Accumulation of the solvent vehicle sulphobutylether beta cyclodextrin sodium in critically ill patients treated with intravenous voriconazole under renal replacement therapy

BACKGROUND: Voriconazole was introduced for the treatment of life-threatening fungal infections. The intravenous form includes the solvent vehicle sulphobutylether beta cyclodextrin sodium which shows an impaired clearance under intermittent dialysis therapy. This investigation aimed to determine first clinical data on sulphobutylether beta cyclodextrin sodium blood levels to verify the risk for accumulation. METHODS: In four patients suffering from renal insufficiency and intermittent dialysis therapy who needed a treatment with intravenous voriconazole as a reserve antifungal at the intensive care unit of the Mainz University Hospital the trough levels of voriconazole and sulphobutylether beta cyclodextrin sodium were measured. RESULTS: A 75-year-old woman showed a maximal sulphobutylether beta cyclodextrin sodium plasma level of 145 μg/ml in the initial phase. After a few days renal function recovered and the plasma levels came down to less than 20 μg/ml. In contrast to this patient with a recovery of renal function the remaining three patients showed renal failure during the complete period of intravenous treatment with voriconazole. In these patients an accumulation of sulphobutylether beta cyclodextrin sodium plasma levels was determined with a maximum of 523 μg/ml in a 18-year-old man, 409 μg/ml in a 57-year-old man, and 581 μg/ml in a 47-year-old man. CONCLUSION: The present data indicate an accumulation of sulphobutylether beta cyclodextrin sodium in patients treated with intravenous voriconazole and dialysis therapy. Fortunately, no toxic effects were observed, although the accumulated dose values were lower but comparable with those used in previous toxicity studies with animals

Novel strategies to fight Candida species infection

In recent years, there has been a significant increase in the incidence of human fungal infections. The increase in cases of infection caused by Candida species, and the consequent excessive use of antimicrobials, has favored the emergence of resistance to conventional antifungal agents over the past decades. Consequently, Candida infections morbidity and mortality are also increasing. Therefore, new approaches are needed to improve the outcome of patients suffering from Candida infections, because it seems unlikely that the established standard treatments will drastically lower the morbidity of mucocutaneous Candida infections and the high mortality associated with invasive candidiasis. This review aims to present the last advances in the traditional antifungal therapy, and present an overview of novel strategies that are being explored for the treatment of Candida infections, with a special focus on combined antifungal agents, antifungal therapies with alternative compounds (plant extracts and essential oils), adjuvant immunotherapy, photodynamic therapy and laser therapy.Consolidating Research Expertise and Resources on Cellular and Molecular Biotechnology at CEB/IBB’’, Ref. FCOMP-01-0124-FEDER-027462BioHealth – Biotechnology and Bioengineering approaches to improve health quality’’, Ref. NORTE-07-0124-FEDER-000027 co-funded by the Programa Operacional Regional do Norte (ON.2 – O Novo Norte), QREN, FEDER

18F-FDG PET/CT for diagnosing infectious complications in patients with severe neutropenia after intensive chemotherapy for haematological malignancy or stem cell transplantation

Item does not contain fulltextPURPOSE: Between 30 and 50% of febrile neutropenic episodes are accounted for by infection. C-reactive protein (CRP) is a nonspecific parameter for infection and inflammation but might be employed as a trigger for diagnosis. The aim of the study was to evaluate whether (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT can be used to detect inflammatory foci in neutropenic patients with elevated CRP and whether it helps to direct treatment. METHODS: Twenty-eight consecutive patients with neutropenia as a result of intensive chemotherapy for haematological malignancies or myeloablative therapy for haematopoietic stem cell transplantation were prospectively included. (18)F-FDG PET/CT was added to the regular diagnostic workup once the CRP level rose above 50 mg/l. RESULTS: Pathological FDG uptake was found in 26 of 28 cases despite peripheral neutrophil counts less than 0.1 x 10(-9)/l in 26 patients: in the digestive tract in 18 cases, around the tract of the central venous catheter (CVC) in 9 and in the lungs in 7 cases. FDG uptake in the CVC tract was associated with coagulase-negative staphylococcal bacteraemia (p < 0.001) and deep venous thrombosis (p = 0.002). The number of patients having Streptococcus mitis bacteraemia appeared to be higher in patients with grade 3 oesophageal FDG uptake (p = 0.08). Pulmonary FDG uptake was associated with the presence of invasive fungal disease (p = 0.04). CONCLUSION: (18)F-FDG PET/CT scanning during chemotherapy-induced febrile neutropenia and increased CRP is able to detect localized foci of infection and inflammation despite the absence of circulating neutrophils. Besides its potential role in detecting CVC-related infection during febrile neutropenia, the high negative predictive value of (18)F-FDG PET/CT is important for avoiding unnecessary diagnostic tests and therapy.1 januari 201

Genetic Control of Susceptibility to Infection with Candida albicans in Mice

Candida albicans is an opportunistic pathogen that causes acute disseminated infections in immunocompromised hosts, representing an important cause of morbidity and mortality in these patients. To study the genetic control of susceptibility to disseminated C. albicans in mice, we phenotyped a group of 23 phylogenetically distant inbred strains for susceptibility to infection as measured by extent of fungal replication in the kidney 48 hours following infection. Susceptibility was strongly associated with the loss-of-function mutant complement component 5 (C5/Hc) allele, which is known to be inherited by approximately 40% of inbred strains. Our survey identified 2 discordant strains, AKR/J (C5-deficient, resistant) and SM/J (C5-sufficient, susceptible), suggesting that additional genetic effects may control response to systemic candidiasis in these strains. Haplotype association mapping in the 23 strains using high density SNP maps revealed several putative loci regulating the extent of C. albicans replication, amongst which the most significant were C5 (P value = 2.43×10−11) and a novel effect on distal chromosome 11 (P value = 7.63×10−9). Compared to other C5-deficient strains, infected AKR/J strain displays a reduced fungal burden in the brain, heart and kidney, and increased survival, concomitant with uniquely high levels of serum IFNγ. C5-independent genetic effects were further investigated by linkage analysis in an [A/JxAKR/J]F2 cross (n = 158) where the mutant Hc allele is fixed. These studies identified a chromosome 11 locus (Carg4, Candida albicans resistance gene 4; LOD = 4.59), and a chromosome 8 locus (Carg3; LOD = 3.95), both initially detected by haplotype association mapping. Alleles at both loci were inherited in a co-dominant manner. Our results verify the important effect of C5-deficiency in inbred mouse strains, and further identify two novel loci, Carg3 and Carg4, which regulate resistance to C. albicans infection in a C5-independent manner

Contribution of Candida biomarkers and DNA detection for the diagnosis of invasive candidiasis in ICU patients with severe abdominal conditions

BACKGROUND: To assess the performance of Candida albicans germ tube antibody (CAGTA), (1 → 3)-ß-D-glucan (BDG), mannan antigen (mannan-Ag), anti-mannan antibodies (mannan-Ab), and Candida DNA for diagnosing invasive candidiasis (IC) in ICU patients with severe abdominal conditions (SAC). METHODS: A prospective study of 233 non-neutropenic patients with SAC on ICU admission and expected stay ≥ 7 days. CAGTA (cutoff positivity ≥ 1/160), BDG (≥80, 100 and 200 pg/mL), mannan-Ag (≥60 pg/mL), mannan-Ab (≥10 UA/mL) were measured twice a week, and Candida DNA only in patients treated with systemic antifungals. IC diagnosis required positivities of two biomarkers in a single sample or positivities of any biomarker in two consecutive samples. Patients were classified as neither colonized nor infected (n = 48), Candida spp. colonization (n = 154) (low-grade, n = 130; high-grade, n = 24), and IC (n = 31) (intra-abdominal candidiasis, n = 20; candidemia, n = 11). RESULTS: The combination of CAGTA and BDG positivities in a single sample or at least one of the two biomarkers positive in two consecutive samples showed 90.3 % (95 % CI 74.2–98.0) sensitivity, 42.1 % (95 % CI 35.2–98.8) specificity, and 96.6 % (95 % CI 90.5–98.8) negative predictive value. BDG positivities in two consecutive samples had 76.7 % (95 % CI 57.7–90.1) sensitivity and 57.2 % (95 % CI 49.9–64.3) specificity. Mannan-Ag, mannan-Ab, and Candida DNA individually or combined showed a low discriminating capacity. CONCLUSIONS: Positive Candida albicans germ tube antibody and (1 → 3)-ß-D-glucan in a single blood sample or (1 → 3)-ß-D-glucan positivity in two consecutive blood samples allowed discriminating invasive candidiasis from Candida spp. colonization in critically ill patients with severe abdominal conditions. These findings may be helpful to tailor empirical antifungal therapy in this patient population

Clinical factors associated with a Candida albicans Germ Tube Antibody positive test in Intensive Care Unit patients

Background: Poor outcomes of invasive candidiasis (IC) are associated with the difficulty in establishing the microbiological diagnosis at an early stage. New scores and laboratory tests have been developed in order to make an early therapeutic intervention in an attempt to reduce the high mortality associated with invasive fungal infections. Candida albicans IFA IgG has been recently commercialized for germ tube antibody detection (CAGTA). This test provides a rapid and simple diagnosis of IC (84.4% sensitivity and 94.7% specificity). The aim of this study is to identify the patients who could be benefited by the use of CAGTA test in critical care setting. Methods: A prospective, cohort, observational multicentre study was carried out in six medical/surgical Intensive care units (ICU) of tertiary-care Spanish hospitals. Candida albicans Germ Tube Antibody test was performed twice a week if predetermined risk factors were present, and serologically demonstrated candidiasis was considered if the testing serum dilution was >= 1: 160 in at least one sample and no other microbiological evidence of invasive candidiasis was found. Results: Fifty-three critically ill non-neutropenic patients (37.7% post surgery) were included. Twenty-two patients (41.5%) had CAGTA-positive results, none of them with positive blood culture for Candida. Neither corrected colonization index nor antifungal treatment had influence on CAGTA results. This finding could corroborate that the CAGTA may be an important biomarker to distinguish between colonization and infection in these patients. The presence of acute renal failure at the beginning of the study was more frequent in CAGTA-negative patients. Previous surgery was statistically more frequent in CAGTA-positive patients. Conclusions: This study identified previous surgery as the principal clinical factor associated with CAGTA-positive results and emphasises the utility of this promising technique, which was not influenced by high Candida colonization or antifungal treatment. Our results suggest that detection of CAGTA may be important for the diagnosis of invasive candidiasis in surgical patients admitted in ICU.This study has been supported by a Pfizer research gran

Invasive fungal infections in neutropenic enterocolitis: A systematic analysis of pathogens, incidence, treatment and mortality in adult patients

BACKGROUND: Neutropenic enterocolitis is a life-threatening complication most frequently occurring after intensive chemotherapy in acute leukaemias. Gramnegative bacteria constitute the most important group of causative pathogens. Fungi have also been reported, but their practical relevance remains unclear. The guidelines do not address concrete treatment recommendations for fungal neutropenic enterocolitis. METHODS: Here, we conducted a metaanalysis to answer the questions: What are frequency and mortality of fungal neutropenic enterocolitis? Do frequencies and microbiological distribution of causative fungi support empirical antimycotic therapy? Do reported results of antimycotic therapy in documented fungal neutropenic enterocolitis help with the selection of appropriate drugs? Following a systematic search, we extracted and summarised all detail data from the complete literature. RESULTS: Among 186 articles describing patients with neutropenic enterocolitis, we found 29 reports describing 53 patients with causative fungal pathogens. We found no randomised controlled trial, no good quality cohort study and no good quality case control study on the role of antifungal treatment. The pooled frequency of fungal neutropenic enterocolitis was 6.2% calculated from all 860 reported patients and 3.4% calculated from selected representative studies only. In 94% of the patients, Candida spp. were involved. The pooled mortality rate was 81.8%. Most authors did not report or perform antifungal therapy. CONCLUSION: In patients with neutropenic enterocolitis, fungal pathogens play a relevant, but secondary role compared to bacteria. Evidence concerning therapy is very poor, but epidemiological data from this study may provide helpful clues to select empiric antifungal therapy in neutropenic enterocolitis

IL-1β Processing in Host Defense: Beyond the Inflammasomes

Stimulation and release of proinflammatory cytokines is an essential step for the activation of an effective innate host defense, and subsequently for the modulation of adaptive immune responses. Interleukin-1β (IL-1β) and IL-18 are important proinflammatory cytokines that on the one hand activate monocytes, macropages, and neutrophils, and on the other hand induce Th1 and Th17 adaptive cellular responses. They are secreted as inactive precursors, and the processing of pro-IL-1β and pro-IL-18 depends on cleavage by proteases. One of the most important of these enzymes is caspase-1, which in turn is activated by several protein platforms called the inflammasomes. Inflammasome activation differs in various cell types, and knock-out mice defective in either caspase-1 or inflammasome components have an increased susceptibility to several types of infections. However, in other infections and in models of sterile inflammation, caspase-1 seems to be less important, and alternative mechanisms such as neutrophil-derived serine proteases or proteases released from microbial pathogens can process and activate IL-1β. In conclusion, IL-1β/IL-18 processing during infection is a complex process in which the inflammasomes are only one of several activation mechanisms