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Introduction For decades, clinicians dealing with immunocompromised and critically ill patients have perceived a link between Candida colonization and subsequent infection. However, the pathophysiological progression from colonization to infection was clearly established only through the formal description of the colonization index (CI) in critically ill patients. Unfortunately, the literature reflects intense confusion about the pathophysiology of invasive candidiasis and specific associated risk factors. Methods We review the contribution of the CI in the field of Candida infection and its development in the 20 years following its original description in 1994. The development of the CI enabled an improved understanding of the pathogenesis of invasive candidiasis and the use of targeted empirical antifungal therapy in subgroups of patients at increased risk for infection. Results The recognition of specific characteristics among underlying conditions, such as neutropenia, solid organ transplantation, and surgical and nonsurgical critical illness, has enabled the description of distinct epidemiological patterns in the development of invasive candidiasis. Conclusions Despite its limited bedside practicality and before confirmation of potentially more accurate predictors, such as specific biomarkers, the CI remains an important way to characterize the dynamics of colonization, which increases early in patients who develop invasive candidiasis.

Background. Delayed antifungal therapy for invasive candidiasis (IC) contributes to poor outcomes. Predictive risk models may allow targeted antifungal prophylaxis to those at greatest risk. Methods. A prospective cohort study of 6685 consecutive nonneutropenic patients admitted to 7 Australian intensive care units (ICUs) for ≥72 hours was performed. Clinical risk factors for IC occurring prior to and following ICU admission, colonization with Candida species on surveillance cultures from 3 sites assessed twice weekly, and the occurrence of IC ≥72 hours following ICU admission or ≤72 hours following ICU discharge were measured. From these parameters, a risk-predictive model for the development of ICU-acquired IC was then derived. Results. Ninety-six patients (1.43%) developed ICU-acquired IC. A simple summation risk-predictive model using the 10 independently significant variables associated with IC demonstrated overall moderate accuracy (area under the receiver operating characteristic curve = 0.82). No single threshold score could categorize patients into clinically useful high- and low-risk groups. However, using 2 threshold scores, 3 patient cohorts could be identified: those at high risk (score ≥6, 4.8% of total cohort, positive predictive value [PPV] 11.7%), those at low risk (score ≤2, 43.1% of total cohort, PPV 0.24%), and those at intermediate risk (score 3–5, 52.1% of total cohort, PPV 1.46%). Conclusions. Dichotomization of ICU patients into high- and low-risk groups for IC risk is problematic. Categorizing patients into high-, intermediate-, and low-risk groups may more efficiently target early antifungal strategies and utilization of newer diagnostic tests.

Background. Invasive candidiasis is the third most common bloodstream infection in the intensive care unit (ICU) and is associated with morbidity and mortality. Prophylaxis and preemptive therapy are attractive strategies for this setting. Methods. We conducted a multicenter, randomized, double-blind, placebo-controlled trial of caspofungin as antifungal prophylaxis in 222 adults who were in the ICU for at least 3 days, were ventilated, received antibiotics, had a central line, and had 1 additional risk factor (parenteral nutrition, dialysis, surgery, pancreatitis, systemic steroids, or other immunosuppressants). Subjects' (1,3)-β-D-glucan levels were monitored twice weekly. The primary endpoint was the incidence of proven or probable invasive candidiasis by EORTC/MSG criteria in patients who did not have disease at baseline. Patients who had invasive candidiasis were allowed to break the blind and receive preemptive therapy with caspofungin. The preemptive approach analysis included patients all patients who received study drug, including those positive at baseline. Results. The incidence of proven/probable invasive candidiasis in the placebo and caspofungin arms was 16.7% (14/84) and 9.8% (10/102), respectively, for prophylaxis (P = .14), and 30.4% (31/102) and 18.8% (22/117), respectively, for the preemptive approach (P = .04); however, this analysis included patients with baseline disease. There were no significant differences in the secondary endpoints of mortality, antifungal use, or length of stay. There were no safety differences. Conclusions. Caspofungin was safe and tended to reduce the incidence of invasive candidiasis when used for prophylaxis, but the difference was not statistically significant. A preemptive therapy approach deserves further study. Clinical Trials Registration. NCT00520234.

Background. Patients undergoing emergency gastrointestinal surgery for intra-abdominal infection are at risk of invasive candidiasis (IC) and candidates for preemptive antifungal therapy. Methods. This exploratory, randomized, double-blind, placebo-controlled trial assessed a preemptive antifungal approach with micafungin (100 mg/d) in intensive care unit patients requiring surgery for intra-abdominal infection. Coprimary efficacy variables were the incidence of IC and the time from baseline to first IC in the full analysis set; an independent data review board confirmed IC. An exploratory biomarker analysis was performed using logistic regression. Results. The full analysis set comprised 124 placebo- and 117 micafungin-treated patients. The incidence of IC was 8.9% for placebo and 11.1% for micafungin (difference, 2.24%; [95% confidence interval, −5.52 to 10.20]). There was no difference between the arms in median time to IC. The estimated odds ratio showed that patients with a positive (1,3)-β-D-glucan (ßDG) result were 3.66 (95% confidence interval, 1.01–13.29) times more likely to have confirmed IC than those with a negative result. Conclusions. This study was unable to provide evidence that preemptive administration of an echinocandin was effective in preventing IC in high-risk surgical intensive care unit patients with intra-abdominal infections. This may have been because the drug was administered too late to prevent IC coupled with an overall low number of IC events. It does provide some support for using ßDG to identify patients at high risk of IC. Clinical Trials Registration. NCT01122368.

Systemic antifungal treatments are empirically administered to the sickest critically ill patients, often without documented invasive fungal infection. To estimate the impact of systemic antifungal treatment on 30-day survival of patients suspected to have invasive candidiasis. All nonneutropenic, nontransplant recipients managed in five intensive care units intubated for at least 5 days, and free of invasive candidiasis, were included. To account for differences in patients' characteristics recorded daily before study end point, a causal model for longitudinal data was used to assess benefits from antifungal treatment. The composite primary end point was hospital mortality or occurrence of invasive candidiasis. Among 1,491 patients, 100 (6.7%) received antifungal treatment for a suspected infection. Patients treated with antifungals were more severely ill than untreated patients. Within the 30-day follow-up period, 363 (24.3%) patients died, and 22 (1.5%) exhibited documented invasive candidiasis. After adjustment on baseline and time-dependent confounders (underlying illness, severity, invasive procedures, Candida colonization), and using a marginal structural model for longitudinal data, treatment was not associated with a decreased risk of mortality or of occurrence of invasive candidiasis (hazard ratio, 1.05; 95% confidence interval, 0.56-1.96; P = 0.91). This study failed to show outcome benefits for empirical systemic antifungal therapy in the sickest critically ill, nonneutropenic, nontransplanted patients. The post hoc power did not allow us to conclude to an absence of treatment effect especially for specific subgroups. Studies to refine indications for empirical treatment based on surrogate markers of invasive candidiasis are warranted.

Extracellular vesicles (EVs) from Candida albicans can elicit immune responses, positioning them as promising acellular vaccine candidates. We characterized EVs from an avirulent C. albicans cell wall mutant (ecm33Δ) and evaluated their protective potential against invasive candidiasis. EVs from the yeast (YEVs) and hyphal (HEVs) forms of the SC5314 wild-type strain were also tested, yielding high survival rates with SC5314 YEV (91%) and ecm33 YEV immunization (64%). Surprisingly, HEV immunization showed a dual effect, resulting in 36% protection but also causing premature death in some mice. Proteomic analyses revealed distinct profiles among the top 100 proteins in the different EVs, which may explain these effects: a shared core of 50 immunogenic proteins such as Pgk1, Cdc19, and Fba1; unique, relevant immunogenic proteins in SC5314 YEVs; and proteins linked to pathogenesis, like Ece1 in SC5314 HEVs. Sera from SC5314 YEV-immunized mice showed the highest IgG2a titers and moderate IL-17, IFN-γ, and TNF-α levels, indicating the importance of both humoral and cellular responses for protection. These findings highlight the distinct immunogenic properties of C. albicans EVs, suggesting their potential in acellular vaccine development while emphasizing the need to carefully evaluate pathogenic risks associated with certain EVs.

•Invasive Candida infections are frequent and occur early after liver transplantation (LT).•Predictors of post-LT invasive Candida infections were massive intraoperative blood loss and prolonged duration of central line. However, post-LT prophylactic antifungal therapy reduced invasive Candida infections.•Patients with invasive Candida infections were more likely to stay longer in the intensive care unit. This study aimed to investigate the incidence, timing, risk factors, and impacts of invasive Candida infections (ICIs) within 3 months after liver transplantation (LT) on LT recipients’ prognosis. Patients undergoing LT from January 2015 to December 2022 in a tertiary university hospital were investigated the incidence, onset, and risk factors of ICIs and the effects of ICIs on the outcome of LT recipients using statistical methods. The mean age of involved 389 LT recipients was 47.3 ± 10.5 years, with 322 (82.8%) being men. The incidence of ICIs was 3.3% (13/389), and the median time between LT and onset of ICIs was 5.0 days. The univariate analysis of predictors of ICIs identified that massive blood loss, prolonged duration of central line and urethral catheter, and prophylactic antifungal therapy were related to post-LT ICI risk. Multivariate logistic regression analysis adjusted for men and age identified that intraoperative blood loss ≥5000 mL (odds ratio [OR] = 7.005, 95% CI: 2.084–23.542, P = 0.002) and central line duration >14 days (OR = 5.270, 95% CI: 1.556–17.854, P = 0.008) were independently associated with the development of post-LT ICIs. Post-LT prophylactic antifungal therapy >3 days reduced ICIs (OR = 0.103, 95% CI: 0.021–0.501, P = 0.005). Regarding clinical outcomes, patients with ICIs were more likely to stay in the intensive care unit for 7 days or longer compared with those without ICIs (OR = 6.910, 95% CI: 1.737−27.493, P = 0.006). ICIs had no impact on hospitalization stay and 1-month all-cause mortality after LT. ICIs are frequent and occur early after LT. Predictors of post-LT ICIs were massive intraoperative blood loss and prolonged duration of the central line. However, post-LT prophylactic antifungal therapy reduced ICIs. Patients with ICIs stayed longer in the intensive care unit than those without ICIs.

Purpose Systemic antifungal therapy (SAT) of invasive candidiasis needs to be initiated immediately upon clinical suspicion. Controversies exist about adequate time and potential harm of antifungal de-escalation (DE) in documented and suspected candidiasis in ICU patients. Our objective was to investigate whether de-escalation within 5 days of antifungal initiation is associated with an increase of the 28-day mortality in SAT-treated non-neutropenic adult ICU patients. Methods From the 835 non-neutropenic adults recruited in the multicenter prospective observational AmarCAND2 study, we selected the patients receiving systemic antifungal therapy for a documented or suspected invasive candidiasis in the ICU and who were still alive 5 days after SAT initiation. They were included into two groups according to the occurrence of observed SAT de-escalation before day 6. The average causal SAT de-escalation effect on 28-day mortality was evaluated by using a double robust estimation. Results Among the 647 included patients, early de-escalation at day 5 after antifungal initiation occurred in 142 patients (22 %), including 48 (34 %) patients whose SAT was stopped before day 6. After adjustment for the baseline confounders, early SAT de-escalation was the solely factor not associated with increased 28-day mortality (RR 1.12, 95 % CI 0.76–1.66). Conclusion In non-neutropenic critically ill adult patients with documented or suspected invasive candidiasis, SAT de-escalation within 5 days was not related to increased day-28 mortality but it was associated with decreased SAT consumption. These results suggest for the first time that SAT de-escalation may be safe in these patients.

Invasive Candida infections represent a significant cause of morbidity and mortality in neonatal intensive care units (NICUs), with a particular impact on preterm and low-birth-weight neonates. In addition to prematurity, several predisposing factors for Candida colonization and dissemination during NICU hospitalization have been identified, including prolonged exposure to broad-spectrum antibiotics, central venous catheters, parenteral nutrition, corticosteroids, H2 antagonist administration, and poor adherence to infection control measures. According to the literature, the implementation of antifungal prophylaxis, mainly fluconazole, in high-risk populations has proven to be an effective strategy in reducing the incidence of fungal infections. This review aims to provide an overview of risk factors for invasive Candida infections and current perspectives regarding antifungal prophylaxis use. Recognizing and reducing people’s exposure to these modifiable risk factors, in conjunction with the administration of antifungal prophylaxis, has been demonstrated to be an effective method for preventing invasive candidiasis in susceptible neonatal populations.

The dosing of fluconazole for young infants remains empirical because of the limited pharmacokinetic (PK) data. We aimed to establish a population PK model and assess the systematic exposure-response of commonly used regimens of fluconazole in Chinese infants. We included infants with a postnatal age of less than 120 days and received intravenous fluconazole. Both scheduled and scavenged plasma samples were collected, and fluconzaole concentration was determined by a validated ultra-performance liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using Phoenix NLME, and then Monte Carlo simulation was conducted to predict the probability of target attainment (PTA) of empirically used regimens of both prophylactic and therapeutic purposes. Based on 304 plasma samples from 183 young infants, fluconazole concentration data was best described by a one-compartment model with first-order elimination. Gestational Age (GA), postnatal age (PNA), and body weight (BW) were included in the final model as CL = 0.02*(GA/214)2.77*(PNA/13)0.24*exp(nCL); V = 1.56*(BW/1435)0.90*exp(nV). Model validation revealed the final model had qualified stability and acceptable predictive properties. Monte Carlo simulation indicated that under the same minimum inhibitory concentration (MIC) value and administration regimen, PTA decreased with GA and PNA. The commonly used prophylactic regimens can meet the clinical need, while higher doses might be needed for treatment of invasive candidiasis. This population PK model of fluconazole discriminated the impact of GA and PNA on CL and BW on V. Dosing adjustment was needed according to the GA and PNA of infants to achieve targeted exposures.