Emerging Echinocandin Resistance – A Review

Worldwide there is a steady increase in the number of fungal infections each year. Simultaneously, there is a high rise of antifungal resistance among the Candida isolates. This has now become a major concern in hospitalized patients resulting in poor treatment outcome. Echinocandins, a new group of antifungals has given promising results inspite of its increasing rate of resistance exhibited by some Candida species.


INTRODUCTION
There is an increasing incidence of fungal infections worldwide [1]. Antifungal therapy is the major treatment option for patients suffering from fungal infections. But treatment options are limited owning to the fewer antifungal drugs and resistance to the existing antifungal drugs. The increased use of antifungals for candidiasis has led in the development of resistant Candida isolates [2].Azoles antifungals and Amphotericin B are a cornerstone for therapy till now. Toxicities associated with amphotericin and increasing azole resistance have urged the need for an alternative replacement in the management of fungal infections [3].

Review Article
Echinocandins, developed over a decade is a milestone in antifungal therapy. Currently, echinocandins are the first line choice for systemic Candida infections and a majority of patients with candida blood stream infections are on echinocandin therapy [4,5].
This article will highlight list the available echinocandin drugs available, their mode of action, the acquired resistance mechanisms and its clinical implications.

ECHINOCANDINS -NEW CLASS OF ANTIFUNGALS
Three echinocandin antifungal drugs caspofungin, micafungin, and anidulafungin are available over a decade. The echinocandins have a distinctive mechanism of action, suppressing the action of [1,3]-D-glucan synthase [6].Echinocandins have been used in invasive candidiasis. In addition, caspofungin is used in febrile neutropenia and invasive aspergillosis, and is safe for use in pediatric patients [7]. Micafungin is the only echinocandin used in bone marrow transplantation [8].

Hot spot diversity
Mutation at Phe641 and Ser645 in C. albicans is most commonly noticed compared to the Cterminal end of hot spot 1, which is less commonly noticed [30,40,41]. Diversity at Pro649 in the C. parapsilosis and at Met633 and Ala634 in C. guilliermondii, causes increased MIC values [42]. Infecting strains with intrinsically reduced susceptibility carries an uncertain clinical significance [43,44].The sensitivity of glutan synthase for echinocandins is lower in candida parasilopsis than candida albicans which causes high MIC value. "But the enzyme, while less sensitive, is still inhibited at typical therapeutic drug concentrations, which accounts for clinical response" [45]. "Mutations at the third region W695 (outside clinical hot spots 1 and 2) of Saccharomyces cerevisiae Fks1 is found but does not cause treatment failure"[46].

Biofilms
Biofilms are " a thin but robust layer of mucilage adhering irreversibly to a solid surface, inert material ,or living tissue producing extracellular polymers that provide a structural matrix and contain a community of bacteria and other microorganisms [47,48]".Candida species have inherent tendency to form biofilms . The beta 1,3 D glucan a component of biofilm matrix seizes the drug and allows less concentration at cellular level [49].Alteration of the transcriptional regulators like R1m and Smi1 and changes in the Fks alter the glutan synthesis which in turn leads to the formation of biofilms conferring resistance [50].

Adaptive cellular factors
All fungi possess various factors to overcome cellular stress. On encountering a cellular stress there in increased MIC level of the drug which does not always correlate with treatment response [25].This is the preliminary state for Fks mechanism of resistance and in turn lead to full blown resistance. Fungal stress adaptive pathways lead to increased production of chitin as a compensatory mechanism leading to resistance [51]. This acts at the level of cell wall. Changes in the cell membrane level can also alter the activity of echinocandin. Alteration in the sphingolipid synthesis and composition alters the efficacy of caspofungin and micafungin [52].

Hsp90
Heat shock proteins are "a family of proteins that are produced by cells in response to exposure to stressful conditions [53]". Hsp90 changes are not only associated with azole resistance but also with echinocandin resistance.Any reduction in the function of Hsp90 causes resistancein C. albicans, C. glabrata, and A. fumigates [54,55]. Though in recent times there is emergence of echinocandin resistant candida species,resistance noticed in candida albicans and some of the other candida spp is still low varying from 2-3%. Contrary to this the level of resistance in Candida glabrata is very high ranging from 8-13%.Increased use of echinocandin for Candida glabrata infections has alarmingly increased resistance from 3% to >13 [60,61].In many cases these echinocandin resistant isolates are also azole resistant leading to multidrug resistant candida spp imposing a treatment challenge [62].

CONCLUSION
Echinocandins in contrast to the other class of antifungals possess several unique merits.when choosing such a drug for patient therapy the treating physician should take in to account the metabolism and drug interaction,the dose,duration to be prescribed and their recommended indications CONSENT It is not applicable.