Population pharmacokinetics of fluconazole given for secondary prevention of oropharyngeal candidiasis in HIV-positive patients

Abstract.: Objectives: To determine fluconazole population pharmacokinetics and explore the relationships between fluconazole average concentration and treatment effectiveness or microbiological resistance induction during a study aimed at evaluating the efficacy, tolerability and resistance induction after secondary prevention with fluconazole (150mg weekly) versus placebo in human immunodeficiency virus-positive (HIV+) patients with oropharyngeal candidiasis. Methods: Population pharmacokinetic parameters of fluconazole determined from 458 serum drug concentration measurements obtained over 37months in 132 HIV+ patients not receiving highly active antiretroviral therapy. Mean estimates and variabilities were generated using non-linear regression analysis. Logistic and linear regression analyses were used to explore the relationships between the estimated average concentration of fluconazole and candidiasis relapse or fungal resistance towards fluconazole. Results: Fluconazole kinetics were best described by a one-compartment model with first-order oral absorption from the gastrointestinal tract. The pharmacokinetics were influenced only by body weight. No effect was observed for gender, age, height or lymphocyte CD4 counts. The mean apparent population clearance was 0.79l/h, the volume of distribution 57l and the absorption constant (ka) 0.93h-1. Inter-occasion variability in clearance (45%) was large relative to inter-subject variability (21%). Taking into account the average fluconazole concentration or the time above the minimal inhibitory concentrations did not clinically improve the prediction of the occurrence of oropharyngeal relapse or microbiological resistance. Conclusion: The relationship between fluconazole concentrations and preventive effectiveness was poor. Together with the rather large inter-occasion variability in fluconazole clearance, this suggests no role of therapeutic drug monitoring in optimising fluconazole treatment for secondary preventio

Physical Activity Programs with Post-Intervention Follow-Up in Children: A Comprehensive Review According to Categories of Intervention.

International audienceOnly 9% of Canadian children meet the National Guidelines of 60 min of daily moderate-to-vigorous intensity physical activity. The aim of this review is to assess the mid- and long-term effectiveness of physical activity interventions and their impact on cardiovascular risk factors in children. We assessed the success of interventions within three different categories: those using a behavioural and social approach, an informational approach or an environmental approach. The average number of children included in these studies was 860 (range of 30-5106); the age range was from 2 to 18 years; and the mean intervention duration was 1607 min (range of 12-8160 min). The length of follow-up post-intervention averaged 13 months (ranging from 0.25 to 96 months). A positive impact on physical activity was found in 74% and on any measured outcomes in 90% of the studies reviewed. However, the benefits of physical activity interventions decreased with longer follow-up. Regardless of the approaches, physical activity interventions improved cardiovascular risk factors. However, the challenge of any program is to maintain beneficial effects once the intervention is completed. These findings will inform the development of future intervention programs in order to optimize sustained cardiovascular benefits

Mutation to ispA Produces Stable Small-Colony Variants of Pseudomonas aeruginosa That Have Enhanced Aminoglycoside Resistance.

Pseudomonas aeruginosa is a major pathogen in burn wound infections. We present one of the first reports of small-colony variant (SCV) emergence of P. aeruginosa, taken from a patient under aminoglycosides for a persistent burn wound infection. We confirm the causative role of a single ispA mutation in SCV emergence and increased aminoglycoside resistance. IspA is involved in the synthesis of ubiquinone, providing a possible link between electron transport and SCV formation in P. aeruginosa

The effect of duration of antimicrobial treatment for bacteremia in critically ill patients on in-hospital mortality - Retrospective double center analysis.

PURPOSE Excessive duration of antibiotic treatment is a major factor for inappropriate antibiotic consumption. Although in some instances shorter antibiotic courses are as efficient as longer ones, no specific recommendations as to the duration of antimicrobial treatment for bloodstream infections currently exist. In the present study, we investigated the effect of antibiotic treatment duration on in-hospital mortality using retrospective data from two cohorts that included patients with bacteremia at two Swiss tertiary Intensive Care Units (ICUs). MATERIALS AND METHODS Overall 8227 consecutive patients requiring ICU admission were screened for bacteremia between 01/2012-12/2013 in Lausanne and between 07/2016-05/2017 in Bern. Patients with an infection known to require prolonged treatment or having single positive blood culture with common contaminant pathogens were excluded. The primary outcome of interest was the time from start of antimicrobial treatment to in-hospital death or hospital discharge, whichever comes first. The predictor of interest was adequate antimicrobial treatment duration, further divided into shorter (≤10 days) and longer (>10 days) durations. A time-dependent Cox model and a cloning approach were used to address immortality bias. The secondary outcomes were the median duration of antimicrobial treatment for patients with bacteremia overall and stratified by underlying infectious syndrome and pathogens in the case of secondary bacteremia. RESULTS Out of the 707 patients with positive blood cultures, 382 were included into the primary analysis. Median duration of antibiotic therapy was 14 days (IQR, 7-20). Most bacteremia (84%) were monomicrobial; 18% of all episodes were primary bacteremia. Respiratory (28%), intra-abdominal (23%) and catheter infections (17%) were the most common sources of secondary bacteremia. Using methods to mitigate the risk of confounding associated with antibiotic treatment durations, shorter versus longer treatment groups showed no differences in in-hospital survival (time-dependent Cox-model: HR 1.5, 95% CI (0.8, 2.7), p = 0.20; Cloning approach: HR 1.0, 95% CI (0.7,1.5) p = 0.83). Sensitivity analyses showed that the interpretation did not change when using a 7 days cut-off. CONCLUSIONS In this restrospective study, we found no evidence for a survival benefit of longer (>10 days) versus shorter treatment course in ICU patients with bacteremia. TRIAL REGISTRATION The study was retrospectively registered on clinicatrials.gov (NCT05236283), 11 February 2022. The respective cantonal ethics commission (KEK Bern # 2021-02302) has approved the study

Predicting Venous Thromboembolic Events in Patients with Coronavirus Disease 2019 Requiring Hospitalization: an Observational Retrospective Study by the COVIDIC Initiative in a Swiss University Hospital.

Coronavirus disease 2019 (COVID-19) can result in profound changes in blood coagulation. The aim of the study was to determine the incidence and predictors of venous thromboembolic events (VTE) among patients with COVID-19 requiring hospital admission. Subjects and Methods. We performed a retrospective study at the Lausanne University Hospital with patients admitted because of COVID-19 from February 28 to April 30, 2020. Among 443 patients with COVID-19, VTE was diagnosed in 41 patients (9.3%; 27 pulmonary embolisms, 12 deep vein thrombosis, one pulmonary embolism and deep vein thrombosis, one portal vein thrombosis). VTE was diagnosed already upon admission in 14 (34.1%) patients and 27 (65.9%) during hospital stay (18 in ICU and nine in wards outside the ICU). Multivariate analysis revealed D-dimer value > 3,120 ng/ml (P < 0.001; OR 15.8, 95% CI 4.7-52.9) and duration of 8 days or more from COVID-19 symptoms onset to presentation (P 0.020; OR 4.8, 95% CI 1.3-18.3) to be independently associated with VTE upon admission. D-dimer value ≥ 3,000 ng/l combined with a Wells score for PE ≥ 2 was highly specific (sensitivity 57.1%, specificity 91.6%) in detecting VTE upon admission. Development of VTE during hospitalization was independently associated with D-dimer value > 5,611 ng/ml (P < 0.001; OR 6.3, 95% CI 2.4-16.2) and mechanical ventilation (P < 0.001; OR 5.9, 95% CI 2.3-15.1). VTE seems to be a common COVID-19 complication upon admission and during hospitalization, especially in ICU. The combination of Wells ≥ 2 score and D - dimer ≥ 3,000 ng/l is a good predictor of VTE at admission

Higher risk for influenza-associated pulmonary aspergillosis (IAPA) in asthmatic patients: A Swiss multicenter cohort study on IAPA in critically ill influenza patients

Background: Influenza-associated pulmonary aspergillosis (IAPA) is an important complication of severe influenza with high morbidity and mortality. Methods: We conducted a retrospective multicenter study in tertiary hospitals in Switzerland during 2017/2018 and 2019/2020 influenza seasons. All adults with PCR-confirmed influenza infection and treatment on intensive-care unit (ICU) for >24 h were included. IAPA was diagnosed according to previously published clinical, radiological, and microbiological criteria. We assessed risk factors for IAPA and predictors for poor outcome, which was a composite of in-hospital mortality, ICU length of stay ≥7 days, mechanical ventilation ≥7 days, or extracorporeal membrane oxygenation. Results: One hundred fifty-eight patients (median age 64 years, 45% females) with influenza were included, of which 17 (10.8%) had IAPA. Asthma was more common in IAPA patients (17% vs. 4% in non-IAPA, P = 0.05). Asthma (OR 12.0 [95% CI 2.1-67.2]) and days of mechanical ventilation (OR 1.1 [1.1-1.2]) were associated with IAPA. IAPA patients frequently required organ supportive therapies including mechanical ventilation (88% in IAPA vs. 53% in non-IAPA, P = 0.001) and vasoactive support (75% vs. 45%, P = 0.03) and had more complications including ARDS (53% vs. 26%, P = 0.04), respiratory bacterial infections (65% vs. 37%, P = 0.04), and higher ICU-mortality (35% vs. 16.4%, P = 0.05). IAPA (OR 28.8 [3.3-253.4]), influenza A (OR 3.3 [1.4-7.8]), and higher SAPS II score (OR 1.07 [1.05-1.10]) were independent predictors of poor outcome. Interpretation: High clinical suspicion, early diagnostics, and therapy are indicated in IAPA because of high morbidity and mortality. Asthma is likely an underappreciated risk factor for IAPA. Keywords: asthma; influenza; influenza-associated aspergillosis; intensive care medicine; invasive aspergillosis

Comparison of temporal evolution of computed tomography imaging features in COVID-19 and influenza infections in a multicenter cohort study

Purpose To compare temporal evolution of imaging features of coronavirus disease 2019 (COVID-19) and influenza in computed tomography and evaluate their predictive value for distinction. Methods In this retrospective, multicenter study 179 CT examinations of 52 COVID-19 and 44 influenza critically ill patients were included. Lung involvement, main pattern (ground glass opacity, crazy paving, consolidation) and additional lung and chest findings were evaluated by two independent observers. Additional findings and clinical data were compared patient-wise. A decision tree analysis was performed to identify imaging features with predictive value in distinguishing both entities. Results In contrast to influenza patients, lung involvement remains high in COVID-19 patients > 14 days after the diagnosis. The predominant pattern in COVID-19 evolves from ground glass at the beginning to consolidation in later disease. In influenza there is more consolidation at the beginning and overall less ground glass opacity (p = 0.002). Decision tree analysis yielded the following: Earlier in disease course, pleural effusion is a typical feature of influenza (p = 0.007) whereas ground glass opacities indicate COVID-19 (p = 0.04). In later disease, particularly more lung involvement (p < 0.001), but also less pleural (p = 0.005) and pericardial (p = 0.003) effusion favor COVID-19 over influenza. Regardless of time point, less lung involvement (p < 0.001), tree-in-bud (p = 0.002) and pericardial effusion (p = 0.01) make influenza more likely than COVID-19. Conclusions This study identified differences in temporal evolution of imaging features between COVID-19 and influenza. These findings may help to distinguish both diseases in critically ill patients when laboratory findings are delayed or inconclusive

Higher risk for influenza-associated pulmonary aspergillosis (IAPA) in asthmatic patients: A Swiss multicenter cohort study on IAPA in critically ill influenza patients.

BACKGROUND Influenza-associated pulmonary aspergillosis (IAPA) is an important complication of severe influenza with high morbidity and mortality. METHODS We conducted a retrospective multicenter study in tertiary hospitals in Switzerland during 2017/2018 and 2019/2020 influenza seasons. All adults with PCR-confirmed influenza infection and treatment on intensive-care unit (ICU) for >24 h were included. IAPA was diagnosed according to previously published clinical, radiological, and microbiological criteria. We assessed risk factors for IAPA and predictors for poor outcome, which was a composite of in-hospital mortality, ICU length of stay ≥7 days, mechanical ventilation ≥7 days, or extracorporeal membrane oxygenation. RESULTS One hundred fifty-eight patients (median age 64 years, 45% females) with influenza were included, of which 17 (10.8%) had IAPA. Asthma was more common in IAPA patients (17% vs. 4% in non-IAPA, P = 0.05). Asthma (OR 12.0 [95% CI 2.1-67.2]) and days of mechanical ventilation (OR 1.1 [1.1-1.2]) were associated with IAPA. IAPA patients frequently required organ supportive therapies including mechanical ventilation (88% in IAPA vs. 53% in non-IAPA, P = 0.001) and vasoactive support (75% vs. 45%, P = 0.03) and had more complications including ARDS (53% vs. 26%, P = 0.04), respiratory bacterial infections (65% vs. 37%, P = 0.04), and higher ICU-mortality (35% vs. 16.4%, P = 0.05). IAPA (OR 28.8 [3.3-253.4]), influenza A (OR 3.3 [1.4-7.8]), and higher SAPS II score (OR 1.07 [1.05-1.10]) were independent predictors of poor outcome. INTERPRETATION High clinical suspicion, early diagnostics, and therapy are indicated in IAPA because of high morbidity and mortality. Asthma is likely an underappreciated risk factor for IAPA