Echinocandin resistance is increasing, including among FLC-resistant isolates. The new Clinical and Laboratory Standards Institute 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.

The galactomannan assay has moderate accuracy for diagnosis of invasive aspergillosis in immunocompromised patients. The test is more useful in patients who have hematological malignancy or who have undergone hematopoietic cell transplantation than in solid-organ transplant recipients. Further studies with attention to the impact of antifungal therapy, rigorous assessment of false-positive test results, and assessment of the utility of the test under nonsurveillance conditions are needed.

For Candida species, a bimodal wild-type MIC distribution for echinocandins exists, but resistance to echinocandins is rare. We characterized isolates from patients with invasive candidiasis (IC) breaking through >3 doses of micafungin therapy during the first 28 months of its use at our center: MICs were determined and hot-spot regions within FKS genes were sequenced. Eleven of 12 breakthrough IC cases identified were in transplant recipients. The median duration of micafungin exposure prior to breakthrough was 33 days (range, 5 to 165). Seventeen breakthrough isolates were recovered: FKS hot-spot mutations were found in 5 C. glabrata and 2 C. tropicalis isolates; of these, 5 (including all C. glabrata isolates) had micafungin MICs of >2 g/ml, but all demonstrated caspofungin MICs of >2 g/ml. Five C. parapsilosis isolates had wild-type FKS sequences and caspofungin MICs of 0.5 to 1 g/ml, but 4/5 had micafungin MICs of >2 g/ml. The remaining isolates retained echinocandin MICs of <2 g/ml and wild-type FKS gene sequences. Breakthrough IC on micafungin treatment occurred predominantly in severely immunosuppressed patients with heavy prior micafungin exposure. The majority of cases were due to C. glabrata with an FKS mutation or wild-type C. parapsilosis with elevated micafungin MICs. MIC testing with caspofungin identified all mutant strains. Whether the naturally occurring polymorphism within the C. parapsilosis FKS1 gene responsible for the bimodal wild-type MIC distribution is also responsible for micafungin MICs of >2 g/ml and clinical breakthrough or an alternative mechanism contributes to the nonsusceptible echinocandin MICs in C. parapsilosis requires further study.Invasive candidiasis (IC) is an important, life-threatening infection in hospitalized patients. The echinocandins (micafungin, caspofungin, and anidulafungin) are the newest class of medications approved for the prophylaxis and treatment of IC. They act via noncompetitive inhibition of ␤-1,3-glucan synthase, the enzyme responsible for producing ␤-1,3-D-glucan in the fungal cell wall (41). These drugs have low toxicity and few drug-drug interactions and possess a broad spectrum of antifungal activity against Candida species, including those resistant to fluconazole. In clinical trials, the echinocandins have demonstrated noninferiority for the treatment of IC versus amphotericin B deoxycholate, liposomal amphotericin B, and fluconazole (25,32,44). The echinocandins are considered interchangeable for clinical use, and a recent study comparing micafungin to caspofungin for IC supports this notion (38). Based on the accumulated experience, echinocandins are now considered a first-line therapeutic choice for IC (37).The echinocandins exhibit a bimodal MIC distribution among Candida species. MICs of C. parapsilosis, C. guilliermondii, and C. famata MICs (MIC 90 , 0.25 to 2 g/ml) are up to 133 times higher than those of C. albicans, C. glabrata, C. tropicalis, C. krusei, and C. kefyr (MIC 90 , 0.015 to 0.25 g/ml) (42). However, this difference has not...

One potential limitation of DNA-based molecular diagnostic tests for Candida bloodstream infection (BSI) is organism burden, which is not sufficiently characterized. We hypothesized that the number of CFU per milliliter (CFU/ml) present in an episode of Candida BSI is too low for reliable DNA-based diagnostics. In this study, we determined Candida burden in the first positive blood culture and explored factors that affect organism numbers and patient outcomes. We reviewed records of consecutive patients with a positive blood culture for Candida in the lysis-centrifugation blood culture system (Isolator, Wampole Laboratories, Cranbury, NJ) from 1987 to 1991. Descriptive statistics and logistic regression analyses were performed. One hundred fifty-two episodes of Candida BSI were analyzed. Patient characteristics included adult age (72%), indwelling central venous catheters (83%), recent surgery (29%), neutropenia (24%), transplant (14%), and other immune suppression (21%). Rates of treatment success and 30-day mortality for candidemia were each 51%. The median CFU/ml was 1 (mode 0.1, range 0.1 to >1,000). In the multivariate analysis, pediatric patients were more likely than adults to have high organism burdens (odds ratio [OR], 10.7; 95% confidence interval [95% CI], 4.3 to 26.5). Initial organism density did not affect patient outcome. Candida CFU/ml in the first positive blood culture of a BSI episode varies greatly; >50% of cultures had <1 CFU/ml, a concentration below the experimental yeast cell threshold for reliable DNA-based diagnostics. DNA-based diagnostics for Candida BSI will be challenged by low organism density and the need for sufficient specimen volume; future research on alternate targets is warranted.Candida is the fourth most common cause of bloodstream infection (BSI) in much of the developed world and is responsible for significant morbidity and mortality in hospitalized patients (19). The standard of care for detecting Candida BSI is the blood culture, a method that is hampered by a sensitivity of only 50 to 60% and a lag time of up to 5 days for identification (2). This poor performance has led to the development of new molecular and protein-based diagnostics for Candida BSI. Unfortunately, no test has emerged as a clear improvement over blood culture, which remains the standard despite several studies demonstrating need for early therapy to improve outcome (6,17).A potentially limiting factor in developing molecular testing for Candida BSIs is organism burden. If the number of Candida CFU per milliliter in blood is low early in disease, then the expected sensitivity of a DNA-based test would be poor. The complexity of detecting a few organisms is compounded by the difficulty of breaking open the fungal cell wall to access DNA. The estimated burden of yeasts required for reliable DNAbased PCR detection is 5 to 10 CFU/ml (4, 13, 14). To date, the organism burden early in clinical candidemia has not been well established. Because automated blood culture systems (BAC-TEC 9240, Becton Dickinson...

BackgroundInvasive candidiasis (IC) is a devastating disease. While prompt antifungal therapy improves outcomes, empiric treatment based on the presence of fever has little clinical impact. Β-D-Glucan (BDG) is a fungal cell wall component detectable in the serum of patients with early invasive fungal infection (IFI). We evaluated the utility of BDG surveillance as a guide for preemptive antifungal therapy in at-risk intensive care unit (ICU) patients.MethodsPatients admitted to the ICU for ≥3 days and expected to require at least 2 additional days of intensive care were enrolled. Subjects were randomized in 3∶1 fashion to receive twice weekly BDG surveillance with preemptive anidulafungin in response to a positive test or empiric antifungal treatment based on physician preference.ResultsSixty-four subjects were enrolled, with 1 proven and 5 probable cases of IC identified over a 2.5 year period. BDG levels were higher in subjects with proven/probable IC as compared to those without an IFI (117 pg/ml vs. 28 pg/ml; p<0.001). Optimal assay performance required 2 sequential BDG determinations of ≥80 pg/ml to define a positive test (sensitivity 100%, specificity 75%, positive predictive value 30%, negative predictive value 100%). In all, 21 preemptive and 5 empiric subjects received systemic antifungal therapy. Receipt of preemptive antifungal treatment had a significant effect on BDG concentrations (p< 0.001). Preemptive anidulafungin was safe and generally well tolerated with excellent outcome.ConclusionsBDG monitoring may be useful for identifying ICU patients at highest risk to develop an IFI as well as for monitoring treatment response. Preemptive strategies based on fungal biomarkers warrant further study.Trial RegistrationClinical Trials.gov NCT00672841