Inter-Institutional Dynamics and Impact of Fluconazole-Resistant Candida parapsilosis.

Infections with fluconazole-resistant Candida parapsilosis have been increasing in Israeli hospitals with unclear implications for patient outcomes. To determine the frequency, mechanisms, molecular epidemiology, and outcomes of azole-resistant C. parapsilosis bloodstream infections in four hospitals in Israel. C. parapsilosis bloodstream isolates were collected at four hospitals in central Israel during varying periods from 2005 to 2022. Antifungal susceptibility testing was done using CLSI broth microdilution. Risk factors for fluconazole resistance were investigated using logistic regression. ERG11 gene sequencing was performed on all isolates. Genetic relatedness was determined using multilocus microsatellite genotyping. Clinical cure, microbiological eradication, and mortality rates were compared between fluconazole-susceptible and resistant isolates. A total of 192 patient-specific C. parapsilosis isolates were analysed. Resistance to fluconazole and voriconazole was detected in 80 (41%) and 14 (7.2%) isolates, respectively. The ERG11 Y132F substitution was found in 91% of fluconazole-resistant and 1% of fluconazole-susceptible isolates. Increasing age, intensive care hospitalisation, haemodialysis, and recent exposure to antibiotics were risk factors for fluconazole-resistant C. parapsilosis. Distinct but related genotypes predominated at each centre, indicating extensive dissemination within hospitals and limited transmission among them. Fluconazole resistance was associated with increased likelihood of microbiological failure but no significant difference in clinical cure and mortality. We found high rates of fluconazole resistance in C. parapsilosis, attributable to nosocomial spread of hospital-specific clones bearing the Y132F substitution. Fluconazole resistance was associated with a higher risk of microbiological but not clinical failure. Strategies to limit nosocomial transmission of C. parapsilosis are needed.

Korem M ，Reich S ，Rahav G ，Yahav D ，Weinberger M ，Novikov A ，Mizrahi N ，Ben-Ami R ... -  《-》

Multicentre Study of Candida parapsilosis Blood Isolates in Türkiye Highlights an Increasing Rate of Fluconazole Resistance and Emergence of Echinocandin and Multidrug Resistance.

Worldwide emergence of clonal outbreaks caused by fluconazole-resistant (FLCR) and the recent emergence of echinocandin- and multidrug-resistant (ECR and MDR) Candida parapsilosis isolates pose serious threats to modern clinics. Conducting large-scale epidemiological studies aimed at determining the genetic composition and antifungal resistance rates is necessary to devise antifungal stewardship and infection control strategies at international, national and local levels. Despite being severely hit by outbreaks due to FLCR C. parapsilosis isolates, such knowledge at the national level is lacking in Türkiye. Herein, we conducted a prospective multicentre study involving five major clinical centres in Türkiye to determine antifungal resistance rates, underlying mechanisms and genetic composition of all isolates. In total, 341 isolates were collected from 265 patients including clinical information. Antifungal susceptibility testing against common antifungals was performed in addition to sequencing of ERG11 and FKS1. Last, isolates were genotyped with short tandem repeat (STR) genotyping to investigate potential nosocomial transmission. The FLCR rate was 26.7% (91/341), out of which 75.8% (69/91) harboured the ERG11Y132F mutation. Patients infected with FLCR isolates had a higher mortality rate compared to their susceptible counterparts (49% for FLCR vs. 42% for susceptible). ECR rate was 2.1% (7/341) and isolates carried FKS1F652L/R658G/W1370R mutations. Concerningly, four ECR isolates were MDR. FLCR isolates grouped in distinct clusters without evidence of inter-hospital transmission, whereas large clusters containing susceptible isolates from all centres were noted. Overall, the increasing prevalence of FLCR C. parapsilosis at national level and the emergence of ECR and MDR isolates pose serious clinical challenges in Türkiye. Therefore, conducting large-scale epidemiological studies are critical to determine the trend of antifungal resistance and to tailor pertinent antifungal stewardship and infection control strategies to effectively curb the spread of drug-resistant C. parapsilosis.

Ünal N ，Spruijtenburg B ，Arastehfar A ，Gümral R ，de Groot T ，Meijer EFJ ，Türk-Dağı H ，Birinci A ，Hilmioğlu-Polat S ，Meis JF ，Lass-Flörl C ，Ilkit M ... -  《-》

Standardization of polymerase chain reaction for detection of fluconazole resistance targeting Y132F mutation in ERG11 gene in Candida parapsilosis.

Candida parapsilosis is the third most commonly isolated species from candidemia patients admitted to Indian intensive care units. Outbreak of infection and emergence of fluconazole resistance associated with this particular species has been increasingly documented since 2018. Worldwide data has documented that Y132F substitution in the ERG11 gene is the predominant fluconazole resistance mechanism among C parapsilosis. Hence, this study aimed to detect fluconazole resistance by targeting Y132F mutation in the ERG11 gene in C. parapsilosis, by conventional polymerase chain reaction (PCR) assay with in-house designed primers. A total of 75 Candida isolates were collected from candidemia patients (Jan-Dec 2023). All the Candida isolates were subjected to phenotypic and genotypic characterization. PCR-restriction fragment length polymorphism was performed for identification and confirmation of C. parapsilosis isolates. The antifungal susceptibility testing by broth microdilution method was performed according to the Clinical and Laboratory Standards Institute guidelines (M27-A3) for all C. parapsilosis against fluconazole, itraconazole, voriconazole, and posaconazole to determine their minimum inhibitory concentration (MIC) values. Candida parapsilosis-specific PCR assay was developed with in-house designed primers to detect Y132F mutation in the ERG11 gene. In this study, among 75 candidemia patients (Jan-Dec 2023), about 24% of the candidemia was caused by C. parapsilosis. Fluconazole resistance among C. parapsilosis was found to be 16.7% with a MIC range of 32-64 µg/ml. The PCR assay successfully identified all three fluconazole-resistant C. parapsilosis with Y132F mutation, thereby confirming the PCR results. Furthermore, validation of the presence and absence of Y132F mutation in resistant and susceptible isolates by DNA sequencing showed that the results were in concordance with our PCR assay. The developed PCR assay successfully detected the Y132F mutation within 3 h. This assay can be useful for early detection of fluconazole-resistant C. parapsilosis isolates in candidemia patients, which helps the provision of early antifungal treatment for better patient management.

Karthika K ，Premamalini T ，Vijayakishore T ，Kindo AJ ... -  《-》

Precise genome editing underlines the distinct contributions of mutations in ERG11, ERG3, MRR1, and TAC1 genes to antifungal resistance in Candida parapsilosis.

Hartuis S ，Ourliac-Garnier I ，Robert E ，Albassier M ，Duchesne L ，Beaufils C ，Kuhn J ，Le Pape P ，Morio F ... -  《-》

Emerging trends in pediatric candidemia: mapping the rise in Candida parapsilosis incidence and antifungal resistance in Turkey.

Candidemia is emerging as a significant concern in children, particularly among those with underlying conditions like malignancies or prematurity. The interpretation of epidemiological data on candidemias and their antifungal resistance plays a vital role in aiding diagnosis and guiding clinicians in treatment decisions. From 2014 to 2021, a retrospective analysis was conducted in İstanbul, Turkey; comparing Candida albicans and non-albicans (NAC) spp in both surviving and deceased groups. Furthermore, an examination of Candida parapsilosis and other species was performed, assessing various clinical and laboratory parameters. Among 93 patients, with a median age of 17 months, C. parapsilosis emerged as the predominant isolated species (44%), followed by C. albicans (34.4%). Resistance to fluconazole, voricanozole, and echinocandins, along with a history of broad-spectrum antibiotic use were found to be significantly higher in the non-albicans Candida group compared to C. albicans group. In the C. parapsilosis group, statistically lower age was identified in comparison to the other groups (P = .018). In addition, high fluconazole and voriconazole resistance was detected in Candida parapsilosis spp. Our study highlights a notable prevalence of C. parapsilosis, particularly in younger children, which is different from similar studies in childhood. This trend may be attributed to the common use of total parenteral nutrition and central venous catheter in gastrointestinal disorders and metabolic diseases. Furthermore, as anticipated, high azole resistance is noted in C. parapsilosis and other non-albicans Candida species. Interestingly, resistance to both amphotericin B and echinocandins within this group has been notably high. It is crucial to emphasize the considerable antifungal resistance seen in C. parapsilosis isolates.

Önal P ，Aygün FD ，Sever GA ，Eren BA ，Kes G ，Aygün F ，Zübarioğlu T ，Beşer ÖF ，Ocak S ，Yazgan Z ，Zeybek ÇA ，Aygün G ，Camcıoğlu Y ，Çokuğraş H ... -  《-》