br Antifungal resistance what is in a name Antifungal resist

Antifungal resistance, what is in a name? Antifungal resistance is an emerging and hot topic in the field of medical mycology. Microbiological resistance is identified by determining minimal inhibitory concentrations (MICs) in vitro for a given antifungal and interpreting this value according to established clinical breakpoints; whereas the term clinical resistance is used for the infection that persists or progresses despite antifungal therapy for a documented infection. Besides elevated MICs, numerous parameters can be responsible for clinical failure, such as the severity of infection, the existence of foreign material that can support biofilm formation, immune host status, suboptimal dosing, drug interactions, pharmacokinetics or the fungal burden. Resistance to a given antifungal can be either intrinsic (primary) or acquired (secondary). Intrinsic resistance concerns all isolates within a given species and is unrelated to prior antifungal exposure; for example, fluconazole resistance in Candida krusei or echinocandin resistance in the basidiomycete Cryptococcus neoformans[1]. Acquired resistance most often arises after antifungal exposure in the individual patient. However, invasive infections due to isolates displaying acquired resistance can also occur in antifungal-naïve patients, because of horizontal transmission of resistant pathogens [2]. Antifungal resistance usually affects one or several compounds within a single antifungal class depending on the underlying molecular mechanisms. Multidrug resistance (MDR) is rare, but apparently emerging, as discussed below. Herein we will focus mostly on Candida species, particularly Candida albicans and Candida glabrata, although other yeasts will be discussed when relevant data are available.
Molecular mechanisms leading to antifungal resistance With few exceptions, the genetic background responsible for resistance is drug-class specific, each having its proper mode of action (Fig. 1). Thus, in the following text, these are described separately.
Biofilm and antifungal resistance Biofilms are dynamic, complex, tridimensional biological community networks of adherent brdu developed in vivo on foreign bodies and various tissues, such as oral mucosa. Biofilms play an important role in antifungal resistance and clinical failure through various mechanisms [54]. These include i) a high density of fungal cells; ii) production of an extracellular exopolysaccharidic matrix, which reduces antifungal penetration; iii) the presence of phenotypic variants known as persister or ‘dormant’ cells, which exhibit tolerance to antifungal drugs; iv) an increased efflux pump activity, and v) modifications in the ergosterol biosynthesis pathway through mutation or modified expression in the encoding genes, thus leading to alterations in sterol membrane content [55], [56]. Biofilm development has been demonstrated for many Candida species, other yeast and filamentous fungi [56]. Azole drug efficacy is mostly affected, whereas echinocandins and, to a lesser extent, liposomal amphotericin B retain some activity against biofilm [57], [58]. Therefore, it is recommended that foreign bodies are removed whenever possible and safe, and that azoles are avoided when this is not possible [59], [60], [61].
How to detect antifungal resistance and which clinical impact?
Conclusions and perspectives The knowledge on molecular mechanisms has expanded considerably over the past decades following the effort of many researchers and the increasing access to advanced molecular tools. Clearly, resistance is emerging and this is occurring most rapidly against the echinocandins, particularly in C. glabrata. This is potentially explained by the fact that a single mutation can render the organism resistant (particularly in haploid species), these compounds are highly protein-bound, and that sub-therapeutic concentrations are not uncommon in biofilms, on mucosal surfaces and in deep foci like the abdominal cavity. If mutations in DNA mismatch repair genes and echinocandin exposure sometimes for short periods (which are both common scenarios for C. glabrata) are put into the equation, it becomes evident that we are facing an important challenge, and that the answer to this may not only be limiting in-hospital use of antifungals, but also systemic antifungal use in the primary healthcare sector.