• Antibiotics
• Corticosteroid
• Fluids
• Inotrope
• Norepinephrine
• Resuscitation
• SIRS
• SOFA
• Sepsis
• Septic shock
• Vasopressin
• Vasopressor
• qSOFA

• Humans
• Shock, Septic/therapy
• Shock, Septic/diagnosis
• Vasoconstrictor Agents/therapeutic use
• Fluid Therapy/methods
• Sepsis/therapy
• Sepsis/diagnosis
• Resuscitation/methods
• Emergency Medicine
• Anti-Bacterial Agents/therapeutic use
• Norepinephrine/therapeutic use
• Emergency Service, Hospital
• Vasopressins/therapeutic use

• Humans
• Sepsis/therapy
• Sepsis/diagnosis
• Sepsis/etiology
• Critical Care/methods
• Acute Care Surgery

• Acute liver failure
• Bacterial infections
• Fungal infections
• Multi-drug resistance
• Viral infections

• Humans
• Liver Failure, Acute/therapy
• Liver Failure, Acute/diagnosis
• Bacterial Infections/therapy
• Bacterial Infections/prevention & control
• Bacterial Infections/diagnosis
• Bacterial Infections/microbiology
• Mycoses/diagnosis
• Mycoses/therapy
• Mycoses/prevention & control
• Cross Infection/prevention & control
• Cross Infection/diagnosis
• Cross Infection/therapy

• critical illness
• fungal infections
• intra-abdominal infections
• invasive candidiasis

• Antifungals
• Echinocandin Resistance
• Glucan Synthase
• Reductive Dehydration
• Site- Selective Modifications

• Antifungal Agents/pharmacology
• Drug Resistance, Fungal/genetics
• Echinocandins/pharmacology
• Echinocandins/genetics
• Glucosyltransferases/genetics
• Glucosyltransferases/metabolism
• Mutation
• Microbial Sensitivity Tests

• 179/19 Israel Science Foundation
• 315461 Ministry of Science, Technology and Space
• 951475 H2020 European Research Council
• 3-18841 ERA NET/JPIAMR, Israel Ministry of Health

• abdominal sepsis
• antibiotics
• antimicrobials
• nosocomial infection
• peritonitis
• sepsis

• machine learning
• statistical methods
• epidemiology

• echinocandin
• infectious diseases
• invasive candidiasis
• pharmacy
• stewardship

• antifungal agents
• empirical therapy
• intensive care
• invasive aspergillosis
• invasive candidiasis

• not applicable Gilead Sciences Middle East

• Empirical antifungal treatment
• Hospital mortality
• Intensive care
• Propensity score matching

(1,3)-β-d-Glucan has been widely used in clinical practice for the diagnosis of invasive Candida infections. However, such serum biomarker showed potential to guide antimicrobial therapy in order to reduce the duration of empirical antifungal treatment in critically ill septic patients with suspected invasive candidiasis.

This was a single-centre, randomized, open-label clinical trial in which critically ill patients were enrolled during the admission to the intensive care unit (ICU). All septic patients who presented invasive Candida infection risk factors and for whom an empirical antifungal therapy was commenced were randomly assigned (1:1) in those stopping antifungal therapy if (1,3)-β-d-glucan was negative ((1,3)-β-d-glucan group) or those continuing the antifungal therapy based on clinical rules (control group). Serum 1,3-β-d-glucan was measured at the enrolment and every 48/72 h over 14 days afterwards. The primary endpoint was the duration of antifungal treatment in the first 30 days after enrolment.

We randomized 108 patients into the (1,3)-β-d-glucan (n = 53) and control (n = 55) groups. Median [IQR] duration of antifungal treatment was 2 days [1–3] in the (1,3)-β-d-glucan group vs. 10 days [6–13] in the control group (between-group absolute difference in means, 6.29 days [95% CI 3.94–8.65], p < 0.001). Thirty-day mortality was similar (28.3% [(1,3)-β-d-glucan group] vs. 27.3% [control group], p = 0.92) as well as the overall rate of documented candidiasis (11.3% [(1,3)-β-d-glucan group] vs. 12.7% [control group], p = 0.94), the length of mechanical ventilation (p = 0.97) and ICU stay (p = 0.23).

In critically ill septic patients admitted to the ICU at risk of invasive candidiasis, a (1,3)-β-d-glucan-guided strategy could reduce the duration of empirical antifungal therapy. However, the safety of this algorithm needs to be confirmed in future, multicentre clinical trial with a larger population.

ClinicalTrials.gov, NCT03117439, retrospectively registered on 18 April 2017

• (1,3)-β-D-Glucan
• Antifungal therapy
• Biomarker
• Candida infection
• Sepsis

• Acute lung injury
• Acute respiratory distress syndrome
• Children
• High-frequency ventilation
• Mechanical ventilation
• Paediatric intensive care unit

• Blood Gas Analysis
• Child
• Child, Preschool
• Female
• High-Frequency Ventilation/methods
• High-Frequency Ventilation/mortality
• High-Frequency Ventilation/standards
• Hospital Mortality/trends
• Humans
• Infant
• Male
• Odds Ratio
• Pediatrics/instrumentation
• Pediatrics/methods
• Respiration, Artificial/methods
• Respiratory Distress Syndrome/epidemiology
• Respiratory Distress Syndrome/mortality
• Respiratory Distress Syndrome/therapy
• Retrospective Studies

• Duke-NUS-KPA/2016/0024 Khoo Pilot Research Award
• R-608-000-172-133 NUS start-up grant
• Khoo Pilot Research Award
• NUS start-up grant

• Antifungal Stewardship
• Antifungal Treatment
• Candida auris
• Candidaemia
• Diagnosis
• Infection Control

• PCR
• antigen testing
• fungal diagnosis
• serology

• Humans
• Candidiasis, Invasive/diagnosis
• Candidiasis, Invasive/immunology
• Critical Care/standards
• Galactose/analogs & derivatives
• Invasive Pulmonary Aspergillosis/diagnosis
• Invasive Pulmonary Aspergillosis/immunology
• Mannans
• Polymerase Chain Reaction/methods
• Serology/methods
• Societies, Medical
• United States

Invasive fungal infections (IFI) are difficult to diagnose, especially in critically ill patients. As the mannose receptor (MR) is shed from macrophage cell surfaces after exposure to fungi, we investigate whether its soluble serum form (sMR) can serve as a biomarker of IFI.

This is a secondary analysis of the multicentre randomised controlled trial (EPaNIC, n = 4640) that investigated the impact of initiating supplemental parenteral nutrition (PN) early during critical illness (Early-PN) as compared to withholding it in the first week of intensive care (Late-PN). Serum sMR concentrations were measured in three matched patient groups (proven/probable IFI, n = 82; bacterial infection, n = 80; non-infectious inflammation, n = 77) on the day of antimicrobial initiation or matched intensive care unit day and the five preceding days, as well as in matched healthy controls (n = 59). Independent determinants of sMR concentration were identified via multivariable linear regression. Serum sMR time profiles were analysed with repeated-measures ANOVA. Predictive properties were assessed via area under the receiver operating curve (aROC).

Serum sMR was higher in IFI patients than in all other groups (all p < 0.02), aROC to differentiate IFI from no IFI being 0.65 (p < 0.001). The ability of serum sMR to discriminate infectious from non-infectious inflammation was better with an aROC of 0.68 (p < 0.001). The sMR concentrations were already elevated up to 5 days before antimicrobial initiation and remained stable over time. Multivariable linear regression analysis showed that an infection or an IFI, higher severity of illness and sepsis upon admission were associated with higher sMR levels; urgent admission and Late-PN were independently associated with lower sMR concentrations.

Serum sMR concentrations were higher in critically ill patients with IFI than in those with a bacterial infection or with non-infectious inflammation. However, test properties were insufficient for diagnostic purposes.

The online version of this article (10.1186/s13054-019-2549-8) contains supplementary material, which is available to authorized users.

• Inflammation
• Invasive fungal infection
• Macrophage activation
• Soluble CD206
• Soluble mannose receptor
• sCD206
• sMR

Candidemia is still a common life-threatening disease and causes significant morbidity and mortality, especially in critically ill patients. We conducted this study to analyze the epidemiology, clinical characteristics, species distribution, antifungal susceptibility and mortality risk factors of candidemia in an intensive care unit.

We retrospectively analyzed patients with candidemia in the intensive care unit of our hospital from 2011 to 2017. The clinical characteristics, including clinical and laboratory data, antibiotic therapies, underlying conditions, and invasive procedures and outcomes, were analyzed. We also performed a logistic regression analysis to identify the independent risk factors for mortality.

In this six-year retrospective study, we identified 82 patients with candidemia. The median age of the patients was 76 years (range, 26 years to 91 years), and 50 of the patients (61%) were male. Candida albicans was the most common fungal species (38/82, 46.3%), followed by Candida parapsilosis (16/82, 19.5%), Candida glabrata (13/82, 15.9%), and Candida tropicalis (12/82, 14.6%). Most isolates were susceptible to the antifungal agents. The all-cause mortality rate was 51.2%. In binary logistic regression analysis, the worst Glasgow coma score (GCS), PaO₂/FiO₂ ratio (P/F ratio), and mean arterial pressure (MAP) within three days after admission were independent risk factors for mortality.

Candida albicans was the most frequently isolated fungal species. Most isolates were susceptible to the antifungal agents. The worst GCS score, P/F ratio, and MAP within three days after admission were independent risk factors for mortality due to candidemia in critically ill patients.

• Antifungal susceptibility
• Candidemia
• Risk factors
• Species distribution

• Antifungal
• Echinocandin
• Fluconazole
• Fungal
• Sepsis
• Shock

Antifungal treatment is common in critically ill patients, but only a small proportion of patients receiving antifungals have a proven fungal infection. However, antifungal treatment has side effects such as toxicity, emergence of resistance, and high cost. Moreover, empirical antifungal treatment is still a matter for debate in these patients. Our study aimed to determine the incidence, associated factors, and safety of de-escalation of antifungals in critically ill patients.

This retrospective study was conducted in a 30-bed mixed ICU, from January 2012 through January 2013. Patients hospitalized for > 5 days and treated with antifungals for first suspected or proven invasive Candida infection were included. Exclusion criteria were prophylactic antifungals, suspected invasive aspergillosis, and neutropenia. De-escalation was defined as switch from initial systemic antifungals (except fluconazole) to triazoles, or stopping initial drugs within the 5 days following their initiation.

One hundred and ninety patients were included. Antifungal treatment was empirical, preemptive, and targeted in 55, 27, and 24% of study patients, respectively. Caspofungin (53%), fluconazole (43%), voriconazole (4%), and liposomal amphotericin B (0.5%) were the more frequently used antifungals. De-escalation was performed in 38 (20%) patients. Invasive mechanical ventilation was independently associated with lower rates of de-escalation (OR 0.25 [95% CI 0.08–0.85], p = 0.013). Total duration of antifungal treatment was significantly shorter in patients with de-escalation, compared with those with no de-escalation (med [IQR] 6 (5, 18) vs. 13 days (7, 25), p = 0.023). No significant difference was found in duration of mechanical ventilation (22 [5–31] vs. 20 days [10–35], p = 0.43), length of ICU stay (25 [14–40) vs. 25 days [11–40], p = 0.99), ICU mortality (45 vs. 59%, p = 0.13), or 1-year mortality (55 vs. 64%, p = 0.33) between patients with de-escalation and those with no de-escalation, respectively.

De-escalation was performed in 20% of patients receiving systemic antifungals for suspected or proven invasive Candida infection. Mechanical ventilation was independently associated with lower rates of de-escalation. De-escalation of antifungal treatment seems to be safe in critically ill patients.

• Candida spp.
• Critical care
• Diagnosis
• Intensive care
• Invasive candidiasis
• Management

• Adult
• Candidemia/diagnosis
• Candidemia/drug therapy
• Critical Care/methods
• Critical Illness
• Disease Management
• Humans
• Societies

• Antifungal Agents/therapeutic use
• Candida/classification
• Candida/drug effects
• Candida/isolation & purification
• Candidiasis, Invasive/diagnosis
• Candidiasis, Invasive/drug therapy
• Diagnostic Tests, Routine/methods
• Disease Management
• Drug Resistance, Fungal
• Drug Therapy/methods
• Drug Therapy/trends
• Echinocandins/therapeutic use
• Fluconazole/therapeutic use
• Humans

• UM1 AI104681 NIAID NIH HHS

• Communicable diseases
• Critical care
• Delirium
• Drug therapy
• Neurology
• Review

• (1,3)-β-D-Glucan
• Antifungal
• Candida
• Critical illness
• Empirical
• Mannan

• Aged
• Algorithms
• Antibodies, Fungal/blood
• Antifungal Agents/therapeutic use
• Biomarkers/blood
• Candidiasis, Invasive/blood
• Candidiasis, Invasive/drug therapy
• Candidiasis, Invasive/immunology
• Critical Illness/therapy
• Drug Administration Schedule
• Female
• Humans
• Intensive Care Units
• Male
• Mannans/blood
• Middle Aged
• Predictive Value of Tests
• Prospective Studies
• Proteoglycans
• beta-Glucans/blood

• acute respiratory failure
• critical care
• mechanical ventilation
• sepsis

• Antifungal therapy
• Candidiasis
• ICU patients

• Antifungal Agents
• Candidiasis
• Candidiasis, Invasive
• Critical Illness
• Humans
• Intensive Care Units

• empirical treatment
• intensive care unit
• invasive candidiasis

• Antifungal therapy
• Candidemia
• Diagnosis
• Guidelines
• Invasive candidiasis
• Resistance

• Antifungal Agents/therapeutic use
• Candida/classification
• Candidemia/diagnosis
• Candidemia/drug therapy
• Candidiasis, Invasive/diagnosis
• Candidiasis, Invasive/drug therapy
• Drug Resistance, Fungal
• Early Diagnosis
• Echinocandins/therapeutic use
• Humans
• Microbial Sensitivity Tests
• Randomized Controlled Trials as Topic

• Candida
• Candidemia
• Candidiasis/microbiology
• Carrier State
• Decontamination/methods
• Female
• Humans
• Incidence
• Intensive Care Units
• Male
• Pneumonia, Ventilator-Associated/epidemiology
• Pneumonia, Ventilator-Associated/etiology
• Respiration, Artificial/adverse effects
• Respiratory System/microbiology

• Preemptive antifungal therapy
• gastrointestinal surgery
• intensive care
• invasive candidiasis
• micafungin

• Adolescent
• Adult
• Aged
• Antifungal Agents/administration & dosage
• Biomarkers/blood
• Candidiasis, Invasive/drug therapy
• Candidiasis, Invasive/prevention & control
• Double-Blind Method
• Echinocandins/administration & dosage
• Female
• Humans
• Intensive Care Units
• Intraabdominal Infections/drug therapy
• Intraabdominal Infections/prevention & control
• Intraabdominal Infections/surgery
• Lipopeptides/administration & dosage
• Male
• Micafungin
• Middle Aged
• Postoperative Complications/prevention & control
• Pre-Exposure Prophylaxis
• Proteoglycans
• Young Adult
• beta-Glucans/blood

Fungal infection is common in critically ill patients. However, this infection is difficult to diagnose, and a large proportion of patients receive empirical antifungal treatment without further confirmation of invasive fungal disease. Whilst prompt appropriate antifungal treatment is associated with better outcome in patients with confirmed infections, this treatment has several drawbacks. In addition, no clear beneficial effect of empirical antifungal treatment was found in patients without confirmed infection. Reducing antifungal treatment in the intensive care unit (ICU) is feasible, and would allow avoiding drawbacks of this treatment without negative impact on outcome. Antifungal stewardship, preemptive antifungal treatment, based on colonization index and fungal biomarkers; and de-escalation of antifungal treatment based on microbiology results and fungal biomarkers could be suggested to reduce antifungal use in the ICU, and are currently under investigation.

• Antifungals
• Biomarkers
• Colonization
• Infection
• Preemptive treatment

• Antifungal
• Causal inference
• De-escalation
• Intensive care unit
• Invasive candidiasis
• Outcome
• Sepsis