First Report of Candidemia Clonal Outbreak Caused by Emerging Fluconazole-Resistant Candida parapsilosis Isolates Harboring Y132F and/or Y132F+K143R in Turkey

Abstract

Clonal outbreak of fluconazole-resistant (FLZR) Candida parapsilosis isolates have been reported in several countries. Despite being the second leading cause of candidemia, the azole resistance mechanisms and the clonal expansion of FLZR C. parapsilosis blood isolates have not been reported in Turkey. Herein, we consecutively collected the C. parapsilosis blood isolates (n=225) from the fifth largest hospital in Turkey (2007–2019), assessed their azole susceptibility pattern using CLSI M27-A3/S4, and sequenced ERG11 for all and MRR1, TAC1, and UPC2 for selected number of C. parapsilosis isolates. The typing resolution of two widely used techniques, AFLP and microsatellite typing (MST), and the biofilm production of FLZR isolates with/without Y132F were compared. Approximately 27% of isolates were FLZR (60/225), among which 90% (54/60) harboured known mutations in Erg11, including Y132F (24/60) and Y132F+K143R (19/60). Several mutations specific to FLZR isolates were found in MRR1, TAC1, and UPC2. AFLP clustered isolates into two clusters, while MST revealed several clusters. The majority of Y132F/Y132F+K143R isolates grouped in clonal clusters, which significantly expanded throughout 2007–2019 in neonatal wards. Candida parapsilosis isolates carrying Y132F were associated with significantly higher mortality and less biofilm production relative to other FLZR isolates. Collectively, we documented the first outbreak of FLZR C. parapsilosis blood isolates in Turkey. The MRR1, TAC1, and UPC2 mutations exclusively found in FLZR isolates establishes basis for future studies, which potentially broaden our knowledge on FLZR mechanisms in C. parapsilosis. MST should be a preferred method for clonal analysis of C. parapsilosis isolates in outbreak scenarios.

Recent Increase in the Prevalence of Fluconazole-Non-susceptible Candida tropicalis Blood Isolates in Turkey: Clinical Implication of Azole-Non-susceptible and Fluconazole Tolerant Phenotypes and Genotyping

“…A recent study explored antifungal susceptibility patterns of Candida bloodstream isolates in Turkey (1997–2017) and reported the lack of drug resistance for C. tropicalis ( Arikan-Akdagli et al, 2019 ). However, our single- and multi-center investigations conducted later in Turkey have revealed a very recent (from 2017 onward) emergence of azole/echinocandin-resistant and even MDR Candida species ( Arastehfar et al, 2020b,c , e ), suggesting the existence of the same trend for C. tropicalis . Therefore, we conducted a comprehensive multi-center study to update the rate of antifungal resistance among C. tropicalis blood isolates recovered in 2017–2019 in Turkey; some isolates recovered before 2017 but not analyzed in the previous study ( Arikan-Akdagli et al, 2019 ) were also included.…”

The Quiet and Underappreciated Rise of Drug-Resistant Invasive Fungal Pathogens

“…Unfortunately, this wave of FLZR C. parapsilosis isolates has also been observed in Kuwait [166], USA [165,185], Brazil [167,168], South Korea [164], India [169], South Africa [182] and Turkey [170]. The high rate of FLZR for a species that used to be susceptible to azoles may have arisen from the disproportionate use of azoles in the hospital [170,182]. The notable increase in the prevalence of FLZR C. parapsilosis isolates could be a major threat in developing countries, in which the vast majority of candidemia cases are treated with FLZ [138,169,182,186].…”

“…Furthermore, a Korean single-center study reported a significant increase in the prevalence of FLZR among 2015-2016 isolates when compared to 2011-2015 isolates (14.3% vs. 0.9%, respectively) [184]. Unfortunately, this wave of FLZR C. parapsilosis isolates has also been observed in Kuwait [166], USA [165,185], Brazil [167,168], South Korea [164], India [169], South Africa [182] and Turkey [170]. The high rate of FLZR for a species that used to be susceptible to azoles may have arisen from the disproportionate use of azoles in the hospital [170,182].…”

“…parapsilosis isolates has also been observed in Kuwait [ 166 ], USA [ 165 , 185 ], Brazil [ 167 , 168 ], South Korea [ 164 ], India [ 169 ], South Africa [ 182 ] and Turkey [ 170 ]. The high rate of FLZR for a species that used to be susceptible to azoles may have arisen from the disproportionate use of azoles in the hospital [ 170 , 182 ]. The notable increase in the prevalence of FLZR C .…”

“…parapsilosis . Y132F and K143R are presumably the most frequently identified amino acid changes causing FLZR and/or VRZR, and we noticed that isolates harboring Y132F in Erg11p are significantly associated with a mortality rate that is higher than that associated with Y132F+K143R isolates [ 170 ]. Beyond the common paradigm of ERG11 and efflux pump involvement in azole resistance, whole genome sequence analysis showed that a laboratory-driven, posaconazole-resistant C. parapsilosis isolate harbored an amino acid substitution in Erg3, R135I, which is believed to confer azole resistance and prevent the formation of toxic sterol intermediates [ 188 ].…”