Outpatient parenteral antifungal therapy (OPAT) for invasive fungal infections with intermittent dosing of liposomal amphotericin B

Triazole resistant A. fumigatus has been documented in many parts of the world. In the Netherlands, incidence is now above 10% and results in the need for long-term parenteral therapy with liposomal amphotericin B (LAmB). The long terminal half-life of LAmB suggests that intermittent dosing could be effective, making the application of outpatient antifungal therapy (OPAT) possible. Here, we report our experience with the use of OPAT for Invasive Fungal Infections (IFI). All adult patients treated with LAmB with a 2 or 3 times weekly administration via the outpatient departments in four academic tertiary care centers in the Netherlands and Belgium since January 2010 were included in our analysis. Patient characteristics were collected, as well as information about diagnostics, therapy dose and duration, toxicity, treatment history and outcome of the IFI. In total, 18 patients were included. The most frequently used regimen (67%) was 5 mg/kg 3 times weekly. A partial response to the daily treatment prior to discharge was confirmed by CT-scan in 17 (94%) of patients. A favorable outcome was achieved in 13 (72%) patients. Decrease in renal function occurred in 10 (56%) cases but was reversible in all and was treatment limiting in one patient only. The 100-day mortality and 1-year mortality after initiation of OPAT were 0% and 6%, respectively. In a selected population, and after confirmation of initial response to treatment, our data support the use of OPAT with LAmB for treatment of IFI in an intermittent dosing regimen

Procalcitonin reflects bacteremia and bacterial load in urosepsis syndrome: a prospective observational study

Introduction: Guidelines recommend that two blood cultures be performed in patients with febrile urinary tract infection (UTI), to detect bacteremia and help diagnose urosepsis. The usefulness and cost-effectiveness of this practice have been criticized. This study aimed to evaluate clinical characteristics and the biomarker procalcitonin (PCT) as an aid in predicting bacteremia. Methods: A prospective observational multicenter cohort study included consecutive adults with febrile UTI in 35 primary care units and 8 emergency departments of 7 regional hospitals. Clinical and microbiological data were collected and PCT and time to positivity (TTP) of blood culture were measured. Results: Of 581 evaluable patients, 136 (23%) had bacteremia. The median age was 66 years (interquartile range 46 to 78 years) and 219 (38%) were male. We evaluated three different models: a clinical model including seven bedside characteristics, the clinical model plus PCT, and a PCT only model. The diagnostic abilities of these models as reflected by area under the curve of the receiver operating characteristic were 0.71 (95% confidence interval (CI): 0.66 to 0.76), 0.79 (95% CI: 0.75 to 0.83) and 0.73 (95% CI: 0.68 to 0.77) respectively. Calculating corresponding sensitivity and specificity for the presence of bacteremia after each step of adding a significant predictor in the model yielded that the PCT > 0.25 mu g/l only model had the best diagnostic performance (sensitivity 0.95; 95% CI: 0.89 to 0.98, specificity 0.50; 95% CI: 0.46 to 0.55). Using PCT as a single decision tool, this would result in 40% fewer blood cultures being taken, while still identifying 94 to 99% of patients with bacteremia. The TTP of E. coli positive blood cultures was linearly correlated with the PCT log value; the higher the PCT the shorter the TTP (R-2 = 0.278, P = 0.007). Conclusions: PCT accurately predicts the presence of bacteremia and bacterial load in patients with febrile UTI. This may be a helpful biomarker to limit use of blood culture resources.Immunogenetics and cellular immunology of bacterial infectious disease

Cognitive Control and Individual Differences in Economic Ultimatum Decision-Making

Much publicity has been given to the fact that people's economic decisions often deviate from the rational predictions of standard economic models. In the classic ultimatum game, for example, most people turn down financial gains by rejecting unequal monetary splits. The present study points to neglected individual differences in this debate. After participants played the ultimatum game we tested for individual differences in cognitive control capacity of the most and least economic responders. The key finding was that people who were higher in cognitive control, as measured by behavioral (Go/No-Go performance) and neural (No-Go N2 amplitude) markers, did tend to behave more in line with the standard models and showed increased acceptance of unequal splits. Hence, the cognitively highest scoring decision-makers were more likely to maximize their monetary payoffs and adhere to the standard economic predictions. Findings question popular claims with respect to the rejection of standard economic models and the irrationality of human economic decision-making

Evidence for Limited Genetic Compartmentalization of HIV-1 between Lung and Blood

BACKGROUND:HIV-1 is frequently detected in the lungs of infected individuals and is likely important in the development of pulmonary opportunistic infections. The unique environment of the lung, rich in alveolar macrophages and with specialized local immune responses, may contribute to differential evolution or selection of HIV-1. METHODOLOGY AND FINDINGS:We characterized HIV-1 in the lung in relation to contemporaneous viral populations in the blood. The C2-V5 region of HIV-1 env was sequenced from paired lung (induced sputum or bronchoalveolar lavage) and blood (plasma RNA and proviral DNA from sorted or unsorted PBMC) from 18 subjects. Compartmentalization between tissue pairs was assessed using 5 established tree or distance-based methods, including permutation tests to determine statistical significance. We found statistical evidence of compartmentalization between lung and blood in 10/18 subjects, although lung and blood sequences were intermingled on phylogenetic trees in all subjects. The subject showing the greatest compartmentalization contained many nearly identical sequences in BAL sample, suggesting clonal expansion may contribute to reduced viral diversity in the lung in some cases. However, HIV-1 sequences in lung were not more homogeneous overall, nor were we able to find a lung-specific genotype associated with macrophage tropism in V3. In all four subjects in whom predicted X4 genotypes were found in blood, predicted X4 genotypes were also found in lung. CONCLUSIONS:Our results support a picture of continuous migration of HIV-1 between circulating blood and lung tissue, with perhaps a very limited degree of localized evolution or clonal replication

Influence of endogenous pro-inflammatory cytokines on neutrophil-mediated damage of Candida albicans pseudohyphae, quantified in a modified tetrazolium dye assay.

Contains fulltext : 48033.pdf (publisher's version ) (Closed access)For quantitative assessment of polymorphonuclear granulocyte (PMN)-mediated pseudohyphal damage, an improved tetrazolium (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide; XTT) dye assay was developed. The modified assay proved to be a reliable indicator of viable pseudohyphal inoculum sizes. In addition, the influence of various endogenous pro-inflammatory cytokines on the capacity of PMN to damage Candida albicans pseudohyphae was investigated. PMN obtained from mice in which the genes encoding for tumor necrosis factor-alpha/lymphotoxin-alpha (TNF/LT), interferon-gamma (IFNgamma), interleukin (IL)-1alpha, or IL-1beta were disrupted, showed a significantly reduced pseudohyphal damage capacity in comparison with control PMN. The reduction amounted 25% for TNF-/- LT-/-, 11% for IFNgamma-/-, 21% for IL-1alpha-/-, and 34% for IL-1alpha-/-beta-/- PMN. In contrast, deficiency of IL-12 or IL-18 did not result in a diminished capacity to damage pseudohyphae and the capacity of PMN to damage Candida pseudohyphae was even slightly increased by 10% in IL-18-/- mice. These data suggest that endogenous pro-inflammatory cytokines are able to modulate antihyphal activity of PMN, the main effector cells against disseminated candidiasis by virtue of their capacity to kill both Candida blastoconidia and pseudohyphae