Fluconazole-Resistant Candida glabrata Bloodstream Isolates, South Korea, 2008-2018.
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ABSTRACT:
SUBMITTER: Won EJ
PROVIDER: S-EPMC7920659 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
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Fluconazole-Resistant Candida glabrata Bloodstream Isolates, South Korea, 2008-2018.
Won Eun Jeong EJ Choi Min Ji MJ Kim Mi-Na MN Yong Dongeun D Lee Wee Gyo WG Uh Young Y Kim Taek Soo TS Byeon Seung Ah SA Lee Seung Yeob SY Kim Soo Hyun SH Shin Jong Hee JH
Emerging infectious diseases 20210301 3
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Project description:We recently observed the emergence of fluconazole-resistant Candida parapsilosis bloodstream isolates harboring a Y132F substitution in Erg11p in South Korea. These Y132F isolates had a higher propensity to cause clonal transmission than other fluconazole-resistant isolates and persisted within hospitals for several years, as revealed by microsatellite typing.
| S-EPMC6106402 | biostudies-literature
Project description:The clonal transmission of fluconazole-resistant Candida glabrata isolates within hospitals has seldom been analyzed by whole-genome sequencing (WGS). We performed WGS on 79 C. glabrata isolates, comprising 31 isolates from three premature infants with persistent C. glabrata bloodstream infection despite antifungal treatment in the same neonatal intensive care unit (NICU) in 2022 and 48 (27 fluconazole-resistant and 21 fluconazole-susceptible dose-dependent) bloodstream isolates from 48 patients in 15 South Korean hospitals from 2010 to 2022. Phylogenetic analysis based on WGS single-nucleotide polymorphisms (SNPs) distinguished the 79 isolates according to multilocus sequence typing (MLST) (17 sequence type [ST]3, 13 ST7, two ST22, 41 ST26, four ST55, and two ST59 isolates) and unveiled two possible clusters of nosocomial transmission among ST26 isolates. One cluster from two premature infants with overlapping NICU hospitalizations in 2022 encompassed 15 fluconazole-resistant isolates harboring pleiotropic drug-resistance transcription factor (Pdr1p) P258L (13 isolates) or N1086I (two isolates), together with 10 fluconazole-susceptible dose-dependent isolates lacking Pdr1p SNPs. The other cluster indicated unforeseen clonal transmission of fluconazole-resistant bloodstream isolates among five patients (four post-lung transplantation and one with diffuse interstitial lung disease) in the same hospital over 8 months. Among these five isolates, four obtained after exposure to azole antifungals harbored distinct Pdr1p SNPs (N1091D, E388Q, K365E, and R376Q). The findings reveal the transmission patterns of clonal bloodstream isolates of C. glabrata among patients undergoing antifungal treatment, exhibiting different levels of fluconazole susceptibility or distinct Pdr1p SNP profiles.ImportanceThe prevalence of fluconazole-resistant bloodstream infections caused by Candida glabrata is increasing globally, but the transmission of these resistant strains within hospitals has rarely been documented. Through whole-genome sequencing and epidemiological analyses, this study identified two potential clusters of C. glabrata bloodstream infections within the same hospital, revealing the transmission of clonal C. glabrata strains with different levels of fluconazole susceptibility or distinct transcription factor pleiotropic drug resistance protein 1 (Pdr1p) single-nucleotide polymorphism profiles among patients receiving antifungal therapy.
| S-EPMC11448407 | biostudies-literature
Project description:Candida glabrata is a major cause of candidemia in immunocompromised patients and is characterized by a high-level of fluconazole resistance. In the present study, the acquisition of antifungal resistance and potential clonal spread of C. glabrata were explored at a single center over a 12-year period by analyzing 187 independent clinical C. glabrata bloodstream isolates. One strain was found to be micafungin resistant due to a mutation in the FKS2 gene. Fluconazole resistance remained stable throughout the period and was observed in 20 (10.7%) of the isolates. An analysis of the antifungal consumption data revealed that recent prior exposure to fluconazole increased the risk to be infected by a resistant strain. In particular, the duration of the treatment was significantly longer for patients infected by a resistant isolate, while the total and mean daily doses received did not impact the acquisition of resistance in C. glabrata No link between genotype and resistance was found. However, multilocus variable-number tandem-repeat analyses indicated a potential intrahospital spread of some isolates between patients. These isolates shared the same genetic profiles, and infected patients were hospitalized in the same unit during an overlapping period. Finally, quantitative real-time PCR analyses showed that, unlike that for other ABC efflux pumps, the expression of CgCDR1 was significantly greater in resistant strains, suggesting that it would be more involved in fluconazole (FLC) resistance. Our study provides additional evidence that the proper administration of fluconazole is required to limit resistance and that strict hand hygiene is necessary to avoid the possible spreading of C. glabrata isolates between patients.
| S-EPMC6105788 | biostudies-literature
Project description:Oceanapiside (OPS), a marine natural product with a novel bifunctional sphingolipid structure, is fungicidal against fluconazole-resistant Candida glabrata at 10 μg/mL (15.4 μM). The fungicidal effect was observed at 3 to 4 h after exposure to cells. Cytological and morphological studies revealed that OPS affects the budding patterns of treated yeast cells with a significant increase in the number of cells with single small buds. In addition, this budding morphology was found to be sensitive in the presence of OPS. Moreover, the number of cells with single medium-sized buds and cells with single large buds were decreased significantly, indicating that fewer cells were transformed to these budding patterns, suggestive of inhibition of polarized growth. OPS was also observed to disrupt the organized actin assembly in C. glabrata, which correlates with inhibition of budding and polarized growth. It was also demonstrated that phytosphingosine (PHS) reversed the antifungal activity of oceanapiside. We quantified the amount of long chain-bases (LCBs) and phytoceramide from the crude extracts of treated cells using LC-ESI-MS. PHS concentration was elevated in extracts of cells treated with OPS when compared with cells treated with miconazole and amphotericin B. Elevated levels of PHS in OPS-treated cells confirms that OPS affects the pathway at a step downstream of PHS synthesis. These results also demonstrated that OPS has a mechanism of action different to those of miconazole and amphotericin B and interdicts fungal sphingolipid metabolism by specifically inhibiting the step converting PHS to phytoceramide.
| S-EPMC7996939 | biostudies-literature
Project description:Abstract Poster session 3, September 23, 2022, 12:30 PM - 1:30 PM Objective To determine the profile of fluconazole-resistant Candida isolates (FRCS) and the proportion of erg11 gene mutation in fluconazole-resistant C. albicans (FRCA) isolates Methods After getting approval from ethics the study was conducted on 150 isolates of FRCS obtained from patients admitted to our tertiary care hospital from September 2019 to December 2021. All the isolates were revived onto Sabouraud dextrose agar (SDA) and identified by Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS). Fluconazole-resistance was detected by VITEK 2 automated system. Deoxyribonucleic acid (DNA) of FRCA isolates were extracted by QIAamp DNA Mini kit (Qiagen-51 304, Hilden, Germany) as per manufacturer's instruction. A single primer pair targeting the nucleotide sequence from 1067 to 1576 bp region of erg11 gene was used for amplification as per Xu et al. with minor modification and 500 bp polymerase chain reaction (PCR) products were observed by gel electrophoresis. A positive clinical isolate of FRCA was used as a positive control. The PCR products were purified and subjected to Sanger sequencing with an ABI PRISM DNA analyzer (Applied Biosystems) and mutations were detected by using Mega (version 7) software by comparing with the published GenBank sequence AF153844.1 of C. albicans strain ATCC 28516. Categorical variables were expressed in percentages and continuous variables were expressed in mean (average). Results Out of the total of 150 FRCS, the most common fluconazole-resistant agent of candidiasis was C. auris, which was isolated from 60 (40%) cases followed by 24 (16%) isolates of C. glabrata, 19 (12.7%) isolates of C. krusei, 18 (12%) isolates of C. parapsilosis, 17 (11.3%) isolates of C. albicans, 10 (6.7%) isolates of C. tropicalis, and only two (1.3%) isolates of C. guilliermondii. Among these 17 FRCA isolates, 9 isolates were obtained from genital swabs, 5 from blood, and a single isolate each from the perianal swab, ear swab, and sputum. A total of 12 (70.6%) out of 17 FRCA isolates yielded 500 bp region in erg11 gene. Gel electrophoresis image of PCR products of erg11 gene is depicted in Figure 1. Sequencing of these products detected a single missense mutation A1309G (V437I) in one FRCA isolate. Most of the FRCA isolates had an average of 4 silent mutations (observed in 6 isolates) and a single isolate had 6 silent mutations. A total of 8 different silent mutations were observed among FRCA isolates T1296C (83.3%), C1203T (66.7%), A1440G (66.7%), C1302T (50%), T1470C (50%), T1140C (25%), T1110C (16.7%), and T1284C (8.3%). Conclusion C. auris was the most common fluconazole resistant isolate observed, followed by C. glabrata, C. krusei, C. parapsilosis, C. albicans, C. tropicalis, and C. guilliermondii. There were many silent mutations observed in erg11 gene of FRCA isolates and detected only a single missense mutation (V437I). Fluconazole-resistant in FRCA isolates may be due to mechanisms other than the studied one in our region.
| S-EPMC9515968 | biostudies-literature
Project description:Candida glabrata is one of the most common causes of systemic candidiasis, often resistant to antifungal medications. To describe the genomic context of emerging resistance, we conducted a retrospective analysis of 82 serially collected isolates from 33 patients from population-based candidemia surveillance in the United States. We used whole-genome sequencing to determine the genetic relationships between isolates obtained from the same patient. Phylogenetic analysis demonstrated that isolates from 29 patients were clustered by patient. The median SNPs between isolates from the same patient was 30 (range: 7-96 SNPs), while unrelated strains infected four patients. Twenty-one isolates were resistant to echinocandins, and 24 were resistant to fluconazole. All echinocandin-resistant isolates carried a mutation either in the FKS1 or FKS2 HS1 region. Of the 24 fluconazole-resistant isolates, 17 (71%) had non-synonymous polymorphisms in the PDR1 gene, which were absent in susceptible isolates. In 11 patients, a genetically related resistant isolate was collected after recovering susceptible isolates, indicating in vivo acquisition of resistance. These findings allowed us to estimate the intra-host diversity of C. glabrata and propose an upper boundary of 96 SNPs for defining genetically related isolates, which can be used to assess donor-to-host transmission, nosocomial transmission, or acquired resistance. IMPORTANCE In our study, mutations associated to azole resistance and echinocandin resistance were detected in Candida glabrata isolates using a whole-genome sequence. C. glabrata is the second most common cause of candidemia in the United States, which rapidly acquires resistance to antifungals, in vitro and in vivo.
| S-EPMC10865870 | biostudies-literature
Project description:We investigated the evolution of fluconazole resistance mechanisms and clonal types of Candida parapsilosis isolates from a tertiary care hospital in South Korea. A total of 45 clinical isolates, including 42 collected between 2017 and 2021 and 3 collected between 2012 and 2013, were subjected to antifungal susceptibility testing, sequencing of fluconazole resistance genes (ERG11, CDR1, TAC1, and MRR1), and microsatellite typing. Twenty-two isolates carried Y132F (n = 21; fluconazole MIC = 2 to >256 mg/L) or Y132F+R398I (n = 1; fluconazole MIC = 64 mg/L) in ERG11 and four isolates harbored N1132D in CDR1 (fluconazole MIC = 16 to 64 mg/L). All 21 Y132F isolates exhibited similar microsatellite profiles and formed a distinct group in the dendrogram. All four N1132D isolates displayed identical microsatellite profiles. Fluconazole MIC values of the Y132F isolates varied depending on their MRR1 mutation status (number of isolates, year of isolation, and MIC): K177N (n = 8, 2012 to 2020, 2 to 8 mg/L); K177N + heterozygous G982R (n = 1, 2017, 64 mg/L); K177N + heterozygous S614P (n = 2, 2019 to 2020, 16 mg/L); and K177N + homozygous S614P (n = 10, 2020 to 2021, 64 to > 256 mg/L). Our study revealed that Y132F in ERG11 and N1132D in CDR1 were the major mechanisms of fluconazole resistance in C. parapsilosis isolates. Furthermore, our results suggested that the clonal evolution of Y132F isolates persisting and spreading in hospital settings for several years occurred with the acquisition of heterozygous or homozygous MRR1 mutations associated with a gradual increase in fluconazole resistance.
| S-EPMC9664844 | biostudies-literature
Project description:It was found in our previous study that berberine (BBR) and fluconazole (FLC) used concomitantly exhibited a synergism against FLC-resistant Candida albicans in vitro. The aim of the present study was to clarify how BBR and FLC worked synergistically and the underlying mechanism. Antifungal time-kill curves indicated that the synergistic effect of the two drugs was BBR dose dependent rather than FLC dose dependent. In addition, we found that BBR accumulated in C. albicans cells, especially in the nucleus, and resulted in cell cycle arrest and significant change in the transcription of cell cycle-related genes. Besides BBR, other DNA intercalators, including methylene blue, sanguinarine, and acridine orange, were all found to synergize with FLC against FLC-resistant C. albicans. Detection of intracellular BBR accumulation by fluorescence measurement showed that FLC played a role in increasing intracellular BBR concentration, probably due to its effect in disrupting the fungal cell membrane. Similar to the case with FLC, other antifungal agents acting on the cell membrane were able to synergize with BBR. Interestingly, we found that the efflux of intracellular BBR was FLC independent but strongly glucose dependent and associated with the drug efflux pump Cdr2p. These results suggest that BBR plays a major antifungal role in the synergism of FLC and BBR, while FLC plays a role in increasing the intracellular BBR concentration.
| S-EPMC3837902 | biostudies-literature
Project description:Peripheral nerve injuries (PNIs) in the upper extremities is an important medical problem, causing significant morbidity at a relatively young age. The epidemiology of PNI in South Korea has not been comprehensively evaluated. The purpose of our study was to examine the incidence of upper extremity PNI in South Korea based on an analysis of nationwide data and to investigate the association between PNI and patients’ demographic characteristics. Patient claims data from the Health Insurance Review and Assessment Service from 2008 to 2018 were collected. Demographic characteristics, such as the age, sex, region, admission route, length of hospital stay, healthcare facility level, and cost were evaluated. Annual incidence, body sites affected, damaged nerves, accompanying injuries, and surgical procedures were analyzed. Annual incidence trends, injured anatomical area, seasonal injury trends, and injury trend according to sex were also evaluated. A total of 57,209 cases were identified during the study period. Mean age was 39.7 ± 16.3 years. Of these cases, 51,651 (90.28%) were surgically treated. About 79% of accompanying injuries occurred in the hand area (hand lacerations, 69.5%; fractures or joint dislocations of the hands, 6.86%; crushing injuries of the hands, 2.67%). Overall, injuries to the digital nerve showed the greatest frequency (62.7%). In the upper arm and forearm, the ulnar nerve was most frequently injured; however, in the hand, radial nerve injuries were most common. The annual incidence rate per 100,000 persons decreased from 10.67 in 2008 to 7.88 in 2018. The annual incidence decreased by 0.98 times per year. PNI occurred 33.91 times more frequently in the finger than in the upper arm, and there were 1.16 times more PNIs in the summer and 2.14 times more in men. We investigated the incidence trend and epidemiologic characteristics of upper extremity peripheral nerve injury in South Korea from 2008 to 2018. A decreasing tendency of annual incidence was observed from 2013 onwards. Finger and digital nerve were most commonly injured, and the incidence of PNI was higher in the summer and in men.
| S-EPMC9726405 | biostudies-literature
Project description:The emergence of resistant Candida albicans has made clinical fluconazole (FLC) treatment difficult. Improving sensitivity to FLC is an effective way to treat resistant isolates. Berberine hydrochloride (BBH) is a commonly used traditional Chinese medicine with antimicrobial effects, especially in resistant isolates. We investigated the molecular mechanisms underlying BBH and FLC synergism on biofilm-positive FLC-resistant C. albicans inhibition. Checkerboard microdilution assays and time-kill assays showed a strong synergistic effect between BBH and FLC in resistant C. albicans isolates, causing a significant 32-512-fold reduction in minimum inhibitory concentrations. BBH combined with FLC inhibited intracellular FLC efflux due to key efflux pump gene CDR1 downregulation, whereas FLC alone induced high CDR1 transcription in resistant strains. Further, BBH + FLC inhibited yeast adhesion, morphological hyphae transformation, and biofilm formation by downregulating the hyphal-specific genes ALS3, HWP1, and ECE1. BBH caused cytoplasmic Ca2+ influx, while FLC alone did not induce high intracellular Ca2+ levels. The vacuolar calcium channel gene YVC1 was upregulated, while the vacuolar calcium pump gene PMC1 was downregulated in the BBH + FLC and BBH alone groups. However, vacuolar calcium gene expression after FLC treatment was opposite in biofilm-positive FLC-resistant C. albicans, which might explain why BBH induces Ca2+ influx. These results demonstrate that BBH + FLC exerts synergistic effects to increase FLC sensitivity by regulating multiple targets in FLC-resistant C. albicans. These findings further show that traditional Chinese medicines have multi-target antimicrobial effects that may inhibit drug-resistant strains. This study also found that the vacuolar calcium regulation genes YVC1 and PMC1 are key BBH + FLC targets which increase cytoplasmic Ca2+ in resistant isolates, which might be critical for reversing biofilm-positive FLC-resistant C. albicans.
| S-EPMC7343717 | biostudies-literature