Invasive fungal diseases in patients with autoimmune diseases: a case series from the French RESSIF network.

OBJECTIVES: We aimed to describe patients with autoimmune diseases (AID) developing invasive fungal disease (IFD) and identify factors associated with short-term mortality. METHODS: We analysed cases of IFD associated with AID from the surveillance network of invasive fungal diseases (Réseau de surveillance des infections fongiques invasives, RESSIF) registry of the French national reference centre for invasive mycoses. We studied association of AID-specific treatments with 30-day mortality. We analysed total lymphocyte and CD4-T cell counts in patients with Pneumocystis jirovecii pneumonia (PCP). RESULTS: From 2012 to 2018, 549 individuals with IFD and AID were included, mainly with PCP (n=227, 41.3%), fungemia (n=167, 30.4%) and invasive aspergillosis (n=84, 15.5%). Rheumatoid arthritis (RA) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) were the most frequent AID in PCP (n=55 and 25, respectively) and invasive aspergillosis (n=15 and 10, respectively), inflammatory bowel diseases (IBDs) were predominant in fungemia (n=36). At IFD diagnosis, 365 (66.5%) patients received glucocorticoids (GCs), 285 (51.9%) immunosuppressants, 42 (7.7%) tumor necrosis factor (TNF)-α blockers, 75 (13.7%) other biologics. Mortality at 30 days was 28.1% (143/508). Fungemia and high-dose GCs were independently associated with higher 30-day mortality. In PCP patients, lymphopenia <1500/mm3 was frequent (132/179, 73.7%) even if CD4+T cell count exceeded 200/mm3 in 56/78 patients (71.8%) (median 472.5/mm3, IQR 160-858). CONCLUSION: IFD associated with AID occurs primarily in RA, AAV and IBD, especially when treated with GCs and immunosuppressants. Mortality is high, especially for patients on high-dose GCs. Lymphopenia may help identify risk of PCP, but normal CD4+T cell count does not rule out the risk. Further studies are needed to assess the individual risk factors for IFD.

You shall not pass! Protective role of autophagic machinery in response to plasma membrane damage triggered by Candida albicans invasion.

Candida albicans (C. albicans) is an opportunistic pathogen causing infections ranging from superficial to life-threatening dissemination, in which C. albicans is able to translocate through the gut barrier into deeper organs. In its filamentous form (hyphae), C. albicans can invade epithelial cells by two mechanisms: epithelial cell-driven endocytosis and C. albicans-driven active penetration of host cell plasma membrane (PM). Autophagic machinery is known to be involved in the epithelial barrier maintenance, especially the intestinal barrier that is continuously challenged by exposure to the gut microbiota or to xenobiotics. The protective role of autophagy during C. albicans infection has been investigated in myeloid cells, however, far less was known regarding its role during infection of epithelial cells. Here, we demonstrated that key proteins of the autophagic machinery and vesicles presenting features of autophagosomes are recruited at C. albicans invasion sites. These events are associated with host PM damage caused by the active penetration of C. albicans. We showed that ATG5 and ATG16L1 proteins contribute to PM repair mediated by lysosomal membrane exocytosis and participate in protection of epithelial cells' integrity against C. albicans-induced cell death. Our findings extend the knowledge on emerging roles of the autophagic machinery in stress-related membrane dynamics.

Evaluation of Serum Mucorales Polymerase Chain Reaction (PCR) for the Diagnosis of Mucormycoses: The MODIMUCOR Prospective Trial.

BACKGROUND: Early diagnosis and prompt initiation of specific antifungal treatment are essential for improving the prognosis of mucormycosis. We aimed to assess the performance of serum Mucorales quantitative polymerase chain reaction (qPCR) for the early diagnosis and follow-up of mucormycosis. METHODS: We prospectively enrolled 232 patients with suspicion of invasive mold disease, evaluated using standard imaging and mycological procedures. Thirteen additional patients with proven or probable mucormycosis were included to analyze DNA load kinetics. Serum samples were collected twice-a-week for Mucorales qPCR tests targeting the Mucorales genera Lichtheimia, Rhizomucor, and Mucor/Rhizopus. RESULTS: The sensitivity was 85.2%, specificity 89.8%, and positive and negative likelihood ratios 8.3 and 0.17, respectively in this prospective study. The first Mucorales qPCR-positive serum was observed a median of 4 days (interquartile range [IQR], 0-9) before sampling of the first mycological or histological positive specimen and a median of one day (IQR, -2 to 6) before the first imaging was performed. Negativity of Mucorales qPCR within seven days after liposomal-amphotericin B initiation was associated with an 85% lower 30-day mortality rate (adjusted hazard ratio = 0·15, 95% confidence interval [.03-.73], P = .02). CONCLUSIONS: Our study argues for the inclusion of qPCR for the detection of circulating Mucorales DNA for mucormycosis diagnosis and follow-up after treatment initiation. Positive results should be added to the criteria for the consensual definitions from the European Organization for the Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium (EORTC/MSGERC), as already done for Aspergillus PCR.

Membrane protective role of autophagic machinery during infection of epithelial cells by Candida albicans.

Candida albicans (C. albicans) is an opportunistic pathogen causing infections ranging from superficial to life-threatening disseminated infections. In a susceptible host, C. albicans is able to translocate through the gut barrier, promoting its dissemination into deeper organs. C. albicans hyphae can invade human epithelial cells by two well-documented mechanisms: epithelial-driven endocytosis and C. albicans-driven active penetration. One mechanism by which host cells protect themselves against intracellular C. albicans is termed autophagy. The protective role of autophagy during C. albicans infection has been investigated in myeloid cells; however, far less is known regarding the role of this process during the infection of epithelial cells. In the present study, we investigated the role of autophagy-related proteins during the infection of epithelial cells, including intestinal epithelial cells and gut explants, by C. albicans. Using cell imaging, we show that key molecular players of the autophagy machinery (LC3-II, PI3P, ATG16L1, and WIPI2) were recruited at Candida invasion sites. We deepened these observations by electron microscopy analyses that reveal the presence of autophagosomes in the vicinity of invading hyphae. Importantly, these events occur during active penetration of C. albicans into host cells and are associated with plasma membrane damage. In this context, we show that the autophagy-related key proteins ATG5 and ATG16L1 contribute to plasma membrane repair mediated by lysosomal exocytosis and participate in protecting epithelial cells against C. albicans-induced cell death. Our findings provide a novel mechanism by which epithelial cells, forming the first line of defense against C. albicans in the gut, can react to limit C. albicans invasion.

Tight Junctions as a Key for Pathogens Invasion in Intestinal Epithelial Cells.

Tight junctions play a major role in maintaining the integrity and impermeability of the intestinal barrier. As such, they act as an ideal target for pathogens to promote their translocation through the intestinal mucosa and invade their host. Different strategies are used by pathogens, aimed at directly destabilizing the junctional network or modulating the different signaling pathways involved in the modulation of these junctions. After a brief presentation of the organization and modulation of tight junctions, we provide the state of the art of the molecular mechanisms leading to permeability breakdown of the gut barrier as a consequence of tight junctions' attack by pathogens, including bacteria, viruses, fungi, and parasites.

Characteristics and outcome according to underlying disease in non-AIDS patients with acute respiratory failure due to Pneumocystis pneumonia.

In the non-AIDS group, several underlying conditions and immune defects could lead to different PCP presentations. This study compared PCP presentation and outcome according to the underlying disease. A secondary analysis of a previously published prospective observational study including 544 PCP patients was done. Only non-AIDS patients were included. Underlying disease was defined as chronic lymphocytic leukemia (CLL), organ transplantation, solid cancer, allogeneic hematopoietic stem cell transplant (AHSCT), other hematological diseases, and immunosuppressive treatment. Clinical characteristics and outcomes were compared between groups. Multiple correspondent analyses compared clinical characteristics at diagnosis. Day 30 mortality was analyzed. Three hundred and twenty-one patients were included in the study. The underlying diseases were hematological malignancy (n = 75), AHSCT (n = 14), CLL (n = 19), solid organ transplant (n = 94), solid tumor (n = 39), and immunosuppressive treatment (n = 57). Compared with other underlying diseases, PCP related to CLL was closer to PCP related to AIDS presentation (long duration of symptoms before diagnosis, high level of dyspnea, and low oxygen saturation at diagnosis). Day 30 mortality was associated with underlying disease, oxygen flow, and shock at ICU admission. PCP presentations may vary according to the underlying reason for immunosuppression. Response to treatment and adjuvant steroid therapy should be analyzed regarding this result.

First Case of Human Primary Vertebral Cystic Echinococcosis Due to Echinococcus Ortleppi.

Cystic echinococcosis (CE) is a cosmopolitan parasitic zoonosis affecting more than one million people worldwide. In humans, primary bone CE is rare and involvement of E. ortleppi is very uncommon. We report here the first case of primary vertebral cystic echinococcosis due to E. ortleppi in Burgundy, France.

Toward the Standardization of Mycological Examination of Sputum Samples in Cystic Fibrosis: Results from a French Multicenter Prospective Study.

Fungal respiratory colonization of cystic fibrosis (CF) patients emerges as a new concern; however, the heterogeneity of mycological protocols limits investigations. We first aimed at setting up an efficient standardized protocol for mycological analysis of CF sputa that was assessed during a prospective, multicenter study: "MucoFong" program (PHRC-06/1902). Sputa from 243 CF patients from seven centers in France were collected over a 15-month period and submitted to a standardized protocol based on 6 semi-selective media. After mucolytic pretreatment, sputa were plated in parallel on cycloheximide-enriched (ACT37), erythritol-enriched (ERY37), benomyl dichloran-rose bengal (BENO37) and chromogenic (CAN37) media incubated at 37 °C and on Sabouraud-chloramphenicol (SAB27) and erythritol-enriched (ERY27) media incubated at 20-27 °C. Each plate was checked twice a week during 3 weeks. Fungi were conventionally identified; time for detection of fungal growth was noted for each species. Fungal prevalences and media performances were assessed; an optimal combination of media was determined using the Chi-squared automatic interaction detector method. At least one fungal species was isolated from 81% of sputa. Candida albicans was the most prevalent species (58.8%), followed by Aspergillus fumigatus (35.4%). Cultivation on CAN37, SAB27, ACT37 and ERY27 during 16 days provided an optimal combination, detecting C. albicans, A. fumigatus, Scedosporium apiospermum complex and Exophiala spp. with sensitivities of 96.5, 98.8, 100 and 100%. Combination of these four culture media is recommended to ensure the growth of key fungal pathogens in CF respiratory specimens. The use of such consensual protocol is of major interest for merging results from future epidemiological studies.

Resveratrol-Induced Xenophagy Promotes Intracellular Bacteria Clearance in Intestinal Epithelial Cells and Macrophages.

Autophagy is a lysosomal degradation process that contributes to host immunity by eliminating invasive pathogens and the modulating inflammatory response. Several infectious and immune disorders are associated with autophagy defects, suggesting that stimulation of autophagy in these diseases should be beneficial. Here, we show that resveratrol is able to boost xenophagy, a selective form of autophagy that target invasive bacteria. We demonstrated that resveratrol promotes in vitro autophagy-dependent clearance of intracellular bacteria in intestinal epithelial cells and macrophages. These results were validated in vivo using infection in a transgenic GFP-LC3 zebrafish model. We also compared the ability of resveratrol derivatives, designed to improve the bioavailability of the parent molecule, to stimulate autophagy and to induce intracellular bacteria clearance. Together, our data demonstrate the ability of resveratrol to stimulate xenophagy, and thereby enhance the clearance of two invasive bacteria involved life-threatening diseases, Salmonella Typhimurium and Crohn's disease-associated Adherent-Invasive Escherichia coli. These findings encourage the further development of pro-autophagic nutrients to strengthen intestinal homeostasis in basal and infectious states.

Evolution of procalcitonin, C-reactive protein and fibrinogen levels in neutropenic leukaemia patients with invasive pulmonary aspergillosis or mucormycosis.

Unlike bacterial infections, the value of procalcitonin (PCT) in detecting fungal infections in leukaemia patients is not clear. To determine whether the monitoring of PCT coupled with C-reactive protein (CRP) and fibrinogen (Fib) could be helpful in the management of pulmonary aspergillosis (IPA) or mucormycosis (PM), we retrospectively analysed the evolution of PCT, CRP and Fib levels in 94 leukaemia patients with proven/probable IPA (n = 77) or PM (n = 17) from D-12 to D12 relative to IFI onset defined as D0. Overall, 2140 assays were performed. From D-12 to D0, 12%, 5% and 1.4% of patients had PCT >0.5, 1 and 1.5 µg l(-1) , respectively, while CRP was >50, 75 and 100 mg l(-1) in 84%, 70% and 57% and Fib was >4, 5 and 6 g l(-1) in 96%, 80% and 61% of cases respectively (P < 10(-7) ). The same trends were observed from D1 to D12. Overall, between D-12 and D12, only 6.4% of patients had PCT >1.5 µg l(-1) , while CRP >100 mg l(-1) and Fib >6 g l(-1) were observed in 80% and 75% of cases respectively (P < 10(-7) ). In leukaemia patients, IPA or PM was accompanied by a significant increase in CRP and Fib while PCT remained low.

Is It Time to Include CT "Reverse Halo Sign" and qPCR Targeting Mucorales in Serum to EORTC-MSG Criteria for the Diagnosis of Pulmonary Mucormycosis in Leukemia Patients?

In 23 leukemia patients with proven (n = 17) or possible (n = 6) pulmonary mucormycosis (PM), the presence of reversed halo sign on computed tomography was strongly associated with the positivity of quantitative polymerase chain reaction assays targeting Mucorales in the serum, confirming the value of these two tools for the diagnosis of PM in this setting.

Candida albicans is able to use M cells as a portal of entry across the intestinal barrier in vitro.

Candida albicans is the most frequent yeast responsible for systemic infections in humans. These infections mainly originate from the gastrointestinal tract where C. albicans can invade the gut epithelial barrier to gain access to the bloodstream. Along the gut, pathogens can use Microfold (M) cells as a portal of entry to cross the epithelial barrier. M cells are specialized cells mainly located in the follicule-associated epithelium of Peyer patches. In this study, we used scanning electron and fluorescence microscopy, adhesion and invasion assays and fungal mutants to investigate the interactions of C. albicans with M cells obtained in an established in vitro model whereby enterocyte-like Caco-2 cells co-cultured with the Raji B cell line undergo a phenotypic switch to morphologically and functionally resembling M cells. Our data demonstrate that C. albicans co-localizes with and invades preferentially M cells, providing evidence that the fungus can use M cells as a portal of entry into the intestinal barrier. In addition to active penetration, F-actin dependent endocytosis contributes to internalization of the fungus into M cells through a mechanism involving hypha-associated invasins including Ssa1 and Als3.

Molecular diagnosis of toxoplasmosis in immunocompromised patients: a 3-year multicenter retrospective study.

Toxoplasmosis is a life-threatening infection in immunocompromised patients (ICPs). The definitive diagnosis relies on parasite DNA detection, but little is known about the incidence and burden of disease in HIV-negative patients. A 3-year retrospective study was conducted in 15 reference laboratories from the network of the French National Reference Center for Toxoplasmosis, in order to record the frequency of Toxoplasma gondii DNA detection in ICPs and to review the molecular methods used for diagnosis and the prevention measures implemented in transplant patients. During the study period, of 31,640 PCRs performed on samples from ICPs, 610 were positive (323 patients). Blood (n = 337 samples), cerebrospinal fluid (n = 101 samples), and aqueous humor (n = 100 samples) were more frequently positive. Chemoprophylaxis schemes in transplant patients differed between centers. PCR follow-up of allogeneic hematopoietic stem cell transplant (allo-HSCT) patients was implemented in 8/15 centers. Data from 180 patients (13 centers) were further analyzed regarding clinical setting and outcome. Only 68/180 (38%) patients were HIV(+); the remaining 62% consisted of 72 HSCT, 14 solid organ transplant, and 26 miscellaneous immunodeficiency patients. Cerebral toxoplasmosis and disseminated toxoplasmosis were most frequently observed in HIV and transplant patients, respectively. Of 72 allo-HSCT patients with a positive PCR result, 23 were asymptomatic; all were diagnosed in centers performing systematic blood PCR follow-up, and they received specific treatment. Overall survival of allo-HSCT patients at 2 months was better in centers with PCR follow-up than in other centers (P < 0.01). This study provides updated data on the frequency of toxoplasmosis in HIV-negative ICPs and suggests that regular PCR follow-up of allo-HSCT patients could guide preemptive treatment and improve outcome.

Invasive infections due to Candida norvegensis and Candida inconspicua: report of 12 cases and review of the literature.

Candida inconspicua and Candida norvegensis are two closely related species rarely involved in invasive infections. The purpose of this study was to depict the epidemiologic and clinical characteristics of candidemia due to these emerging fluconazole less susceptible species. A retrospective analysis of the epidemiology of C. inconspicua and C. norvegensis during the period 2006-2010 was initiated in six French University hospitals. From this, demographics, clinical, diagnostic and therapeutic data of C. inconspicua or C. norvegensis candidemia were recorded and compared to the observations reported in the literature. C. inconspicua was more frequently isolated compared to C. norvegensis (ratio 2.6) but from the same preferential body sites: mainly digestive (56.4% and 48.37%, respectively, for C. inconspicua and C. norvegensis) and respiratory (26% and 28.2%, respectively). Thirteen cases of candidemia were recorded and five additional cases were found in the literature. Hematogical malignancy was the main underlying disease (n = 12). Associated factors were the presence of a vascular catheter (n = 18), broad-spectrum antibiotics (n = 15), and neutropenia (n = 14). In 13 cases (72%), prior colonization was noted before the candidemia diagnosis. Combining the results for the two species, Minimal Inhibitory Concentrations (MIC50) of amphotericin B, fluconazole, voriconazole and caspofungin were 0.125, 48, 0.25, and 0.19 mg/l, respectively. These two species must be added to the growing list of emerging Candida species poorly susceptible to fluconazole.

Candida albicans-epithelial interactions: dissecting the roles of active penetration, induced endocytosis and host factors on the infection process.

Candida albicans frequently causes superficial infections by invading and damaging epithelial cells, but may also cause systemic infections by penetrating through epithelial barriers. C. albicans is a remarkable pathogen because it can invade epithelial cells via two distinct mechanisms: induced endocytosis, analogous to facultative intracellular enteropathogenic bacteria, and active penetration, similar to plant pathogenic fungi. Here we investigated the contributions of the two invasion routes of C. albicans to epithelial invasion. Using selective cellular inhibition approaches and differential fluorescence microscopy, we demonstrate that induced endocytosis contributes considerably to the early time points of invasion, while active penetration represents the dominant epithelial invasion route. Although induced endocytosis depends mainly on Als3-E-cadherin interactions, we observed E-cadherin independent induced endocytosis. Finally, we provide evidence of a protective role for serum factors in oral infection: human serum strongly inhibited C. albicans adhesion to, invasion and damage of oral epithelial cells.

From attachment to damage: defined genes of Candida albicans mediate adhesion, invasion and damage during interaction with oral epithelial cells.

Candida albicans frequently causes superficial infections by invading and damaging epithelial cells, but may also cause systemic infections by penetrating through epithelial barriers. C. albicans is an unusual pathogen because it can invade epithelial cells via two distinct mechanisms: induced endocytosis, analogous to facultative intracellular enteropathogenic bacteria, and active penetration, similar to plant pathogenic fungi. Here we investigated the molecular basis of C. albicans epithelial interactions. By systematically assessing the contributions of defined fungal pathways and factors to different stages of epithelial interactions, we provide an expansive portrait of the processes and activities involved in epithelial infection. We strengthen the concept that hyphal formation is critical for epithelial invasion. Importantly, our data support a model whereby initial epithelial invasion per se does not elicit host damage, but that C. albicans relies on a combination of contact-sensing, directed hyphal extension, active penetration and the expression of novel pathogenicity factors for further inter-epithelial invasion, dissemination and ultimate damage of host cells. Finally, we explore the transcriptional landscape of C. albicans during the early stages of epithelial interaction, and, via genetic analysis, identify ICL1 and PGA34 as novel oral epithelial pathogenicity factors.

Cellular interactions of Candida albicans with human oral epithelial cells and enterocytes.

The human pathogenic fungus Candida albicans can cause systemic infections by invading epithelial barriers to gain access to the bloodstream. One of the main reservoirs of C. albicans is the gastrointestinal tract and systemic infections predominantly originate from this niche. In this study, we used scanning electron and fluorescence microscopy, adhesion, invasion and damage assays, fungal mutants and a set of fungal and host cell inhibitors to investigate the interactions of C. albicans with oral epithelial cells and enterocytes. Our data demonstrate that adhesion, invasion and damage by C. albicans depend not only on fungal morphology and activity, but also on the epithelial cell type and the differentiation stage of the epithelial cells, indicating that epithelial cells differ in their susceptibility to the fungus. C. albicans can invade epithelial cells by induced endocytosis and/or active penetration. However, depending on the host cell faced by the fungus, these routes are exploited to a different extent. While invasion into oral cells occurs via both routes, invasion into intestinal cells occurs only via active penetration.

A prospective survey of air and surface fungal contamination in a medical mycology laboratory at a tertiary care university hospital.

BACKGROUND: Invasive filamentous fungi infections resulting from inhalation of mold conidia pose a major threat in immunocompromised patients. The diagnosis is based on direct smears, cultural symptoms, and culturing fungi. Airborne conidia present in the laboratory environment may cause contamination of cultures, resulting in false-positive diagnosis. Baseline values of fungal contamination in a clinical mycology laboratory have not been determined to date. METHODS: A 1-year prospective survey of air and surface contamination was conducted in a clinical mycology laboratory during a period when large construction projects were being conducted in the hospital. Air was sampled with a portable air system impactor, and surfaces were sampled with contact Sabouraud agar plates. The collected data allowed the elaboration of Shewhart graphic charts. RESULTS: Mean fungal loads ranged from 2.27 to 4.36 colony forming units (cfu)/m(3) in air and from 0.61 to 1.69 cfu/plate on surfaces. CONCLUSIONS: Strict control procedures may limit the level of fungal contamination in a clinical mycology laboratory even in the context of large construction projects at the hospital site. Our data and the resulting Shewhart graphic charts provide baseline values to use when monitoring for inappropriate variations of the fungal contamination in a mycology laboratory as part of a quality assurance program. This is critical to the appropriate management of the fungal risk in hematology, cancer and transplantation patients.

A prospective analysis of the genotypic diversity and dynamics of the Candida albicans colonizing flora in neutropenic patients with de novo acute leukemia.

BACKGROUND: Genotyping studies have shown heterogeneity of Candida albicans flora in patients with human immunodeficiency virus infection, with possible co-existence of multiple clones with distinct resistance patterns. We report the result of a prospective study aimed at investigating the dynamics and heterogeneity of C. albicans flora in patients with de novo acute leukemia. DESIGN AND METHODS: Between 2001 and 2003, 66 consecutive adults with newly diagnosed acute leukemia were monitored for Candida colonization. From 19 patients with repeated multi-site C. albicans colonization, eight were randomly selected and multiple isolates from each individual mucosal site were genotyped sequentially over time using microsatellite markers. RESULTS: Despite topical use of polyenes, 60.6% of the patients were colonized repeatedly and at multiple sites. Altogether, 2,730 peripheral samples were cultured, 379 (13.9%) of which yielded yeasts. C. albicans was the most common species recovered (68%). From eight randomly selected patients colonized with C. albicans, 429 isolates were genotyped. Seven patients carried a unique genotype which was identical in all body niches and over the period of study. In one case, minor genotypic differences were observed. None of the patients shared C. albicans clones with identical genotypic profiles. Candidemia occurred in one of eight patients and the blood strain genotype did not differ from those of colonizing isolates. The genotypic profile was not altered by topical and/or systemic use of antifungal agents in any of the patients. CONCLUSIONS: In patients with de novo acute leukemia, genetic evolution of the colonizing C. albicans flora and selection of variants or replacement of the original strain upon antifungal drug pressure or nosocomial transmission are rare events.

Candidemia in critically ill patients: difference of outcome between medical and surgical patients.

OBJECTIVE: Candidemia is increasingly encountered in critically ill patients with a high fatality rate. The available data in the critically ill suggest that patients with prior surgery are at a higher risk than others. However, little is known about candidemia in medical settings. The main goal of this study was to compare features of candidemia in critically ill medical and surgical patients. DESIGN: Ten-year retrospective cohort study (1990-2000). SETTING: Medical and surgical intensive care units (ICUs) of a teaching hospital. PATIENTS: Fifty-one patients with at least one positive blood culture for Candida species. MAIN RESULTS: Risk factors were retrieved in all of the patients: central venous catheter (92.1%), mechanical ventilation (72.5%), prior bacterial infection (70.6%), high fungal colonization index (45.6%). Candida albicans accounts for 55% of all candidemia. The overall mortality was 60.8% (85% and 45.2% in medical and surgical patients, respectively). Independent factors associated with survival were prior surgery (hazard ratio [HR] =0.25; 0.09-0.67 95% confidence interval [CI], p<0.05), antifungal treatment (HR =0.11; 0.04-0.30 95% CI, p<0.05) and absence of neutropenia (HR =0.10; 0.02-0.45 95% CI, p<0.05). Steroids, neutropenia and high density of fungal colonization were more frequently found among medical patients compared to surgical ones. CONCLUSIONS: Candidemia occurrence is associated with a high mortality rate among critically ill patients. Differences in underlying conditions could account for the poorer outcome of the medical patients. Screening for fungal colonization could allow identification of such high-risk patients and, in turn, improve outcome.