In recent years, the medical community has faced a grow-ing concern: the emergence of Candida species that exhibit intrinsic resistance to commonly used antifungal drugs. This alarming trend poses a significant challenge in the management of fungal infections and demands immediate attention and action. In this editorial, we shed light on the implications of intrinsic resistance in Candida species and emphasize the urgent need for enhanced strategies to combat this threat.

Understanding intrinsic resistanceThe 2022 document M27M44SEd3E from the Clinical and Lab-oratory Standards Institute (CLSI) defines intrinsic resistance (IR) as the ''inherent or innate (not acquired) resistance to an antifungal, which is reflected in the non-wild-type susceptibility patterns of all or almost all representatives of a species’’. This characterization implies that a correct taxonomical identification would be enough to classify an isolate as intrinsically resistant or not. As an important achievement, the first list of intrinsically resistant species was published in the same document. This list includes Candida krusei (also recognized under the taxonomic name Pichia kudriavzevii), showing intrinsic resistance (IR) to fluconazole, and three basidiomycetous fungi (Cryptococ-cus spp., Rhodotorula spp., and Trichosporon spp.)2 that should be considered intrinsically resistant to echinocan-dins, with Rhodotorula also being resistant to fluconazole. In this list has disappointed a part of the scientific community since intrinsic resistance limits the effectiveness of standard treatment options from the onset.

Implications for Public HealthThe impact of intrinsic resistance in Candida species on public health cannot be overstated. Infections caused by these resistant species often result in prolonged hospital stays, increased healthcare costs, and elevated mortality rates. Deep-seated Candida spp. infections are associated with mortality rates of ~50% and these ratios are higher in the context of infections with drug-resistant Candida spp. Patients with compromised immune systems, such as those with HIV/AIDS or undergoing chemotherapy, are particu-larly vulnerable to these infections. In addition, the limited arsenal of effective antifungal drugs against these resistant Candida strains leaves healthcare providers with few treat-ment options, making it challenging to achieve successful outcomes.

Contributing factorsSeveral factors contribute to the emergence of intrinsic overuse and misuse of antifungal agents. Inappropriate prescribing practices, inadequate dosing, and failure to complete treatment regimens have fueled the selection pressure of Candida spp. populations, leading to the devel-opment and propagation of resistant species. Furthermore, it was proposed that the extensive use of antifungals in agriculture and animal husbandry has contributed to the creation of reservoirs of resistant strains, which can be transmitted to humans.

The rise of Candida auris and the Candida haemulonii species complexCandida auris has rapidly gained attention as an emerging global health threat and has recently been included as one of the four fungal pathogens of the critical priority group of the WHOs fungal priority pathogens list due to its mor-bidity and mortality rate, antifungal resistance and major knowledge gaps on its global burden1. Although C. auris was proposed to be included as a fluconazole IR species in the aforementioned CLSI document, it does not strictly meet the inclusion criteria since not all but more than 93% of the stud-ied C. auris strains show high fluconazole MICs (and some high voriconazole MICs). Moreover, more than 35% of the strains showed high MIC values for amphotericin B and over 10% of the strains exhibited high MIC values for echinocan-dins (multidrug resistant: non-susceptible to one or more drugs of two or more antifungal classes). Their antifungal susceptibilities, resistance mechanisms and other charac-teristics are linked to different clonal populations that were partially kept geographically restricted3. In Argentina, the first two C. auris isolates reported in October 2022 were classified as clade III (known as the South African clade) and showed high azole, polyene and echinocandin MICs. These strains were clonal, demonstrating that they were transmit-ted among patients5,6.

The Candida haemulonii complex comprises four species that are considered human pathogens: C. haemulonii, C. duobushaemulonii, C. pseudohaemulonii and C. vulturna. These species showed high MIC values for multiple antifun-gals. In many cases, those MICs are higher than the ones shown by C. auris. For instance, the susceptibility profile of 25 Argentinian strains of this complex showed that all but two strains had high fluconazole MIC values, 13 strains exhibited cross-high MICs for all tested azole and echinocandin drugs, while 8 strains displayed pan-resistance (resistance to amphotericin B, echinocandins and azole drugs)⁴.

Transmission and clinical impact of C. auris and the C. haemulonii species complexC. auris has been associated with nosocomial outbreaks, as well as the potential for rapid dissemination and high mortality rates among affected patients. In addition, C. auris has the ability to persist better than other Candida spp. on environmental surfaces. These facts have led the CDC to recommend the isolation of the affected patients. In order to comply with these recommendations, the cor-rect identification of this species in clinical laboratories is essential. However, both C. auris and the C. haemu-lonii species complex pose challenges to accurate species identification, which can hinder appropriate treatment and surveillance efforts. There are two unique recommended methods for unequivocal identification: molecular-based procedures and/orMALDI-TOF, since most of the phenotype-based methods misidentify these species.

The ability of the C. haemulonii species complex to per-sist and cause outbreaks has not been thoroughly studied as in the case of C. auris. Nevertheless, the fact that they are taxonomically related -they all belong to the yeast family Metshnikowiaceae- allows to infer that something similar could happen. In Argentina, the isolation of yeasts from the C. haemulonii species complex is relatively common. Tak-ing into account only the published data from the Malbrán Institute group -25 strains- and the autochthonous isolates that we keep in our laboratory, we can count more than 40 strains in the last six years. This leads us to ponder why there is such an alarm for two C. auris isolates and not such a stir for the regular and constant isolation of multi- and pan-resistant yeast strains that have the potential to cause outbreaks.

Addressing the ChallengeAddressing the emergence of yeasts of the Met-shnikowiaceae family requires a multi-pronged approach. Enhanced surveillance and rapid identification methods are crucial for the early detection and containment of outbreaks. Constant training is needed in the techniques necessary for the identification of these species, including strict adherence to hand hygiene protocols and envi-ronmental decontamination procedures. Interdisciplinary collaboration among healthcare professionals, mycologists and other members of the infection control teams is vital to prevent and manage infections caused by these resistant species. Furthermore, research efforts should focus on exploring alternative treatment options.