Incidence and outcome of invasive candidiasis in intensive care units (ICUs) in Europe: results of the EUCANDICU project.

BACKGROUND: The objective of this study was to assess the cumulative incidence of invasive candidiasis (IC) in intensive care units (ICUs) in Europe. METHODS: A multinational, multicenter, retrospective study was conducted in 23 ICUs in 9 European countries, representing the first phase of the candidemia/intra-abdominal candidiasis in European ICU project (EUCANDICU). RESULTS: During the study period, 570 episodes of ICU-acquired IC were observed, with a cumulative incidence of 7.07 episodes per 1000 ICU admissions, with important between-center variability. Separated, non-mutually exclusive cumulative incidences of candidemia and IAC were 5.52 and 1.84 episodes per 1000 ICU admissions, respectively. Crude 30-day mortality was 42%. Age (odds ratio [OR] 1.04 per year, 95% CI 1.02-1.06, p < 0.001), severe hepatic failure (OR 3.25, 95% 1.31-8.08, p 0.011), SOFA score at the onset of IC (OR 1.11 per point, 95% CI 1.04-1.17, p 0.001), and septic shock (OR 2.12, 95% CI 1.24-3.63, p 0.006) were associated with increased 30-day mortality in a secondary, exploratory analysis. CONCLUSIONS: The cumulative incidence of IC in 23 European ICUs was 7.07 episodes per 1000 ICU admissions. Future in-depth analyses will allow explaining part of the observed between-center variability, with the ultimate aim of helping to improve local infection control and antifungal stewardship projects and interventions.

Epidemiology and treatment approaches in management of invasive fungal infections in hematological malignancies: Results from a single-centre study.

Invasive fungal infections (IFIs) are a leading cause of morbidity and attributable mortality in oncohematologic patients. Timely diagnosis is essential but challenging. Herein we retrospectively describe 221 cases of antifungal treatments (AFT) administered in a monocentric real-life cohort of hematological malignancies. Between January 2010 and July 2017, 196 oncohematologic patients were treated with AFT at our Hematology Department. Diagnosis of IFIs was carried out according to EORTC/MSG-2008 guidelines.The most represented disease was acute myeloid leukemia (104 patients). Median age was 61 years; at fever onset 177 (80%) patients had a neutrophil count<0.5x109/L. Twenty-nine (13%) patients were receiving antifungal prophylaxis (26 posaconazole, 2 fluconazole, 1 itraconazole). The incidence of AFT was 13%. Serum galactomannan antigen (GM) was positive in 20% of the tested cases, while 85% of the patients had a CT scan suggestive for IFI. Twenty-one percent of these cases had a GM positive. Sixty-five out of 196 patients (33%) showed positive culture results, in particular Candida spp. were identified in 45 isolates, while Aspergillus spp. in 16 cases. Fourteen patients presented multiple positivity. Twenty-two (10%) cases were classified as proven IFIs, 61 (28%) as probable and 81 (37%) as possible, but 57 (26%) cases could not be classified. Fifty-nine percent of the patients received single agent AFT, 37% sequential AFT, 8% a combination regimen. Liposomal-amphotericin-B was the most used AFT. IFIs attributable mortality was 20%. This epidemiologic survey underlined a persistent significant use of AFT and a high mortality rate of IFIs. We suggest that further powerful diagnostic approaches should be investigated to improve the diagnostic accuracy and potential therapeutic implication.

Economic evaluation of micafungin versus liposomal amphotericin B (LAmB) for treating patients with candidaemia and invasive candidiasis (IC) in Turkey.

Micafungin was reported to be non-inferior to liposomal amphotericin B (LAmB) in treating patients with candidaemia and invasive candidiasis (IC). The current study aimed to evaluate the economic impact of using micafungin versus LAmB for treatment of candidaemia and IC in Turkey. A decision analytic model, which depicted economic consequences upon administration of micafungin or LAmB for treating patients with candidaemia and IC in the Turkish hospitals, was constructed. Patients were switched to an alternative antifungal agent if initial treatment failed due to mycological persistence. All patients were followed up until treatment success or death. Outcome probabilities were obtained from published literature and cost inputs were derived from the latest Turkish resources. Expert panels were used to estimate data that were not available in the literature. Cost per patient treated for each intervention was then calculated. Sensitivity analyses including Monte Carlo simulation were performed. For treatment of candidaemia and IC, micafungin (€4809) was associated with higher total cost than LAmB (€4467), with an additional cost of €341 per treated patient. Cost of initial antifungal treatment was the major cost driver for both comparators. The model outcome was robust over a wide variation in input variables except for drug acquisition cost and duration of initial antifungal treatment with micafungin or LAmB. LAmB is cost-saving relative to micafungin for the treatment of candidaemia and IC from the Turkish hospital perspective, with variation in drug acquisition cost of the critical factor affecting the model outcome.

The continuous changes in the aetiology and epidemiology of invasive candidiasis: from familiar Candida albicans to multiresistant Candida auris.

Recent changes in the aetiology and epidemiology of invasive candidiasis have serious implications for current and future diagnosis, treatment and prognosis. The aim of the current review was to discuss the epidemiology of invasive candidiasis, the distribution of Candida species in different regions of the world, the medical concerns of the changing aetiology and the emergence of antifungal resistance. Overall burden of invasive candidiasis remains high, especially in vulnerable persons, such as the elderly, immunosuppressed or debilitated patients. Moreover, there is a progressive shift in the aetiology of invasive candidiasis from Candida albicans to other species of Candida, probably related to the increased use of azole drugs with a clear trend towards increased antifungal resistance. Finally, the emergence and rise of multiresistant species, such as Candida auris or Candida glabrata, is a major threat making necessary invasive candidiasis worldwide surveillances. These changes have serious implications for the diagnosis, treatment and prognosis of invasive candidiasis. Updated knowledge of the current local epidemiology of invasive candidiasis is critical for the clinical management.

Pharmacoeconomic evaluation of micafungin versus caspofungin as definitive therapy for candidaemia and invasive candidiasis (IC) in Turkey.

Micafungin was shown to be as efficacious as caspofungin in treating patients with candidaemia and invasive candidiasis (IC). However, it remains unknown if micafungin or caspofungin is a cost-effective definitive therapy for candidaemia and IC in Turkey. The present study aimed to determine the economic impact of using micafungin versus caspofungin for treatment of candidaemia and IC in the Turkish setting. A decision analytic model was constructed and was populated with data (i.e. transition probabilities, duration of initial antifungal treatment, reasons for treatment failure, percentage of patients who stepped down to oral fluconazole, and duration on oral fluconazole) obtained from a published randomised clinical trial. Cost inputs were derived from the latest Turkish resources while data that were not readily available in the literature were estimated by expert panels. One-way sensitivity analyses, threshold analyses, scenario analyses and probabilistic sensitivity analyses were conducted. Caspofungin (€2693) incurred a lower total cost than micafungin (€4422), with a net cost saving of €1729 per treated patient. Drug acquisition cost was the main cost driver for both study arms. The model outcome was robust over wide variations (of ±100.0% from the base case value) for all input parameters except for micafungin drug cost and the duration of initial treatment with micafungin. Caspofungin appears to be a cost-saving option in treating candidaemia and IC from the Turkish hospital perspective.

Cost Analysis of Fluconazole Prophylaxis for Prevention of Neonatal Invasive Candidiasis.

BACKGROUND: Fluconazole prophylaxis (FP) in premature infants is well studied and has been shown to decrease invasive candidiasis (ICs). IC in neonates has significant financial costs; determining the cost-benefit of FP may provide additional justification for targeting high-risk neonates. We aimed to determine the IC rate in premature infants at which FP is cost-beneficial. METHODS: A decision tree cost-analysis model using cost of FP related to costs associated with IC was used. We searched PubMed for all papers that used intravenous FP and reported rates of IC in very low birth weight neonates. Average IC rates in those who received FP (2.0%; range, 0-6.1%) and in those who did not receive FP (9.2%; range, 0-20.5%) were used. Incremental hospital costs because of IC and for FP were retrieved from the literature. Sensitivity analysis was performed to determine the incremental cost of FP across the range of published IC rates. RESULTS: The average cost per patient attributed to IC in patients receiving FP was $785 versus $2617 in those not receiving FP. Sensitivity analysis demonstrates the rate of IC would need to be <2.8% for FP to lose its cost-benefit. In Monte Carlo simulation, targeting infants <1000 g would lead to $50,304,333 in cost savings per year in the United States. CONCLUSIONS: FP provides a cost-advantage across most IC rates seen in the youngest premature infants. Using a rate of 2.8% for their individual high-risk neonatal intensive care unit patients, providers can determine if FP is cost-beneficial in determining for whom to provide IC prophylaxis.

A practice-based observational study on the use of micafungin in Surgical Critical Care Units.

INTRODUCTION: Echinocandins are first-line therapy in critically ill patients with invasive Candida infection (ICI). This study describes our experience with micafungin at Surgical Critical Care Units (SCCUs). METHODS: A multicenter, observational, retrospective study was performed (12 SCCUs) by reviewing all adult patients receiving 100 mg/24h micafungin for ≥72h during ad-mission (April 2011-July 2013). Patients were divided by ICI category (possible, probable + proven), 24h-SOFA (<7, ≥7) and outcome. RESULTS: 72 patients were included (29 possible, 13 probable, 30 proven ICI). Forty patients (55.6%) presented SOFA ≥7. Up to 78.0% patients were admitted after urgent surgery (64.3% with SOFA <7 vs. 90.3% with SOFA ≥7, p=0.016), and 84.7% presented septic shock. In 66.7% the site of infection was intraabdominal. Forty-nine isolates were recovered (51.0% C. albicans). Treatment was empirical (59.7%), microbiologically directed (19.4%), rescue therapy (15.3%), or anticipated therapy and prophylaxis (2.8% each). Empirical treatment was more frequent (p<0.001) in possible versus probable + proven ICI (86.2% vs. 41.9%). Treatment (median) was longer (p=0.002) in probable + proven versus possible ICI (13.0 vs. 8.0 days). Favorable response was 86.1%, without differences by group. Age, blood Candida isolation, rescue therapy, final MELD value and %MELD variation were significantly higher in patients with non-favorable response. In the multivariate analysis (R2=0.246, p<0.001) non-favorable response was associated with positive %MELD variations (OR=15.445, 95%CI= 2.529-94.308, p=0.003) and blood Candida isolation (OR=11.409, 95%CI=1.843-70.634, p=0.009). CONCLUSION: High favorable response was obtained, with blood Candida isolation associated with non-favorable response, in this series with high percentage of patients with intraabdominal ICI, septic shock and microbiological criteria for ICI.

Echinocandins in the treatment of candidaemia and invasive candidiasis: clinical and economic perspectives.

Candidaemia and invasive candidiasis (IC) complicate modern medical therapy, contributing to high morbidity and mortality. Managing candidiasis is costly, with an additional healthcare expenditure of nearly US$300 million annually. Recent consensus guidelines have suggested the use of newer antifungal agents, such as echinocandins, for the treatment of candidaemia and IC owing to promising clinical outcomes compared with older-generation antifungal agents, but at higher drug acquisition and administration costs. Comprehensive cost-effectiveness data for echinocandins in treating candidaemia and IC remain relatively scant, underlining the need for more studies to incorporate robust economic analyses into clinical decisions. Assessment of the cost efficiencies of these expensive antifungal agents is essential for maximising health outcomes within the constraints of healthcare resources. This review will explore the epidemiology of candidaemia and IC in the context of clinical and economic aspects of the antifungal agents used to treat IC, especially the echinocandins. Standardising the outcome measure, methodology and reporting of results used in economic studies is central to ensure validity and comparability of the findings. Future studies comparing the economic advantages of all available antifungal treatment options and in the context of new diagnostic tools for fungal infections are anticipated.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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.

BACKGROUND: 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. OBJECTIVES: 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. DESIGN: Systematic review, prospective data collection, statistical modelling, economic decision modelling and value of information analysis. SETTING: Ninety-six UK adult general critical care units. PARTICIPANTS: Consecutive admissions to participating critical care units. INTERVENTIONS: None. MAIN OUTCOME MEASURES: 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. RESULTS: 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 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. CONCLUSIONS: 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: Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.

Lung-enriched organisms and aberrant bacterial and fungal respiratory microbiota after lung transplant.

RATIONALE: Long-term survival after lung transplantation is limited by infectious complications and by bronchiolitis obliterans syndrome (BOS), a form of chronic rejection linked in part to microbial triggers. OBJECTIVES: To define microbial populations in the respiratory tract of transplant patients comprehensively using unbiased high-density sequencing. METHODS: Lung was sampled by bronchoalveolar lavage (BAL) and upper respiratory tract by oropharyngeal wash (OW). Bacterial 16S rDNA and fungal internal transcribed spacer sequencing was used to profile organisms present. Outlier analysis plots defining taxa enriched in lung relative to OW were used to identify bacteria enriched in lung against a background of oropharyngeal carryover. MEASUREMENTS AND MAIN RESULTS: Lung transplant recipients had higher bacterial burden in BAL than control subjects, frequent appearance of dominant organisms, greater distance between communities in BAL and OW indicating more distinct populations, and decreased respiratory tract microbial richness and diversity. Fungal populations were typically dominated by Candida in both sites or by Aspergillus in BAL but not OW. 16S outlier analysis identified lung-enriched taxa indicating bacteria replicating in the lower respiratory tract. In some cases this confirmed respiratory cultures but in others revealed enrichment by anaerobic organisms or mixed outgrowth of upper respiratory flora and provided quantitative data on relative abundances of bacteria found by culture. CONCLUSIONS: Respiratory tract microbial communities in lung transplant recipients differ in structure and composition from healthy subjects. Outlier analysis can identify specific bacteria replicating in lung. These findings provide novel approaches to address the relationship between microbial communities and transplant outcome and aid in assessing lung infections.

Anidulafungin for the treatment of invasive candidiasis.

Candidaemia/invasive candidiasis (C/IC) is the most frequently occurring invasive fungal infection worldwide, with a particularly strong impact and high incidence in the intensive-care unit, where there is a need for new treatment options and strategies. The echinocandin anidulafungin has broad in vitro activity against a wide range of Candida species, along with favourable pharmacokinetics that allow administration in hepatic and renal impairment and with any comedication without the need for dose adjustments. The efficacy and safety of anidulafungin for the treatment of C/IC were demonstrated in a number of clinical studies and by some limited data from clinical practice. In a randomized comparative trial for the treatment of C/IC in adults, 76% of patients receiving anidulafungin and 60% of those given fluconazole were treated successfully (95% CI for difference: 4-27; p 0.01). Post hoc analyses suggest that anidulafungin is significantly more effective than standard-dose fluconazole for the treatment of candidaemia in critically ill patients. Anidulafungin is generally well tolerated, with commonly reported side effects including headache, hypokalaemia, gastrointestinal symptoms, abnormal liver function test results, and rash. In pharmaco-economic analyses, anidulafungin compared favourably with fluconazole (in terms of overall costs and hospital resource use) as well as with other echinocandins. Echinocandins, including anidulafungin, are now generally recommended as first-line therapy in moderately to severely ill patients, those with prior azole exposure, and patients with C/IC caused by Candida glabrata or Candida krusei.

Cost and resource utilization associated with fluconazole as first-line therapy for invasive candidiasis: a retrospective database analysis.

BACKGROUND: Fluconazole is a standard first-line therapy for candidemia/invasive candidiasis (C/IC), based on its efficacy, safety profile, and comparatively low acquisition cost. However, little is known about the total costs associated with fluconazole treatment for this indication, particularly in cases of clinical failure. OBJECTIVE: The aim of this study was to examine overall costs, resource use, and treatment outcomes associated with fluconazole as first-line therapy for invasive Candida infections in the United States. METHODS: A retrospective analysis of data from a US hospital-based (>500 hospitals), service-level database was performed. All patients aged >16 years with primary or secondary International Classification of Diseases, Ninth Revision, Clinical Modification codes for IC or septicemia, receiving intravenous fluconazole treatment, and discharged between October 1, 2004 and September 30, 2005 were selected. Costs and resource use were calculated from the start of antifungal therapy until discharge. Two groups were analyzed: patients who received fluconazole only and those who required a second-line antifungal. Separate analyses for the survivor subpopulations were also conducted. RESULTS: A total of 7170 patients met the inclusion criteria; 21.2% required an additional antifungal agent. Overall mortality was 27.1%, and total mean treatment cost for all patients was $44,482 (in 2005 US dollars). Patients treated with fluconazole alone incurred mean costs of $36,319. Mean hospital and intensive care unit stays in the fluconazole monotherapy group were 17.9 days and 7.1 days, respectively. Patients requiring additional therapy had a mortality rate of 34.5% and a mean treatment cost of $76,329; in this group, the mean hospital and intensive care unit stays were 31.7 days and 14.8 days, respectively. CONCLUSIONS: The overall resource use associated with fluconazole as first-line treatment for C/IC was high, especially in patients who required additional antifungal therapy. Future studies should examine the patterns of care and costs associated with alternative treatment options as first-line C/IC therapy.