Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Amphotericin B and Flucytosine

Espinel-Ingroff, Ana; Chowdhary, Anuradha; Cuenca‐Estrella, Manuel; Fothergill, A.; Fuller, Jeffrey; Hagen, Ferry; Govender, Nelesh P.; Guarro, Josep; Johnson, Elizabeth; Lass‐Flörl, Cornelia; Lockhart, Shawn R.; Martins, Marilena dos Anjos; Meis, Jacques F.; Melhem, Márcia de Souza Carvalho; Ostrosky-Zeichner, Luis; Peláez, Teresa; Pfaller, Michael A.; Schell, Wiley A.; Trilles, Luciana; Kidd, Sarah; Turnidge, John

doi:10.1128/aac.06252-11

Cited by 135 publications

(120 citation statements)

References 47 publications

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“…Subsequently, MICs of fluconazole were noted to be increased among isolates from C. gattii VGII case clusters (see discussion below). This prompted an ongoing large-scale study of MIC CBPs and of epidemiological MIC cutoff values (ECVs) based on MIC distributions of wildtype strains (357)(358)(359) ). ECVs are useful adjuncts for identifying isolates with acquired or intrinsic resistance or those that need further study.…”

Section: Epidemiological Cutoff Values For C Gattiimentioning

confidence: 99%

Cryptococcus gattii Infections

2014

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SUMMARY Understanding of the taxonomy and phylogeny of Cryptococcus gattii has been advanced by modern molecular techniques. C. gattii probably diverged from Cryptococcus neoformans between 16 million and 160 million years ago, depending on the dating methods applied, and maintains diversity by recombining in nature. South America is the likely source of the virulent C. gattii VGII molecular types that have emerged in North America. C. gattii shares major virulence determinants with C. neoformans , although genomic and transcriptomic studies revealed that despite similar genomes, the VGIIa and VGIIb subtypes employ very different transcriptional circuits and manifest differences in virulence phenotypes. Preliminary evidence suggests that C. gattii VGII causes severe lung disease and death without dissemination, whereas C. neoformans disseminates readily to the central nervous system (CNS) and causes death from meningoencephalitis. Overall, currently available data indicate that the C. gattii VGI, VGII, and VGIII molecular types more commonly affect nonimmunocompromised hosts, in contrast to VGIV. New, rapid, cheap diagnostic tests and imaging modalities are assisting early diagnosis and enabling better outcomes of cerebral cryptococcosis. Complications of CNS infection include increased intracranial pressure, severe neurological sequelae, and development of immune reconstitution syndrome, although the mortality rate is low. C. gattii VGII isolates may exhibit higher fluconazole MICs than other genotypes. Optimal therapeutic regimens are yet to be determined; in most cases, initial therapy with amphotericin B and 5-flucytosine is recommended.

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Section: Epidemiological Cutoff Values For C Gattiimentioning

confidence: 99%

Cryptococcus gattii Infections

2014

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“…The ECV, a term previously used in similar fungal reports and also known as the CO WT , is the highest wild-type (WT) cutoff susceptible value (19)(20)(21)(22)44). ECVs are based on MIC distributions where there are two distinct populations: (i) the WT population of isolates/MICs with no detectable acquired or mutational resistance to the drug being evaluated and (ii) the non-WT population or isolates that harbor one or more resistance markers (14,52).…”

Section: Isolatesmentioning

confidence: 99%

“…b Modes were not listed for 9 of the 25 laboratories because only 24-h (from 4 to 5 laboratories) or a single (from two to four laboratories) MIC(s) for QC isolates (C. parapsilosis and C. krusei) were reported for small subsets of isolates (8 to Y 4 101 3 3 26 32 17 13 7 VGIIa Y 3 200 2 1 16 93 80 6 2 VGIIb Y 2 106 3 9 31 54 9 VGIIc Y 2 42 1 2 21 17 1 All VGII isolates Y 6 449 2 7 28 151 168 53 32 8 VGIII Y 3 43 1 1 6 12 18 4 1 VGIV Y 3 86 2 3 21 19 32 5 4 All isolates Both 10 975 2 24 63 149 360 258 68 40 11 a Fluconazole MICs were determined by the CLSI broth microdilution method (12). b RPMI and YNB, RPMI 1640 and yeast nitrogen base, respectively, as described by the CLSI M27-A3 document (12 three laboratories were used to calculate ECVs by the statistical method (52), where the modeled population is based on fitting a normal distribution at the lower end of the MIC range, working out the mean and standard deviation of that normal distribution, and using those parameters to calculate the MIC that captures at least 95%, 97.5%, and 99% of the modeled WT population (19)(20)(21)(22). A search for outlier laboratories in each distribution was also performed, and only one outlier set of voriconazole MICs was excluded from the analysis.…”

Section: Isolatesmentioning

confidence: 99%

“…by the Clinical and Laboratory Standards Institute (CLSI) and the European Committee for Antimicrobial Susceptibility Testing (AFST-EUCAST) (19-21, 40, 42, 44, 47). More recently, CLSI amphotericin B and flucytosine ECVs were defined for the Cryptococcus neoformans-Cryptococcus gattii species complex (22). CBPs are based on MIC distributions, pharmacokinetic and pharmacodynamic (PK/PD) parameters, animal studies, and clinical outcomes to therapy, while the ECV is based mostly on MIC distributions.…”

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confidence: 99%

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Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Fluconazole, Itraconazole, Posaconazole, and Voriconazole

Espinel-Ingroff

Aller

Cantón

et al. 2012

Antimicrob Agents Chemother

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MICs measured using CLSI yeast nitrogen base (YNB) medium instead of CLSI RPMI medium for C. neoformans were evaluated. CLSI RPMI medium ECVs for distributions originating from at least three laboratories, which included >95% of the modeled WT population, were as follows: fluconazole, 8 g/ml (VNI, C. gattii nontyped, VGI, VGIIa, and VGIII), 16 g/ml (C. neoformans nontyped, VNIII, and VGIV), and 32 g/ml (VGII); itraconazole, 0.25 g/ml (VNI), 0.5 g/ml (C. neoformans and C. gattii nontyped and VGI to VGIII), and 1 g/ml (VGIV); posaconazole, 0.25 g/ml (C. neoformans nontyped and VNI) and 0.5 g/ml (C. gattii nontyped and VGI); and voriconazole, 0.12 g/ml (VNIV), 0.25 g/ml (C. neoformans and C. gattii nontyped, VNI, VNIII, VGII, and VGIIa,), and 0.5 g/ml (VGI). The number of laboratories contributing data for other molecular types was too low to ascertain that the differences were due to factors other than assay variation. In the absence of clinical breakpoints, our ECVs may aid in the detection of isolates with acquired resistance mechanisms and should be listed in the revised CLSI M27-A3 and CLSI M27-S3 documents.

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“…This study is unique in that molecular methods were used to confirm the IDs of the less-common species of Candida, as well as those of the non-Candida yeasts and all of the filamentous fungi (8). Furthermore, we applied the newly revised CBPs for the echinocandins, fluconazole, and voriconazole to determine the resistance profiles of various Candida species (11,(29)(30)(31) and the ECVs for these agents, as well as itraconazole and posaconazole, to detect emerging resistance among less-common species of Candida (11) and among isolates of Aspergillus fumigatus (37) and Cryptococcus neoformans (39). Furthermore, we provide a molecular characterization of the mechanisms of echinocandin resistance among isolates of Candida spp.…”

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confidence: 99%

Echinocandin and Triazole Antifungal Susceptibility Profiles for Clinical Opportunistic Yeast and Mold Isolates Collected from 2010 to 2011: Application of New CLSI Clinical Breakpoints and Epidemiological Cutoff Values for Characterization of Geographic and Temporal Trends of Antifungal Resistance

et al. 2013

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The SENTRY Antimicrobial Surveillance Program monitors global susceptibility and resistance rates of newer and established antifungal agents. We report the echinocandin and triazole antifungal susceptibility patterns for 3,418 contemporary clinical isolates of yeasts and molds. The isolates were obtained from 98 laboratories in 34 countries during 2010 and 2011. Yeasts not presumptively identified by CHROMagar, the trehalose test, or growth at 42°C and all molds were sequence identified using internal transcribed spacer (ITS) and 28S (yeasts) or ITS, translation elongation factor (TEF), and 28S (molds) genes. Susceptibility testing was performed against 7 antifungals (anidulafungin, caspofungin, micafungin, fluconazole, itraconazole, posaconazole, and voriconazole) using CLSI methods. Rates of resistance to all agents were determined using the new CLSI clinical breakpoints and epidemiological cutoff value criteria, as appropriate. Sequencing of fks hot spots was performed for echinocandin non-wildtype (WT) strains. Isolates included 3,107 from 21 Candida spp., 146 from 9 Aspergillus spp., 84 from Cryptococcus neoformans, 40 from 23 other mold species, and 41 from 9 other yeast species. Among Candida spp., resistance to the echinocandins was low (0.0 to 1.7%). Candida albicans and Candida glabrata that were resistant to anidulafungin, caspofungin, or micafungin were shown to have fks mutations. Resistance to fluconazole was low among the isolates of C. albicans (0.4%), Candida tropicalis (1.3%), and Candida parapsilosis (2.1%); however, 8.8% of C. glabrata isolates were resistant to fluconazole. Among echinocandin-resistant C. glabrata isolates from 2011, 38% were fluconazole resistant. Voriconazole was active against all Candida spp. except C. glabrata (10.5% non-WT), whereas posaconazole showed decreased activity against C. albicans (4.4%) and Candida krusei (15.2% non-WT). All agents except for the echinocandins were active against C. neoformans, and the triazoles were active against other yeasts (MIC 90 , 2 g/ml). The echinocandins and triazoles were active against Aspergillus spp. (MIC 90 /minimum effective concentration [MEC 90 ] range, 0.015 to 2 g/ml), but the echinocandins were not active against other molds (MEC 90 range, 4 to >16 g/ml). Overall, echinocandin and triazole resistance rates were low; however, the fluconazole and echinocandin coresistance among C. glabrata strains warrants continued close surveillance.

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Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Amphotericin B and Flucytosine

Cited by 135 publications

References 47 publications

Cryptococcus gattii Infections

Cryptococcus gattii Infections

Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Fluconazole, Itraconazole, Posaconazole, and Voriconazole

Echinocandin and Triazole Antifungal Susceptibility Profiles for Clinical Opportunistic Yeast and Mold Isolates Collected from 2010 to 2011: Application of New CLSI Clinical Breakpoints and Epidemiological Cutoff Values for Characterization of Geographic and Temporal Trends of Antifungal Resistance

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