Limited data are present regarding the steady-state pharmacokinetics and pharmacodynamics of colistin in critically ill patients suffering from multi-drug-resistant gram-negative bacterial (MDR-GNB) infections. We aimed to profile the steady-state pharmacokinetics and pharmacodynamics of colistin in critically ill patients with MDR-GNB infections, along with determining the predictors that could influence the clinical, microbiological and safety outcome. We recruited 30 critically ill patients suffering from MDR-GNB infections in our prospective open-label study. Intravenous colistimethate sodium (CMS) 2 million IU was administered concurrently with inhalational CMS 1 million IU every 8 hours. Steady-state plasma colistin levels were measured. Logistic regression analysis was used to identify various predictors of clinical, microbiological and safety outcome. A large variability was observed in the steady-state colistin pharmacokinetic/pharmacodynamic parameters, along with the factors that influenced the clinical, microbiological and safety outcome. In conclusion, steady-state colistin pharmacokinetic and pharmacodynamic parameters observed in our study were largely consistent with those reported in previous studies. High acute physiology and chronic health evaluation II scores were associated with poor clinical outcome. Log-transformed colistin maximum concentration, area under the plasma concentration curve for 8 hours, apparent total body clearance and apparent volume of distribution were significantly associated with the safety outcome.

Objectives Non‐vitamin K oral anticoagulants (NOACs) or vitamin K antagonists (VKAs) are used for the prophylaxis and treatment of thromboembolic events. A potential drug–drug interaction and increased bleeding events have been reported with co‐medication of selective serotonin receptor inhibitors (SSRIs) and VKA. The aim of this study was to investigate the bleeding risk of a coprescription of NOAC or VKA with SSRI. Methods Patients with prescription of NOAC or VKA and an antidepressant drug therapy (ADTx) were selected from the drug reimbursement database of 13 Austrian health insurance funds. For this cohort, hospital discharge diagnoses for gastrointestinal bleeding, cerebral haemorrhage, and bleeding anaemia between 2010 and 2015 were analysed. Results Data were available from 50 196 female and 31 308 male patients. Among these, 892 patients had 987 hospitalisations with bleeding events. The most frequent bleeding cases were gastrointestinal bleedings with 588 events (59.6%), followed by cerebral haemorrhage with 344 (34.8%), and bleeding anaemia with 55 events (5.6%), respectively. The risk of bleeding events was similar between SSRI and other ADTx, when combined with oral anticoagulants (p = 0.51). Concomitant treatment of patients with SSRI or other ADTx and NOAC was associated with an increased bleeding risk compared with cotreatment with VKA (1.21, 95% CI: 1.05‐1.40; p = 0.0097). Conclusion Co‐medication of SSRI with VKA or NOAC has little if any impact on hospital discharge diagnoses for bleeding events compared with cotreatment of those anticoagulants with other antidepressant medications.

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Studies have determined the serum concentration of ceftriaxone in the adult population, but there are only a few studies that measured the tissue concentrations. However, no studies have concurrently evaluated the serum and tissue concentrations of ceftrixaone in elective pediatric surgery patients. Therefore, our study was planned to evaluate the serum and tissue concentrations of single dose intravenous prophylactic ceftriaxone intra-operatively during an ongoing pediatric surgery and the outcome of surgical-site infections (SSIs). We did a correlation analysis to determine the relationship of various concentrations and surgery related risk factors with the outcome of SSIs. It was an open label prospective study in 50 patients who underwent elective pediatric surgery under prophylactic cover of ceftriaxone. Serum and tissue concentration were estimated by High Pressure Liquid Chromatography (HPLC). Subjects were observed for post operative complications including SSI. Serum and tissue concentrations of ceftriaxone were significant at test value of 4 ​mg/L. Tissue concentrations of ceftriaxone at incision (p ​= ​0.02) and closure (p ​= ​0.04) were significantly correlated with SSI but there was no significant association. The measured serum ceftriaxone concentrations were more than 20 times the susceptible minimum inhibitory concentration (MIC) at any given point of the surgery. On the other hand, this target level was achieved at the tissue levels in the majority of the patient. The factors associated with SSI were duration of surgery, wound category of contaminated clean type, the use of urinary catheter and implants in the surgery. An intra-operative re-dose, extension of dose or addition of another antibiotic may be considered for such patients.

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We hypothesized that body mass index (BMI) dependent changes in myocardial gene expression and energy-related metabolites underlie the biphasic association between BMI and mortality (the obesity paradox) in cardiac surgery. We performed transcriptome profiling and measured a panel of 144 metabolites in 53 and 55, respectively, myocardial biopsies from a cohort of sixty-seven adult patients undergoing coronary artery bypass grafting (registration: NCT02908009). The initial analysis identified 239 transcripts with biphasic BMI dependence. 120 displayed u-shape and 119 n-shape expression patterns. The identified local minima or maxima peaked at BMI 28-29. Based on these results and to best fit the WHO classification, we grouped the patients into three groups: BMI<25, 25≤BMI≤32, and BMI>32. The group analysis indicated that protein translation-related pathways were downregulated in 25≤BMI≥32 compared with BMI<25 patients. Muscle contraction transcripts were upregulated in 25≤BMI≥32 patients, and cholesterol synthesis and innate immunity transcripts were upregulated in the BMI>32 group. Transcripts involved in translation, muscle contraction and lipid metabolism also formed distinct correlation networks with biphasic dependence on BMI. Metabolite analysis identified acylcarnitines and ribose-5-phosphate increasing in the BMI>32 group and α-ketoglutarate increasing in the BMI<25 group. Molecular differences in the myocardium mirror the biphasic relationship between BMI and mortality.

Background Childhood primary angiitis of the CNS (cPACNS) is an increasingly recognized, reversible cause of severe neurological and psychiatric deficit such as stroke, refractory seizures and hallucination in previously healthy children. Aggressive immunosuppression has significantly decreased the mortality, however little is known about the long-term neurocognitive burden of cPACNS. Objectives To describe the neuropsychological outcome of children with cPACNS, compare the cognitive burden between distinct disease subtypes and identify risk factors for poor neurocognitive outcome. Methods A single-centre cohort study of children with cPACNS based on Calabrese criteria was performed. Children had to have completed a standard neurocognitive evaluation. Demographic characteristics, disease subtypes, clinical features, laboratory markers, neuroimaging studies, brain biopsy findings and treatment regimens were captured. Neurocognitive function was evaluated with a previously reported comprehensive battery of neuropsychological tests including domains of cognitive, social, emotional and adaptive function. The primary study outcome was the Full Scale IQ (FSIQ). Secondary outcomes included neurological function as defined by the Paediatric Stroke Outcome Measure PSOM, Health-related Quality of Life (PedsQL), disease activity and disease damage (VAS). Analysis: Univariate analysis compared variables between distinct disease subtypes; a multivariate prediction model for adverse cognitive outcome was developed. Results A total of 111 children were diagnosed with primary CNS vasculitis in the study interval, of whom 70 (63%) completed the neuropsychological assessment. Of these 21 had small vessel CNS vasculitis (SVcPACNS) and 49 angiography-positive CNS vasculitis (APcPACNS). The cohort included 31 girls (17 SVcPACNS, 14 APcPACNS) and 39 boys (4 SVcPACNS, 35 APcPACNS), median age at diagnosis was 8.1 years; SVcPACNS patients were significantly older (9.3 vs. 7.6 years, p=0.04)). At diagnosis, SVcPACNS patients present significantly more commonly with seizures (67%, p=0.003) and diffuse deficits, (90%, p=0.05), while stroke features were more frequently seen in APcPACNS (94%, p=0.01). Outcome: The mean FSIQ was significantly lower at 82 (54-119) in SVcPACNS compared to 97 (52-132) in APcPACNS (p=0.04). Abnormal FSIQ scores (<85) were seen in 52% of the SVcPACNS and 25% of APcPACNS patients. Children with SVcPACNS had lower scores in the domains of verbal comprehension (p=0.04), perceptual reasoning (p=0.007), working memory (p=0.06) and processing speed (p=0.03). Prediction model: Children presenting with seizures were at the highest risk of cognitive deficits (p=0.005). Conclusions Children with cPACNS carry significant disease burden. The inflammation causes drastically impaired cognitive functioning including comprehension, processing speed and memory deficits. Children with SVcPACNS and in particular those presenting with seizures are at the highest risk for adverse cognitive outcome. Early rehabilitation interventio...