Invasive Candidiasis In Patients Research Articles

The association between Geriatric Nutritional Risk Index and the risk of Invasive Candidiasis in critically ill older adults

BackgroundInvasive candidiasis is the most common hospital-acquired fungal infection in intensive care units (ICU). The Geriatric Nutritional Risk Index (GNRI) score was developed to evaluate the nutritional status of elderly adults. We aimed to assess the association between the GNRI score and the risk of invasive candidiasis in elderly patients admitted to ICU.MethodsHospitalization information of elderly patients with invasive candidiasis was collected retrospectively from Medical Information Mart for Intensive Care (MIMIC) IV and MIMIC-III Clinical Database CareVue subset from 2001 to 2019. The main outcome of this study was the diagnosis of invasive candidiasis in patients. We employed a multivariable Cox regression and propensity score matching to balance the influence of confounding factors on the outcome. Furthermore, we conducted sensitivity analyses by categorizing the GNRI into classes based on thresholds of 98, 92, and 81.ResultsA total of 6739 patients were included in the study, among whom 134 individuals (2%) were diagnosed with invasive candidiasis. The GNRI scores of patients with invasive candidiasis upon admission to the ICU were significantly lower, measuring 88.67 [79.26–98.27], compared to the control group with a score of 99.36 [87.98-110.45] (P < 0.001). The results of the multivariable Cox regression analysis demonstrated a strong association between higher GNRI scores and a decreased risk of invasive candidiasis infection (HR: 0.98, 95% CI: 0.97–0.99, P = 0.002). Consistently, similar results were obtained when analyzing the propensity score-matched cohort (HR: 0.99, 95% CI: 0.98-1, P = 0.028). Sensitivity analyses further confirmed a significantly increased risk of invasive candidiasis infection with lower GNRI scores. Specifically, the following associations were observed: GNRI ≤ 98 (HR: 1.83, 95% CI: 1.23–2.72, P = 0.003), GNRI ≤ 92 (HR: 1.68, 95% CI: 1.17–2.4, P = 0.005), 82 ≤ GNRI ≤ 92 (HR: 1.63, 95% CI: 1.01–2.64, P = 0.046), GNRI ≤ 81 (HR: 2.31, 95% CI: 1.44–3.69, P < 0.001).ConclusionsLower GNRI score was significantly associated with an increased risk of invasive candidiasis in elderly patients in ICU. Further research is needed to validate whether improving nutrition can prevent invasive candidiasis.

Epidemiology of Invasive Candidiasis in Patients with Hematologic Malignancy on Antifungal Prophylaxis.

The landscape of invasive Candida infections in patients with hematologic malignancy has evolved due to the adoption of anti-fungal prophylaxis, advances in oncological therapies, and developments in antifungal therapies and diagnostics. Despite these scientific gains, the morbidity and mortality caused by these infections remain unchanged, highlighting the importance of an updated understanding of its epidemiology. Non-albicans Candida species are now the predominant cause of invasive candidiasis in patients with hematological malignancy. This epidemiological shift from Candida albicans to non-albicans Candida species is partially a consequence of selective pressure from extensive azole use. Further analysis of this trend suggests other contributing factors including immunocompromise caused by the underlying hematologic malignancy and the intensity of its associated treatments, oncological practices, and regional or institution specific variables. This review characterizes the changing distribution of Candida species in patients with hematologic malignancy, describes the causes driving this change, and discusses clinical considerations to optimize management in this high-risk patient population.

Invasive Candidiasis in Patients with Solid Tumors: A Single-Center Retrospective Study.

Invasive candidiasis (ICs) is one of the common causes of death in patients with solid tumors. However, studies on the clinical characteristics of ICs with solid tumors are limited. The purpose of this study was to retrospectively analyse the clinical characteristics, laboratory results and risk factor prediction of inpatients with ICs and solid tumors. We reviewed the clinical data and candida specimen information of hospitalized patients diagnosed with solid tumors combined with ICs at the First Hospital of China Medical University from January 2016 to December 2020. Multivariate logistic regression analysis was used to assess the prognostic factors associated with mortality in these patients. A total of 243 ICs patients with solid tumors were included in this study. The average ± SD age was 62.8 ± 11.7 (range: 27-93 years old), of which nearly 41% were ≥ 65 years old (99/243, 40.7%), and most were male (162/243, 66.6%). Most patients had malignant tumors of the digestive system. The most common candida was Candida parapsilosis (101/243, 41.5%), followed by Candida guilliermondii (83/243, 34.1%), Candida albicans (32/243, 13.1%), Candida glabrata (17/243, 6.9%), Candida tropicalis (7/243, 2.8%) and Candida krusei (3/243, 1.2%). Multivariate logistic regression analysis showed that the length of stay in the ICU, urinary catheter, total parenteral nutrition, stay in the ICU, renal failure and neutrophil count were prognostic factors related to death. In this study, based on the clinical data of solid tumor patients with ICs in the past 5 years, the results showed that the length of stay in the ICU, urinary catheter, total parenteral nutrition, stay in the ICU, renal failure and neutrophil count were identified as the main prognostic factors. This study can be used to help clinicians carry out early intervention for high-risk patients.

Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy.

We conducted population pharmacokinetic (PPK) analysis and Monte Carlo simulations to determine the appropriate prophylactic dose of fluconazole to prevent invasive candidiasis in patients with hematological malignancies. Patients receiving chemotherapy or hematopoietic stem cell transplantation at Yokohama City University Hospital between November 2018 and March 2020 were included. Additionally, patients receiving oral fluconazole for prophylaxis were recruited. We set the free area under the curve/minimum inhibitory concentration (MIC) = 50 as the target and determined the largest MIC (breakpoint MIC) that could achieve more than 90% probability of target attainment. The blood fluconazole concentration of 54 patients (119 points) was used for PPK analysis. The optimal model was the one-compartment model with first-order administration and first-order elimination incorporating creatinine clearance (CLcr) as a covariate of clearance and body weight as a covariate of distribution volume. We conducted Monte Carlo simulation with fluconazole at 200 mg/day or 400 mg/day dosing schedules and patient body weight and CLcr ranging from 40 to 70 kg and 40–140 mL/min, respectively. The breakpoint MICs on the first dosing day and at steady state were 0.5–1.0 μg/mL and 1.0–2.0 μg/mL for 200 mg/day and 1.0–2.0 μg/mL and 2.0–4.0 μg/mL for 400 mg/day, respectively. The recommended dose was 400–700 mg/day for the loading dose and 200–400 mg/day for the maintenance dose. Our findings suggest that the optimal prophylactic dose of fluconazole in hematological malignancy patients depends on CLcr and body weight, and a sufficient loading and maintenance dose may be needed to completely prevent invasive candidiasis.

Invasive Candidiasis in Patients with Solid Tumors Treated with Anidulafungin: A Post Hoc Analysis of Efficacy and Safety of Six Pooled Studies.

BackgroundSolid tumors are a common predisposing factor for invasive candidiasis (IC) or candidemia due to IC.ObjectivesPost hoc analysis of patient-level efficacy and safety data from six studies of anidulafungin (with similar protocols/endpoints) in adults with IC/candidemia summarized by past or recent diagnosis of solid tumors.Patients/methodsPatients received a single intravenous (IV) dose of anidulafungin 200 mg, followed by 100 mg once daily. After ≥ 5 to ≥ 10 days of IV treatment, switch to oral voriconazole/fluconazole was permitted in all but one study. Time of solid tumor diagnosis was defined as past, ≥ 6; and recent, < 6 months prior to study entry. Primary endpoint: global response of success (GRS) rate at the end of IV therapy (EOIVT). Secondary endpoints included the GRS rate at the end of all therapy (EOT), all-cause mortality, and safety.ResultsThe GRS rate in the overall population was 73.4% at EOIVT and 65.5% at EOT. Past or recent solid tumor diagnosis did not affect GRS at EOIVT or EOT (past: 75.5% and 71.4%; recent: 72.2% and 62.2%, respectively). All-cause mortality was 14.4% on day 14 and 20.1% at day 28. Most treatment-emergent adverse events were mild/moderate in severity (81.6%).ConclusionsTreatment of IC was effective regardless of the time of solid tumor diagnosis.Trial RegistrationData were pooled from six studies: NCT00496197 (first posted on ClinicalTrials.gov on July 4, 2007); NCT00548262 (first posted on ClinicalTrials.gov on October 23, 2007); NCT00537329 (first posted on ClinicalTrials.gov on October 1, 2007); NCT00689338 (first posted on ClinicalTrials.gov on June 3, 2008); NCT00806351 (first posted on ClinicalTrials.gov on December 10, 2008); NCT00805740 (first posted on ClinicalTrials.gov on December 10, 2008).

Clinical Usefulness of Serum (1,3)-β-D-glucan to predict invasive candidiasis in patients with severe burn trauma.

(1,3)-β-D-glucan (BD) assays were developed as a method to rapidly diagnose invasive candidiasis (IC). The incidence of fungal infections and the demands for BD assay are gradually increasing in patients with severe trauma and under intensive care. However, the ideal BD cut-off value to predict IC has not been clarified. In this study, we evaluate the predictability of the BD assay and investigate the optimal cut-off value in patients with severe burn injuries. From July to December 2018, 134 samples from 86 patients with severe burns were analyzed. Serum BD levels were measured utilizing a Fungitell (Cape Cod Inc.) assay. A receiver operator characteristic (ROC) curve was generated, and the cumulative progression of IC was studied using a Cox proportional hazards model. Partial dependence plots (PDP) was applied to predict the risk of IC. Eleven patients were diagnosed with IC. BD over 120pg/mL (HR=8.68; P=0.001) was found to be independent predictor of the occurrence of IC, when the multivariable Cox model was adjusted for age, total body surface area, inhalation injury, and antifungal agents. The area under the ROC curve was 0.658 (95% CI, 0.513-0.803), at an optimal cut-off value of 124.7pg/mL. PDP analysis showed the higher predicted IC occurrence at a BD level of 120-150pg/mL and TBSA over 60%. Our findings suggest that BD is an independent predictor for IC, and that a BD level between 120 and 150pg/mL could be utilized for IC prediction.

Biofi lm production among Candida spp. causing invasive candidiasis in patients with hematological malignancies and without hematological malignancies

Introduction. Biofi lm-forming ability among Candida spp. on indwelling medical devices may have a negative infl uence on the outcome of invasive candidiasis in various groups of patients. Aim. The objective of this study was to evaluate the biofi lm-forming ability among Candida spp. isolated from clinical specimens in patients with hematological malignancies and patients without hematological malignancies. Materials and methods. Biofi lm production among Candida spp. was studied using XTT (Sigma-Aldrich, USA) reduction assay. Candida spp. were classifi ed as biofi lm-forming, having optical density equal to and more than 0.1, and non-biofi lmforming with optical density less than 0.1. Results. A total of 428 Candida spp. (C. albicans n = 192, C. parapsilosis n = 121, C. krusei n = 40, C. tropicalis n = 38, C. glabrata n = 37) were evaluated (172 from hematological patients, 256 from non-hematological patients, 361 from blood culture, 67 from other sterile specimens). Biofi lm-forming ability was detected among 179 (41.8%) Candida spp. with the same rate in hematological patients and non-hematological patients (41.9 % and 41.8 %, respectively). Biofi lm production predominated among non-C. albicans (52.5 %) compared to C. albicans (28.6 %, p = 0.001). Biofi lm production prevailed among C. tropicalis (89.5 %) and C. krusei (75 %) compared to C. parapsilosis (41.3 %), C. albicans (28.6 %), and C. glabrata (27 %, respectively, p &lt; 0.05). Biofi lm-forming ability among C. tropicalis and C. krusei dominated in both groups of patients. Biofi lm production among C. albicans prevailed in non-hematological patients compared to hematological patients (34.1% vs 18.2%, p = 0.03). There were no differences in biofi lm production among Candida spp. isolated from blood culture (42.9%) and other sterile specimens (35.8%, p = 0.3). Conclusion. Biofi lm-forming ability varied among the Candida spp. and prevailed among C. tropicalis and C. krusei. Biofi lm production among Candida spp. was detected with the same rate in hematological and non-hematological patients.

Role of Antifungal Therapy in Complicated Intra-abdominal Infections

In this narrative review, we discuss key questions about the antifungal treatment of complicated intrabdominal infections (cIAI). Although less common than bacteria, Candida spp. are not an infrequent cause of cIAI. Considering that invasive abdominal candidiasis (IAC) may be accompanied by septic shock in up to 40% of cases, empirical antifungal treatment should be considered while waiting for rapid tests and cultures results, and it should be guided by the presence of risk factors for invasive candidiasis in patients with consistent signs and symptoms. Early antifungal therapy before availability of culture results can be partly based on the results of rapid diagnostic tests such as antigen/antibody assays or other rapid methods, although it should be noted that most data pertaining to the use of rapid tests refer to candidemia or invasive candidiasis in general, and not specifically to IAC, thus clinical judgment still remains crucial. Although cultures are hampered by a slow turnaround time, they remain of paramount importance, by allowing identification at species level and antifungal susceptibility testing. Together with source control, adequate antifungal therapy is an essential component of the correct approach to IAC. Future research should focus on enriching our knowledge on the diagnostic performance of rapid tests in cIAI, and on providing a standardized definition for IAC. Advancements in these fields are crucial for improving the correct use of antifungals at the bedside of cIAI patients and also for reducing unnecessary antifungal use in line with antifungal stewardship principles.

Association of Immune Cell Subtypes and Phenotype With Subsequent Invasive Candidiasis in Patients With Abdominal Sepsis.

In nonneutropenic intensive care unit (ICU) patients, current risk stratification scores lack specificity to reliably predict the risk of a prospective invasive candidiasis (IC). We aimed to explore possible associations of distinct immunological markers with different degrees of Candida affection in patients with abdominal sepsis. The presented explorative, noninterventional diagnosis study recruited patients admitted to the surgical ICU at Heidelberg University Hospital with abdominal sepsis. Over 5 days, we determined white blood cell count, 1,3-β-D-glucan, and HLA-DR expression; the amount of Th1, Th17, regulatory T, T helper, and cytotoxic T cells; Dectin-1 and TLR2-expression; the amount of T, B, and NK cells; the ex vivo secretion of IL-8 upon stimulation with LPS, flagellin, and zymosan; and the distribution of distinct T-cell cytokines in a daily manner. On day 21, patients' Candida infection status was stratified in no colonization or IC, colonization or IC. A total of 26 patients were included. On day 21, five patients showed no colonization or IC, in 13 patients a colonization was detected, and eight patients were diagnosed with IC. On study inclusion, the stratification groups showed comparable values in standard laboratory parameters and morbidity scores. Decreased B and NK cell counts, as well as reduced IL-8 secretion after ex vivo stimulation with LPS or flagellin seemed to be associated with a higher risk of subsequent Candida colonization. Even lower values could distinguish the therapy-relevant difference between prospective IC from colonization alone. We were able to show distinct immune system impairments in early abdominal sepsis by specific immune-based measurements. A possible association of these impairments with a subsequent Candida affection is shown.

Whole-body physiology-based pharmacokinetics of caspofungin for general patients, intensive care unit patients and hepatic insufficiency patients.

Caspofungin is an echinocandin antifungal agent licensed as a first-line therapy for invasive candidiasis in patients with moderate to severe illness or recent exposure to azoles. In this study we developed a whole-body physiology-based pharmacokinetics (WB-PBPK) model to predict the pharmacokinetics (PK) of caspofungin, and combined with Monte Carlo simulation (MCS) to optimize clinical dosage regimens of caspofungin in different kinds of patients. A WB-PBPK model of caspofungin was built and validated with raw data from 4 previous trials of general patients, intensive care unit (ICU) patients with Child-Pugh B, ICU patients on continuous renal replacement therapy, mild and moderate hepatic insuffciency (HI) patients. MCS was used to optimize clinical dosage regimens of caspofungin in these patients. A cumulative fraction of response (CFR) value of ≥90% was considered to be the minimum for achieving optimal empirical therapy. The simulated results of the WB-PBPK model were in good agreement with observed values of all trials. For general and ICU patients with caspofungin 70/50 mg, AUC and Cmax were decreased with the increase of body weight (BW) and showed great variation. MCS showed all general patients achieved CFR≥90% regardless of BW. But not all ICU patients with higher BW (≥70 kg) could achieve CFR≥90%. Compared with standard dosage regimens in general patients, caspofungin 70/35 mg in ICU patients with Child-Pugh B achieved significantly decreased AUC and Cmax, but obtained similar AUC and Cmax in moderate HI patients with Child-Pugh B. The WB-PBPK model of caspofungin is able to predict PK of all populations correctly. The combined WB-PBPK model with MCS can successfully optimize clinical dosage regimens of caspofungin in all patient populations.

Echinocandins for management of invasive candidiasis in patients with liver disease and liver transplantation.

Candida species remains one of the most important causes of opportunistic infections worldwide. Invasive candidiasis (IC) is associated with considerable morbidity and mortality in liver disease (LD) patients if not treated promptly. Echinocandins are often recommended as a first-line empirical treatment for managing IC and can especially play a critical role in managing IC in LD patients. However, advanced LD patients are often immunocompromised and critically ill. Hence altered pharmacokinetics, drug interactions as well as tolerance issues of antifungal treatments are a concern in these patients. This comprehensive review examines the epidemiology, risk factors and diagnosis of IC in patients with LD and evaluates differences between three available echinocandins for treating this group of patients.

Evaluating predictors of invasive candidiasis in patients with and without candidemia on micafungin

ABSTRACTNumerous risk factors have been linked to invasive candidiasis; however, they are nonspecific and often trigger empiric antifungal therapy in a large number of patients. Identification of more precise predictors could promote judicious use of empiric echinocandins. In this retrospective review, 127 patients with blood cultures positive for Candida spp. were compared to a randomly selected cohort of 134 patients on empiric micafungin for ≥3 days and with blood cultures negative for Candida spp. Factors associated with candidemia included total parenteral nutrition (TPN; 26.0% vs 15.7%, P = 0.040), multifocal Candida colonization (23.6% vs 3.0%, P < 0.001), and positive 1,3-β-d-glucan assay (95.0% vs 35.0%, P < 0.001). Patients without candidemia on empiric micafungin were more likely to receive antibiotic therapy in the previous 10 days (55.9% vs 79.9%, P < 0.001) and to be taking immunosuppressive medications (11.0% vs 30.6%, P < 0.001). Receipt of TPN (odds ratio [OR] = 2.07, 95% confidence interval [CI], 1.02–4.21), severe sepsis (OR = 2.20, 95% CI, 1.00–4.83), and multifocal Candida colonization (OR = 13.87, 95% CI, 4.43–43.37) were independently associated with candidemia in the multivariable logistic regression model. Therefore, the absence of these risk factors, especially in conjunction with a negative 1,3-β-d-glucan assay, may be used to recommend de-escalation of empiric micafungin therapy.

Candida tropicalis Isolates from Mexican Republic Exhibit High Susceptibility to Bleomycin and Variable Susceptibility to Hydrogen Peroxide.

Candida sp. are found as part of the commensal flora in humans but can cause invasive candidiasis in patients with severe underlying disease, especially cancer patients. These patients are frequently subjected to nonsurgical anticancer treatments such as ionizing radiation and anticancer drugs, which kill proliferating human cells by damaging DNA but also affect the microbiota of the patient. C. tropicalis, an emerging fungal pathogen, is associated with high mortality rates of cancer patients especially in tropical regions. In this study, we have investigated the in vitro susceptibility of 38 C. tropicalis clinical isolates from several Mexican hospitals to chronic treatments with several DNA damaging agents, including oxidizing compounds and anticancer drugs. C. tropicalis isolates displayed a high variability in their susceptibility to hydrogen peroxide (H2O2) while showing a high susceptibility to bleomycin (BLM), an anticancer drug that causes double-strand breaks in DNA. This contrasted with the moderate-to-high resistance exhibited by several C. albicans laboratory strains. At least for the C. tropicalis reference strain MYA3404, this susceptibility was hardly modified by the presence of serum. Our results open the possibility of using susceptibility to BLM to differentiate between C. tropicalis and C. albicans; however, analysis of a larger number of isolates is required. The use of BLM for prevention of C. tropicalis infections in neutropenic patients with cancer should be also evaluated. Finally, the variable susceptibility to H2O2 might be due to allelic variation of the histone acetyl-transferase complex which modulates the induction kinetics of H2O2-induced genes in C. tropicalis.

EPICO 4.0. ‘Total quality’ in the management of invasive candidiasis in critically ill patients by analysing the integrated process

BackgroundA high quality integrated process in the clinical setting of non-neutropenic critically ill patients at risk for invasive candidiasis is a necessary tool to improve the management of these patients. AimsTo identify the key points on invasive candidiasis in order to develop a set of recommendations with a high level of consensus required for the creation of a total quality integrated process for the management of non-neutropenic critically ill patients at risk of invasive candidiasis. MethodsAfter a thorough review of the literature of the previous five years, a Spanish prospective questionnaire, which measured consensus by the Delphi technique, was anonymously conducted by e-mail, including 31 national multidisciplinary experts with extensive experience in invasive fungal infections, from six national scientific societies. The experts included a specialist in intensive care medicine, anesthetists, microbiologists, pharmacologists, and specialists in infectious diseases that responded 27 questions prepared by the coordination group. The educational objectives considered six processes that included knowledge of the local epidemiology, the creation and development of multidisciplinary teams, the definitions of the process, protocols, and indicators (KPI), an educational phase, hospital implementation, and the measurement of outcomes. The level of agreement among experts in each category to be selected should exceed 70%. In a second phase, after drawing up the recommendations of the selected processes, a face to face meeting with more than 60 specialists was held. The specialists were asked to validate the pre-selected recommendations. Measures and main outcomesFirstly, 20 recommendations from all the sections were pre-selected: Knowledge of local epidemiology (3 recommendations), creation and development of multidisciplinary teams (3), definition of the process, protocols and indicators (1), educational phase (3), hospital implementation (3), and measurement of outcomes (7). After the second phase, 18 recommendations were validated, and it was concluded that the minimum team or core necessary for the development of an efficient program in the use of antifungal drugs in non-neutropenic critically ill patients must consist of a specialist in infectious diseases, a clinical pharmacist, a microbiologist, a specialist in intensive care medicine, a specialist in anesthesia and recovery, and an administrator or member of the medical management team, and, in order to be cost-effective, it should be implemented in hospitals with over 200 beds. In addition, it is recommended to apply a consensual check list for the evaluation of the diagnostic process and treatment of invasive candidiasis in patients that have started an antifungal treatment. The management of external knowledge and individual learning stand out as active educational strategies. The main strategies for measuring patient safety outcomes are the analysis of the results achieved, and learning activities; assess, review and refine the deployment of the processes; quality control; epidemiological surveillance and applied research; benchmarking; and basic research. The results of the integrated process should be annually disseminated outside the hospital. ConclusionsOptimizing the management of invasive candidiasis requires the application of the knowledge and skills detailed in our recommendations. These recommendations, based on the Delphi methodology, facilitate the creation of a total quality integrated process in critically-ill patients at risk for invasive candidiasis.

Risk Adjustment for Congenital Heart Surgery Score as a Risk Factor for Candidemia in Children Undergoing Congenital Heart Defect Surgery.

Candida species are the primary cause of invasive fungal infection in hospitalized children. There are few data on risk factors for postoperative candidemia in pediatric patients with congenital heart defects. This study aimed to identify risk factors for candidemia in patients with congenital heart defects who underwent cardiac surgery. This was a case-control study conducted in patients admitted to a pediatric cardiology intensive care unit from January 2006 to December 2013. Candidemia cases were matched with control patients without candidemia. Multivariate analyses were conducted to determine predictive probabilities for the incidence of candidemia at a risk higher than 10%. Thirty patients diagnosed with candidemia (incidence: 0.7 cases/1000 patient days) were matched with 75 controls. Risk factors independently associated with candidemia included Risk Adjustment for Congenital Heart Surgery (RACHS-1) category ≥3 [odds ratio (OR) = 3.165, 95% confidence interval: 1.377-8.467], use of acid suppression therapy (OR = 1.9, 95% confidence interval: 0.949-3.979) and thrombocytopenia (OR = 2.2, 95% confidence interval: 1.2-4.2). Predictive probabilities ranged from 11% (only in RACHS-1 category ≥3) to 58% (combined RACHS-1 ≥3, thrombocytopenia and acid suppression therapy use). The case fatality rate within 30 days after candidemia was 50%. This is the first report using the RACHS-1 category as a risk factor for invasive candidiasis in patients with congenital heart defects in the pediatric intensive care unit. Further studies must be conducted to validate the risk factors for candidemia in this pediatric population.

EPICO 3.0. Recommendations on invasive candidiasis in patients with complicated intra-abdominal infection and surgical patients with ICU extended stay

BackgroundAlthough in the last decade the management of invasive fungal infections has improved, a number of controversies persist regarding the management of complicated intra-abdominal infection and surgical extended length-of-stay (LOS) patients in intensive care unit (ICU). AimsTo identify the essential clinical knowledge and elaborate a set of recommendations, with a high level of consensus, necessary for the management of postsurgical patients with complicated intra-abdominal infection and surgical patients with ICU extended stay. MethodsA Spanish prospective questionnaire, which measures consensus through the Delphi technique, was anonymously answered and e-mailed by 30 multidisciplinary national experts, all of them specialists in fungal invasive infections from six scientific national societies; these experts were intensivists, anesthesiologists, microbiologists, pharmacologists and specialists in infectious diseases. They answered 11 questions drafted by the coordination group after conducting a thorough review of the literature published in the last few years. For a category to be selected, the level of agreement among the experts in each should be equal to or greater than 70%. In a second round, 73 specialists attended a face-to-face meeting which was held after extracting recommendations from the chosen topics and in which they validated the pre-selected recommendations and derived algorithm. ResultsAfter the second Delphi round, the following 11 recommendations with high degree of consensus were validated. For “surgical patients” seven recommendations were validated: (1) risk factors for invasive candidiasis (IC), (2) usefulness of blood culture and direct examination of abdominal fluid to start empirical treatment; (3) PCR for treatment discontinuation; (4) start antifungal treatment in patients with anastomotic leaks; (5) usefulness of Candida score (CS) but not (6) the Dupont score for initiating antifungal therapy in the event of anastomotic leakage or tertiary peritonitis, and (7) the administration of echinocandins as first line treatment in this special population. For “surgical ICU extended LOS patients” four recommendations were validated: (1) risk factors for IC, (2) presence of multi-colonization by Candida as a required variable of the CS, (3) starting antifungal treatment with CS≥4, and (4) to perform non-culture-based microbiological techniques in stable septic patients without evident focus. ConclusionsThe diagnosis and management of IC in ICU surgical patients requires the application of a broad range of knowledge and skills that we summarize in our recommendations. These recommendations, based on the DELPHI methodology, may help to identify potential patients, standardize their global management and improve their outcomes.

Comparison of the probability of target attainment of anidulafungin against Candida spp. in patients with acute leukaemia

This study aimed to investigate the probability of target attainment (PTA) of various anidulafungin dosing regimens against Candida spp. in patients with acute leukaemia. A Monte Carlo simulation was performed using a previously published population pharmacokinetic model. The following dosing scenarios were evaluated: 200mg loading dose (LD) on Day 1 then 100mg daily (manufacturer's recommended dosing regimen); 200mg LD on Day 1 then 100mg every 48h (q48h); and 200mg q48h, 200mg every 72h (q72h) and 300mg q72h. For each dosing regimen, free drug concentrations were calculated to evaluate the effect of 99% protein binding. The PTA at various pharmacodynamic (PD) targets was determined as the percentage of subjects who achieved a free drug area under the plasma concentration–time curve over the minimum inhibitory concentration ratio (ƒAUC/MIC) or a free drug maximum plasma concentration over the minimum inhibitory concentration ratio (ƒCmax/MIC) above the PD targets. PTA expectation values were then calculated for each dosing regimen. The currently recommended dosing regimen of anidulafungin was not optimal for invasive candidiasis in patients with acute leukaemia. Alternate dosing strategies with higher doses and extended dosing intervals (intermittent dosing) achieved better target attainment. This is the first study to optimise therapy with anidulafungin using Monte Carlo simulation. These results provide a rationale in support of future clinical investigation of intermittent dosing of anidulafungin.

Fluconazole prophylaxis for prevention of invasive candidiasis in infants.

Invasive candidiasis is a serious infection in hospitalized infants that results in significant mortality and morbidity. Fluconazole is approved by the US Food and Drug Administration for prophylaxis of invasive candidiasis in patients undergoing bone marrow transplantation but is not approved for use in infants. This review will describe the history of fluconazole use for prophylaxis in infants. Limiting fluconazole prophylaxis to infants with risk factors, in addition to low birth weight and early gestational age, reduces the number of infants treated with fluconazole and the duration of fluconazole therapy for each infant. Fluconazole prophylaxis appears to be well tolerated for use in premature infants. Reduction in the incidence of invasive candidiasis is observed even when prophylaxis is limited to infants with multiple risk factors. Centers with a low incidence of invasive candidiasis may not benefit from fluconazole prophylaxis. Significant short-term and long-term toxicity and increases in fluconazole-resistant organisms have not been observed with fluconazole use in the intensive care nursery.

Candidemia in Neurosurgical Intensive Care Unit: preliminary analysis of the effect of topical Nystatin prophylaxis and adequate source control on patients with early tracheostomy intubation.

The present study represents a preliminary evaluation of the impact of topical nystatin prophylaxis administration and adequate CVC management on reducing the chance of developing candidemia in neurosurgical intensive care unit (NICU) patients. We conducted a case-control study at the nine bed NICU of the Policlinico "Umberto I" teaching hospital in Rome, Italy, during the period from January 2011 to July 2012. We compared eight patients with culture proven Candida bloodstream infection (CBSI) with a control group of 19 patients who did not have evidence of CBSI. When the CBSI group was compared with the control group, the former were more likely than controls to not have received nystatin prophylaxis and adequate catheter care (p= 0,008). When CBSI group was matched with patients with no adequate source control and nystatin prophylaxis, average NICU stay (71.13 days vs 19.0 days) was significant (mean difference = -52.12 days, 95% CI -97.11 to -7.14, p= 0.028). The same was true for mean time of glucocorticoid exposure (mean difference = -10.5 days, 95% CI -17.35 to -3.65, p<0.01). Binary logistic regression analysis demonstrated no significant association between topical nystatin prophylaxis (p= 0.99), length of NICU stay (p= 0.99), time of glucocorticoid exposure (p= 0.99) and candidemia. Topical prophylaxis with nystatin and adequate source control proved to be effective in preventing invasive candidiasis in patients admitted to the NICU.

Value of β-d-glucan and Candida albicans germ tube antibody for discriminating between Candida colonization and invasive candidiasis in patients with severe abdominal conditions

To assess the value of (1→3)-β-D: -glucan (BDG), Candida albicans germ tube antibody (CAGTA), C-reactive protein (CRP), and procalcitonin (PCT) levels for the diagnosis of invasive candidiasis (IC) and for differentiating Candida spp. colonization from infection in ICU patients with severe abdominal conditions (SAC). Prospective study of 176 non-neutropenic patients, with SAC at ICU admission, and expected to stay at least 7 days. Surveillance cultures and BDG, CAGTA, CRP, and PCT levels were performed on the third day of ICU stay and twice a week for four consecutive weeks. Patients were grouped into invasive candidiasis (IC), Candida colonization, and neither colonized/nor infected. The classification and regression tree (CART) analysis was used to predict IC in colonized patients. The discriminatory ability of the obtained prediction rule was assessed by the area under the ROC curve (AUC). The probabilities of IC were 59.3 % for the terminal node of BDG greater than 259 pg/mL and 30.8 % for BDG less than 259 pg/mL and CAGTA positivity, whereas there was a 93.9 % probability in predicting the absence of IC for BDG less than 259 pg/mL and negative CAGTA. Using a cutoff of 30 % for IC probability, the prediction rule showed 90.3 % sensitivity, 54.8 % specificity, 42.4 % positive predictive value, and 93.9 % negative predictive value with an AUC of 0.78 (95 % confidence interval 0.76-0.81). Significant differences in CRP (p = 0.411) and PCT (p = 0.179) among the studied groups were not found. BDG with a positive test for CAGTA accurately differentiated Candida colonization from IC in patients with SAC, whereas CRP and PCT did not.