Clonality of Fluconazole-Nonsusceptible Candida tropicalis in Bloodstream Infections, Taiwan, 2011-2017.
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ABSTRACT:
SUBMITTER: Chen PY
PROVIDER: S-EPMC6711239 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Candida tropicalis is a globally distributed human pathogenic yeast, and its increasing resistance to azoles makes clinical treatment difficult. In this study, we investigated the clinical features, azole resistance and genetic relatedness of 87 C. tropicalis isolates from central China and combined with the global database to explore the relationship between genetic information and fluconazole susceptibility. Of the 55 diploid sequence types (DSTs) identified by multilocus sequence typing (MLST), 27 DSTs were new to the C. tropicalis MLST database. Fluconazole-nonsusceptible (FNS) isolates were genetically closely related. goeBURST analysis showed that DST225, DST376, DST506, and DST546 formed a distinct and unique FNS clonal complex (CC) in Wuhan. The local FNS CC belongs to the large FNS CC (CC2) in China, in which the putative founder DST225 has been reported from the environment. The three most prevalent types (DST506, DST525, and DST546) in Wuhan had high minimum inhibitory concentrations (MICs) for antifungal azoles, and the six possible nosocomial transmissions we captured were all FNS strains, most of which were from CC2. Unique FNS CCs have been found in Singapore (CC8) and India (CC17) and are close to China's CC2 in the minimum spanning tree. There were no FNS CCs outside Asia. This study is the first to reveal a significant correlation between genetic information and fluconazole susceptibility worldwide and to trace geographical locations, which is of great value for molecular epidemiological surveillance and azole-resistance study of C. tropicalis globally.
| S-EPMC7705220 | biostudies-literature
Project description:We investigated the azole resistance mechanisms and clinical features of fluconazole-nonsusceptible (FNS) isolates of Candida tropicalis recovered from Korean surveillance cultures in comparison with fluconazole-less-susceptible (FLS) isolates. Thirty-five clinical isolates of C. tropicalis, comprising 9 FNS (fluconazole MIC, 4 to 64 ?g/ml), 12 FLS (MIC, 1 to 2 ?g/ml), and 14 control (MIC, 0.125 to 0.5 ?g/ml) isolates, were assessed. CDR1, MDR1, and ERG11 expression was quantified, and the ERG11 and UPC2 genes were sequenced. Clinical features of 16 patients with FNS or FLS bloodstream isolates were analyzed. Both FNS and FLS isolates had >10-fold higher mean expression levels of CDR1, MDR1, and ERG11 genes than control isolates (P values of <0.02 for all). When FNS and FLS isolates were compared, FNS isolates had 3.4-fold higher mean ERG11 expression levels than FLS isolates (P = 0.004), but there were no differences in those of CDR1 or MDR1 Of all 35 isolates, 4 (2 FNS and 2 FLS) and 28 (8 FNS, 11 FLS, and 9 control) isolates exhibited amino acid substitutions in Erg11p and Upc2p, respectively. Both FNS and FLS bloodstream isolates were associated with azole therapeutic failure (3/4 versus 4/7) or uncleared fungemia (4/6 versus 4/10), but FNS isolates were identified more frequently from patients with previous azole exposure (6/6 versus 3/10; P = 0.011) and immunosuppression (6/6 versus 3/10; P = 0.011). These results reveal that the majority of FNS C. tropicalis isolates show overexpression of CDR1, MDR1, and ERG11 genes, and fungemia develops after azole exposure in patients with immunosuppression.
| S-EPMC4879413 | biostudies-literature
Project description:Candida tropicalis is less commonly isolated from clinical specimens than Candida albicans. Unlike C. albicans, which can be occasionally found as a commensal, C. tropicalis is almost always associated with the development of fungal infections. In addition, C. tropicalis has been reported to be resistant to fluconazole (FLC). To analyze the development of FLC resistance in C. tropicalis, an FLC-susceptible strain (ATCC 750) (MIC = 1.0 microg/ml) was cultured in liquid medium containing increasing FLC concentrations from 8.0 to 128 microg/ml. The strain developed variable degrees of FLC resistance which paralleled the concentrations of FLC used in the medium. The highest MICs of FLC were 16, 256, and 512 microg/ml for strains grown in medium with 8.0, 32, and 128 microg of FLC per ml, respectively. Development of resistance was rapid and could be observed already after a single subculture in azole-containing medium. The resistant strains were cross-resistant to itraconazole (MIC > 1.0 microg/ml) and terbinafine (MIC > 512 microg/ml) but not to amphotericin B. Isolates grown in FLC at concentrations of 8.0 and 32 microg/ml reverted to low MICs (1.0 microg/ml) after 12 and 11 passages in FLC-free medium, respectively. The MIC for one isolate grown in FLC (128 microg/ml) (128 R) reverted to 16 microg/ml but remained stable over 60 passages in FLC-free medium. Azole-resistant isolates revealed upregulation of two different multidrug efflux transporter genes: the major facilitators gene MDR1 and the ATP-binding cassette transporter CDR1. The development of FLC resistance in vitro correlated well with the results obtained in an experimental model of disseminated candidiasis. While FLC given at 10 mg/kg of body weight/day was effective in reducing the fungal burden of mice infected with the parent strain, the same dosing regimen was ineffective in mice infected with strain 128 R. Finally, the acquisition of in vitro FLC resistance in strain 128 R was related to a loss of virulence. The results of our study elucidate important characteristics and potential mechanisms of FLC resistance in C. tropicalis.
| S-EPMC89916 | biostudies-literature
Project description: Not available
| S-EPMC7920659 | biostudies-literature
Project description:BACKGROUND:Candida tropicalis is a virulent fungal pathogen for which echinocandins are the primary therapy. Emergence of resistance to echinocandins of C. tropicalis carries potentially ominous therapeutic implications. METHODS:We describe herein two patients with breakthrough C. tropicalis fungemia during echinocandin therapy, characterize their molecular mechanism of resistance, and systematically review 13 previously reported cases of echinocandin-resistant C. tropicalis bloodstream infections (BSIs) and other diseases. RESULTS:Among these 15 patients with echinocandin-resistant C. tropicalis infections, the median age was 61 years (ages 28-84 years) and 13 (86%) were immunocompromised. Thirteen (86%) of all patients had a history of pervious or concurrent exposure to echinocandins. Isolates of C. tropicalis from 11 cases, including the two index cases, underwent DNA sequencing of the FKS1 gene for mutations known to confer echinocandin resistance. The amino acid substitution Ser654Pro was shown in four cases, while other FKS1 mutations encoded Ser80S/Pro, Phe641Leu, Phe641Ser, Ser80S/Pro substitutions. These mutational events were not associated with collateral increases in minimum inhibitory concentrations to antifungal triazoles and amphotericin B. Overall mortality in patients with echinocandin-resistant C. tropicalis infections was 40%. Among those six patients who died, two received monotherapy with voriconazole, one was treated with fluconazole, one remained on caspofungin, and two were switched to liposomal amphotericin B. Nine patients (60%) survived after being treated with an antifungal agent other than an echinocandin. CONCLUSIONS:Emergence of resistance to echinocandins by C. tropicalis, occurs during antifungal therapy, is associated with high mortality, is mediated by a diverse range of FKS1 mutations, retains in vitro susceptibility to triazoles and amphotericin B, and constitutes an emerging threat to patients with hematological malignancies.
| S-EPMC7151208 | biostudies-literature
Project description:Azole-resistant Candida tropicalis has emerged in Asia in the context of its trailing nature, defined by residual growth above minimum inhibitory concentrations (MICs). However, limited investigations in C. tropicalis have focused on the difference of genotypes and molecular mechanisms between these two traits. Sixty-four non-duplicated C. tropicalis bloodstream isolates collected in 2017 were evaluated for azole MICs by the EUCAST E.def 7.3.1 method, diploid sequence type (DST) by multilocus sequencing typing, and sequences and expression levels of genes encoding ERG11, its transcription factor, UPC2, and efflux pumps (CDR1, CDR2 and MDR1). Isavuconazole showed the highest in vitro activity and trailing against C. tropicalis, followed by voriconazole and fluconazole (geometric mean [GM] MIC, 0.008, 0.090, 1.163 mg/L, respectively; trailing GM, 27.4%, 20.8% and 19.5%, respectively; both overall p < 0.001). Fourteen (21.9%) isolates were non-WT to fluconazole/voriconazole, 12 of which were non-WT to isavuconazole and clustered in clonal complex (CC) 3. Twenty-five (39.1%) isolates were high trailing WT, including all CC2 isolates (44.0%) (containing DST140 and DST98). All azole non-WT isolates carried the ERG11 mutations A395T/W and/or C461T/Y, and most carried the UPC2 mutation T503C/Y. These mutations were not identified in low and high trailing WT isolates. Azole non-WT and high trailing WT isolates exhibited the highest expression levels of ERG11 and MDR1, 3.91- and 2.30-fold, respectively (both overall p < 0.01). Azole resistance and trailing are phenotypically and genotypically different in C. tropicalis. Interference with azole binding and MDR1 up-regulation confer azole resistance and trailing, respectively.
| S-EPMC8396981 | biostudies-literature
Project description:Candida auris-a fungus (yeast) that can cause hospital outbreaks was first recognized in 2009. The authors report data on 38 cases of C. auris bloodstream infections in multidisciplinary hospitals situated in two distantly located regions of Russia, considering predisposing factors, antifungal susceptibility of isolates, treatment, and outcomes. Interhospital transfers of patients and labor migration contributed to the spread of C. auris. The South Asian lineage of the studied strains was indicated by K143R substitution in ERG11 gene and phylogenetic analysis of internal transcribed spacer and D1-D2 domain. All isolates from C. auris candidemia cases were susceptible to echinocandins. High-level resistance to fluconazole and resistance to amphotericin B were present in the majority of strains. The overall all-cause mortality rate in C. auris bloodstream infections was 55.3% and the 30-day all-cause mortality rate 39.5%. The attributable mortality was 0%. Eradication of C. auris from blood was associated with the favourable outcomes in patients. It was achieved irrespective of whether antifungal preparations within or outside the susceptibility range were administered. Further international surveillance and studies providing consensus guidelines for the management of C. auris infections are needed.
| S-EPMC7559283 | biostudies-literature
Project description:A total of 1135 carbapenem-resistant (nonsusceptible) Enterobacteriaceae (CRE) isolates were recovered between November 2010 and July 2012 (517 from 2010-2011 and 618 from 2012) from 4 hospitals in Taiwan. Carbapenemase-producing Enterobacteriaceae (CPE) comprised 5.0% (57 isolates), including 17 KPC-2 (16 Klebsiella pneumoniae and 1 Escherichia coli), 1 NDM-1 (K. oxytoca), 37 IMP-8 (26 Enterobacter cloacae, 4 Citrobacter freundii, 4 Raoultella planticola, 1 K. pneumoniae, 1 E. coli and 1 K. oxytoca), and 2 VIM-1 (1 E. cloacae, 1 E. coli). The KPC-2-positive K. pneumoniae were highly clonal even in isolates from different hospitals, and all were ST11. IMP-8 positive E. cloacae from the same hospitals showed higher similarity in PFGE pattern than those from different hospitals. A total of 518 CRE isolates (45.6%) were positive for blaESBL, while 704 (62.0%) isolates were blaAmpC-positive, 382 (33.6% overall) of which carried both blaESBL and blaAmpC. CTX-M (414, 80.0%) was the most common blaESBL, while DHA (497, 70.6%) and CMY (157, 22.3%) were the most common blaAmpC. Co-carriage of blaESBL and blaAmpC was detected in 31 (54.4%) and 15 (26.3%) of the 57 CPE, respectively. KPC-2 was the most common carbapenemase detected in K. pneumoniae (2.8%), while IMP-8 was the most common in E. cloacae (9.7%). All KPC-2-positive CRE were resistant to all three tested carbapenems. However, fourteen of the 37 IMP-8-positive CRE were susceptible to both imipenem and meropenem in vitro. Intra- and inter-hospital spread of KPC-2-producing K. pneumoniae and IMP-8-producing E. cloacae likely occurred. Although the prevalence of CPE is still low, careful monitoring is urgently needed. Non-susceptibility to ertapenem might need to be considered as one criterion of definition for CRE in areas where IMP type carbapenemase is prevalent.
| S-EPMC4368706 | biostudies-literature
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:BACKGROUND:Marked increases in fluconazole resistance in Candida tropicalis have been recently reported. In this study, the molecular mechanisms behind fluconazole resistance were investigated. METHODS:Twenty-two C. tropicalis clinical isolates, including 12 fluconazole-resistant isolates and 10 fluconazole-susceptible isolates, were collected from a tertiary care teaching hospital in Beijing between 2013 and 2017. Antifungal susceptibility testing, multilocus sequence typing, ERG11 amplification and sequencing, quantitative real-time reverse transcription-polymerase chain reaction (ERG11, UPC2, MDR1, and CDR1), and clinical data collection were performed for all C. tropicalis isolates. RESULTS:Multilocus sequence typing revealed that the 10 fluconazole-susceptible isolates and 12 fluconazole-resistant isolates were divided into nine and seven diploid sequence types, respectively. Of the 12 patients with fluconazole-resistant isolates, six had been previously exposed to azole and four had a fatal outcome. Y132F and S154F amino acid substitutions in Erg11p were found in all fluconazole-resistant isolates except one. MDR1 gene overexpression was identified in fluconazole-resistant isolates. In particular, seven high-level fluconazole resistant isolates (minimum inhibitory concentration???128 mg/L) and three pan-azole resistant isolates were identified. CDR1, ERG11, and UPC2 gene expression levels in fluconazole-resistant isolates were not significantly different from the control isolates (P?=?0.262, P?=?0.598, P?=?0.114, respectively). CONCLUSIONS:This study provides evidence that the combination of MDR1 gene overexpression and ERG11 missense mutations is responsible for high-level fluconazole resistance and pan-azole resistance in C. tropicalis clinical isolates. To the best of our knowledge, this is the first study investigating the relationship between MDR1 gene overexpression and increased fluconazole resistance.
| S-EPMC5891969 | biostudies-literature