Genetically related micafungin-resistant Candida parapsilosis blood isolates harbouring novel mutation R658G in hotspot 1 of Fks1p: a new challenge?

Abstract

Background Echinocandin resistance rarely occurs in clinical Candida parapsilosis isolates and the underlying mechanism is unknown. Objectives To determine the prevalence of echinocandin resistance and the underlying mechanism for a large collection of C. parapsilosis blood isolates and to determine whether the echinocandin-resistant isolates were clonally related. Methods C. parapsilosis blood isolates (n = 213) were subjected to antifungal susceptibility testing (CLSI M27), for micafungin, anidulafungin, amphotericin B and, if appropriate, caspofungin. Hotspot (HS) 1 and HS2 of FKS1 were sequenced for all isolates (n = 213) and microsatellite typing was performed for echinocandin-resistant isolates. Results All isolates were susceptible to amphotericin B and two isolates were intermediate to anidulafungin (MIC = 4 mg/L), while micafungin resistance was noted in four isolates (MIC >8 mg/L); three of which were also fluconazole resistant and therefore were MDR. Interestingly, micafungin-resistant isolates, but not those intermediate to anidulafungin, carried novel mutation R658G in HS1 of Fks1p; three of which also harboured Y132F+K143R in Erg11. The first isolate (MICR1) was recovered in November 2017 from a patient admitted to paediatric gastroenterology who showed therapeutic failure under caspofungin treatment. MICR2–MICR4 were collected during 2018–19 and were recovered from three echinocandin-naive paediatric-surgery patients; the isolates shared the same genotype. Conclusions Herein, for the first time (to the best of our knowledge), we identified micafungin-resistant C. parapsilosis blood isolates harbouring a novel mutation in HS1 of FKS1, which was likely attributable to in vitro micafungin resistance and in vivo caspofungin therapeutic failure. The acquisition of micafungin-resistant C. parapsilosis isolates in echinocandin-naive patients likely implicates clonal expansion, as supported by the close genetic relatedness of MICR2–MICR4.

COVID-19-Associated Candidiasis (CAC): An Underestimated Complication in the Absence of Immunological Predispositions?

“…Of note, approximately 82% of CVC-recovered yeast isolates were C. albicans (9/ 11) ( Table 1 ), which also shows that other Candida species have the potential to cause CVC-related invasive yeast infections. Unlike endogenously acquired Candida species, such as C. glabrata , that require previous exposure to antifungals drugs to become drug-resistant, drug-resistant C. auris and C. parapsilosis can persist on the hospital environments, devices, and hands of healthcare workers and subsequently cause drug-resistant candidiasis and/or candidemia among antifungal-naïve patients [ 15 , 16 , 17 , 50 , 51 , 52 , 53 ]. It is also noteworthy that some studies have found an association between antibiotic use and the emergence of candidemia due to Candida species exhibiting a high minimum inhibitory concentration (MIC) and/or intrinsic resistance to fluconazole [ 54 , 55 ].…”

Drug-Resistant Fungi: An Emerging Challenge Threatening Our Limited Antifungal Armamentarium

“…parapsilosis blood isolates in Turkey, which harbored a novel amino acid substitution R658G in HS1-Fks1. These isolates were genetically related and resulted in caspofungin therapeutic failure in a patient infected with one of those isolates [ 157 ].…”

Environmental Clonal Spread of Azole-Resistant Candida parapsilosis with Erg11-Y132F Mutation Causing a Large Candidemia Outbreak in a Brazilian Cancer Referral Center

“…Candida parapsilosis is known to be susceptible to azole-class drugs; however, emerging studies have implicated the surge of clonal outbreaks as due to azole-resistant C. parapsilosis (ARCP) isolates in numerous countries [10][11][12][13][14][15], possibly fueled by azole overuse, which complicates the treatment of azole-naïve patients and is potentially associated with a higher mortality rate [16]. More alarming is the emergence of multidrug-resistant (MDR) C. parapsilosis isolates, resistant to both of the most widely used frontline antifungals, i.e., fluconazole and echinocandins [17], and the lack of effectiveness of these drugs against C. parapsilosis biofilms [18].…”