Invasive Candida Research Articles

Native valve endocarditis due to Candida parapsilosis in an adult patient

Candida endocarditis is rare, but associated with a high mortality. The most common species implicated is Candida albicans. The epidemiology of invasive Candida infections is changing, with a predominance of non-albicans species causing invasive disease. We describe a case of Candida parapsilosis endocarditis in an HIV-positive patient with pre-existing mitral valve disease and renal failure on haemodialysis. The patient presented with fever and malaise. Clinical examination revealed pulmonary oedema and severe mitral regurgitation. Blood cultures were positive for C. parapsilosis. β-D-glucan assay levels were elevated. An echocardiogram showed large, friable vegetations on the mitral valve. C. parapsilosis was cultured from the haemodialysis tip and the vegetations. The patient responded well to mitral valve replacement and antifungal therapy. A high index of suspicion and aggressive diagnostic modalities and therapy are essential in patients with candidaemia, to decrease mortality due to this condition.

Clinical practice guidelines for the management of invasive Candida infections in adults in the Middle East region: Expert panel recommendations

Invasive Candida infections contribute to significant morbidity and mortality in patients with healthcare-associated infections. They represent a major burden on the public health system, and are challenging to diagnose and treat. A multidisciplinary expert panel critically reviewed available evidence to provide consensus recommendations for the management of invasive Candida infections in the Middle East. Based on diagnosis, recommendations were provided for the management of Candida infections in non-neutropenic and neutropenic patients. Polyenes (amphotericin B-deoxycholate [AmB-d] and lipid formulations amphotericin B [LFAmB]), triazoles (fluconazole, itraconazole and voriconazole), echinocandins (caspofungin, anidulafungin, and micafungin) and flucytosine are the recommended categories of antifungal agents for treatment of Candida infections. Echinocandins are preferred for treatment of proven and suspected Candida infections, especially in critically ill patients or those with previous exposure to azoles. Recommendations were also provided for infections caused by specific Candida species as well as management of different disease conditions. The experts highlighted that the guidelines should be used along with clinical judgment. Given the paucity of published data from the region, research in the form of randomized clinical trials should be given priority.

Invasive candidiasis in intensive care units in China: in vitro antifungal susceptibility in the China-SCAN study

The objectives of this study were to determine species distribution and in vitro antifungal susceptibility of Candida isolates identified in the multicentre China-SCAN study of invasive Candida infection (ICI) in intensive care units (ICUs) across China. Candida isolates from patients in the China-SCAN study with documented ICI were evaluated by a central laboratory. Species were identified using chromogenic culture media or the API 20C AUX kit. Susceptibility to fluconazole, voriconazole, itraconazole, caspofungin and amphotericin B was determined using the CLSI broth microdilution method (M27-A3) and updated clinical breakpoints or epidemiological cut-off values. A total of 389 isolates from 244 patients were analysed. Species identified most frequently were Candida albicans (40.1%), Candida parapsilosis (21.3%), Candida tropicalis (17.2%) and Candida glabrata (12.9%). Rarer species such as Lodderomyces elongisporus and Candida ernobii were also identified. Fluconazole susceptibility was evident in 85.9% (134/156) of C. albicans, 62.7% (42/67) of C. tropicalis and 48.2% (40/83) of C. parapsilosis isolates. Susceptibility to voriconazole was ≥ 90% among all species. All isolates were susceptible to amphotericin B and caspofungin except C. glabrata [86.0% (43/50) susceptible to caspofungin]. Cross-resistance between fluconazole and voriconazole was observed for C. parapsilosis and C. glabrata. Although C. albicans was the predominant single species, non-albicans species constituted >50% of isolates. Fluconazole susceptibility was lower in most non-albicans species, indicating that fluconazole resistance should be closely monitored. Susceptibility to voriconazole, amphotericin B and caspofungin is encouraging. Differences between these data and those from other regions emphasize the importance of assessing regional variations.

Fluconazole and selective digestive decontamination for prevention of Candida infection in high risk critically ill patients

ObjectiveInvasive fungal infections are common in critically ill patients specially those on prolonged mechanical ventilation. Fungal prophylaxis has been proven effective in certain high-risk patients such as bone marrow transplant and other immunocompromized patients. This study aimed to evaluate prophylactic use of fluconazole and selective digestive decontamination (SDD) in the prevention of invasive Candida infections in high risk critically ill patients. DesignA prospective, randomized, placebo-controlled trial. SettingCritical care department, Main Alexandria University Hospital. PatientsSeventy five critically ill patients with anticipated prolonged mechanical ventilation. MethodsThey were randomly assigned to three groups; control group, SDD group, and SDD+fluconazole according to the type of the drug they had received. Cultures were obtained after 5, 10, and 15days. End point was 15days from admission or the occurrence of Candida infection. ResultsIn a time-to-event analysis, the SDD+fluconazole group showed an absolute risk reduction of 48% when compared to the control group, and 28% when compared to the SDD group. The number needed to treat was 2.08 in the SDD+Fluconazole group, while in the SDD group it was 5. ConclusionSDD+fluconazole safely and effectively decreased the incidence of Candida infections in the high-risk, critically ill patients.

Risk factors of invasive fungal infections in patients admitted to non- hematological oncology department and pediatric intensive care unit

To determine risk factors of invasive fungal infections (IFI) in patients admitted to non-hematological oncology department and pediatric intensive care unit (PICU), in order to improve diagnostic level of invasive fungal infections. We retrospectively assessed 85 hospitalized pediatric patients with invasive fungal infections in Beijing Children's Hospital Affiliated to Capital Medical University from Jan.2007 to Nov.2012. All the cases were either from non-hematological oncology department or the PICU.We reviewed risk factors of invasive fungal infections. Among 85 patients, 42 had invasive candida infection, 20 invasive aspergillus infection, 21 cryptococcus infection, 1 Histoplasma capsulatum infection and 1 Mucor mucedo infection.In the 42 patients with invasive candida infection, 5 were young infants, 3 had combined immunodeficiency, 1 cellular immunodeficiency, 25 secondary infection due to long term use of corticosteroids and/or combined use of more than 2 kinds of antibiotics with primary disease, 5 prior intestinal tract surgery or chronic diarrheal disease, 1 reflux gastritis.In the 20 patients with invasive aspergillosis infection, 10 patients had chronic granulomatous disease, 5 long term use of corticosteroids ≥ 1 month, 3 long term use of corticosteroids and combined use of more than 2 kinds of antibiotics, 2 had no apparent host factors.In the 21 patients with cryptococcus infection, 2 patients had used corticosteroids ≥ 1 month, 2 had immunodeficiency mainly for lack of antibodies, while others had no apparent host factors. The child with Mucor mucedo infection had diabetes mellitus. And the one with Histoplasma capsulatum infection had immunodeficiency. High risk factors for IFI in patients admitted to non-hematological oncology department and PICU are primary immunodeficiency disease and long term use of corticosteroids and/or long term combined use of more than 2 kinds of antibiotics. Besides, young infant is also a high risk factor for invasive candida infection. Most of the cryptococcus infections and certain aspergillosis had no obvious host factors.

Surveillance of the prevalence, antibiotic susceptibility, and genotypic characterization of invasive candidiasis in a teaching hospital in China between 2006 to 2011

BackgroundInvasive candidiasis is an important nosocomial infection associated with high mortality among immunosuppressive or critically ill patients. We described the incidence of invasive candidiasis in our hospital over 6 years and showed the antifungal susceptibility and genotypes of the isolated yeast.MethodThe yeast species were isolated on CHROMagar Candida medium and identified using an yeast identification card, followed by analysis of the D1/D2 domain of 26S rDNA. The susceptibilities of the isolates to flucytosine, amphotericin B, fluconazole, itraconazole, and voriconazole were tested using the ATB FUNGUS 3 system, and that to caspofungin was tested using E-test strips. C. albicans was genotyped using single-strand conformation polymorphism of CAI (Candida albicans I) microsatellite DNA combined with GeneScan data.ResultsFrom January 2006 to December 2011, a total of 259 isolates of invasive Candida spp. were obtained from 253 patients, among them 6 patients had multiple positive samples. Ninety-one stains were from blood and 168 from sterile fluids, accounting for 6.07% of all pathogens isolated in our hospital. Most of these strains were C. albicans (41.29% in blood/59.06% in sterile body fluids), followed by C. tropicalis (18.06%/25.72%), C. parapsilosis (17.42%/5.43%), C. glabrata (11.61%/3.99%) and other Candida spp. (11.61%/5.80%). Most Candida spp. were isolated from the ICU. The new species-specific CLSI candida MIC breakpoints were applied to these date. Resistance to fluconazole occurred in 6.6% of C. albicans isolates, 10.6% of C. tropicalis isolates and 15.0% of C. glabrata isolates. For the 136 C. albicans isolates, 54 CAI patterns were recognized. The C. albicans strains from blood or sterile body fluids showed no predominant CAI genotypes. C. albicans isolates from different samples from the same patient had the same genotype.ConclusionsInvasive candidiasis has been commonly encountered in our hospital in the past 6 years, with increasing frequency of non-C. albicans. Resistance to fluconazole was highly predictive of resistance to voriconazole. CAI SSCP genotyping showed that all C. albicans strains were polymorphic. Invasive candidiasis were commonly endogenous infection.

A Mouse Model for Candida glabrata Hematogenous Disseminated Infection Starting from the Gut: Evaluation of Strains with Different Adhesion Properties

Adhesion to digestive mucosa is considered a crucial first step in the pathogenicity of invasive Candida infections. Candida glabrata disseminated infections predominantly start from the gut. A mouse model of disseminated infection starting from the gut was set up. Hematogenous dissemination was obtained after a low-protein diet followed by a regimen of cyclophosphamide-methotrexate and an oral inoculation of the yeasts via the drinking water. The liver was the first organ infected (day 7 post-infection), and lethality was 100% at day 21 post-infection. This new mouse model was used to compare the mortality rate and fungal burden in deep organs induced by 5 strains exhibiting different levels of adhesion to enterocyte Caco-2 cells, as determined in a test on 36 C. glabrata strains. In this model, no statistical difference of lethality was demonstrated between the strains, and fungal burden varied in kidneys and lungs but without correlation with the level of adhesion to enterocytes. Further studies using the model developed here allow analysis of the crossing of the digestive mucosa by yeasts, and help relate this to yet-poorly understood adhesion phenotypes.

Cost-effectiveness of anidulafungin in confirmed candidaemia and other invasive Candida infections in Spain

Candidaemia and invasive Candida infections can cause patient death and are expensive. Anidulafungin, a newly-licensed candin, has proven effective in treating candidaemia. Our study evaluates the cost-effectiveness of anidulafungin compared with fluconazole, the current standard of care, for treating invasive candidiasis and candidaemia in Spain. A decision tree model from the hospital perspective was constructed to examine the cost-effectiveness of anidulafungin compared with fluconazole in treating confirmed candidaemia. Treatment success, patient treatment patterns, and patient survival were based on the results from a randomised, double-blind multicentre trial (Reboli et al., 2007 [41]). Only in-hospital (2011 €) direct costs per-patient obtained from a Spanish national database were considered. Renal toxicity probabilities and costs were extracted from the published literature. The incremental cost per successfully treated patient was calculated. One-way sensitivity analyses were performed to test model robustness. The percentage of successfully treated patients was higher with anidulafungin than with fluconazole (74% versus 57%). Treatment with anidulafungin resulted in higher antifungal drug costs (5991€ versus 3149€) but lower overall costs (40047€ versus 41350€) due to reductions in other medical costs. Univariate sensitivity analyses showed that anidulafungin was the most cost-effective. Anidulafungin demonstrated improved clinical efficacy versus fluconazole in treating confirmed candidaemia. Despite increased drug costs, treating confirmed candidaemia with anidulafungin is a cost-effective strategy.

Candidaemia in a Polish tertiary paediatric hospital, 2000 to 2010

Data on the epidemiology of invasive Candida infections in paediatric patients in Europe are still limited. The aim of this retrospective study was to analyse the epidemiology of candidaemia in a tertiary paediatric hospital in Poland from 2000 to 2010. Using microbiological records, a total of 118 episodes of candidaemia were identified in 114 children, with an annual incidence of 0.35 episodes/1000 discharges. The highest incidences were found in the medical intensive care unit (5.28), and in neonatal intensive care (1.47). The mortality rate was 8.5%. Candida albicans and C. parapsilosis were the most prevalent species (39.8% and 35.6% respectively). The prevalence of non-albicans species increased from 12.5% in 2000 to 70% in 2010. No differences were found between C. albicans and C. non-albicans episodes in terms of demographics, risk factors or mortality. The highest resistance rates (overall 7.6%) were observed for fluconazole (4.3% in C. albicans, 7.1% in C. parapsilosis and 13.8% in other Candida species). Resistance to amphotericin B (2.5%) was limited to non-albicans isolates. The dynamic changes in species distribution and increasing resistance of fungal pathogens confirm the importance of epidemiological surveillance.

Cardiac effects of echinocandin preparations - three case reports

Echinocandins are antifungal agents, routinely used in invasive candida infections in critically ill patients. Their excellent anticandidal activity and their low frequency of reported adverse events and drug interactions make them first-line guideline treatments of candidiasis especially in intensive care units (ICU). We report on three ICU patients who developed cardiac insufficiency and hemodynamic instability during administration of loading doses of an echinocandin. Three ICU patients showed a substantial drop in their cardiac index or a deterioration of the mean arterial pressure following start of echinocandin administration. The patients were 75 years (female), 71 years (male) and 66 years (male) old. One patient received caspofungin, and two patients received anidulafungin as empirical antifungal treatment for severe sepsis. Our cases suggest that the observed cardiac impairment could be associated with echinocandin administration. Therefore, we recommend close hemodynamic monitoring of critically ill patients receiving echinocandins.

Leberfunktionsstörungen in der Intensivmedizin – Konsequenzen für die Therapie invasiver Candidainfektionen

Liver dysfunction is common among patients on intensive care units (ICU) due to sepsis, chronic liver disease, ischemic hepatitis, drug toxicity and intensive care measures. Critically ill patients with invasive fungal infections should therefore be treated with antifungals that are not metabolized by the liver. This may help to avoid therapeutic complications by drug accumulation, inadequate dosages or drug-drug interactions. Echinocandins are established as the antifungal class of choice in the treatment of invasive Candida infections. Anidulafungin is not hepatically metabolized and may be used without dose adjustments in patients with severe liver dysfunction. It has no known clinically relevant drug interactions. In the primary endpoint of the randomized pivotal trial in patients with candidemia or invasive candidiasis, anidulafungin was statistically superior versus the former standard therapy (fluconazole), with a favourable overall safety profile. More recent study data particularly in ICU patients confirm the efficacy of anidulafungin for these patient groups. Therefore, anidulafungin is an important antifungal treatment option for patients with liver dysfunction.

Evaluation of Candida Colonization in Intensive Care Unit Patients and the Use of Candida Colonization Index

Parallel to the developments in the field of diagnosis and treatment, an increase in the incidence of fungal infections and the number of patients who are in the risk group for the development of opportunistic fungal infections have been observed in the recent years. Among the hospitalized patients, those most at risk in terms of fungal infections are intensive care unit (ICU) patients. The rate of Candida colonization of mucous membranes in hospitalized patients may reach to 80%, and this may predispose to the establishment of severe infections especially in patients under risk. The aim of this study was to evaluate the rate of Candida colonization and to use Candida colonization index in the intensive care unit patients in Ankara Training and Research Hospital, Ankara, Turkey. A total of 100 adult patients (46 female, 54 male; age range: 18-93 years, mean age: 65.28 ± 17.53 years) who were hospitalized for ≥ 7 days in the neurology (n= 56), anesthesia-reanimation (n= 24) and neurosurgery (n= 20) intensive care units between September 2008 to February 2009, were included in the study. Throat, nose, skin (axilla), urine, rectal swab cultures and additionally when necessary tracheal aspirates, drain and central vascular catheter cultures were taken weekly from each patient. Candida colonies were identified by using germ tube test, CHROMagar Candida Medium (Becton Dickinson, Germany) and ID 32 C (BioMeriux, France) yeast identification kit. Candida colonization index (CI) was calculated for each patient, and CI was defined as the ratio of the number of culture-positive distinct body sites to the total number of body sites cultured. Patients with CI > 0.2 were considered as Candida colonized. In our study, Candida colonization was found in 42 of 100 (42%) patients, of them 8 were heavily colonized (CI ≥ 0.50), and 34 were slightly colonized (C I < 0.50). The highest Candida colonization was detected in throat, urine and rectal swab samples, while none of the tracheal aspirate samples yielded Candida spp. growth. Invasive Candida infections subsequently developed in 21.4% (9/42) of the colonized patients, namely candidemia in five and Candida associated urinary tract infections in four cases. Our data indicated that, the number of colonized patients were higher in the surgical (anesthesia-reanimation and neurosurgery) intensive care units (p< 0.05), in patients staying in the ICU for longer periods (p= 0.000) and in patients with higher number of application of invasive instruments (p< 0.05) compared to those of non-colonized cases. Additionally Candida colonization emerged more often in patients with bacterial sepsis and in those exposed to broad spectrum antibiotics (p< 0.05). Use of broad spectrum antibiotics in the ICU, length of stay in the ICU and having central venous catheter were found as independent risk factors for Candida colonization. The sensitivity, specificity, positive and negative predictive values of colonization index for the detection of developing Candida infections in colonized patients were estimated as 100%, 64%, 21% and 100%, respectively. In conclusion, Candida colonization and Candida colonization index may be used as useful parameters to predict invasive Candida infections.

Association of high levels of α-defensins and S100A proteins with Candida mannan detection in bronchoalveolar lavage fluid of preterm neonates

Candida mannan (Mn) detection in bronchoalveolar lavage fluid (BALF) was shown to be useful for earlier identification and preemptive therapy targeting in preterm infants at high risk of invasive Candida infection. We investigated whether early detection of Candida Mn in BALF is associated with the presence of some neutrophilic products, as markers of prenatal infection/inflammation. BALF specimens were collected during the first 48 h of life from mechanically ventilated preterm newborns. Samples were analyzed by high-performance liquid chromatography-electrospray ionization-mass spectrometry. The relative amounts of α-defensins 1-4 and S100A proteins were measured by extracted ion current peak area. Absolute and differential white cell counts in BALF were obtained. Mn antigen concentrations were determined by the Platelia Candida antigen kit. Twenty-five studied neonates were divided into two groups: Mn-positive group and Mn-negative group. Levels of α-defensins 1-4 and S100A12 were significantly higher in the Mn-positive group than in the Mn-negative group. Moreover, positive significant correlations between the absolute number of neutrophils and the levels of α-defensins 1-4 and S100A8 were observed. The detection of Mn antigen in BALF of preterm infants is consistent with evidence of an innate immune response in their lungs as demonstrated by higher levels of α-defensins and S100A proteins.

Treatment of Invasive Candida Infections in the Neonatal Intensive Care Unit

Invasive Candida infections are a leading cause of morbidity and mortality in the neonatal intensive care unit (NICU). Extremely preterm and very low birth weight infants are at the highest risk of infection. There are currently no antifungal agents that have FDA-labeling for the treatment of invasive candidiasis in the neonatal population. Based on the current IDSA guidelines, amphotericin and fluconazole are considered first-line options for neonatal candidiasis. The newer antifungal agents (i.e., echinocandins and voriconazole) are currently considered second-line or salvage therapy; however, evidence supporting their use is emerging. This review focuses on the supporting evidence for the selection of antifungal agents for treatment of invasive Candida infections in the NICU.

Invasive candidiasis in intensive care units in China: a multicentre prospective observational study

To describe the epidemiology, microbiology and management of invasive Candida infection (ICI) in intensive care units (ICUs) in China. A multicentre, prospective, observational study in 67 hospital ICUs across China. Patients were ≥18 years old with clinical signs of infection and at least one of the following diagnostic criteria: (i) histopathological, cytopathological or microscopic confirmation of yeast cells from a normally sterile site; (ii) at least one peripheral blood culture positive for Candida; and (iii) positive Candida culture from a normally sterile site. The China-SCAN study is registered with ClinicalTrials.gov (NCT T01253954). ICI incidence was 0.32% (306 patients/96,060 ICU admissions) and median time between ICU admission and diagnosis was 10.0 days. Candida albicans was the most prevalent single isolate (41.8% of patients), although non-albicans species accounted for the majority of infections. Diagnostic confirmation was based solely on at least one positive blood culture in 290 (94.8%) cases. Treatment was initiated after diagnostic confirmation in 166/268 (61.9%) patients. Triazoles (62.7%) and echinocandins (34.2%) were the most commonly used antifungal agents; first-line therapy was typically fluconazole (37.7%). The median duration of antifungal therapy was 14 days. The mortality rate was 36.6% (112/306); the median time between diagnosis and death was 14.5 days. Mortality was higher in older individuals, those with solid tumours, those with recent invasive mechanical ventilation and those with a higher sequential organ failure assessment score at diagnostic confirmation. Susceptibility to first-line antifungals was associated with lower mortality than dose-dependent susceptibility or complete resistance (P=0.008). More infections were caused by non-albicans than Candida albicans strains. The majority of patients were treated only after diagnostic confirmation, rather than empirically. First-line antifungal susceptibility was associated with lower mortality.

Immunomodulatory Agents as Adjunctive Therapy for the Treatment of Resistant Candida Species

Invasive Candida infections have increased fivefold over the past 20 years. During this time, the incidence of antifungal resistance and infection due to non-albicans species has risen with the increasing use of broad spectrum antifungals. As few new antifungal agents are in development, strategies to improve outcomes in the treatment of Candida infections are sorely needed. The use of immunotherapy to augment the host immune response as an adjunctive treatment for Candida infections is a potentially robust and promising approach. The purpose of this review is to focus on new developments in the use of adjunctive immunotherapy for the treatment of Candida infections, and discuss the potential impact of antifungal resis- tance on the host immune response.

The effects of virulence factors on invasion in various species of Candida

In the present study, we determined the in vitro and in vivo virulence characteristics ofCandida isolates from 75 non-neutropenic patients with candidemia and analyzed the isolates by receiver-operating characteristics (ROC) analysis to define threshold values of adhesion and hydrophobicity occurring in invasive Candida isolates. Specific virulence traits that were measured included hydrophobicity, epithelial cell adhesion, phospholipase and proteinase activity. In our in vivo investigations, all isolates were diluted in phosphate-buffered saline (PBS) and were administered to mice (Swiss albino) through tail-vein injection. Liver and spleen tissues were evaluated for evidence of invasion. Though onlyCandida albicans isolates produced detectable phospholipase activity, all isolates secreted proteinase enzyme. However, while this observation was significant among C. albicans and Candida parapsilosis isolates, the reverse was seen for Candida tropicalisand Candida krusei isolates. Interestingly, in contrast with C. parapsilosis and C. tropicalis, lower median adhesion values were determined for C. albicans and C. krusei, particularly in isolates that showed invasion in mouse experiments. It has not been possible to identify meaningful threshold values for adhesion and hydrophobicity in the repeated ROC analysis on the sub-groups in differentiating the isolates that cause and do not cause invasion in mice among the various Candida isolates. Key words: Candidemia, virulence factors, ROC analysis

A prospective analysis of invasive candidiasis following cardiac surgery: Severity markers are predictive

Invasive Candida infections (ICI) in intensive care unit (ICU) patients are associated with high mortality. A 2-year prospective study was performed to improve clinical decision making in long-term ICU patients after cardiac surgery. Demographic, clinical and physiological data, the incidence of ICI and Candida colonisation scores were analysed. To assess severity of illness the new simplified acute physiology score (SAPS II score), the European system for cardiac operative risk evaluation (EuroSCORE) and the sequential organ failure assessment (SOFA) score were calculated. To define independent risk factors univariate and multivariate Cox-regression analyses with time-dependent covariates were calculated. One hundred and sixty-nine cardiac surgery patients with ICU admittance ≥ 4 days out of 513 admittances were enrolled. Ten patients had proven ICI. In the multivariate analysis the SOFA score (HR = 1.29, p = 0.009) was associated with proven ICI. In 71 patients receiving empiric antifungal therapy for presumptive but unproven ICI the SOFA score (HR = 1.18, p = 0.029) and corrected Candida colonisation index (HR 11.08; p = 0.030) were significantly associated to ICI. Neither SAPS II score nor EuroScore were associated with ICI in either patient group. The mortality rate of patients receiving empiric antifungal therapy was significantly lower compared to that of patients with proven ICI (36.6% vs. 80%, respectively). Time-associated SOFA score assessing acute organ failure was the only independent risk factor for proven ICI. Cardiovascular procedures did not confer risk to develop ICI. Empiric antifungal therapy may be warranted in severely ill cardiac surgery patients.

Development and validation of a risk model for identification of non-neutropenic, critically ill adult patients at high risk of invasive Candida infection: the Fungal Infection Risk Evaluation (FIRE) Study

There is increasing evidence that invasive fungal disease (IFD) is more likely to occur in non-neutropenic patients in critical care units. A number of randomised controlled trials (RCTs) have evaluated antifungal prophylaxis in non-neutropenic, critically ill patients, demonstrating a reduction in the risk of proven IFD and suggesting a reduction in mortality. It is necessary to establish a method to identify and target antifungal prophylaxis at those patients at highest risk of IFD, who stand to benefit most from any antifungal prophylaxis strategy. To develop and validate risk models to identify non-neutropenic, critically ill adult patients at high risk of invasive Candida infection, who would benefit from antifungal prophylaxis, and to assess the cost-effectiveness of targeting antifungal prophylaxis to high-risk patients based on these models. Systematic review, prospective data collection, statistical modelling, economic decision modelling and value of information analysis. Ninety-six UK adult general critical care units. Consecutive admissions to participating critical care units. None. Invasive fungal disease, defined as a blood culture or sample from a normally sterile site showing yeast/mould cells in a microbiological or histopathological report. For statistical and economic modelling, the primary outcome was invasive Candida infection, defined as IFD-positive for Candida species. Systematic review: Thirteen articles exploring risk factors, risk models or clinical decision rules for IFD in critically ill adult patients were identified. Risk factors reported to be significantly associated with IFD were included in the final data set for the prospective data collection. Data were collected on 60,778 admissions between July 2009 and March 2011. Overall, 383 patients (0.6%) were admitted with or developed IFD. The majority of IFD patients (94%) were positive for Candida species. The most common site of infection was blood (55%). The incidence of IFD identified in unit was 4.7 cases per 1000 admissions, and for unit-acquired IFD was 3.2 cases per 1000 admissions. Statistical modelling: Risk models were developed at admission to the critical care unit, 24 hours and the end of calendar day 3. The risk model at admission had fair discrimination (c-index 0.705). Discrimination improved at 24 hours (c-index 0.823) and this was maintained at the end of calendar day 3 (c-index 0.835). There was a drop in model performance in the validation sample. Economic decision model: Irrespective of risk threshold, incremental quality-adjusted life-years of prophylaxis strategies compared with current practice were positive but small compared with the incremental costs. Incremental net benefits of each prophylaxis strategy compared with current practice were all negative. Cost-effectiveness acceptability curves showed that current practice was the strategy most likely to be cost-effective. Across all parameters in the decision model, results indicated that the value of further research for the whole population of interest might be high relative to the research costs. The results of the Fungal Infection Risk Evaluation (FIRE) Study, derived from a highly representative sample of adult general critical care units across the UK, indicated a low incidence of IFD among non-neutropenic, critically ill adult patients. IFD was associated with substantially higher mortality, more intensive organ support and longer length of stay. Risk modelling produced simple risk models that provided acceptable discrimination for identifying patients at 'high risk' of invasive Candida infection. Results of the economic model suggested that the current most cost-effective treatment strategy for prophylactic use of systemic antifungal agents among non-neutropenic, critically ill adult patients admitted to NHS adult general critical care units is a strategy of no risk assessment and no antifungal prophylaxis. Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.

The control of invasiveCandidainfection in very low birth weight infants by reduction in the use of 3rd generation cephalosporin

PurposeTo evaluate the effectiveness of new management policies on the incidence of invasive Candida infectionsMethodsThis observational study involved a retrospective analysis of the patients' medical records. In total, 99 very low birth weight infants, who were admitted to the neonatal intensive care unit at Ajou University Hospital from January 2010 to December 2011, were enrolled for the study. Period I, defined as the period before the revision of management policies, comprised 57 infants; whereas, period II, defined as the period after the implementation of new management policies, comprised 42 infants. The new management policies entailed a reduction in antibiotic and histamine type 2 receptor blocker (H2 blocker) use, duration of central venous catheterization, and duration of endotracheal intubation.ResultsThere was a significant overall decrease in the use of antibiotics including 3rd generation cephalosporin and H2 blockers (P<0.05), and a significantly lower incidence of invasive Candida infections in period II as compared to period I (0/42 vs. 6/57, respectively; P=0.037). Comparison between infants with invasive Candida infections (n=6) and those without (n=93) showed that gestational age (odds ratio [OR], 0.909; 95% confidence interval [CI], 0.829 to 0.996; P=0.042) and the duration of 3rd generation cephalosporin use (OR, 1.093; 95% CI, 1.009 to 1.183; P=0.029) were statistically significant risk factors.ConclusionThe new management policies effectively decreased overall use of antibiotics, especially 3rd generation cephalosporin, and H2 blockers, which led to a significantly lower incidence of invasive Candida infections.