<i>In Vitro</i>
            Exposure to Increasing Micafungin Concentrations Easily Promotes Echinocandin Resistance in Candida glabrata Isolates

Bordallo-Cardona, María Ángeles; Escribano, Pilar; Pedrosa, Elia Gómez G. de la; Marcos-Zambrano, Laura Judith; Bouza, Emilio; Guinea, Jesús

doi:10.1128/aac.01542-16

Cited by 31 publications

(26 citation statements)

References 15 publications

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“…The different HS1 mutations did not result in different MIC values. This contrasts with previous studies that suggested that C. glabrata isolates harboring the D666Y mutation in FKS2 show weak resistance, while the S663P mutation confers strong resistance (22,23). Additionally, we did not find any mutations in HS2 and like in previous studies, most of the mutations influencing C. glabrata echinocandin susceptibility were located in HS1 of either FKS gene (6,8,24).…”

Section: Discussioncontrasting

confidence: 99%

“…Fourteen resistant isolates were detected by the MBT ASTRA that had no HS mutations in FKS genes. In routine clinical practice, in which usually no gene sequencing is performed, it has obviously not been noticed that there are C. glabrata isolates with elevated MIC values for echinocandins without mutations in the FKS1 and/or FKS2 gene (22,28). However, there are some possible explanations for this observation, which is also known as adaptive response (29,30).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, upon extensive exposure to different antifungals, C. glabrata activates stress responses to compensate for the growth inhibition and to avoid death. Accordingly, growth of C. glabrata isolates on plates containing even low concentrations of echinocandins can cause the emergence of resistant isolates (22). Furthermore, exposure to echinocandins activates the cell wall integrity (CWI) pathway in C. glabrata.…”

Section: Discussionmentioning

confidence: 99%

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Anidulafungin Susceptibility Testing of Candida glabrata Isolates from Blood Cultures by the MALDI Biotyper Antibiotic (Antifungal) Susceptibility Test Rapid Assay

Vatanshenassan

Arastehfar

Boekhout

et al. 2019

Antimicrob Agents Chemother

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Echinocandins are the recommended first-line antifungals for treatment of invasive candidiasis. The increasing number of Candida glabrata strains resistant against echinocandins is an emerging health care concern. The rapid detection of resistant C. glabrata isolates is an urgent requirement for clinical laboratories. In this study, we developed the MALDI Biotyper antibiotic (antifungal) susceptibility test rapid assay (MBT ASTRA) for the rapid detection of anidulafungin-resistant C. glabrata isolates directly from positive blood cultures. Of 100 C. glabrata strains, MBT ASTRA classified 69 as susceptible and 29 as resistant. Microdilution assays performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines, used as a standard reference, identified 65 susceptible, 9 intermediate, and 26 resistant isolates. Sequencing of hot spot 1 and hot spot 2 regions of the FKS1 and FKS2 genes classified 86 susceptible and 14 resistant isolates. The MBT ASTRA had sensitivity and specificity of 80% and 95%, respectively, compared to the microdilution method. Positive and negative agreement of MBT ASTRA was calculated at 100% and 80%, respectively, compared with the molecular sequencing approach. Together, these results revealed a high accuracy of MBT ASTRA compared to microdilution according to the CLSI and PCR analysis, resulting in a categorical agreement of 90% and 83%, respectively. The validity of MBT ASTRA was 98%. Importantly, MBT ASTRA provided antifungal susceptibility testing (AFST) within 6 h that was both accurate and reliable compared to the other two approaches, which require at least 24 h or are costly. Therefore, this method has the potential to facilitate clinical AFST rapidly at low sample costs for clinical labs already equipped with matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS).

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Anidulafungin Susceptibility Testing of Candida glabrata Isolates from Blood Cultures by the MALDI Biotyper Antibiotic (Antifungal) Susceptibility Test Rapid Assay

Vatanshenassan

Arastehfar

Boekhout

et al. 2019

Antimicrob Agents Chemother

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“…The emergence of echinocandin resistance in Denmark follows a significant increase in echinocandin consumption from 2004 to 2015. These observations suggest that longer-term administration of echinocandin, including its empirical use, should be minimized if possible (63,64).…”

Section: Discussionmentioning

confidence: 96%

Update from a 12-Year Nationwide Fungemia Surveillance: Increasing Intrinsic and Acquired Resistance Causes Concern

et al. 2018

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New data from the years 2012 to 2015 from the Danish National Fungemia Surveillance are reported, and epidemiological trends are investigated in a 12-year perspective (2004 to 2015). During 2012 to 2015, 1,900 of 1,939 (98%) fungal bloodstream isolates were included. The average incidence was 8.4/100,000 inhabitants, and this appears to represent a stabilizing trend after the increase to 10.1/100,000 in 2011. The incidence was higher in males than females (10.0 versus 6.8) and in patients above 50 years, and those changes were mainly driven by an increasing incidence among 80-to-89-year-old males (65.3/100,000 in 2014 to 2015). The proportion of isolates decreased from 2004 to 2015 (64.4% to 42.4%) in parallel with a doubling of the proportion of isolates (16.5% to 34.6%, < 0.0001). was more common among females (34.0% versus 30.4% in males). Following an increase in 2004 to 2011, the annual drug use stabilized during the last 2 to 3 years of that time period but remained higher than in other Nordic countries. This was particularly true for the fluconazole and itraconazole use in the primary health care sector, which exceeded the combined national levels of use of these compounds in each of the other Nordic countries. Fluconazole susceptibility decreased (68.5%, 65.2%, and 60.6% in 2004 to 2007, 2008 to 2011, and 2012 to 2015, respectively, < 0.0001), and echinocandin resistance emerged in (0%, 0.6%, and 1.7%, respectively, < 0.001). Amphotericin B susceptibility remained high (98.7%). Among 16 (2.7%) echinocandin-resistant isolates (2012 to 2015), 13 harbored FKS mutations and 5 (31%) were multidrug resistant. The epidemiological changes and the increased incidence of intrinsic and acquired resistance emphasize the importance of continued surveillance and of strengthened focus on antifungal stewardship.

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“…Parental isolates were phenotypically echinocandin susceptible, and isogenic ones were phenotypically echinocandin resistant. Pairs 1 to 8 came from a previous study and involved susceptible isolates from blood samples exposed in vitro to either micafungin or anidulafungin and the corresponding resistant ones generated (27,28). Pairs 9 and 10 originated in two patients with candidemia who developed concomitant echinocandin-resistant endocarditis.…”

Section: Discussionmentioning

confidence: 99%

Detection of Echinocandin-Resistant Candida glabrata in Blood Cultures Spiked with Different Percentages of FKS2 Mutants

Bordallo-Cardona

Sánchez‐Carrillo

Bouza

et al. 2019

Antimicrob Agents Chemother

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Infections caused by the coexistence ofCandida glabrataechinocandin-resistant and echinocandin-susceptible cells may be possible, and the detection ofFKSmutants when the proportions ofFKSmutants are underrepresented poses a problem. We assessed the role of EUCAST and methods directly performed on positive blood cultures—Etest (ETDIR) and anidulafungin-containing agar plate assays—for detecting resistance inC. glabrataisolates containing different amounts of echinocandin-susceptible and -resistantCandida glabrataisolates. We studied 10 pairs ofC. glabrataisolates involving parental echinocandin-susceptible isolates and isogenic echinocandin-resistantFKSmutant isolates. Three inocula per pair (1 × 103to 5 × 103, 1 × 102to 5 × 102, and 10 to 50 CFU/ml) spanning suspensions with different amounts of susceptible/resistant isolates (9/1, 5/5, and 1/9 proportions for each the three inocula) were prepared. The suspensions were spiked in Bactec bottles and incubated until they were positive, and the three methods were compared. The EUCAST method showed echinocandin resistance when the bottles were spiked with susceptible/resistant isolates at 5/5 and 1/9 proportions; the results for the suspensions with a 9/1 proportion of susceptible/resistant isolates were susceptible for three pairs. We observed with the ETDIRresistance to both echinocandins in all pairs (resistance to micafungin and anidulafungin; MICs, ≥0.064 mg/liter and ≥0.125 mg/liter, respectively) and a double ring of growth inhibition in two pairs. The anidulafungin-containing plates showed fungal growth in the 90 spiked blood cultures at 48 h. Testing of echinocandin susceptibility with the ETDIRdirectly on the positive blood culture bottles is a reliable and rapid method to detect echinocandin resistance inC. glabrata. On the other hand, resistance can be missed with the EUCAST method when resistant isolates are underrepresented.

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In Vitro Exposure to Increasing Micafungin Concentrations Easily Promotes Echinocandin Resistance in Candida glabrata Isolates

Cited by 31 publications

References 15 publications

Anidulafungin Susceptibility Testing of Candida glabrata Isolates from Blood Cultures by the MALDI Biotyper Antibiotic (Antifungal) Susceptibility Test Rapid Assay

Anidulafungin Susceptibility Testing of Candida glabrata Isolates from Blood Cultures by the MALDI Biotyper Antibiotic (Antifungal) Susceptibility Test Rapid Assay

Update from a 12-Year Nationwide Fungemia Surveillance: Increasing Intrinsic and Acquired Resistance Causes Concern

Detection of Echinocandin-Resistant Candida glabrata in Blood Cultures Spiked with Different Percentages of FKS2 Mutants

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