Fluconazole‐resistant Candida parapsilosis strains with a Y132F substitution in the ERG11 gene causing invasive infections in a neonatal unit, South Africa

Abstract

Summary Introduction The prevalence of azole resistance in C parapsilosis is very low in most parts of the world. However, South Africa has reported an exceptionally high prevalence of azole resistance in C parapsilosis strains isolated from candidaemia cases. We aimed to determine the possible molecular mechanisms of fluconazole resistance in C parapsilosis isolates obtained through surveillance at a large neonatal unit at a South African academic hospital. Methods We sequenced the ERG11 and MRR1 genes of C parapsilosis isolates recovered from cases of neonatal candidemia, followed by microsatellite genotyping. A total of 73 isolates with antifungal susceptibility results were analysed. Results Of these, 57 (78%) were resistant, 11 (15%) susceptible dose‐dependent and 5 (7%) susceptible. The most commonly identified amino acid substitution within the ERG11 gene was Y132F in 68% (39/57) of fluconazole‐resistant isolates and none in susceptible isolates. Three amino acid substitutions (R405K, G583R and A619V) and 1 nucleotide deletion at position 1331 were identified within MRR1 gene in 19 (26%) isolates. Microsatellite genotyping grouped isolates into four clusters (50 isolates). Cluster 1 accounted for 23% (17/73) of all cases, cluster 2 for 22% (16/73), cluster 3 for 14% (10/73) and cluster 4 for 10% (7/73). We found an association between cluster type and fluconazole resistance (P‐value = .004). Isolates harbouring the Y132F substitution were more likely to belong to a cluster than non‐Y132F isolates. Conclusion Fluconazole resistance in C parapsilosis strains from a single South African neonatal unit was associated with cluster type and predominantly driven by Y123F amino acid substitutions in the ERG11 gene.

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

“…Although ARCP isolates have been increasingly reported [10][11][12][13][14][15][16], FLC resistance rates remain low, ranging from 2 to 5% globally [19]. In contrast, our investigation showed high FLC resistance rates in isolates from pericatheter skins (100%), blood cultures (90%), nosocomial surfaces (54.5%), and HCWs (14.3%), with VRC cross-resistance in 92.1% among them.…”

“…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].…”

Sterol 14α-Demethylase Ligand-Binding Pocket-Mediated Acquired and Intrinsic Azole Resistance in Fungal Pathogens

“…A 2009-2010 study showed that approximately 80% of all C. parapsilosis strains are FLC resistant. The SDM Y132F mutant was found in 68% of all FLC-resistant strains [27]. The incidence of FLC resistance in C. parapsilosis is alarming as FLC is the antifungal drug used most often in developing countries [91].…”

“…Different mechanisms at the genetic and transcriptional levels allow fungi to become resistant to azole antifungals. The most common of these resistance mechanisms are: (1) amino acid (AA) substitutions in the SDM, affecting the active site of the enzyme, (2) overexpression of the SDM, and (3) overexpression of efflux pumps such as ATP-binding cassette (ABC) transporters and/or major facilitator superfamily (MFS) transporters [22,25,27].…”

Prevalence and Clonal Distribution of Azole-Resistant Candida parapsilosis Isolates Causing Bloodstream Infections in a Large Italian Hospital

“…It should also be essential to investigate clustered C. parapsilosis isolates for the presence of point mutations in the ERG11 gene when azole resistance appears (Pristov and Ghannoum, 2019). Until recently, data documented the Y132F amino acid substitution in ERG11p-the ERG11-encoded enzyme lanosterol 14-α-demethylase-as the prevalent fluconazole resistance mechanism in isolates (mainly bloodstream isolates) of C. parapsilosis worldwide (Grossman et al, 2015;Asadzadeh et al, 2017;Choi et al, 2018;Magobo et al, 2020). Surprisingly, an Indian multicenter laboratory-based surveillance study revealed that in many centers in Delhi and a single center in South India, the K143R amino acid substitution was most prevalent as a single resistance mechanism in either bloodstream or non-bloodstream isolates of C. parapsilosis (Singh et al, 2019).…”