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ABSTRACT: Background. Fluconazole (FLC) resistance is common in C. glabrata and echinocandins are often used as first line therapy. Resistance to echinocandin therapy has been associated with FKS1 and FKS2 gene alterations. Methods. We reviewed records of all patients with C. glabrata bloodstream infection at Duke Hospital over the past decade (2001-10) and correlated treatment outcome with MIC results and the presence of FKS gene mutations. For each isolate, MICs to FLC and echinocandins (anidulafungin [ANF], caspofungin [CSF], and micafungin [MCF]) and FKS1 and FKS2 gene sequences were determined. Results. Two hundred ninety-three episodes (313 isolates) of C. glabrata bloodstream infection were analyzed. Resistance to echinocandins increased from 4.9% to 12.3% and to FLC from 18% to 30% between 2001 and 2010, respectfully. Among the 78 FLC resistant isolates, 14.1% were resistant to one or more echinocandins. Twenty-five (7.9%) isolates harbored a FKS mutation. The predictor of a FKS mutant strain was prior echinocandin therapy (stepwise multivariable analysis, OR 19.647, 95% CI 7.19-58.1). Eighty percent (8/10) of patients infected with FKS mutants demonstrating intermediate or resistant MICs to an echinocandin and treated with an echinocandin failed to respond or responded initially but recurred. Conclusions. Echinocandin resistance is increasing, including among FLC resistant isolates. The new CLSI clinical breakpoints differentiate wild-type from C. glabrata strains bearing clinically significant FKS1/FKS2 mutations. These observations underscore the importance of knowing the local epidemiology and resistance patterns for Candida within institutions and susceptibility testing of echinocandins for C. glabrata to guide therapeutic decision making.
Clinical Infectious Diseases 03/2013; · 9.15 Impact Factor
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ABSTRACT: Rapid detection of multiple-drug resistant organism (MDRO) carriers could help reduce MDRO infections by allowing for faster institution of prevention measures. However, improving the turnaround time (TAT) of a test requires attention to more than the analytic TAT, and will only occur if post-analytic processes (test reporting and care interventions) are also rapid and efficient. Obstacles to rapid MDRO test development include complex evolving resistance mechanisms, performance directly on mixed samples (e.g. nares, stool), and adaptation of new methods for routine clinical diagnostic use. Existing data to support the clinical utility of rapid detection (versus standard culture methods) are scant. For these reasons, rapid detection of MDRO carriers remains a work-in-progress. Future efforts should be on developing rapid tests to detect multiple-drug resistant gram negative rods, particularly those harboring β-lactamases, and on performing clinical trials to determine how best to incorporate rapid detection of MDRO carriage into HAI prevention efforts.
Clinical Infectious Diseases 01/2013; · 9.15 Impact Factor
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ABSTRACT: MK-3118, a glucan synthase inhibitor derived from enfumafungin, and comparator agents were tested against 71 Aspergillus spp., including itraconazole-resistant strains (MIC, ≥4 μg/ml), using CLSI and EUCAST reference broth microdilution methods. CLSI MEC/MIC(90) values (μg/ml) for MK-3118, amphotericin B, and caspofungin, respectively, were: Aspergillus flavus species complex (SC), 0.12, 2, 0.03; A. fumigatus SC, 0.25, 2, 0.06; A. terreus SC, 0.12, 2, 0.06 and A. niger SC, 0.06, 1, 0.03. Essential agreement between CLSI and EUCAST (±2 log(2) dilution steps) was 94.3%. MK-3118 was determined to be a potent agent regardless of the in vitro method applied, with excellent activity against contemporary wild type and itraconazole-resistant strains of Aspergillus spp.
Antimicrobial Agents and Chemotherapy 12/2012; · 4.84 Impact Factor
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ABSTRACT: OBJECTIVES: To evaluate the activity of the orally bioavailable enfumafungin derivative MK-3118 and comparator antifungal agents tested against a collection of 113 clinical isolates of Candida spp. using CLSI and EUCAST broth microdilution (BMD) methods. METHODS: Candida spp. isolates (n = 113) were tested by CLSI and EUCAST methods. The collection contained 29 Candida albicans, 29 Candida glabrata, 21 Candida tropicalis, 15 Candida parapsilosis and 19 Candida krusei, including azole- and echinocandin-resistant isolates. CLSI and EUCAST MIC endpoints of 50% and 100% inhibition were determined using visual reading at 24 and 48 h of incubation and spectrophotometric reading at 24 h of incubation, respectively. RESULTS: MK-3118 CLSI MIC results ranged from 0.06 to 16 mg/L depending on species, duration of incubation and endpoint criteria (EC) used. Comparison of CLSI and EUCAST following 24 h of incubation and either 50% or 100% inhibition revealed an essential agreement (EA; ±2 doubling dilutions) of 99.1% using the 50% inhibition EC and 93.2% using the 100% inhibition EC. MK-3118 (24 h of incubation and 50% EC) was active against all the species tested and displayed similar potency to caspofungin (using CLSI BMD) against C. albicans (MIC(90), 1 and 2 mg/L, respectively), C. tropicalis (1 and 1 mg/L, respectively), C. parapsilosis (0.5 and 0.5 mg/L, respectively) and C. krusei (2 and 1 mg/L, respectively), but was 8-fold more potent than caspofungin against C. glabrata strains (MIC(90), 2 and 16 mg/L, respectively). MK-3118 was active against fluconazole-resistant strains as well as caspofungin-resistant strains with documented fks mutations. CONCLUSIONS: MK-3118 was documented to have potent in vitro activity against Candida spp. when tested by both CLSI and EUCAST BMD methods, with the highest overall EA (99.1%) obtained when MK-3118 MIC results were read after 24 h of incubation using a partial inhibition EC (50%).
Journal of Antimicrobial Chemotherapy 11/2012; · 5.07 Impact Factor
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ABSTRACT: Candida famata (teleomorph Debaryomyces hansenii) has been described as a medically relevant yeast and this species has been included in many commercial identification systems that are currently used in clinical laboratories. Among 53 strains collected during the SENTRY and ARTEMIS surveillance programs and previously identified as C. famata (includes all submitted strains with this identification) by a variety of commercial methods (Vitek, MicroScan, API and AuxaColor), DNA sequencing methods demonstrated that 19 strains were C. guilliermondii, 14 were C. parapsilosis, 5 were C. lusitaniae, 4 were C. albicans, 3 were C. tropicalis and five isolates belonged to other Candida species (two C. fermentati, one each of C. intermedia, C. pelliculosa and Pichia fabianni). Additionally, three misidentified C. famata strains were correctly identified as Kodomaea ohmeri, Debaryomyces nepalensis and Debaryomyces fabryi using ITS and/or IGS sequencing. The Vitek 2 system identified three isolates with high confidence to be C. famata and another 15 with low confidence between C. famata and C. guilliermondii or C. parapsilosis, displaying only 56.6% agreement with DNA sequencing results. MALDI-TOF results displayed 81.1% agreement with DNA sequencing. One of each C. metapsilosis, C. fermentati and C. intermedia demonstrated a low score for identification (<2.0) in the MALDI Biotyper. K. ohmeri, D. nepalensis and D. fabryi identified by DNA sequencing in this study were not in the current database for the MALDI Biotyper. These results suggest that the occurrence of C. famata in fungal infections is much lower than previously appreciated and that commercial systems do not produce accurate identifications except for the newly introduced MALDI-TOF instruments.
Journal of clinical microbiology 10/2012; · 4.16 Impact Factor
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ABSTRACT: Ceftaroline fosamil, the prodrug form of the active metabolite ceftaroline, is a new broad-spectrum parenteral cephalosporin with antibacterial activity against the prevalent respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. Bacterial resistance surveillance (5330 isolates) was conducted in the United States between 2008 and 2010 to assess the in vitro activity of ceftaroline and comparator antibacterial agents against invasive respiratory isolates of S. pneumoniae (3329 isolates), H. influenzae (1545 isolates), and M. catarrhalis (456 isolates). All organisms were cultured from patient infections in 71 US hospital laboratories and were submitted to a central reference monitor for broth microdilution testing by Clinical and Laboratory Standards Institute reference methods. Against S. pneumoniae, ceftaroline inhibited 98.7% of strains at the susceptible breakpoint of ≤ 0.25 µg/mL (50% minimum inhibitory concentration [MIC(50)], 0.01 µg/mL; 90% MIC [MIC(90)], 0.12 µg/mL) and was 16-fold more active than ceftriaxone (MIC(90), 2 µg/mL). Among 70 ceftriaxone-resistant pneumococcal isolates, all were inhibited by ≤ 0.5 µg/mL of ceftaroline. Haemophilus influenzae (MIC(50), ≤ 0.008 µg/mL; MIC(90), 0.015 µg/mL) and M. catarrhalis (MIC(50), 0.06 µg/mL; MIC(90), 0.12 µg/mL) were very susceptible to ceftaroline regardless of β-lactamase production. Whereas the high-level of activity of ceftaroline was maintained against S. pneumoniae and H. influenzae from 2008 through 2010, increased rates of nonsusceptibility were observed for amoxicillin/clavulanate, erythromycin, and levofloxacin among S. pneumoniae and for trimethoprim/sulfamethoxazole and azithromycin among H. influenzae. In summary, ceftaroline resistance surveillance (Assessing Worldwide Antimicrobial Resistance Evaluation [AWARE] Program) in the United States (2008-2010) documented in vitro sustained potency and spectrum against Gram-positive and Gram-negative pathogens known to cause community-acquired bacterial pneumonia.
Clinical Infectious Diseases 09/2012; 55 Suppl 3:S187-93. · 9.15 Impact Factor
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ABSTRACT: The increasing diversity of opportunistic fungi causing serious invasive fungal infections (IFI) has been documented. Accurate identification (ID) is important in guiding therapy, determining prognosis for IFIs and in epidemiological surveys. We assessed the utility of PCR-based methods for the ID of yeasts and moulds that either were uncommon, failed conventional ID, or represented unusual biochemical or phenotypic profiles of common species. Among 1,790 viable fungal clinical isolates received during the SENTRY Program in 2010, 322 strains from 40 study sites had ID confirmed by molecular methods. Isolates were previously identified in participant institutions. Yeasts that were not confirmed by morphology on CHROMagar, growth at 45 °C (Candida albicans/dubliniensis), or assimilation of trehalose (C. glabrata) as well as non-Candida yeasts and all moulds were amplified and sequenced using primers amplifying one or more of the following genes: ITS, 28S, β-tubulin (Aspergillus spp.), TEF (Fusarium spp.), IGS (Trichosporon spp.). The isolates selected for molecular ID included 149 isolates of Candida species, 77 of Aspergillus species, 73 non-Candida yeasts, and 23 other moulds (a total of 41 different species). Overall, the ID determined by the submitting site was confirmed for 189 isolates (58.7 %): Aspergillus spp. (64.1 % correct); Candida spp. (60.1 % correct); non-Candida yeasts (58.9 % correct); non-Aspergillus moulds (30.4 % correct). Species with high levels of concordance between conventional and molecular ID included A. fumigatus (95.0 %), C. lusitaniae (100 %), C. dubliniensis (92.3 %), C. kefyr (100 %), and C. neoformans (90.2 %). Only 50.0 % of isolates of C. albicans and 59.1 % of C. glabrata selected due to unusual phenotypic or biochemical features were found to be correctly identified by the submitting site. Molecular methods for the identification of fungal pathogens are an important adjunct to the conventional identification of many less common clinically relevant yeasts and moulds including species of Candida with unusual or erroneous phenotypic or biochemical profiles. Molecular confirmation of fungal identification is essential in epidemiological surveys such as SENTRY.
Mycopathologia 05/2012; 174(4):259-71. · 1.65 Impact Factor
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ABSTRACT: Antifungal susceptibility testing of Candida against the echinocandin antifungal agents (anidulafungin [ANF], caspofungin [CSF], micafungin [MCF]) has been standardized
by the Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antifungal Testing. The CLSI proposed a single set
of clinical breakpoints (CBPs) for all three echinocandins and all species of Candida: susceptible, minimum inhibitory concentration (MIC) ≤ 2μg/mL; nonsusceptible, MIC > 2μg/mL. Subsequently, these CBPs have
been shown to lack sensitivity in detecting strains of Candida with acquired resistance mechanisms associated with treatment failure. Studies using the CLSI method have defined wild-type
(WT) MIC distributions and epidemiologic cutoff values (ECVs) for each echinocandin and the common species of Candida. The ECVs serve as a sensitive means of discriminating WT strains from those with acquired resistance mechanisms. WT MIC
distributions revealed ECV ranges of 0.03 to 0.25μg/mL for all major species except C. parapsilosis (1–4μg/mL) and C. guilliermondii (4–16μg/mL). These ECVs reliably differentiate WT strains of each species from non-WT strains containing fks mutations. These data, coupled with additional biochemical, clinical, pharmacokinetic, and pharmacodynamic considerations,
have resulted in new CBPs of ≤0.25μg/mL (susceptible), 0.5μg/mL (intermediate), and ≥1μg/mL (resistant) for ANF, CSF, and
MCF for C. albicans, C. tropicalis, and C. krusei. For these agents and C. parapsilosis, the new CBPs are ≤2μg/mL (susceptible), 4μg/mL (intermediate), and ≥8μg/mL (resistant). For C. glabrata, the CBPs for ANF and CSF are ≤0.12μg/mL (susceptible), 0.25μg/mL (intermediate), and ≥0.5μg/mL (resistant), whereas those
for MCF are ≤0.06μg/mL, 0.12μg/mL, and ≥0.25μg/mL, respectively. Application of both ECVs and the lower species-specific
CBPs for the echinocandins has proven useful in both resistance surveillance and clinical care and will serve as an important
step in international harmonization of in vitro susceptibility testing of this important antifungal class.
KeywordsEchinocandins–Candida–In vitro testing–Epidemiology–Susceptibility–Epidemiology–Resistance–Antifungal agents–Anidulafungin–Caspofungin–Micafungin–MIC–Clinical breakpoint.
Current Fungal Infection Reports 04/2012; 5(3):120-127.
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ABSTRACT: Antifungal susceptibility testing of Candida against fluconazole has been standardized by both the Clinical and Laboratory Standards Institute (CLSI) and the European
Committee on Antimicrobial Susceptibility Testing (EUCAST). Both CLSI and EUCAST have developed clinical breakpoint (CBP)
criteria for fluconazole, but these differ in both magnitude and target species. Studies using the EUCAST method have also
defined wild-type minimum inhibitory concentration (MIC) distributions and epidemiologic cutoff values (ECVs or ECOFFs) for
the common species of Candida. The ECVs serve as a sensitive means of discriminating wild-type strains from those with acquired resistance mechanisms and
include MICs of 1μg/mL for C. albicans, 2μg/mL for C. tropicalis and C. parapsilosis, 32μg/mL for C. glabrata, and 128μg/mL for C. krusei. Because the CLSI CBPs may be too insensitive to detect emerging resistance among strains of C. albicans, C. tropicalis, and C. parapsilosis, and bisect the WT MIC distribution of C. glabrata, we sought to establish the wild-type MIC distribution and ECVs for fluconazole and Candida spp. The establishment of the wild-type MIC distributions and ECVs for fluconazole using CLSI methods will be useful in resistance
surveillance and may prove to be an important step in the development of species-specific CBPs for this important antifungal
agent.
KeywordsAntifungal susceptibility testing-Fluconazole-Epidemiologic cutoff values-Clinical breakpoints-
Candida
Current Fungal Infection Reports 04/2012; 4(3):168-174.
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ABSTRACT: Fusarium (n = 67) and Scedosporium (n = 63) clinical isolates were tested by two reference broth microdilution (BMD) methods against a novel broad-spectrum (active against both yeasts and molds) antifungal, E1210, and comparator agents. E1210 inhibits the inositol acylation step in glycophosphatidylinositol (GPI) biosynthesis, resulting in defects in fungal cell wall biosynthesis. Five species complex organisms/species of Fusarium (4 isolates unspeciated) and 28 Scedosporium apiospermum, 7 Scedosporium aurantiacum, and 28 Scedosporium prolificans species were identified by molecular techniques. Comparator antifungal agents included anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B. E1210 was highly active against all of the tested isolates, with minimum effective concentration (MEC)/MIC(90) values (μg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B, respectively, for Fusarium of 0.12, >16, >16, >8, >8, 8, and 4 μg/ml. E1210 was very potent against the Scedosporium spp. tested. The E1210 MEC(90) was 0.12 μg/ml for S. apiospermum, but 1 to >8 μg/ml for other tested agents. Against S. aurantiacum, the MEC(50) for E1210 was 0.06 μg/ml versus 0.5 to >8 μg/ml for the comparators. Against S. prolificans, the MEC(90) for E1210 was only 0.12 μg/ml, compared to >4 μg/ml for amphotericin B and >8 μg/ml for itraconazole, posaconazole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparator agents. The essential agreement (EA; ±2 doubling dilutions) was >93% for all comparisons, with the exception of posaconazole and F. oxysporum species complex (SC) (60%), posaconazole and S. aurantiacum (85.7%), and voriconazole and S. aurantiacum (85.7%). In conclusion, E1210 exhibited very potent and broad-spectrum antifungal activity against azole- and amphotericin B-resistant strains of Fusarium spp. and Scedosporium spp. Furthermore, in vitro susceptibility testing of E1210 against isolates of Fusarium and Scedosporium may be accomplished using either of the CLSI or EUCAST BMD methods, each producing very similar results.
Antimicrobial Agents and Chemotherapy 11/2011; 56(1):352-7. · 4.84 Impact Factor
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ABSTRACT: When clinical susceptibility breakpoints (CBPs) are absent, establishing wild-type (WT) MIC distributions and epidemiologic cutoff values (ECVs) provides a sensitive means for detecting emerging resistance to antimicrobials. We determined species-specific ECVs for fluconazole (FLC), posaconazole (PSC), and voriconazole (VRC) using a large global collection of Cryptococcus neoformans (CNEO) isolates obtained from the ARTEMIS and SENTRY Antimicrobial Surveillance Programs. From 2006 to 2009, 285 invasive clinical isolates of CNEO were collected from 61 centers worldwide (178 isolates from ARTEMIS and 107 from SENTRY) and susceptibility testing was performed against FLC, PSC, and VRC using Clinical and Laboratory Standards Institute M27-A3 broth microdilution method (72 h of incubation). The ARTEMIS isolates were tested at the University of Iowa and the SENTRY Program isolates were tested at JMI Laboratories, and the results were combined for analysis. An additional collection of 986 isolates tested against FLC between 1996 and 2008 were used to assess temporal trends in the frequency of non-WT isolates. The modal MICs (mg/L) for FLC, PSC, and VRC were 4, 0.12, and 0.06, respectively. The ECVs expressed as milligrams per liter (% of isolates that had MIC ≤ECV) for FLC, PSC, and VRC were 8 (96.9), 0.25 (96.5), and 0.12 (95.1), respectively. Temporal trends in the emergence of non-WT strains (% of isolate MICs >ECV) for the time periods 1996-2000, 2001-2004, and 2005-2008 for FLC were 4.2, 3.8, and 0.5, respectively. In the absence of CBPs for FLC, PSC, and VRC, these WT MIC distributions and ECVs will be useful in surveillance for detection of emergence of azole reduced susceptibility among CNEO. Application of the FLC ECV to a large collection of CNEO tested over time (1996-2008) revealed a decrease in the frequency of non-WT strains. These findings are consistent with those of more limited surveys in developed countries, suggesting that CNEO susceptibility to FLC has improved since the introduction of antiretroviral therapy. Continued surveillance using these ECVs for the azoles and CNEO appears warranted.
Diagnostic microbiology and infectious disease 09/2011; 71(3):252-9. · 2.45 Impact Factor
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ABSTRACT: When clinical susceptibility breakpoints (CBPs) are absent, establishing wild-type (WT) MIC distributions and epidemiological cutoff values (ECVs) provides a sensitive means for detecting emerging resistance. We determined species-specific ECVs for anidulafungin (ANF), caspofungin (CSF), micafungin (MCF), fluconazole (FLC), posaconazole (PSC), and voriconazole (VRC) for six rarer Candida species (819 strains) using isolates obtained from the ARTEMIS Program and the SENTRY Antimicrobial Surveillance Program, all tested by a reference broth microdilution method. The calculated ECVs, expressed in μg/ml (and the percentages of isolates that had MICs less than or equal to the ECVs), for ANF, CSF, MCF, FLC, PSC, and VRC, respectively, were 0.12 (95.2), 0.12 (97.8), 0.12 (100.0), 0.5 (95.7), 0.12 (98.6), and 0.03 (100.0) for Candida dubliniensis; 4 (100.0), 2 (96.0), 2 (99.1), 8 (95.0), 0.5 (97.5), and 0.25 (98.0) for C. guilliermondii; 0.25 (98.9), 0.03 (98.0), 0.12 (97.5), 1 (99.1), 0.25 (99.1), and 0.015 (100.0) for C. kefyr; 2 (100.0), 1 (99.6), 0.5 (96.6), 2 (96.1), 0.25 (98.6), and 0.03 (96.6) for C. lusitaniae; and 2 (100.0), 0.5 (100.0), 1 (100.0), 2 (98.0), 0.25 (97.1), and 0.06 (98.0) for C. orthopsilosis, but for C. pelliculosa, ECVs could be determined only for CSF (0.12 [94.4]), FLC (4 [98.2]), PSC (2 [98.2]), and VRC (0.25 [98.2]). In the absence of species-specific CBP values, these WT MIC distributions and ECVs will be useful for monitoring the emergence of reduced susceptibility to the triazole and echinocandin antifungals.
Journal of clinical microbiology 09/2011; 49(11):3800-4. · 4.16 Impact Factor
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ABSTRACT: To compare European Committee on Antimicrobial Susceptibility Testing (EUCAST) and CLSI broth microdilution (BMD) methods for testing the novel antifungal E1210 against a recent collection of 102 clinical isolates of Candida spp.
Candida isolates (102) were tested by CLSI and EUCAST methods; 21 Candida albicans, 20 Candida glabrata, 25 Candida parapsilosis, 24 Candida tropicalis and 12 Candida krusei, including echinocandin- and azole-resistant isolates. CLSI and EUCAST MIC endpoints of 50% and 100% inhibition were determined using visual reading at 24 and 48 h of incubation and spectrophotometric reading at 24 h of incubation, respectively.
E1210 CLSI MIC results ranged from ≤0.008 to only 1 mg/L (excluding C. krusei) depending on species, duration of incubation and endpoint criteria (EC). E1210 was not active against C. krusei (MIC(50) >16 mg/L). Overall essential agreement (EA; ±2 doubling dilutions) between the 24 and 48 h CLSI readings was 100% and 97.6% using the 50% and 100% inhibition EC, respectively. Slightly more trailing growth at 48 h was observed with the 100% inhibition EC. Comparison of the 50% and 100% endpoints at 24 h of incubation showed an overall EA of 100%. Comparison of CLSI and EUCAST read at 24 h of incubation and either 50% or 100% inhibition revealed an EA of 97.8% using the 50% inhibition EC and 88.9% using the 100% inhibition EC.
E1210 was found to have potent in vitro activity against Candida spp. when tested by both CLSI and EUCAST BMD methods, with the highest overall EA (97.8%) obtained when E1210 MIC results were read after 24 h of incubation using a partial inhibition EC.
Journal of Antimicrobial Chemotherapy 08/2011; 66(11):2581-4. · 5.07 Impact Factor
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ABSTRACT: E1210 is a first-in-class broad-spectrum antifungal that suppresses hyphal growth by inhibiting fungal glycophosphatidylinositol (GPI) biosynthesis. In the present study, we extend these findings by examining the activity of E1210 and comparator antifungal agents against Aspergillus spp. by using the methods of the Clinical and Laboratory Standards Institute (CLSI) and the European Committee for Antimicrobial Susceptibility Testing (EUCAST) to test wild-type (WT) as well as amphotericin B (AMB)-resistant (-R) and azole-R strains (as determined by CLSI methods). Seventy-eight clinical isolates of Aspergillus were tested including 20 isolates of Aspergillus flavus species complex (SC), 22 of A. fumigatus SC, 13 of A. niger SC, and 23 of A. terreus SC. The collection included 15 AMB-R (MIC, ≥ 2 μg/ml) isolates of A. terreus SC and 10 itraconazole-R (MIC, ≥ 4 μg/ml) isolates of A. fumigatus SC (7 isolates), A. niger SC (2 isolates), and A. terreus SC (1 isolate). Comparator antifungal agents included anidulafungin, caspofungin, amphotericin B, itraconazole, posaconzole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparators. The essential agreement (EA; ± 2 log(2) dilution steps) was 100% for all comparisons with the exception of posaconazole versus A. terreus SC (EA = 91.3%). The minimum effective concentration (MEC)/MIC(90) values (μg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, and voriconazole, respectively, were as follows for each species: for A. flavus SC, 0.03, ≤ 0.008, 0.12, 1, 1, and 1; for A. fumigatus SC, 0.06, 0.015, 0.12, >8, 1, and 4; for A. niger SC, 0.015, 0.03, 0.12, 4, 1, and 2; and for A. terreus SC, 0.06, 0.015, 0.12, 1, 0.5, and 1. E1210 was very active against AMB-R strains of A. terreus SC (MEC range, 0.015 to 0.06 μg/ml) and itraconazole-R strains of A. fumigatus SC (MEC range, 0.03 to 0.12 μg/ml), A. niger SC (MEC, 0.008 μg/ml), and A. terreus SC (MEC, 0.015 μg/ml). In conclusion, E1210 was a very potent and broad-spectrum antifungal agent regardless of in vitro method applied, with excellent activity against AMB-R and itraconazole-R strains of Aspergillus spp.
Antimicrobial Agents and Chemotherapy 08/2011; 55(11):5155-8. · 4.84 Impact Factor
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ABSTRACT: Minimum inhibitory concentration (MIC) data from the SENTRY Antimicrobial Surveillance Program generated by reference methods were analysed to compare the antifungal resistance profiles and species distribution of Candida bloodstream infection (BSI) isolates obtained from patients in the Intensive Care Unit (ICU) and those from non-ICU locations. Results from 79 medical centres between 2008 and 2009 were tabulated. MIC values were obtained for anidulafungin, caspofungin, micafungin, fluconazole, posaconazole and voriconazole. Recently revised Clinical and Laboratory Standards Institute breakpoints for resistance were employed. A total of 1752 isolates of Candida spp. were obtained from ICU (779; 44.5%) and non-ICU (973; 55.5%) settings. The frequency of ICU-associated Candida BSI was higher in Latin America (56.5%) compared with Europe (44.4%) and North America (39.6%). The frequency of candidaemia in the ICU decreased both in Latin America and North America over the 2-year study period. Approximately 96% of isolates both in ICU and non-ICU settings were caused by only five species (Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis and Candida krusei). Resistance both to azoles and echinocandins was uncommon in ICU and non-ICU settings. Overall, fluconazole resistance was detected in 5.0% of ICU isolates and 4.4% of non-ICU isolates. Candida glabrata was the only species in which resistance to azoles and echinocandins was noted, and this multidrug-resistant phenotype was found in both settings. In conclusion, the findings from this global survey indicate that invasive candidiasis can no longer be considered to be just an ICU-related infection, and efforts to design preventive and diagnostic strategies must be expanded to include other at-risk populations and hospital environments. Concern regarding C. glabrata must now include resistance to echinocandins as well as azole antifungal agents.
International journal of antimicrobial agents 07/2011; 38(1):65-9. · 3.03 Impact Factor
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Michael A Pfaller,
David Andes,
Maiken C Arendrup,
Daniel J Diekema,
Ana Espinel-Ingroff,
Barbara D Alexander,
Steven D Brown,
Vishnu Chaturvedi,
Cynthia L Fowler,
Mahmoud A Ghannoum,
Elizabeth M Johnson,
Cynthia C Knapp,
Mary R Motyl,
Luis Ostrosky-Zeichner,
Thomas J Walsh
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ABSTRACT: We reassessed the Clinical and Laboratory Standards Institute (CLSI) clinical breakpoints (CBPs) for voriconazole. We examined i) the essential (EA: ±2 dilutions) and categorical agreement between 24-h CLSI and EUCAST methods for voriconazole testing of Candida, ii) wild-type (WT) MICs and epidemiologic cutoff values (ECVs) for voriconazole by both CLSI and EUCAST methods, and iii) correlation of MICs with outcomes from previously published data using CLSI methods. We applied these findings to propose new 24-h species-specific CLSI CBPs. Adjusted 24-h CBPs for voriconazole and C. albicans, C. tropicalis, and C. parapsilosis (susceptible, ≤ 0.125 μg/mL; intermediate, 0.25-0.5 μg/mL; resistant, ≥ 1 μg/mL) should be more sensitive for detecting emerging resistance among common Candida species and provide consistency with EUCAST CBPs. In the absence of CBPs for voriconazole and C. glabrata (and less common species), we recommend that their respective ECVs be used to detect the emergence of non-WT strains.
Diagnostic microbiology and infectious disease 07/2011; 70(3):330-43. · 2.45 Impact Factor
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ABSTRACT: The in vitro activity of the novel antifungal agent E1210 and four comparators (caspofungin, fluconazole, posaconazole, and voriconazole) was determined against 90 clinical isolates of Candida using Clinical and Laboratory Standards Institute methods. The collection was composed of 21 Candida albicans, 20 C. glabrata, 25 C. parapsilosis, and 24 C. tropicals, and also included 21 fluconazole-resistant and 15 caspofungin-resistant strains. E1210 was highly active against all the species tested and was more potent than all comparators. The MIC(90) results (μg/mL) for E1210, caspofungin, fluconazole, posaconazole, and voriconazole, respectively, were as follows by species: C. albicans (0.06, 4, ≥64, 0.5, 0.5), C. glabrata (0.06, 2, 32, 1, 1), C. parapsilosis (0.06, 4, 16, 0.12, 0.25), and C. tropicalis (0.06, 4, ≥64, 0.5, 2). E1210 was also the most active agent against fluconazole-resistant strains of C. albicans (MIC range, 0.015-0.12 μg/mL), C. glabrata (0.06 μg/mL), C. parapsilosis (MIC range, 0.06-0.05 μg/mL), and C. tropicalis (MIC range, 0.008-0.06 μg/mL), and was the most potent agent tested against caspofungin-resistant strains of C. albicans (MIC range, 0.008-0.12 μg/mL), C. glabrata (MIC range, 0.03-0.06 μg/mL), and C. tropicalis (MIC range, 0.015-0.06 μg/mL).
Diagnostic microbiology and infectious disease 06/2011; 71(2):167-70. · 2.45 Impact Factor
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ABSTRACT: We surveyed 497 isolates of Aspergillus fumigatus collected from 2008 to 2009 as part of the ARTEMIS global surveillance study for elevated MIC values to itraconazole, voriconazole, and posaconazole. Sequencing of the cyp51A gene revealed that 8/29 isolates with elevated MIC values to one or more triazoles, all originating in China, contained the TR/L98H mutation associated with resistant European isolates of A. fumigatus. This is the first time the TR/L98H mutation has been identified outside Europe.
Antimicrobial Agents and Chemotherapy 06/2011; 55(9):4465-8. · 4.84 Impact Factor
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ABSTRACT: The performance of the automated Vitek 2 (bioMérieux, Inc., Marcy l'Etoile, France) antifungal susceptibility system was compared to that of broth microdilution (BMD) for the determination of MICs of various antifungal drugs. A total of 112 challenge strains and 755 clinical isolates of Candida spp. were tested against caspofungin and micafungin. An additional 452 clinical isolates of Candida albicans were tested against posaconazole. Reference BMD MIC endpoints were established after 24 h of incubation for caspofungin and micafungin and after 48 h of incubation for posaconazole. Essential agreements (EAs) between the Vitek 2 and BMD methods for caspofungin and micafungin were 99.5% and 98.6%, respectively. EA between the Vitek 2 and BMD methods was 95.6% for posaconazole. The overall categorical agreements (CAs) between the Vitek 2 system and BMD were 99.8% for caspofungin, 98.2% for micafungin, and 98.1% for posaconazole. The Vitek 2 system reliably determined caspofungin and micafungin MICs among Candida spp. and posaconazole MICs among C. albicans isolates and demonstrated excellent quantitative and qualitative agreement with the reference BMD method.
Journal of clinical microbiology 03/2011; 49(5):1765-71. · 4.16 Impact Factor
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ABSTRACT: Community-onset (CO) candidemia, defined as a positive blood culture taken at or within 2 days of hospital admission, represents a distinct clinical entity associated with substantial morbidity and mortality. Reference MIC results from the SENTRY Antimicrobial Surveillance Program (2008-2009) were analyzed to compare the antifungal resistance patterns and species distributions from patients with CO and nosocomial bloodstream infections (BSI) in 79 medical centers. Among 1,354 episodes of BSI, 494 (36.5%) were classified as CO and 860 (63.5%) as nosocomial in origin. More than 95% of the isolates from both BSI types were contributed by Candida albicans (48.4%), C. glabrata (18.2%), C. parapsilosis (17.1%), C. tropicalis (10.6%), and C. krusei (2.0%). C. albicans was more common in CO BSI (51.0%) than nosocomial BSI (46.9%), whereas C. parapsilosis and C. krusei were more common in nosocomial BSIs (18.1 and 2.7%, respectively) than in CO BSIs (15.4 and 0.8%, respectively). C. glabrata and C. tropicalis were comparable in both CO (18.4 and 10.5%, respectively) and nosocomial (18.1 and 10.6%, respectively) episodes. Resistance to azoles (fluconazole, posaconazole, and voriconazole) and echinocandins (anidulafungin, caspofungin, and micafungin) was uncommon (<5%) in CO BSI using recently established Clinical and Laboratory Standards Institute breakpoint criteria. Resistance to echinocandins (anidulafungin [3.8%], caspofungin [5.1%], and micafungin [3.2%]) and azoles (fluconazole [7.7%], posaconazole [5.1%], and voriconazole [6.4%]) was most prevalent among nosocomial BSI isolates of C. glabrata. CO candidemia is not uncommon and appears to be increasing worldwide due to changing health care practices. Although resistance to the azoles and echinocandins remains uncommon among CO isolates, we demonstrate the emergence of nosocomial occurrences of C. glabrata expressing resistance to both monitored classes of antifungal agents.
Antimicrobial Agents and Chemotherapy 02/2011; 55(2):561-6. · 4.84 Impact Factor
