scholarly journals Caspofungin MICs Correlate with Treatment Outcomes among Patients with Candida glabrata Invasive Candidiasis and Prior Echinocandin Exposure

2013 ◽  
Vol 57 (8) ◽  
pp. 3528-3535 ◽  
Author(s):  
Ryan K. Shields ◽  
M. Hong Nguyen ◽  
Ellen G. Press ◽  
Cassaundra L. Updike ◽  
Cornelius J. Clancy
Keyword(s):  
Treatment Outcomes ◽  
Sensitivity And Specificity ◽  
Invasive Candidiasis ◽  
Candida Glabrata ◽  
Susceptibility Testing ◽  
Treatment Success ◽  
Resistant Isolate ◽  
Content Type ◽  
Sterile Site ◽  
Independent Risk Factors

ABSTRACTMutations inCandida glabrata FKSgenes, which encode the echinocandin target enzyme, are independent risk factors for treatment failures during invasive candidiasis. We retrospectively compared the ability of caspofungin susceptibility testing methods to identifyC. glabrataFKSmutant isolates and predict outcomes among patients at our center. Eight percent (10/120) of sterile-siteC. glabrataisolates harboredFKS1(n= 3) orFKS2(n= 7) mutations, including 32% (10/32) recovered from patients with prior echinocandin exposure. Median echinocandin exposures for mutant and nonmutant isolates were 55 (range, 7 to 188) and 13 (3 to 84) days, respectively (P= 0.004). Sensitivity and specificity of the CLSI caspofungin resistance breakpoint MIC (>0.12 μg/ml by broth microdilution using RPMI medium [BMD-RPMI]) were 90% (9/10) and 3% (3/110), respectively, for identifyingFKSmutants. Sensitivity and specificity of receiver-operator characteristic (ROC) curve-derived breakpoints by BMD-RPMI, BMD-antibiotic medium 3, Etest, and YeastOne ranged from 70 to 100% and 89 to 95%, respectively; susceptibility rates varied from 83 to 90%. The 14-day echinocandin treatment success rate was 67% (44/66); failure was more likely with prior echinocandin exposure (P= 0.002) or infection with anFKSmutant (P= 0.0001) or echinocandin-resistant isolates by BMD-AM3, Etest, and YeastOne (P≤ 0.03). The failure rate among patients with prior exposure and infection with a resistant isolate was 91% (10/11); it was 22% (12/55) among others (P< 0.0001). In conclusion, ROC-derived caspofungin MIC breakpoints by several methods were sensitive and specific for identifyingC. glabrataFKSmutant isolates. Mutations were seen exclusively among patients with prior echinocandin exposure. A paradigm that considers prior echinocandin exposure and caspofungin MICs accurately classified treatment outcomes forC. glabratainvasive candidiasis.

scholarly journals Implications of the EUCAST Trailing Phenomenon inCandida tropicalisfor theIn VivoSusceptibility in Invertebrate and Murine Models

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
K. M. T. Astvad ◽  
D. Sanglard ◽  
E. Delarze ◽  
R. K. Hare ◽  
M. C. Arendrup
Keyword(s):  
Susceptibility Testing ◽  
Galleria Mellonella ◽  
Growth Control ◽  
Resistant Isolate ◽  
Murine Models ◽  
Wild Type ◽  
Content Type ◽  
Gradual Loss

ABSTRACTCandida tropicalisisolates often display reduced but persistent growth (trailing) over a broad fluconazole concentration range during EUCAST susceptibility testing. Whereas weak trailing (<25% of the positive growth control) is common and found not to impair fluconazole efficacy, we investigated if more pronounced trailing impacted treatment efficacy. Fluconazole efficacy against two weakly (≤25% growth), two moderately (26% to 50% growth), and one heavily (>70% growth) trailing resistant isolate and one resistant (100% growth) isolate were investigatedin vitroandin vivo(in aGalleria mellonellasurvival model and two nonlethal murine models).CDR1expression levels andERG11sequences were characterized. The survival in fluconazole-treatedG. mellonellawas inversely correlated with the degree of trailing (71% to 9% survival in treatment groups). In mice, resistant and heavily trailing isolates responded poorly to fluconazole treatment.CDR1expression was significantly higher in trailing and resistant isolates than in wild-type isolates (1.4-fold to 10-fold higher). All isolates exhibitedERG11wild-type alleles. Heavily trailing isolates were less responsive to fluconazole in allin vivomodels, indicating an impact on fluconazole efficacy.CDR1upregulation may have contributed to the observed differences. Moderately trailing isolates responded less well to fluconazole in larvae only. This confirms clinical data suggesting fluconazole is effective against infections with such isolates in less severely ill patients and supports the current 50% growth endpoint for susceptibility testing. However, it is still unclear if the gradual loss of efficacy observed for moderately trailing isolates in the larva model may be a reason for concern in selected vulnerable patient populations.

scholarly journals Genomewide Expression Profile Analysis of the Candida glabrata Pdr1 Regulon

2010 ◽  
Vol 10 (3) ◽  
pp. 373-383 ◽  
Author(s):  
Kelly E. Caudle ◽  
Katherine S. Barker ◽  
Nathan P. Wiederhold ◽  
Lijing Xu ◽  
Ramin Homayouni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differentially Expressed Genes ◽  
Candida Glabrata ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Differentially Expressed ◽  
Resistant Isolate ◽  
Content Type ◽  
Activating Mutations ◽  
Zinc Cluster

ABSTRACTThe ABC transportersCandida glabrataCdr1 (CgCdr1), CgPdh1, and CgSnq2 are known to mediate azole resistance in the pathogenic fungusC. glabrata. Activating mutations inCgPDR1, a zinc cluster transcription factor, result in constitutive upregulation of these ABC transporter genes but to various degrees. We examined the genomewide gene expression profiles of two matched azole-susceptible and -resistantC. glabrataclinical isolate pairs. Of the differentially expressed genes identified in the gene expression profiles for these two matched pairs, there were 28 genes commonly upregulated withCgCDR1in both isolate sets includingYOR1,LCB5,RTA1,POG1,HFD1, and several members of theFLOgene family of flocculation genes. We then sequencedCgPDR1from each susceptible and resistant isolate and found two novel activating mutations that conferred increased resistance when they were expressed in a common background strain in whichCgPDR1had been disrupted. Microarray analysis comparing these reengineered strains to their respective parent strains identified a set of commonly differentially expressed genes, includingCgCDR1,YOR1, andYIM1, as well as genes uniquely regulated by specific mutations. Our results demonstrate that while CgPdr1 activates a broad repertoire of genes, specific activating mutations result in the activation of discrete subsets of this repertoire.

scholarly journals Caspofungin Dose Escalation for Invasive Candidiasis Due to Resistant Candida albicans

2011 ◽  
Vol 55 (7) ◽  
pp. 3254-3260 ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Laura K. Najvar ◽  
Rosie A. Bocanegra ◽  
William R. Kirkpatrick ◽  
Thomas F. Patterson
Keyword(s):  
Candida Albicans ◽  
Dose Escalation ◽  
Invasive Candidiasis ◽  
Hot Spot ◽  
Kidney Tissue ◽  
Resistant Isolate ◽  
Content Type ◽  
Tissue Burden ◽  
Higher Doses

ABSTRACTPreviousin vivostudies have reported caspofungin dose escalation to be effective againstCandida glabratawith reduced susceptibility. We hypothesized that higher doses of caspofungin would be effective against invasive candidiasis caused by the more virulent speciesCandida albicans, including isolates resistant to this echinocandin. Immunocompetent mice were inoculated with one of threeC. albicansisolates, including one susceptible and two resistant isolates with differentFKS1hot spot 1 point mutations. Mice received daily caspofungin treatment for 7 days and were then followed off therapy for 2 weeks to assess survival. Kidney tissue and blood were collected, and fungal burden and serum (1→3)-β-d-glucan were measured. Significant differences in virulence were observed among the threeC. albicansisolates, which translated into differences in responses to caspofungin. The most virulent of the resistant isolates studied (isolate 43001; Fks1p F641S) did not respond to caspofungin doses of up to 10 mg/kg of body weight, as there were no differences in survival (survival range, 0 to 12% with treatment), tissue burden, or (1→3)-β-d-glucan concentration compared to those for untreated controls. Higher doses of caspofungin did improve survival against the second resistant isolate (53264; Fks1p S645P) that demonstrated reduced virulence (5 and 10 mg/kg; 80% survival). In contrast, caspofungin doses as low as 1 mg/kg improved survival (85 to 95%) and reduced tissue burden and (1→3)-β-d-glucan concentration against the susceptible isolate (ATCC 90028). These data suggest that caspofungin dose escalation for invasive candidiasis may not be consistently effective against resistantC. albicansisolates, and this may be associated with the virulence of the strain.

scholarly journals Effect of pH onIn VitroSusceptibility of Candida glabrata and Candida albicans to 11 Antifungal Agents and Implications for Clinical Use

2012 ◽  
Vol 56 (3) ◽  
pp. 1403-1406 ◽  
Author(s):  
Claire S. Danby ◽  
Dina Boikov ◽  
Rina Rautemaa-Richardson ◽  
Jack D. Sobel
Keyword(s):  
Amphotericin B ◽  
Candida Glabrata ◽  
Antifungal Agents ◽  
Susceptibility Testing ◽  
Low Ph ◽  
Clinical Use ◽  
Effect Of Ph ◽  
Content Type ◽  
Clinical Observations

ABSTRACTThe treatment of vulvovaginal candidiasis (VVC) due toCandida glabratais challenging, with limited therapeutic options. Unexplained disappointing clinical efficacy has been reported with systemic and topical azole antifungal agents in spite ofin vitrosusceptibility. Given that the vaginal pH of patients with VVC is unchanged at 4 to 4.5, we studied the effect of pH on thein vitroactivity of 11 antifungal agents against 40C. glabrataisolates and compared activity against 15 fluconazole-sensitive and 10 reduced-fluconazole-susceptibilityC. albicansstrains.In vitrosusceptibility to flucytosine, fluconazole, voriconazole, posaconazole, itraconazole, ketoconazole, clotrimazole, miconazole, ciclopirox olamine, amphotericin B, and caspofungin was determined using the CLSI method for yeast susceptibility testing. Test media were buffered to pHs of 7, 6, 5, and 4. Under conditions of reduced pH,C. glabrataisolates remained susceptible to caspofungin and flucytosine; however, there was a dramatic increase in the MIC90for amphotericin B and every azole drug tested. Although susceptible to other azole drugs tested at pH 7,C. albicansstrains with reduced fluconazole susceptibility also demonstrated reduced susceptibility to amphotericin B and all azoles at pH 4. In contrast, fluconazole-sensitiveC. albicansisolates remained susceptible at low pH to azoles, in keeping with clinical observations. In selecting agents for treatment of recurrentC. glabratavaginitis, clinicians should recognize the limitations ofin vitrosusceptibility testing utilizing pH 7.0.

scholarly journals Impact of Vancomycin MIC on Treatment Outcomes in Invasive Staphylococcus aureus Infections

2016 ◽  
Vol 61 (3) ◽  
Author(s):  
Kyoung-Ho Song ◽  
Moonsuk Kim ◽  
Chung Jong Kim ◽  
Jeong Eun Cho ◽  
Yun Jung Choi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Staphylococcus Aureus ◽  
Treatment Outcomes ◽  
Sufficient Evidence ◽  
Current Clinical Practice ◽  
Broth Microdilution ◽  
Content Type ◽  
Increased Risk ◽  
Sterile Site ◽  
The Relationship

ABSTRACT There are conflicting data on the association of vancomycin MIC (VAN-MIC) with treatment outcomes in Staphylococcus aureus infections. We investigated the relationship between high VAN-MIC and 30-day mortality and identified the risk factors for mortality in a large cohort of patients with invasive S. aureus (ISA) infections, defined as the isolation of S. aureus from a normally sterile site. Over a 2-year period, 1,027 adult patients with ISA infections were enrolled in 10 hospitals, including 673 (66%) patients with methicillin-resistant S. aureus (MRSA) infections. There were 200 (19.5%) isolates with high VAN-MIC (≥1.5 mg/liter) by Etest and 87 (8.5%) by broth microdilution (BMD). The all-cause 30-day mortality rate was 27.4%. High VAN-MIC by either method was not associated with all-cause 30-day mortality, and this finding was consistent across MIC methodologies and methicillin susceptibilities. We conclude that high VAN-MIC is not associated with increased risk of all-cause 30-day mortality in ISA infections. Our data support the view that VAN-MIC alone is not sufficient evidence to change current clinical practice.

scholarly journals Evaluation of the “Dip Effect” Phenomenon in Antifungal Susceptibility Testing of Candida spp. against Echinocandins by Use of Gradient Concentration Strips

2015 ◽  
Vol 53 (11) ◽  
pp. 3654-3659 ◽  
Author(s):  
Maria Siopi ◽  
Marilena Tsala ◽  
Nikolaos Siafakas ◽  
Loukia Zerva ◽  
Joseph Meletiadis
Keyword(s):  
Candida Albicans ◽  
Candida Tropicalis ◽  
Candida Glabrata ◽  
Susceptibility Testing ◽  
Antifungal Susceptibility ◽  
Antifungal Susceptibility Testing ◽  
Practical Approach ◽  
Candida Spp ◽  
Content Type ◽  
Inhibition Zones

The “dip effect” phenomenon complicates antifungal susceptibility testing with gradient concentration strips. Of 60Candidaisolates tested with the three echinocandins, this phenomenon was observed only for caspofungin with most (>90%)Candida albicans,Candida glabrata, andCandida tropicalisisolates and for isolates with CLSI MICs of ≤0.25 mg/liter. In order to facilitate MIC determination, a practical approach was developed using the inhibition zones at 32, 8, 2, and 1 mg/liter, increasing the agreement with the CLSI method >86%.

scholarly journals Role of FKS Mutations in Candida glabrata: MIC Values, Echinocandin Resistance, and Multidrug Resistance

2014 ◽  
Vol 58 (8) ◽  
pp. 4690-4696 ◽  
Author(s):  
Cau D. Pham ◽  
Naureen Iqbal ◽  
Carol B. Bolden ◽  
Randall J. Kuykendall ◽  
Lee H. Harrison ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Susceptibility Testing ◽  
Hot Spot ◽  
Case Reports ◽  
Multidrug Resistant ◽  
High Rate ◽  
Primary Therapy ◽  
Content Type ◽  
Major Mechanism ◽  
Echinocandin Resistance

ABSTRACTCandida glabratais the second leading cause of candidemia in U.S. hospitals. Current guidelines suggest that an echinocandin be used as the primary therapy for the treatment ofC. glabratadisease due to the high rate of resistance to fluconazole. Recent case reports indicate thatC. glabrataresistance to echinocandins may be increasing. We performed susceptibility testing on 1,380 isolates ofC. glabratacollected between 2008 and 2013 from four U.S. cities, Atlanta, Baltimore, Knoxville, and Portland. Our analysis showed that 3.1%, 3.3%, and 3.6% of the isolates were resistant to anidulafungin, caspofungin, and micafungin, respectively. We screened 1,032 of these isolates, including all 77 that had either a resistant or intermediate MIC value with respect to at least one echinocandin, for mutations in the hot spot regions ofFKS1andFKS2, the major mechanism of echinocandin resistance. Fifty-one isolates were identified with hot spot mutations, 16 inFKS1and 35 inFKS2. All of the isolates with anFKSmutation except one were resistant to at least one echinocandin by susceptibility testing. Of the isolates resistant to at least one echinocandin, 36% were also resistant to fluconazole. Echinocandin resistance among U.S.C. glabrataisolates is a concern, especially in light of the fact that one-third of those isolates may be multidrug resistant. Further monitoring of U.S.C. glabrataisolates for echinocandin resistance is warranted.

scholarly journals Performance of a Quantitative PCR-Based Assay and Beta-d-Glucan Detection for Diagnosis of Invasive Candidiasis in Very-Low-Birth-Weight Preterm Neonatal Patients (CANDINEO Study)

2017 ◽  
Vol 55 (9) ◽  
pp. 2752-2764 ◽  
Author(s):  
Jose Tomas Ramos ◽  
Sonia Villar ◽  
Emilio Bouza ◽  
Elena Bergon-Sendin ◽  
Alfredo Perez Rivilla ◽  
...  
Keyword(s):  
Birth Weight ◽  
Low Birth Weight ◽  
Blood Serum ◽  
Sensitivity And Specificity ◽  
Invasive Candidiasis ◽  
Very Low Birth Weight ◽  
Multiorgan Failure ◽  
Preterm Neonates ◽  
Suspected Sepsis ◽  
Content Type

ABSTRACT An epidemiological, multicenter, noninterventional, observational case-control study was conducted to describe the performance of serum beta- d -glucan (BDG) and Candida PCR in blood, serum, and sterile samples for the diagnosis of invasive candidiasis (IC) in very-low-birth-weight (VLBW) preterm neonates and to compare these techniques with culture of samples from blood and other sterile sites. Seventeen centers participated in the study, and the number of episodes analyzed was 159. A total of 9 episodes of IC from 9 patients (7 confirmed and 2 probable) and 150 episodes of suspected sepsis from 117 controls were identified. The prevalence of IC was 5.7% (95% confidence interval [95% CI], 2.1 to 9.3). The mortality was significantly higher in episodes of IC (44.4%) than in the non-IC episodes (11.1%, P < 0.01). The sensitivity and specificity of the PCR performed on blood/serum samples were 87.5% and 81.6%, respectively. The sensitivity and specificity of the BDG results were lower (75.0% and 64.6%). For cases with negative culture results, the PCR and the BDG results were positive in 27 (17.4%) and 52 (33.5%) episodes, respectively. The presence of multiorgan failure, improvement with empirical antifungal therapy, thrombocytopenia, and Candida colonization were significantly associated ( P < 0.01) with PCR or BDG positivity regardless of the results of the cultures. Serum BDG analysis and Candida PCR could be used as complementary diagnostic techniques to detect IC in VLBW neonates.

scholarly journals Diagnostic Accuracy of BD Phoenix CPO Detect for Carbapenemase Production in 190 Enterobacteriaceae Isolates

2018 ◽  
Vol 56 (12) ◽  
Author(s):  
Chiou Horng Ong ◽  
Lasantha Ratnayake ◽  
Michelle L. T. Ang ◽  
Raymond Tzer Pin Lin ◽  
Douglas Su Gin Chan
Keyword(s):  
Confidence Interval ◽  
Infection Control ◽  
Diagnostic Accuracy ◽  
Positive Result ◽  
Sensitivity And Specificity ◽  
Patient Management ◽  
Susceptibility Testing ◽  
Control Measures ◽  
Content Type ◽  
Infection Control Measures

ABSTRACT The rapid and accurate detection of carbapenemase-producing Enterobacteriaceae (CPE) is necessary for patient management and infection control measures. We compared the performance of the BD Phoenix CPO Detect with that of a homemade Carba NP assay and a modified carbapenem inactivation method (mCIM) by challenging all 3 assays with 190 isolates of Enterobacteriaceae with meropenem MICs of >0.125 mg/liter. A total of 160 isolates produced KPC-, IMI-1-, NDM-, IMP-, and OXA-type carbapenemases, while 30 isolates were negative for carbapenemase production. The sensitivity and specificity were 90.6% (95% confidence interval [CI], 85.0% to 94.7%) and 100.0% (95% CI, 88.4% to 100.0%), respectively, for the Carba NP; 100.0% (95% CI, 97.7% to 100.0%) and 96.7% (95% CI, 82.7% to 99.9%), respectively, for the mCIM; and 89.4% (95% CI, 83.5% to 93.7%) and 66.7% (95% CI, 47.2% to 82.7%), respectively, for the BD Phoenix CPO Detect. In particular, the BD CPO Detect failed to detect a significant number of CPE with IMI-1. While the BD Phoenix CPO Detect is able to classify carbapenemases and is built into routine susceptibility testing with the potential to reduce the time to CPE detection, its low specificity means that a positive result will need confirmatory testing by another method.

scholarly journals Anidulafungin and Micafungin MIC Breakpoints Are Superior to That of Caspofungin for IdentifyingFKSMutant Candida glabrata Strains and Echinocandin Resistance

2013 ◽  
Vol 57 (12) ◽  
pp. 6361-6365 ◽  
Author(s):  
Ryan K. Shields ◽  
M. Hong Nguyen ◽  
Ellen G. Press ◽  
Cassaundra L. Updike ◽  
Cornelius J. Clancy
Keyword(s):  
Invasive Candidiasis ◽  
Candida Glabrata ◽  
Content Type ◽  
Mutant Strains ◽  
Echinocandin Resistance

ABSTRACTBy CLSI interpretive criteria, anidulafungin and micafungin MICs determined by various methods were sensitive (60 to 70%) and highly specific (94 to 100%) for identifyingFKSmutations among 120Candida glabrataisolates. Anidulafungin and micafungin breakpoints were more specific than CLSI's caspofungin breakpoint in identifyingFKSmutant strains and patients with invasive candidiasis who were likely to fail echinocandin treatment (P≤ 0.0001 for both). Echinocandin MICs were most useful clinically when interpreted in the context of prior echinocandin exposure.

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