Biomarkers for the diagnosis of invasive candidiasis in immunocompetent and immunocompromised patients.

Blood culture methods show low sensitivity, so reliable non-culture diagnostic tests are needed to help clinicians with the introduction, de-escalation, and discontinuation of antifungal therapy in patients with suspected invasive candidiasis (IC). We evaluated different biomarkers for the diagnosis of IC in immunocompetent and immunocompromised patients at risk for developing invasive fungal diseases. The specificity of Candida albicans germ-tube antibodies (CAGTA) detection was high (89%-100%), but sensitivity did not exceed 61% even after raising the cut-off from 1/160 to 1/80. We developed enzyme-linked immunoassays detecting antibodies against C. albicans proteins (Als3-N, Hwp1-N, or Met6) that resulted more sensitive (66%-92%) but less specific than CAGTA assay. The combination of 1,3-beta-D-glucan (BDG) detection and CAGTA results provided the highest diagnostic usefulness in immunocompetent patients. However, in immunocompromised patients, anti-Met6 antibodies was the best biomarker, both, alone or in combination with BDG.

Molecular genotyping of Candida albicans isolated from different sites may trace the etiological infection routes: Observation in China.

BACKGROUND: Invasive candidiasis is a growing concern worldwide, especially in immunocompromised patients, including ICU patients. OBJECTIVES: As Candida albicans is the leading cause of candidaemia, it is important to investigate the evolution of C. albicans in patients with candidaemia. METHODS: We analysed 238 strains of C. albicans isolated from different body sites. Antifungal susceptibility testing, CAI loci genotyping and multilocus sequence typing (MLST) of all isolates were performed. The relationships among the total isolates that differed in sequence at only one of the seven housekeeping gene loci were analysed using eBURST. RESULTS: Multilocus sequence typing analysis in 238 isolates by combining seven housekeeping alleles revealed 175 diploid sequence types, in which 84 were newly identified. eBURST analysis for these data recognised 19 clonal complexes (CCs) and 79 singletons. Besides, seventy-three CAI genotypes were identified. Blood isolates showed maximum genotypes (49), and the dominant genotypes were CAI 17-21 and CAI 21-21. Oral isolates possessed 25 CAI genotypes, and the dominant genotypes were CAI 17-21 and CAI 21-21 as well. Since isolates with CAI allele numbers <30 showed easier transmission, CAI 17-21 and CAI 21-21 were the most frequently transmitted. Finally, the CAI genotypes were classified into six groups. CONCLUSIONS: This work revealed the oral and blood strains isolated from the patients with candidaemia in ICU shared the identical dominant CAI genotypes. Our data expanded the C. albicans MLST database and helped with understanding the evolution and spread of invasive candidiasis.

Comparative performance evaluation of Wako ß-glucan test and Fungitell assay for the diagnosis of invasive fungal diseases.

The Fungitell assay (FA) and the Wako ß-glucan test (GT) are employed to measure the serum/plasma 1,3-ß-D-glucan (BDG), a well-known invasive fungal disease biomarker. Data to convincingly and/or sufficiently support the GT as a valuable alternative to the FA are yet limited. In this study, we evaluated the FA and the GT to diagnose invasive aspergillosis (IA), invasive candidiasis (IC), and Pneumocystis jirovecii pneumonia (PJP). The FA and GT performances were compared in sera of patients with IA (n = 40), IC (n = 78), and PJP (n = 17) with respect to sera of control patients (n = 187). Using the manufacturer's cutoff values of 80 pg/mL and 11 pg/mL, the sensitivity and specificity for IA diagnosis were 92.5% and 99.5% for the FA and 60.0% and 99.5% for the GT, respectively; for IC diagnosis were 100.0% and 97.3% for the FA and 91.0% and 99.5% for the GT, respectively; for PJP diagnosis were 100.0% and 97.3% for the FA and 88.2% and 99.5% for the GT, respectively. When an optimized cutoff value of 7.0 pg/mL for the GT was used, the sensitivity and specificity were 80.0% and 97.3% for IA diagnosis, 98.7% and 97.3% for IC diagnosis, and 94.1% and 97.3% for PJP diagnosis, respectively. At the 7.0-pg/mL GT cutoff, the agreement between the assays remained and/or became excellent for IA (95.1%), IC (97.3%), and PJP (96.5%), respectively. In conclusion, we show that the GT performed as well as the FA only with a lowered cutoff value for positivity. Further studies are expected to establish the equivalence of the two BDG assays.

Species distribution and antifungal susceptibility profile of Candida isolates from blood and other normally sterile foci from pediatric ICU patients in Tehran, Iran.

As data on pediatric invasive candidiasis (IC) and the antifungal susceptibility pattern of associated isolates are scarce in Iran, this study aimed to determine species distribution and antifungal susceptibility profile of Candida species isolated from pediatric patients with suspected or documented IC. A total of 235 yeast strains recovered from normally sterile body fluids of patients admitted at the intensive care units of Children's Medical Centre, Tehran, Iran, were identified using CHROMagar Candida, molecular methods (ITS PCR-RFLP and sequencing), and MALDI-TOF. Susceptibility to amphotericin B, fluconazole, voriconazole, micafungin, and anidulafungin was determined according to the European on Antimicrobial Susceptibility testing reference microdilution method (EUCAST E.Def 7.3.1). Candida albicans (53.6%), C. parapsilosis (24.7%), and C. tropicalis (8.5%) were the most common species, followed by C. lusitaniae (4.3%), C. glabrata (3.0%), C. guilliermondii and C. orthopsilosis (each 1.7%), C. kefyr (1.3%), C. dubliniensis (0.8%), and C. intermedia (0.4%). Amphotericin B MICs were ≤1 mg/l for all Candida isolates. C. albicans isolates were susceptible to all five antifungal agents. All C. parapsilosis isolates categorised as intermediate to micafungin and anidulafungin, except two isolates that had the MICs >2 mg/l for micafungin. MIC50, MIC90, and MIC range for fluconazole were 0.25 mg/l, 1 mg/l, and 0.125 - ≥32 mg/l, respectively. Fluconazole and voriconazole showed 100% activity against the most prevalent Candida species. The low resistance rate, favorable safety profile and low cost of fluconazole make it a reasonable choice for treatment of candidemia/invasive candidemia in Iran.

Diagnostic accuracy of serum (1,3)-beta-d-glucan for neonatal invasive candidiasis: systematic review and meta-analysis.

OBJECTIVES: Neonatal invasive candidiasis (NIC) is a leading cause of infection-related morbidity and mortality in preterm neonates. Several studies have shown that (1,3)-Beta-d-glucan (BDG) was accurate in detecting invasive fungal infection in adults, but studies in neonates are scarce. The aim was to obtain summary estimates of the accuracy of BDG detection in serum for the diagnosis of NIC. METHODS: We searched Medline, Embase, Clinicaltrials.gov, and Google Scholar (inception to July 2019). We checked the reference lists of included studies, clinical guidelines, and review articles. We included studies that assessed the accuracy of BDG against a reference standard that defined groups of patients with ordinal levels of NIC probability (e.g. proven, probable, possible) and included fungal blood culture. Participants were neonates suspected of having NIC. The intervention was BDG measurement in serum (Fungitell® assay). We assessed risk of bias and applicability using QUADAS-2. We used bivariate meta-analysis to produce summary estimates of diagnostic accuracy at prespecified positivity thresholds of 80 and 120 pg/mL. This study was registered with PROSPERO (CRD42018089545). RESULTS: We included eight studies (465 participants). Of these, two were judged at low overall risk of bias. There was substantial variability across studies in the reference standards used. At a positivity threshold of 80 pg/mL, summary estimates of sensitivity and specificity of BDG were 89% (95% CI: 80-94%) and 60% (53-66%), respectively; summary sensitivity for detecting proven cases of NIC was 99% (93-100%). At a positivity threshold of 120 pg/mL, summary estimates of sensitivity and specificity were 81% (71-88%) and 80% (67-88%), respectively. CONCLUSIONS: Because of high sensitivity, BDG seems promising to rule-out NIC. It might be too early to recommend its use because of the scarcity of reliable clinical data, heterogeneity in case definitions, and unstable accuracy estimates.

Roles of the multiplex real-time PCR assay and ß-D-glucan in a high-risk population for intra-abdominal candidiasis (IAC).

Multiplex quantitative real-time PCR (MRT-PCR) using blood can improve the diagnosis of intra-abdominal candidiasis (IAC). We prospectively studied 39 patients with suspected IAC in the absence of previous antifungal therapy. Blood cultures, MRT-PCR, and ß-D-glucan (BDG) in serum were performed in all patients. IAC was defined according to the 2013 European Consensus criteria. For MRT-PCR, the probes targeted the ITS1 or ITS2 regions of ribosomal DNA. Candidaemia was confirmed only in four patients (10%), and IAC criteria were present in 17 patients (43.6%). The sensitivity of MRT-PCR was 25% but increased to 63.6% (P = .06) in plasma obtained prior to volume overload and transfusion; specificity was above 85% in all cases. BDG performance was improved using a cutoff > 260 pg/ml, and improvement was not observed in samples obtained before transfusion. In this cohort of high risk of IAC and low rate of bloodstream infection, the performance of non-culture-based methods (MRT-PCR or BDG) was moderate but may be a complementary tool given the limitations of diagnostic methods available in clinical practice. Volume overload requirements, in combination with other factors, decrease the accuracy of MRT-PCR in patients with IAC.

Rezafungin treatment in mouse models of invasive candidiasis and aspergillosis: Insights on the PK/PD pharmacometrics of rezafungin efficacy.

Rezafungin acetate is a novel echinocandin in clinical development for prevention and treatment of invasive fungal infections. Rezafungin is differentiated by a pharmacokinetic/pharmacodynamic (PK/PD) profile that includes a long half-life allowing once-weekly administration, front-loaded plasma drug exposures associated with antifungal efficacy, and penetration into deep-seated infections, such as intra-abdominal abscesses. In this series of in vivo studies, rezafungin demonstrated efficacy in the treatment of neutropenic mouse models of disseminated candidiasis, including infection caused by azole-resistant Candida albicans, and aspergillosis. These results contribute to a growing body of evidence demonstrating the antifungal efficacy and potential utility of rezafungin in the treatment of invasive fungal infections.

The diagnostic value of (1,3)-ß-D-glucan alone or combined with traditional inflammatory markers in neonatal invasive candidiasis.

BACKGROUND: Asymptom of invasive candidiasis (IC) and low positive rate of blood culture lead to delay diagnose of neonatal infection. Serum (1,3)-ß-D-glucan (BDG) performs well in adult IC, but its use in neonatal IC is unclear. We evaluated the use of BDG, procalcitonin (PCT), high-sensitive C-reactive protein (hsCRP) or platelet count (PC) in neonatal IC. METHODS: We collected the data of neonates admitted to our institute. Eighty neonates were enrolled, and divided into IC group, bacterial infection (BI) group and control (CTRL) group. We analyzed the difference of these indicators between groups, and generated Receiver operator characteristic (ROC) curve. The value of BDG in antifungal therapy efficacy assessment was also investigated. RESULTS: The BDG level was higher in IC group compared with BI and CTRL group. C. albicans lead to significant increase of BDG compared with C. parapsilosis. IC group had highest hsCRP level and lowest PC. PCT level was similar between groups. ROC showed that BDG or hsCRP performs well in neonatal IC, the optimal cut-off for BDG was 13.69 mg/ml. Combined BDG with hsCRP, PCT and PC increased diagnostic value. Serum BDG level was decreased during antifungal treatment. CONCLUSION: Serum BDG performs well in identification of neonatal IC and in monitoring the antifungal therapy efficacy.

T2 magnetic resonance for the diagnosis of deep-seated invasive candidiasis in a liver recipient without candidemia.

BACKGROUND: T2 magnetic resonance imaging (T2MR) is a new method for the diagnosis of invasive candidiasis, although most studies have analyzed its role in patients with candidemia or not infection. CASE REPORT: We present the case of a patient with arteritis and thrombosis of the hepatic graft resulted from an undocumented fungal infection in the explanted liver.T2MR in serum was a suitable diagnostic tool for the diagnosis of the deep-seated invasive candidiasis in the absence of candidemia or the isolation of the yeast in culture. CONCLUSIONS: T2MR allowed the diagnosis of deep-seated invasive candidiasis in an immunodepressed patient without candidemia, even before the onset of symptoms.

(1,3)-ß-D-glucan-based diagnosis of invasive Candida infection versus culture-based diagnosis in patients with sepsis and with an increased risk of invasive Candida infection (CandiSep): study protocol for a randomized controlled trial.

BACKGROUND: The time to diagnosis of invasive Candida infection (ICI) is often too long to initiate timely antifungal therapy in patients with sepsis. Elevated serum (1,3)-ß-D-glucan (BDG) concentrations have a high diagnostic sensitivity for detecting ICI. However, the clinical significance of elevated BDG concentrations is unclear in critically ill patients. The goal of this study is to investigate whether measurement of BDG in patients with sepsis and a high risk for ICI can be used to decrease the time to empiric antifungal therapy and thus, increase survival. METHODS/DESIGN: This prospective multicenter open randomized controlled trial is being conducted in 19 German intensive care units. All adult patients with severe sepsis or septic shock and an increased risk for ICI are eligible for enrolment. Risk factors are total parenteral nutrition, previous abdominal surgery, previous antimicrobial therapy, and renal replacement therapy. Patients with proven ICI or those already treated with systemic antifungal substances are excluded. Patients are allocated to a BDG or standard care group. The standard care group receives targeted antifungal therapy as necessary. In the BDG group, BDG serum samples are taken after randomization and 24 h later. Antifungal therapy is initiated if BDG is ≥80 pg/ml in at least one sample. We plan to enroll 312 patients. The primary outcome is 28-day mortality. Other outcomes include antifungal-free survival within 28 days after enrolment, time to antifungal therapy, and the diagnostic performance of BDG compared to other laboratory tests for early ICI diagnosis. The statistical analysis will be performed according to the intent-to-treat principle. DISCUSSION: Because of the high risk of death, American guidelines recommend empiric antifungal therapy in sepsis patients with a high risk of ICI despite the limited evidence for such a recommendation. In contrast, empiric antifungal therapy is not recommended by European guidelines. BDG may offer a way out of this dilemma since BDG potentially identifies patients in need of early antifungals. However, the evidence for such an approach is inconclusive. This clinical study will generate solid evidence for health-care providers and authors of guidelines for the use of BDG in critically ill patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02734550 . Registered 12 April 2016.

The patterns of colonization and antifungal susceptibility of Candida, isolated from preterm neonates in Khorramabad, South West of Iran.

OBJECTIVE: Usually, 7-20% of preterm neonates colonized by Candida species present invasive candidiasis. Candida albicans, and several non-albicans species cause invasive infection with C. albicans being the most dominant agent. In the last two decades, infection due to non-albicans have been increased dramatically due to their low sensitivity to antifungal drugs such as fluconazole. The aim of present study was to evaluate Candida colonization pattern and antifungal susceptibility among preterm neonates from Khorramabad, South west of Iran. MATERIALS AND METHODS: Samples were collected from 80 preterm neonates, cultured on CHROMagar Candida and incubated at 37°C. All recovered isolates were primarily screened based on classical methods and identified by PCR-RFLP targeting the ITS-rDNA regions. Antifungal susceptibility testing of all isolates was performed according to the CLSI method against amphotericin B, caspofungin, itraconazole, fluconazole and voriconazole. RESULTS: Totally 23 isolates of Candida species were recovered from 20 patients (female: male, 50:50) including, C. albicans (18), C. parapsilosis (2) and C. glabrata (1). Furthermore, the blood cultures from two patients were yielded C. albicans and C. parapsilosis so that patient with C. albicans died after five days. Generally, in this study, 9 (39.1%) isolates were resistant to amphotericin B including; 7 (30.4%) C. albicans and 2 (8.7%) C. parapsilosis. In addition, 2 (8.7%) and 4 (17.4%) isolates were also resistant to itraconazole and caspofungin, respectively. CONCLUSION: In conclusion, Candida colonization among preterm neonates is still an important issue in hospitals. In addition, in spite of a significant amphotericin B resistant Candida, voriconazole, fluconazole, and itraconazole are valuable antifungals, due to fully sensitivity to Candida.

A Phase 3 Study of Micafungin Versus Amphotericin B Deoxycholate in Infants With Invasive Candidiasis.

BACKGROUND: Amphotericin B deoxycholate (AmB-D) is standard of care treatment for neonatal invasive candidiasis (IC). Micafungin (MCA) has broad-spectrum fungicidal activity against Candida spp. We compared the efficacy and safety of intravenous MCA with intravenous AmB-D and assessed the pharmacokinetics of MCA in infants >2-120 days of age with proven IC in a phase 3, randomized, double-blind, multicenter, parallel-group, noninferiority study (NCT00815516). METHODS: Infants were randomized 2:1 to MCA (10 mg/kg/d) or AmB-D (1 mg/kg/d) for ≥21 days. Primary efficacy endpoint was fungal-free survival (FFS) 1 week after last study drug dose. MCA population pharmacokinetics included simulated area under the curve (AUC) at steady state and maximum plasma concentration after 2-hour infusion. AUC pharmacodynamic target exposure was 170 µg·h/mL. RESULTS: Thirty infants received MCA (n = 20) or AmB-D (n = 10). The trial was terminated early because of slow recruitment. FFS was observed in 12 of 20 [60%; 95% confidence interval (CI): 36%-81%] MCA-group infants and in 7 of 10 (70%; 95% CI: 35%-93%) AmB-D-group infants. The most common treatment-emergent adverse events were anemia [MCA: n = 9 (45%); AmB-D: n = 3 (30%)] and thrombocytopenia [n = 2 (10%) and n = 3 (30%), respectively]. Model-derived mean AUC at steady state for MCA was 399.3 ± 163.9 µg·h/mL (95% prediction interval: 190.3-742.3 µg/mL); steady state and maximum plasma concentration after 2-hour infusion was 31.1 ± 10.5 µg/mL (95% prediction interval: 17.0-49.7 µg/mL). MCA exposures were above the AUC pharmacodynamic target exposure. CONCLUSIONS: Within the study limitations, infants with IC treated with MCA achieved similar FFS compared with AmB-D. Both agents were safe and well tolerated.

Comparative virulence of Candida auris with Candida haemulonii, Candida glabrata and Candida albicans in a murine model.

The incidence of invasive fungal infections (IFIs) caused by uncommon Candida species with diverse virulence and susceptibility profiles has increased in recent years. Due to scarce clinical and experimental data on the pathogenicity of Candida auris, the aim of this study was to evaluate and compare the virulence of two rare clinically relevant species, C. auris and Candida haemulonii with Candida glabrata and Candida albicans in an immunocompetent murine model of disseminated infection. Immunocompetent ICR female mice were infected with three inoculum sizes (1 × 105 , 1 × 106 and 1 × 107 CFU/mouse) of two C. auris strains and one isolate of C. haemulonii, C. glabrata and C. albicans. Tissue burden on days 5 and 10 postchallenge and mortality rate were used as virulence markers. A high virulence was found for C. albicans, followed by C. auris, C. glabrata and C. haemulonii, respectively. Candida albicans showed high virulence with a medium survival time of 9.5 days for mice infected with 1 × 107 CFU/mouse. For inocula at 1 × 106 and 1 × 107 CFU/mouse, there were significant differences in fungal burden at day 10 between C. albicans, C. auris and C. glabrata isolates compared with C. haemulonii (P < .0001). Overall, no significant differences between C. albicans with C. auris and C. glabrata were observed in mice infected with three different inocula (P > .05). In general, the highest fungal load of all isolates was detected in kidney followed by spleen, liver and lung tested with three different inocula on the two different experimental days. Histopathological examination revealed the abundant presence of yeast cells with pseudohyphae for C. albicans and only yeast cells for C. auris, C. glabrata and C. haemulonii, in all the kidney tissue samples. In conclusion, C. albicans is a highly virulent opportunistic fungus, as the clinical and experimental data demonstrate, and also our results demonstrate a low virulence of C. haemulonii in immunocompetent animals. Altogether, this study highlights the pathogenic potential of C. auris.

Diagnosing Invasive Candidiasis.

Cultures are negative in ∼50% of invasive candidiasis. Data are emerging for the performance of nonculture tests such as mannan/antimannan, Candida albicans germ tube antibody, 1,3-ß-d-glucan, PCR, and the T2Candida panel in diagnosing both candidemia and deep-seated candidiasis. In most settings, positive predictive values of nonculture test are low, and negative predictive values are high. For tests to be useful, clinicians must understand the pretest likelihood of invasive candidiasis and test performance for the most common disease manifestation in a given patient. This paper reviews nonculture Candida diagnostics and discusses how they might be used effectively in patient care.

Candida-reactive T cells for the diagnosis of invasive Candida infection of the lumbar vertebral spine.

Invasive Candida infection is the fourth most common bloodstream infection. Blood cultures are the current gold standard diagnostic method, however, false negatives remain a clinical challenge. We developed a new technique measuring Candida-reactive T cells as diagnostic read-out for invasive Candida infection. In a pilot study, we followed the treatment course of a patient with an invasive Candida infection of the lumbar vertebral spine. We present the case of a 56-year-old patient with HIV-associated Burkitt lymphoma who developed septic shock during chemotherapy-induced neutropenia. For the first time, we provide flow cytometry-based diagnostics with Candida-reactive T cells for invasive candidiasis with comprehensive MRI imaging. The Candida-reactive T cell assay has potential to complement current diagnostic assays for invasive Candida infection and thus to support targeted treatment.

[The 1,3-ß-d-glucan in critical adult patients as diagnostic tool for invasive Candida spp. infection, performance evaluation]. / Evaluación del rendimiento de 1,3-ß-d-glucano como apoyo diagnóstico de infecciones invasoras por Candida spp. en pacientes críticos adultos.

BACKGROUND: Invasive fungal infections are important causes of morbimortality in critical patients. Most of these infections are caused by Candida spp. which diagnosis has important limitations. AIM: Initial evaluation of the utility of 1,3-ß-D-glucan (BDG) as a diagnostic tool for invasive candida infections in critical patients. PATIENTS AND METHODS: Adult patients over 18 years old, hospitalized in intensive care units for more than five days, with fever > 38 °C of unclear origin and two or more risk factors for invasive Candida spp. infection were included. Samples for BDG were obtained on two consecutive days. The results were compared with definitive diagnosis of candidemia/invasive candidiasis (C/IC) confirmed by cultures. RESULTS: Median value of BDG in patients with C/IC was 224.3 ± 213.7 pg/ml and in patients without C/IC was 63.8 ± 76.7 pg/ml (p: 0.02). Sensitivity and specificity for the diagnosis of C/IC were 60 and 92%, respectively. Positive predictive value was 60% and negative predictive value was 92%. CONCLUSION: BDG could be considered as a complementary diagnostic tool for the diagnosis of C/IC in critical patients with risk factors.

Pharmacokinetic Properties of Micafungin in Critically Ill Patients Diagnosed with Invasive Candidiasis.

The estimated attributable mortality rate for invasive candidiasis (IC) in the intensive care unit (ICU) setting varies from 30 to 40%. Physiological changes in critically ill patients may affect the distribution and elimination of micafungin, and therefore, dosing adjustments might be mandatory. The objective of this study was to determine the pharmacokinetic parameters of micafungin in critically ill patients and assess the probability of target attainment. Micafungin plasma concentrations were measured to estimate the pharmacokinetic properties of micafungin. MIC values for Candida isolates were determined to assess the probability of target attainment for patients. Data from 19 patients with suspected or proven invasive candidiasis were available for analysis. The median area under the concentration-time curve from 0 to 24 h at steady state (AUC0-24) was 89.6 mg · h/liter (interquartile range [IQR], 75.4 to 113.6 mg · h/liter); this was significantly lower than the median micafungin AUC0-24 values of 152.0 mg · h/liter (IQR, 136.0 to 162.0 mg · h/liter) and 134.0 mg · h/liter (IQR, 118.0 to 148.6 mg · h/liter) in healthy volunteers (P = <0.0001 and P = <0.001, respectively). All Candida isolates were susceptible to micafungin, with a median MIC of 0.016 mg/liter (IQR, 0.012 to 0.023 mg/liter). The median AUC0-24/MIC ratio was 5,684 (IQR, 4,325 to 7,578), and 3 of the 17 evaluable patients (17.6%) diagnosed with proven invasive candidiasis did not meet the AUC/MIC ratio target of 5,000. Micafungin exposure was lower in critically ill patients than in healthy volunteers. The variability in micafungin exposure in this ICU population could be explained by the patients' body weight. Our findings suggest that healthier patients (sequential organ failure assessment [SOFA] score of <10) weighing more than 100 kg and receiving 100 mg micafungin daily are at risk for inappropriate micafungin exposure and potentially inadequate antifungal treatment. (This study has been registered at ClinicalTrials.gov under identifier NCT01716988.).

Biomarker-based strategy for early discontinuation of empirical antifungal treatment in critically ill patients: a randomized controlled trial.

PURPOSE: The aim of this study was to determine the impact of a biomarker-based strategy on early discontinuation of empirical antifungal treatment. METHODS: Prospective randomized controlled single-center unblinded study, performed in a mixed ICU. A total of 110 patients were randomly assigned to a strategy in which empirical antifungal treatment duration was determined by (1,3)-ß-D-glucan, mannan, and anti-mannan serum assays, performed on day 0 and day 4; or to a routine care strategy, based on international guidelines, which recommend 14 days of treatment. In the biomarker group, early stop recommendation was determined using an algorithm based on the results of biomarkers. The primary outcome was the percentage of survivors discontinuing empirical antifungal treatment early, defined as a discontinuation strictly before day 7. RESULTS: A total of 109 patients were analyzed (one patient withdraw consent). Empirical antifungal treatment was discontinued early in 29 out of 54 patients in the biomarker strategy group, compared with one patient out of 55 in the routine strategy group [54% vs 2%, p < 0.001, OR (95% CI) 62.6 (8.1-486)]. Total duration of antifungal treatment was significantly shorter in the biomarker strategy compared with routine strategy [median (IQR) 6 (4-13) vs 13 (12-14) days, p < 0.0001). No significant difference was found in the percentage of patients with subsequent proven invasive Candida infection, mechanical ventilation-free days, length of ICU stay, cost, and ICU mortality between the two study groups. CONCLUSIONS: The use of a biomarker-based strategy increased the percentage of early discontinuation of empirical antifungal treatment among critically ill patients with suspected invasive Candida infection. These results confirm previous findings suggesting that early discontinuation of empirical antifungal treatment had no negative impact on outcome. However, further studies are needed to confirm the safety of this strategy. This trial was registered at ClinicalTrials.gov, NCT02154178.

Evaluación del rendimiento de 1, 3-β -d-glucano como apoyo diagnóstico de infecciones invasoras por Candida spp. en pacientes críticos adultos / The 1,3-β -d-glucan in critical adult patients as diagnostic tool for invasive Candida spp. infection, performance evaluation

Resumen Introducción: La enfermedad fúngica invasora (EFI) se reconoce como causa importante de morbi-mortalidad en pacientes críticos. La mayoría de estas infecciones son provocadas por Candida spp. para cuyo diagnóstico existen importantes limitaciones. Objetivo: Realizar una evaluación inicial de la utilidad de la medición del 1,3-β-D- glucano (BDG) como herramienta diagnóstica de apoyo de las infecciones invasoras por Candida spp. en pacientes críticos. Pacientes y Método: Estudio prospectivo de pacientes mayores de 18 años hospitalizados en unidades de pacientes críticos por más de cinco días, con fiebre sin foco claro y dos o más factores de riesgo para EFI por Candida spp. Se obtuvieron muestras para BDG en dos días consecutivos. Los resultados se confrontaron con el diagnóstico definitivo de candidemia/candidiasis invasora (C/CI) demostrado según cultivos. Resultados: El valor promedio de BDG en los pacientes con diagnóstico de C/CI fue 224,3 ± 213,7 pg/ml y en aquellos sin C/CI 63,8 ± 76,7 pg/ml (p: 0,02). La sensibilidad y especificidad de BDG para diagnóstico de C/CI fue 60 y 92%, respectivamente. El valor predictor positivo fue 60% y el valor predictor negativo de 92%. Conclusión: BDG puede considerarse como un examen de apoyo en el diagnóstico de C/CI en pacientes críticos con factores de riesgo.

Background: Invasive fungal infections are important causes of morbimortality in critical patients. Most of these infections are caused by Candida spp. which diagnosis has important limitations. Aim: Initial evaluation of the utility of 1,3-β-D-glucan (BDG) as a diagnostic tool for invasive candida infections in critical patients. Patients and Methods: Adult patients over 18 years old, hospitalized in intensive care units for more than five days, with fever > 38 °C of unclear origin and two or more risk factors for invasive Candida spp. infection were included. Samples for BDG were obtained on two consecutive days. The results were compared with definitive diagnosis of candidemia/invasive candidiasis (C/IC) confirmed by cultures. Results: Median value of BDG in patients with C/IC was 224.3 ± 213.7 pg/ml and in patients without C/IC was 63.8 ± 76.7 pg/ml (p: 0.02). Sensitivity and specificity for the diagnosis of C/IC were 60 and 92%, respectively. Positive predictive value was 60% and negative predictive value was 92%. Conclusion: BDG could be considered as a complementary diagnostic tool for the diagnosis of C/IC in critical patients with risk factors.