Combination of Sequential Organ Failure Assessment (SOFA) score and Charlson Comorbidity Index (CCI) could predict the severity and prognosis of candidemia more accurately than the Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score.

BACKGROUND: Candidemia has emerged as an important nosocomial infection, with a mortality rate of 30-50%. It is the fourth most common nosocomial bloodstream infection (BSI) in the United States and the seventh most common nosocomial BSI in Europe and Japan. The aim of this study was to assess the performance of the Sequential Organ Failure Assessment (SOFA) score for determining the severity and prognosis of candidemia. METHODS: We performed a retrospective study of patients admitted to hospital with candidemia between September 2014 and May 2018. The severity of candidemia was evaluated using the SOFA score and the Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score. Patients' underlying diseases were assessed by the Charlson Comorbidity Index (CCI). RESULTS: Of 70 patients enrolled, 41 (59%) were males, and 29 (41%) were females. Their median age was 73 years (range: 36-93 years). The most common infection site was catheter-related bloodstream infection (n=36, 51%).The 30-day, and in-hospital mortality rates were 36 and 43%, respectively. Univariate analysis showed that SOFA score ≥5, APACHE II score ≥13, initial antifungal treatment with echinocandin, albumin < 2.3, C-reactive protein > 6, disturbance of consciousness, and CCI ≥3 were related with 30-day mortality. Of these 7, multivariate analysis showed that the combination of SOFA score ≥5 and CCI ≥3 was the best independent prognostic indicator for 30-day and in-hospital mortality. CONCLUSIONS: The combined SOFA score and CCI was a better predictor of the 30-day mortality and in-hospital mortality than the APACHE II score alone.

Creation and assessment of a clinical predictive model for candidaemia in patients with candiduria.

Candidaemia is the most common clinical presentation of invasive candidiasis and is a major cause of morbidity and mortality. Candiduria is a predictor for candidaemia; however, patient characteristics that are associated with concurrent candidaemia in the setting of candiduria are unclear. Identifying these characteristics could aid in the early detection of systemic disease. We performed a retrospective cohort analysis of hospitalised patients with candiduria at our institution over a 13-year period. Our evaluation of patient characteristics included demographics, comorbidities, medications, procedures, devices, vital signs and laboratory values. We developed a multivariable logistic model to identify factors associated with candidaemia in patients with candiduria. We identified 4240 patients with candiduria, 263 (6.2%) of whom had candidaemia. Predictors for increased risk of candidaemia with candiduria included hospitalisations > 12 days, central venous catheter, parenteral nutrition, haematological and gynaecological malignancy, and receipt of ß-lactam/ß-lactamase inhibitors. Vital signs and laboratory values associated with candidaemia included elevated heart rate, temperature and creatinine, along with neutropenia and neutrophilia. Factors that demonstrated a decreased risk of candidaemia included diabetes mellitus, gastrostomy and urinary catheter with antibiotic use. The c-statistic was 0.741 (95% CI, 0.710-0.772). We identified a set of clinical characteristics that can predict the presence of candidaemia with candiduria.

Updates in the epidemiology and management of candidemia and Clostridioides difficile coinfection.

Introduction: In recent years, more and more studies have focused on the association between candidemia and Clostridioides difficile infection (CDI), highlighting the risk of subsequent candidemia in patients with CDI. However, a more recent model focuses on the Candida-Clostridioides difficile coinfection as a clinical entity in which candidemia could occur before or after the CDI episode. Areas covered: In this review we analyzed the physiopathological mechanisms underlying the Candida-Clostridioides difficile coinfection, both in case of candidemia preceding and following the CDI. We highlighted that gut alterations occurring during a CDI play a crucial role in the risk of subsequent candidemia. Moreover, we identified areas of interest about the management of Candida-Clostridioides difficile coinfection and proposed answers to relevant clinical questions. Expert opinion: The evaluation of risk factors for candidemia in patients with CDI and the rational antibiotic use in patients with candidemia remain the most efficacious and cost-free instruments to optimally manage the Candida-Clostridioides difficile coinfection. However, further studies are required to cover some unmet needs, such as the development of rapid diagnostic methods of candidemia and the use of new available drugs with minimal effect on the microbiome biodiversity in patients with CDI at high risk of fungemia.

Desirability of outcome ranking (DOOR) for comparing diagnostic tools and early therapeutic choices in patients with suspected candidemia.

Desirability of outcome ranking (DOOR) has been developed for assessing desirability of outcome in interventional studies. However, its possible use in observational studies of the diagnosis and early treatment of infectious diseases has not been explored so far, and it might introduce interesting features in specific scenarios. This was a post hoc analysis of a prospective observational study in intensive care unit patients with sepsis and at risk of candidemia. The probabilities that a randomly selected patient would have a more, less, and equally cost-effective early therapeutic choice following a BDG-based diagnostic strategy rather than the empirical administration of antifungals to all patients were calculated using DOOR methods. The probability of a more cost-effective therapeutic choice following the BDG-based rather than the empirical strategy was 67.81% (95% CI 67.32-68.30), whereas the probabilities of a less and equally cost-effective early therapeutic choice were 19.68% (95% CI 19.27-20.10) and 12.50% (95% CI 12.16-12.85), respectively. The application of DOOR methods to observational studies focused on diagnosis and early treatment is a novel field that could merit further investigation.

Candidemia in children: Epidemiology, prevention and management.

Candidemia is the leading cause of invasive fungal infections in hospitalised children. The highest rates of candidemia have been recorded in neonates and infants <1 year of age. Candidemia is more frequent in neonates and young infants than in adults, and is associated with better clinical outcomes, but higher inpatient costs. Over the last 10 years, a declining trend has been noted in the incidence of paediatric candidemia in the US and elsewhere due to the hospital-wide implementation of central-line insertion and maintenance bundles that emphasise full sterile barrier precautions, chlorhexidine skin preparation during line insertion, meticulous site and tubing care, and daily discussion of catheter necessity. Additional interventions aiming at reducing gut-associated candidemia are required in immunocompromised and critically ill children.

Molecular identification of Candida species isolated from cases of neonatal candidemia using polymerase chain reaction-restriction fragment length polymorphism in a tertiary care hospital.

CONTEXT: Candida spp. is an emerging cause of bloodstream infections worldwide. Delay in speciation of Candida isolates by conventional methods and resistance to antifungal drugs in various Candida species are responsible for the increase in morbidity and mortality due to candidemia. Hence, the rapid identification of Candida isolates is very important for the proper management of patients with candidemia. AIMS: The aim was to re-evaluate the identification of various Candida spp. by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) and to evaluate the accuracy, speed, and cost of phenotypic methodology versus PCR-RFLP. SETTINGS AND DESIGN: Hospital-based cross-sectional study. MATERIALS AND METHODS: Ninety consecutive clinical isolates of seven Candida species, isolated from blood of neonates and identified by routine phenotypic methods, were re-evaluated using universal primers internal transcribed spacer 1 (ITS1) and ITS4 for PCR amplification and Msp I restriction enzyme for RFLP. STATISTICAL ANALYSIS USED: Kappa test for agreement. RESULTS: The results of PCR-RFLP were 100% in agreement with those obtained using conventional phenotypic methods. Identification could be achieved within 3 work days by both the methods. Our routine methods proved to be cost effective than PCR-RFLP. CONCLUSIONS: We can continue with our routine phenotypic methods and PCR-RFLP can be used for periodic quality control or when conventional methods fail to identify a species.

Candidemia in Patients with Body Temperature Below 37°C and Admitted to Internal Medicine Wards: Assessment of Risk Factors.

BACKGROUND: An increasing number of candidemia episodes has been reported in patients cared for in internal medicine wards. These usually older and frail patients may not be suspected as having candidemia because they lack fever at the onset of the episode. To identify the risk factors associated with the lack of fever at the onset of candidemia (ie, the collection of the first positive blood culture for Candida spp.) in patients cared for in internal medicine wards, we compared 2 group of patients with or without fever. METHODS: We retrospectively review data charts from 3 tertiary care, university hospitals in Italy, comparing patients with or without fever at onset of candidemia. Consecutive candidemic episodes in afebrile patients and matched febrile controls were identified during the 3-year study period. Patient baseline characteristics and several infection-related variables were examined. Random forest analysis was used, given the number of predictors to be considered and the potential complexity of their relations with the onset of fever. RESULTS: We identified 147 candidemic episodes without fever at onset and 147 febrile candidemia episodes. Factors associated with the lack of fever at onset of candidemia were diabetes, Clostridium difficile infection, and a shorter delta time from internal medicine wards admission to the onset of candidemia. The only variable associated with fever was the use of intravascular devices. Quite unexpectedly, antifungal therapy was administered more frequently to patients without fever, and no differences on 30-day mortality rate were documented in the 2 study groups. CONCLUSIONS: Clinicians should be aware that an increasing number of patients with invasive candidiasis cared for in internal medicine wards may lack fever at onset, especially those with diabetes and C. difficile infection. Candidemia should be suspected in patients with afebrile systemic inflammatory response syndrome or in worsening clinical condition: blood cultures should be taken, and a timely and appropriate antifungal therapy should be considered.

Cost-Effectiveness Analysis of Multiplex PCR with Magnetic Resonance Detection versus Empiric or Blood Culture-Directed Therapy for Management of Suspected Candidemia.

Candida bloodstream infections (BSI) are associated with significant morbidity, mortality, and increased health care costs. Early treatment is essential, because delayed therapy detrimentally impacts clinical outcomes. The FDA recently approved the first culture-independent direct molecular detection method for Candida BSIs (T2Candida). The speed and sensitivity of this assay give it the potential to improve patient care, but the reagents and instrumentation are expensive. We used an analytic decision tree model to compare the cost-effectiveness of T2Candida-directed antifungal therapy (T2DT) to that of either empirical therapy (ET) or blood culture-directed therapy (BCDT). The costs included those of T2Candida testing, antifungal treatment, and hospital length of stay. The effectiveness measure was survival status at hospital discharge. T2DT was less costly and more effective than BCDT but was less costly and less effective than ET with an echinocandin (incremental cost-effectiveness ratio, $111,084 per additional survivor). One-way sensitivity analyses demonstrated that the cost-effectiveness of T2DT was highly dependent on Candida BSI prevalence and the cost of antifungal therapy and T2Candida test reagents. The use of T2DT reduced the number of unnecessarily treated patients by 98% relative to that with ET. Reduced drug exposure might lessen the possibility of drug-related adverse events and may also prevent the development of antifungal resistance or emergence of drug-resistant Candida species. The greatest benefit of T2Candida appears to be the ability to confidently withhold or stop empirical antifungal therapy in low-to-moderate-risk patients who are unlikely to benefit from treatment.

The economic impact of rapid Candida species identification by T2Candida among high-risk patients.

INTRODUCTION: This study estimates the cost-effectiveness and hospital budget impact of rapid candidemia identification using T2Candida, a novel diagnostic panel with same-day species-specific results. MATERIALS & METHODS: A 1-year decision-tree model estimates hospital costs (2013 US$) and effects (candidemia-related deaths) for faster diagnostics versus blood culture (BC), accounting for disease prevalence, distribution of Candida species, test characteristics (sensitivity/specificity/time to result), antifungal medication and differential length-of-stay and mortality by appropriate treatment timing. RESULTS: The model estimates a hospital with 5100 annual high-risk patients could possibly save $5,858,448 with T2Candida versus BC, a 47.6% decrease in candidemia diagnosis and treatment budget ($1149/patient tested), while averting 60.6% of candidemia-related mortality. CONCLUSION: Hospitals may observe lower candidemia-related inpatient costs and mortality with rapid Candida diagnosis.

Antibiotic overuse as a risk factor for candidemia in an Indian pediatric ICU.

OBJECTIVE: To identify risk factors and mycological characteristics of candidemia in Pediatric ICU of a tertiary-care hospital. METHODS: Patients were screened for candidemia by blood culture. Recovered isolates were speciated and subjected to antifungal susceptibility testing. For every candidemic patient, three controls were matched for age, underlying diagnosis and period of hospitalization. Premature neonates were also matched for birth-weight. Proportion of cases and controls on specific antibiotics or indwelling devices was compared using Chi-square test, while unpaired t-test was used for comparing the number of antibiotics used and the number of days of antibiotic administration. Concordance between susceptibility testing methods was evaluated using Chi-square test. RESULTS: Significantly wider spectrum of antibiotic coverage was observed among the 28 candidemic patients. While every patient received antibiotic against enteric gram-negative bacilli, antibiotic usage for additional groups of microorganisms was significantly higher among cases. Association of candidemia with increasing use of indwelling devices was also observed. Endogenous colonization was higher in candidemic infants. Candida albicans was the commonest species (n = 18), followed by C. tropicalis (n = 7). Fluconazole and ketoconazole resistance was observed in 10.7 % cases. CONCLUSIONS: This information on pediatric candidemia could be used to devise locally-tailored strategies for identifying at-risk patients, underline the importance of routine antifungal susceptibility testing and formulate appropriate guidelines for management.

Automation of serum (1→3)-beta-D-glucan testing allows reliable and rapid discrimination of patients with and without candidemia.

Testing for (1→3)-beta-D-glucan (BDG) is used for detection of invasive fungal infection. However, current assays lack automation and the ability to conduct rapid single-sample testing. The Fungitell assay was adopted for automation and evaluated using clinical samples from patients with culture-proven candidemia and from culture-negative controls in duplicate. A comparison with the standard assay protocol was made in order to establish analytical specifications. With the automated protocol, the analytical measuring range was 8-2500 pg/ml of BDG, and precision testing resulted in coefficients of variation that ranged from 3.0% to 5.5%. Samples from 15 patients with culture-proven candidemia and 94 culture-negative samples were evaluated. All culture-proven samples showed BDG values >80 pg/ml (mean 1247 pg/ml; range, 116-2990 pg/ml), which were considered positive. Of the 94 culture-negative samples, 92 had BDG values <60 pg/ml (mean, 28 pg/ml), which were considered to be negative, and 2 samples were false-positive (≥80 pg/ml; up to 124 pg/ml). Results could be obtained within 45 min and showed excellent agreement with results obtained with the standard assay protocol. The automated Fungitell assay proved to be reliable and rapid for diagnosis of candidemia. It was demonstrated to be feasible and cost efficient for both single-sample and large-scale testing of serum BDG. Its 1-h time-to-result will allow better support for clinicians in the management of antifungal therapy.

Evaluation of PNA-FISH yeast traffic light for rapid identification of yeast directly from positive blood cultures and assessment of clinical impact.

The PNA-FISH Yeast Traffic Light assay was performed on 54 clinical isolates of yeasts inoculated into blood culture bottles. The assay showed high sensitivity (Candida albicans/C. parapsilosis, 100%; C. glabrata/C. krusei, 92.3%; C. tropicalis, 100%) and specificity (C. albicans/C. parapsilosis, 100%; C. glabrata/C. krusei, 94.8%; C. tropicalis, 100%). Case note review estimated a change in therapy in 29% of cases had the PNA-FISH result been available to the clinician.

Do all candidemic patients need an ophthalmic examination?

Intraocular candidiasis is a potentially sight-threatening complication of candidemia. While the incidence of candidemia in North America has increased, the prevalence of intraocular candidiasis appears to be decreasing. In the USA and Europe, an ophthalmic examination is recommended for all candidemic patients to rule out intraocular involvement. However, improvements in management, clarification of the diagnosis, and trends in the epidemiology of intraocular candidiasis suggest that some candidemia patients might be safely managed without the recommended dilated ophthalmic examination.

Recent developments and current issues in the epidemiology, diagnosis, and management of bacterial and fungal neonatal sepsis.

Identifying neonates with sepsis is complicated by variability in clinical presentation. The incidence of early onset sepsis (EOS) resulting from invasive group B streptococcal (GBS) infections has been notably reduced by the widespread delivery of intrapartum antibiotic prophylaxis. Rates of EOS attributable to non-GBS etiologies have remained constant, and ampicillin-resistant Escherichia coli has become more prevalent. Late-onset sepsis (LOS) attributable to gram-positive organisms including coagulase-negative Staphylococci and Staphylococcus aureus is associated with increased morbidity and mortality among premature infants. Invasive candidiasis is an emerging cause of LOS, especially among infants who receive broad-spectrum antimicrobial agents. Prophylactic fluconazole administration to very low-birth-weight (VLBW) neonates during the first 6 weeks of life prevents invasive candidiasis in neonatal intensive care units (NICU) with high rates of fungal infections. Targeted fluconazole prophylaxis may be beneficial in VLBW neonates who receive care in NICUs with lower rates of invasive fungal infections. Assessment of immune function, neutrophil markers, acute phase reactants, and utilization of sepsis screening scores may contribute to the management of sepsis. Maternal decolonization, antimicrobial stewardship, early enteral feeding, and optimal infection control practices are potential practical strategies for reducing the burden of neonatal sepsis.

Attributable costs of patients with candidemia and potential implications of polymerase chain reaction-based pathogen detection on antifungal therapy in patients with sepsis.

PURPOSE: The purposes of this study were to calculate attributable costs of candidemia in patients with severe sepsis and to obtain preliminary data regarding the potential effects of polymerase chain reaction-based pathogen detection on antifungal therapy for these patients. METHODS: Patients treated between 2004 and 2010 because of severe sepsis were included into this retrospective analysis. The hospital management provided annual fixed costs per patient-day; data for variable intensive care unit costs were taken from the literature. Multiplex polymerase chain reaction (PCR) was used (VYOO, SIRS-Lab, Jena, Germany) for pathogen detection in the blood. RESULTS: Thirty-two patients with candidemia were identified. Of 874 patients with sepsis, propensity score matching found 32 corresponding patients with sepsis but without candida infection but similar risk factors for developing candidemia. Attributable costs of candidemia were 7713.79 Euro (cost increase, 19.4%). Initiation of antifungal therapy was reduced from 67.5 (52.4, 90) hours in the group, where candida infection was determined by blood culture, to 31.0 (28.0, 37.5; P < .01) hours after detection by multiplex PCR. CONCLUSIONS: Candidemia increases costs of care in patients with septic shock. Polymerase chain reaction-based pathogen detection significantly reduces the time to initiation of antifungal therapy. This might impact on the clinical course of the disease but need to be confirmed in further trials.

Assessment of candidemia-attributable mortality in critically ill patients using propensity score matching analysis.

INTRODUCTION: Candidemia in critically ill patients is usually a severe and life-threatening condition with a high crude mortality. Very few studies have focused on the impact of candidemia on ICU patient outcome and attributable mortality still remains controversial. This study was carried out to determine the attributable mortality of ICU-acquired candidemia in critically ill patients using propensity score matching analysis. METHODS: A prospective observational study was conducted of all consecutive non-neutropenic adult patients admitted for at least seven days to 36 ICUs in Spain, France, and Argentina between April 2006 and June 2007. The probability of developing candidemia was estimated using a multivariate logistic regression model. Each patient with ICU-acquired candidemia was matched with two control patients with the nearest available Mahalanobis metric matching within the calipers defined by the propensity score. Standardized differences tests (SDT) for each variable before and after matching were calculated. Attributable mortality was determined by a modified Poisson regression model adjusted by those variables that still presented certain misalignments defined as a SDT > 10%. RESULTS: Thirty-eight candidemias were diagnosed in 1,107 patients (34.3 episodes/1,000 ICU patients). Patients with and without candidemia had an ICU crude mortality of 52.6% versus 20.6% (P < 0.001) and a crude hospital mortality of 55.3% versus 29.6% (P = 0.01), respectively. In the propensity matched analysis, the corresponding figures were 51.4% versus 37.1% (P = 0.222) and 54.3% versus 50% (P = 0.680). After controlling residual confusion by the Poisson regression model, the relative risk (RR) of ICU- and hospital-attributable mortality from candidemia was RR 1.298 (95% confidence interval (CI) 0.88 to 1.98) and RR 1.096 (95% CI 0.68 to 1.69), respectively. CONCLUSIONS: ICU-acquired candidemia in critically ill patients is not associated with an increase in either ICU or hospital mortality.

Is (1→3)-ß-D-glucan the missing link from bedside assessment to pre-emptive therapy of invasive candidiasis?

Invasive candidiasis is a frequent life-threatening complication in critically ill patients. Early diagnosis followed by prompt treatment aimed at improving outcome by minimizing unnecessary antifungal use remains a major challenge in the ICU setting. Timely patient selection thus plays a key role for clinically efficient and cost-effective management. Approaches combining clinical risk factors and Candida colonization data have improved our ability to identify such patients early. While the negative predictive value of scores and predicting rules is up to 95 to 99%, the positive predictive value is much lower, ranging between 10 and 60%. Accordingly, if a positive score or rule is used to guide the start of antifungal therapy, many patients may be treated unnecessarily. Candida biomarkers display higher positive predictive values; however, they lack sensitivity and are thus not able to identify all cases of invasive candidiasis. The (1→3)-ß-D-glucan (BG) assay, a panfungal antigen test, is recommended as a complementary tool for the diagnosis of invasive mycoses in high-risk hemato-oncological patients. Its role in the more heterogeneous ICU population remains to be defined. More efficient clinical selection strategies combined with performant laboratory tools are needed in order to treat the right patients at the right time by keeping costs of screening and therapy as low as possible. The new approach proposed by Posteraro and colleagues in the previous issue of Critical Care meets these requirements. A single positive BG value in medical patients admitted to the ICU with sepsis and expected to stay for more than 5 days preceded the documentation of candidemia by 1 to 3 days with an unprecedented diagnostic accuracy. Applying this one-point fungal screening on a selected subset of ICU patients with an estimated 15 to 20% risk of developing candidemia is an appealing and potentially cost-effective approach. If confirmed by multicenter investigations, and extended to surgical patients at high risk of invasive candidiasis after abdominal surgery, this bayesian-based risk stratification approach aimed at maximizing clinical efficiency by minimizing health care resource utilization may substantially simplify the management of critically ill patients at risk of invasive candidiasis.

Assessment of two new molecular methods for identification of Candida parapsilosis sensu lato species.

Candida parapsilosis sensu stricto, C. orthopsilosis, and C. metapsilosis replaced C. parapsilosis groups I, II, and III in 2005. Since then, an increased interest in studying their epidemiology has arisen based on the observed differences in antifungal susceptibilities and virulence the three species. A strict differentiation of these species cannot be achieved by phenotypic methods. We evaluate two new molecular methodologies to differentiate among these species by the use of a collection of 293 bloodstream infection isolates of C. parapsilosis sensu lato. For the first method, the isolates were studied using PCR amplification of a fragment of the C. parapsilosis sensu lato FKS1 gene and a universal primer pair followed by EcoRI enzyme digestion. The other method used the allele discrimination ability of molecular beacons in a multiplex real-time PCR format. Both methods of identification showed 100% concordance with internal transcribed spacer 1 (ITS1)/ITS2 sequencing and proved to be effective for clinical applications, even with mixed-species DNAs.