungin. These data are also consistent with recent observations showing that rare Candida /yeast species exhibit non-susceptibility to antifungal drugs, including echinocandins [ 78 , 79 , 80 ].…”

A Pragmatic Approach to Susceptibility Classification of Yeasts without EUCAST Clinical Breakpoints

“…MIC ≤0.06 mg/L separated wild-type from non-wild-type isolates of C. dubliniensis and included the wild-type populations of C. inconspicua, C. norvegensis (Pichia norvegensis), C. pelliculosa (Wickerhamomyces anomala), C. nivariensis, P. kluyveri and L. elongisporus. The modal MICs against C. intermedia, C. palmioleophila, C. kefyr and C. lusitaniae, which have been shown to respond to candin therapy unless having acquired an FKS mutation [56][57][58], were approximately one two-fold dilution higher, suggesting a tentative threshold for suspicion of resistance of >0.125 mg/L for these species [39,45]. When possible, FKS sequencing is, however, recommended for isolates for which repeated MICs are greater than or equal to 0.06 mg/L as this will enable detecting mutations around the likely ECOFF (Table 5).…”

“…Second, we recommend comparing the MICs to existing MIC distributions for that drug and species to determine if the MIC is most likely "normal" or "elevated" (indicating possible acquired resistance). In Tables 4-7, we summarised our data for more than 4000 isolates and documented alignment to published EUCAST data [25,[34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] (for details on this data, see Supplementary Text S2). These tables can be used for comparison if the local susceptibility testing is confirmed to align with EUCAST testing.…”

“…One isolate of C. lipolytica (Yarrowia lipolytica) had an MIC of 2 mg/L but grew very poorly, likely influencing the reading. Another series of 27 C. lipolytica isolates reported an MIC 90 of 1 mg/L [45]. It is therefore reasonable to assume that MICs are normally ≤1 mg/L.…”

“…BIIu-CIII) n = 59; 0.06/0.25[42]; n = 37; 1/32[36], n = 29; (0.03-0.5)[37]; n = 2 (0.25)[49]; n = 1 (0.25)[50] ; 0.5/1[48], n = 9; (≤0.015-0.25)[42], n = 6, 0.25/0.5[45] ; 2/4[42], n = 5 (0.5->8)[50], n = 1; (16)[49] …”