Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-3 (of 3 Records) |
Query Trace: Grossman NT[original query] |
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The investigational fungal Cyp51 inhibitor VT-1129 demonstrates potent in vitro activity against Cryptococcus neoformans and Cryptococcus gattii
Lockhart SR , Fothergill AW , Iqbal N , Bolden CB , Grossman NT , Garvey EP , Brand SR , Hoekstra WJ , Schotzinger RJ , Ottinger E , Patterson TF , Wiederhold NP . Antimicrob Agents Chemother 2016 60 (4) 2528-31 The in vitro activity of the novel fungal Cyp51 inhibitor VT-1129 was evaluated against a large panel of C. neoformans and C. gattii isolates. VT-1129 demonstrated potent activity against both Cryptococcus species as demonstrated by low MIC50 and MIC90 values. Against C. gattii, the in vitro potency was maintained against all genotypes. In addition, significantly lower geometric mean MICs were observed for VT-1129 compared to fluconazole against C. neoformans, including isolates with reduced fluconazole susceptibility. |
Epidemiology of echinocandin resistance in Candida
Grossman NT , Chiller TM , Lockhart SR . Curr Fungal Infect Rep 2014 8 (4) 243-248 Echinocandins are the newest antifungal agents approved for use in treating Candida infections in the US. They act by interfering with 1,3-β-D-glucan synthase and therefore disrupt cell wall production and lead to Candida cell death. There is no intrinsic resistance to echinocandins among Candida species, and isolates from historic collections archived before the release of the echinocandins show no resistance. Resistance to the echinocandins remains low among most Candida species and ranges overall from 0-1%. Among isolates of Candida glabrata, the proportion of resistant isolates is higher and has been reported to be as high as 13.5% in at least one hospital. Antifungal resistance is due to specific amino acid mutations in the Fksp subunit(s) of the 1,3-β-D-glucan synthase protein which are localized to one of two hotspots. These mutations are being recognized in isolates from patients who have failed echinocandin therapy, and often lead to a poor outcome. While the future looks bright for the echinocandins against most Candida species, C. glabrata remains a species of concern and resistance rates of C. glabrata to the echinocandins should be monitored closely. |
Molecular mechanisms of fluconazole resistance in Candida parapsilosis isolates from a U.S. surveillance system.
Grossman NT , Pham CD , Cleveland AA , Lockhart SR . Antimicrob Agents Chemother 2014 59 (2) 1030-7 Candida parapsilosis is the second or third most common cause of candidemia in many countries. The Infectious Disease Society of America recommends fluconazole as primary therapy for C. parapsilosis candidemia. Although fluconazole resistance among C. parapsilosis isolates is low in most US institutions, the resistance rate can be as high as 7.5%. This study was designed to assess the mechanisms of fluconazole resistance in 706 incident bloodstream isolates from US hospitals. We sequenced the ERG11 and MRR1 genes of 122 C. parapsilosis isolates with resistant (30 isolates; 4.2%), susceptible dose-dependent (37 isolates; 5.2%) and susceptible (55 isolates) fluconazole MIC values, and used RT-PCR on RNA from 17 isolates to investigate the regulation of MDR1. By comparing these isolates to fully fluconazole susceptible isolates we detected at least two mechanisms of fluconazole resistance: an amino acid substitution in the 14-alpha-demethylase gene ERG11, and overexpression of the efflux pump MDR1, possibly due to point mutations in the MRR1 transcription factor that regulates MDR1. The ERG11 single nucleotide polymorphism (snp) was found in 57% of the fluconazole resistant isolates and in no susceptible isolates. The MRR1 snps were more difficult to characterize, as not all resulted in overexpression of MDR1 and not all MDR1 overexpression was associated with a snp in MRR1. Further work to characterize the MRR1 snps and search for overexpression of other efflux pumps is needed. |
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