1. Abstract Etiological diagnosis of lower respiratory tract infections (LRTIs) relies on sputum or bronchoalveolar lavage (BAL), which may be difficult to obtain or invasive. Exhaled breath aerosol (XBA) sampling offers a non-invasive alternative for pathogen detection. We evaluated the performance of the AveloMask, a face mask–based device designed to capture XBAs for molecular testing. In this prospective paired-sample study, hospitalized adults with pneumonia at three hospitals in Switzerland and Georgia provided an XBA sample using the AveloMask and a lower respiratory tract (LRT) specimen (sputum or BAL). XBA samples were analyzed by multiplex PCR using the Roche LightMix® panel and LRT samples were tested using the BioFire® FilmArray® Pneumonia Panel. Concordance between XBA and LRT samples was assessed using positive percent agreement (PPA), negative percent agreement (NPA), and overall percent agreement (OPA). Ninety-three participants were enrolled and 63 participants provided paired samples. AveloMask sampling identified the dominant pathogen (lowest Ct value in the LRT sample) in 40/47 LRT-positive cases (85.1%). Across all targets, PPA was 61% (95%CI, 50–72%), NPA was 100% (95%CI, 99–100%), and OPA was 95% (95% CI, 92–96%). PPA was higher for bacteria than for viruses and lower PPA was largely driven by reduced detection of low-abundance or co-infecting pathogens. In a subset analysis, AveloMask results showed substantial overlap with standard-of-care testing and could have supported antimicrobial de-escalation. Breath aerosol sampling using the AveloMask enabled non-invasive molecular detection of LRT pathogens in pneumonia cases and may complement conventional standard-of-care testing, particularly when sputum is unavailable.

OBJECTIVES:To assess amikacin target attainment in patients with a haematological disorder treated for febrile neutropenia or severe infection and to develop a population pharmacokinetic (PK) model. METHODS:This prospective observational single-centre study was conducted at the University Hospital Basel, Switzerland between December 2022 and February 2024. Adult patients with a haematological disorder treated with amikacin for 1-3 days were included. Total amikacin concentrations in blood were measured 1 h and 8 h after each administration. The primary objective was target attainment (Cmax ≥60 mg/L) at all time points evaluated (in the context of the amikacin ECOFF of 8 mg/L for Enterobacterales). A population PK model was developed to derive individual exposure estimates. RESULTS:Overall, 57 patients with 119 amikacin applications and 174 concentration measurements were included. The median age was 61 years [interquartile range (IQR) 53-68] and 33% were female. Targets of Cmax ≥60 mg/L were attained in 11/57 patients (19.3%) and Cmax/MIC≥8 in 10/10 patients (100%), in whom a pathogen was identified. In the population PK model, weight and GFR were correlated with PK parameters in the multivariable analysis. CONCLUSIONS:Amikacin target attainment was low in patients with a haematological malignancy treated empirically for FN, when pathogens with higher MICs are considered. Dosing optimisation may be needed to improve target attainment.

Given the high morbidity and mortality of Gram-negative bloodstream infections (GN-BSI), follow-up blood cultures (FUBCs) have received increasing attention in clinical practice. However, evidence on their impact remains conflicting. This study assessed the association of FUBCs with 90-day all-cause mortality, accounting for immortal time bias. This retrospective cohort study included 637 hospitalized adults with GN-BSI from two Swiss tertiary-care hospitals (April 2022–April 2024). FUBCs were defined as blood cultures obtained after availability of the index culture result up to 168 h after collection. Endpoints included predictors of FUBC collection and association with 90-day mortality. Sensitivity analyses evaluated FUBCs collected 48–120 h after the index culture. Mean age was 71.3 years and 46

Rationale: Early detection, standardized therapy, adequate infrastructure, and strategies for quality improvement should constitute essential components of every hospital's sepsis plan. Objectives: To investigate the extent to which recommendations from the sepsis guidelines are implemented and the availability of infrastructure for the care of patients with sepsis in acute-care hospitals. Methods: A multidisciplinary cross-sectional questionnaire was used to investigate sepsis care in hospitals. This included the use of sepsis definitions, the implementation of sepsis guideline recommendations, diagnostic and therapeutic infrastructure, antibiotic stewardship, and quality improvement initiatives (QIIs) in hospitals. Measurements and Main Results: A total of 1,023 hospitals in 69 countries were included. Most of them, 835 (81.6%), were in Europe. Sepsis screening was used in 54.2% of emergency departments (EDs), 47.9% of wards, and 61.7% of ICUs. Sepsis management was standardized in 57.3% of EDs, 45.2% of wards, and 70.7% of ICUs. The implementation of comprehensive QIIs was associated with increased screening (EDs, +33.3%; wards, +44.4%; ICUs, +23.8% absolute difference) and increased standardized sepsis management (EDs, +33.6%; wards, +40.0%; ICUs, +17.7% absolute difference) compared with hospitals without QIIs. A total of 9.8% of hospitals had implemented ongoing QIIs, and 4.6% had invested in sepsis programs. Conclusions: The findings indicate that there is considerable room for improvement in a large number of mainly European hospitals, particularly with regard to early identification and standardized management of sepsis, the availability of guidelines, diagnostic and therapeutic infrastructure, and the implementation of QIIs. Further efforts are required to implement a more comprehensive and appropriate quality of care.

Background: The benefit of adjunctive aminoglycosides in the treatment of patients with febrile neutropenia (FN) is controversial. We investigated the incidence of acute kidney injury (AKI) in patients with FN or suspected infection according to empirical amikacin treatment. Methods: This two-centre, retrospective cohort study was conducted at the University Hospitals of Basel (amikacin group) and Bern (non-amikacin group), Switzerland, between 2016 and 2022. Adult patients requiring antibiotic treatment after autologous hematopoietic stem cell transplantation (HSCT) were included. All patients received empiric beta-lactam treatment combined with amikacin in the amikacin group (only University Hospital Basel). The primary endpoint was the incidence of AKI within seven days after the initiation of antibiotic treatment. Results: Overall, 250 patients were included. The majority was male (n = 163, 65.2%) and had a median age of 61 years (interquartile range (IQR) 55 to 67). The median baseline eGFR was similar in both groups (>90 mL/min/1.7 m2). There was no statistically significant difference in the incidence of AKI (4/125 vs. 5/125, p = 1.0). The maximum decline in eGFR from baseline within 7 days was significantly higher in the amikacin group (-4 mL/min/1.7 m2 (IQR 8 to -12) vs. -2 mL/min/1.7 m2 (IQR -7 to -1), p = 0.001). Two patients suffered from an infection with an extended spectrum beta-lactamase producing (ESBL) pathogen. Conclusions: Amikacin treatment did not significantly impact the incidence of AKI in patients undergoing autologous HSCT. The short-term administration of amikacin in patients with normal to high baseline eGFR is safe regarding renal function. However, in a low-resistance setting, the omission of empirical amikacin treatment should be considered.

Background:Blood cultures (BCs) are key diagnostic elements for sepsis patients. Accurate preanalytical procedures are substantial, and results should be available as soon as possible to guide adequate antimicrobial treatment. This study aimed to evaluate BC collection practices and diagnostic capacity across European hospitals. Methods:This cross-sectional survey investigated BC diagnostics in acute care hospitals across 37 European countries in the years 2021 and 2022. Analyses included BC guidelines, collection sites, number of BC sets in emergency departments (EDs), wards, and intensive care units (ICUs). We also examined transfer after collection, the use of on-site vs. external laboratories, opening hours, rapid testing capacity, and turn-around times of BCs processed in microbiology laboratories with different infrastructures. Findings:Responses were collected from 907 hospitals in Europe. BC guidelines were available in 84·4% (741/878) of the hospitals. BCs were preferably collected by multiple-site sampling in EDs (62·7%, 461/735), in wards (64·0%, 513/802) and ICUs (68·5%, 518/756). One BC set was preferred in EDs in 38·4% (270/704), in wards in 40·5% (314/775), and ICUs in 34·9% (261/748). Two BC sets were preferred in EDs in 31·0% (218/704), in wards in 28·1% (218/775), and ICUs in 39·2% (293/748). 48·0% (402/838) of hospitals used on-site and 52·0% (436/838) external microbiology laboratories. Around-the-clock microbiological services were available in 10⋅0% (91/907), and rapid pathogen identification in 43·7% (396/907) of hospitals. Infrastructure with around-the-clock microbiological service and rapid testing was available in 7·4% (62/840) of hospitals, and probability of a final microbiological result within two days was highest in these hospitals compared to hospitals with limited microbiology service (for BC collected on wards: 19·6% vs. 52·7%, Odds Ratio 4·59 [95% CI 2·50-7·79], p < 0·0001). Interpretation:Despite the availability of BC guidelines in many hospitals, current recommendations for BC collection were often neglected. Rapid testing capacity was limited in most microbiological laboratories, and around-the-clock service for BCs was very rare. As delay in results may have a detrimental impact on patient outcomes, strategies to improve these processes are urgently needed. Funding:The European Sepsis Alliance and a grant by Becton and Dickinson.

We present a severe case of hypocomplementemic urticarial vasculitis syndrome (HUVS) and its diagnostic and therapeutic challenges. A 56-year-old male presenting with fever and impaired kidney function was diagnosed with HUVS. Before the initiated treatment was effective, he developed severe colon ischemia, and a subtotal colectomy was required. We discuss other affected organs, such as kidneys, lungs, the heart, and the skin. Pathophysiology is briefly reviewed and the difficulty of overlapping autoimmune diseases is discussed. Treatment continues to be challenging, as there is no consensus about the optimal immunosuppressive therapy.

This study aimed to determine cefazolin target attainment in patients with invasive Staphylococcus aureus (S. aureus) infections and to develop a population pharmacokinetic (PK) model. Adult patients with invasive S. aureus infections treated with cefazolin bolus infusions were included. Unbound and total trough and mid-dose cefazolin concentrations were measured, and strain-specific MICs were determined. The primary outcome was the proportion of patients attaining 100% fT>MIC at all time points evaluated. A population PK model was developed, using non-linear mixed-effects modelling. Overall, 51 patients were included, with a total of 226 unbound and total cefazolin concentrations measured (mean: 4.4 per patient). The median daily dosage in patients with an estimated glomerular filtration rate of >60 mL/min/m2 was 8 g. The median age was 74 years (interquartile range (IQR) 57–82) and 26% were female. A history of chronic kidney disease and acute kidney injury were present in 10/51 (19.6%) and 6/51 (11.7%), respectively. Achievement of 100% fT>MIC occurred in 86% of the patients and decreased to 45% when a target of 100% fT>4xMIC was evaluated. The mean unbound cefazolin fraction was 27.0% (standard deviation (SD) 13.4). Measured and estimated mean cefazolin trough concentrations differed significantly [13.1 mg/L (SD 23.5) vs. 7.4 mg/L (SD 7.9), p < 0.001]. In the population PK model, elevated estimated creatinine clearance and bolus instead of continuous application were covariates for target non-attainment. In conclusion, cefazolin target achievement was high, and the measurement of the unbound cefazolin concentration may be favored. The Monte Carlo simulations indicated that target attainment was significantly improved with continuous infusion.

This study compared SARS-CoV-2 RNA loads at different anatomical sites, and the impact of self-swabbing and food intake. Adult symptomatic patients with SARS-CoV-2 or non-SARS-CoV-2 respiratory tract infection were included between 2021 and 2022. Patients performed a nasal and buccal swab before a professionally collected nasopharyngeal/oropharyngeal swab (NOPS). Buccal swabs were collected fasting and after breakfast in a subgroup of patients. SARS-CoV-2 RNA loads were determined by nucleic acid testing. Swabbing convenience was evaluated using a survey. The median age of 199 patients was 54 years (interquartile range 38–68); 42% were female and 52% tested positive for SARS-CoV-2. The majority of patients (70%) were hospitalized. The mean SARS-CoV-2 RNA load was 6.6 log10 copies/mL (standard deviation (SD), ±1.5), 5.6 log10 copies/mL (SD ± 1.9), and 3.4 log10 copies/mL (SD ± 1.9) in the professionally collected NOPS, and self-collected nasal and buccal swabs, respectively (p < 0.0001). Sensitivity was 96.1% (95% CI 90.4–98.9) and 75.3% (95% CI 63.9–81.8) for the nasal and buccal swabs, respectively. After food intake, SARS-CoV-2 RNA load decreased (p = 0.0006). Buccal swabbing was the preferred sampling procedure for the patients. In conclusion, NOPS yielded the highest SARS-CoV-2 RNA loads. Nasal self-swabbing emerged as a reliable alternative in contrast to buccal swabs. If buccal swabs are used, they should be performed before food intake.

Background/Objective: Narrow-spectrum beta-lactam antibiotics such as benzylpenicillin and flucloxacillin are increasingly used in outpatient parenteral antimicrobial therapy (OPAT) programs to mitigate the adverse effects associated with broad-spectrum antibiotics. These beta-lactams require continuous administration via portable infusion devices during OPAT. However, the use of benzylpenicillin in OPAT requires special consideration because of its limited stability at elevated temperatures. Methods: We tested the benzylpenicillin stability, pH, and degradation of products in elastomeric pumps at different concentrations in saline and in buffered solution containing sodium citrate during a prolonged storage and at high temperatures (seven days at 2–8 °C followed by 24 h at 37 °C). Additionally, drug concentrations during intermittent bolus infusion and during OPAT were determined in five patients. The concentrations and degradation products of benzylpenicillin were measured using liquid chromatography mass spectrometry (LC-MS/MS). Results: Unbuffered benzylpenicillin solutions that were already degraded during refrigerator storage and analyte concentration were not measurable after 8 days. The stability of the buffered solutions was acceptable at all three of the tested concentrations (97.6 ± 1.3%, 96.3 ± 0.8%, and 94.9 ± 1.1% for 10 Mio IU, 20 Mio IU, and 40 Mio IU of benzylpenicillin). The stability was influenced by benzylpenicillin concentration, and several breakdown products were identified. Benzylpenicillin concentrations were measured in five patients during OPAT and ranged from 7.2 to 60 mg/L. Conclusions: Benzylpenicillin buffered with sodium citrate is a safe and convenient option for use in continuous infusions during OPAT and should be favored over broad-spectrum antibiotics. Therapeutic drug monitoring data indicate sufficient to high plasma levels when patients received benzylpenicillin as continuous infusions.

BACKGROUND: Common causes of severely elevated transaminases, especially alanine transaminase, due to liver diseases include drug-induced liver injury and acute viral hepatitis, especially hepatitis E, which can present similarly in clinical practice. Broad differential diagnostic workup in patients with elevated transaminases is required to not overlook the possibility of hepatitis E infection. CASE REPORT: We report on a 65-year-old asymptomatic man who was referred to the Emergency Department from the rehabilitation center due to markedly elevated liver transaminases. Physical examination revealed no jaundice or abdominal pain. Laboratory findings included severely elevated aspartate transaminase, alanine transaminase, and bilirubin levels. He was previously treated with imipenem/cilastatin and clindamycin for a surgical site infection of his jaw after the removal of a squamous cell carcinoma 2 weeks earlier. An ultrasound of the liver was unremarkable. Drug-induced liver injury was suspected, and all potentially hepatotoxic drugs, including antibiotics, were stopped. Due to the rapid and marked increase in liver transaminases, further tests were performed, including testing for hepatitis E. Serum anti-hepatitis E virus immunoglobulin M, immunoglobulin G antibodies, and hepatitis E virus-ribonucleic acid-polymerase chain reaction turned positive, and the diagnosis of hepatitis E was confirmed. Supportive care was applied. Liver transaminases decreased spontaneously. CONCLUSIONS: The diagnostic workup in patients with markedly elevated liver transaminases and suspected drug-induced liver injury should include the screening for hepatitis E. Making the correct diagnosis is crucial given the differing treatment approaches, the implications on further therapy, and the risk of contagion of hepatitis E.

OBJECTIVES:This study aims to assess pharmacodynamic target attainment in critically ill patients and identify factors influencing target attainment and mortality outcomes. METHODS:We analysed data from the DOLPHIN trial. Beta-lactam and ciprofloxacin peak and trough concentration were measured within the first 36 h (T1) after initiation of treatment. The study outcome included the rate of pharmacodynamic target attainment of 100 % ƒT>1xEpidemiological cut-off value (ECOFF) for beta-lactams, and of fAUC0-24h/ECOFF>125 for ciprofloxacin at T1. RESULTS:The target attainment rates were 78.1 % (n = 228/292) for beta-lactams, and 41.5 % (n = 39/94) for ciprofloxacin, respectively. Lower estimated glomerular filtration rate and higher SOFA score were associated with target attainment. In patients receiving beta-lactams, 28-day mortality was significantly higher in patients who attained 100 % ƒT>1xECOFF (28.9 % vs. 12.5 %; p = 0.01). In the multivariate analysis, attainment of 100 % ƒT>4xECOFF, but not 100 % ƒT>1xECOFF, was associated with a higher 28-day mortality (OR 2.70, 95 % CI 1.36-5.48 vs. OR 1.28, 95 % CI 0.53-3.34). CONCLUSIONS:A high rate of target attainment (100 % ƒT>1xECOFF) for beta-lactams and a lower rate for ciprofloxacin was observed. Achieving exposures of 100 % ƒT>4xECOFF was associated with 28-day mortality. The impact of antibiotic target attainment on clinical outcome needs to be a focus of future research.

BackgroundThe Biofire® FilmArray® Meningitis/Encephalitis (ME) PCR panel covers 14 viral, bacterial, and fungal pathogens and has been implemented in many institutions worldwide. Post-marketing studies indicate a reduced sensitivity and overutilization underscoring the need for a more targeted usage. The aim of our study is to describe the utilization of the ME panel and to develop a diagnostic-stewardship based decision rule.MaterialsAdult patients, who underwent CSF analysis with the ME panel between August 2016 and June 2021 at the University Hospital Basel, were included. Demographic, clinical, microbiological, and laboratory data were extracted from the electronic health record. Factors associated with a positive ME panel result were identified, and a decision rule was developed to potentially optimize the diagnostic yield and reduce the number of unnecessary tests.Results1,236 adult patients received at least one panel in the observed period, of whom 106 panels tested positive (8.6%). The most frequently observed pathogens were Varicella Zoster Virus (VZV, 27%), Streptococcus pneumoniae (19%), Enterovirus (16%), Herpes simplex Virus 1/2 (16%), and Human Herpesvirus 6 (HHV-6, 13%). Fever, vomiting, headache, and photophobia were more frequently present in test positive patients as were significantly higher CSF leukocytes and protein concentrations. When simulating a decision rule based on CSF leukocytes and protein concentration, only 35% of all patients would have qualified for a ME panel tests, thereby increasing the positivity rate to 22.7%. 10 of 106 positive ME panels would have been missed, only involving HHV-6 and VZV (6 and 4 cases, respectively). As these subjects were either severely immunocompromised or had clinical features of shingles we propose extending the testing algorithm by including those criteria.ConclusionThe ME panel positivity rate at our institution was similar as previously published. Our results highlight the need for diagnostic-stewardship interventions when utilizing this assay by implementing a stepwise approach based on a limited number of clinical and laboratory features. This decision rule may improve the pretest probability of a positive test result, increase the quality of test utilization, and reduce costs.

Model-informed precision dosing (MIPD) might be used to optimize antibiotic treatment. Procalcitonin (PCT) is a biomarker for severity of infection and response to antibiotic treatment. The aim of this study was to assess the impact of MIPD on the course of PCT and to investigate the association of PCT with pharmacodynamic target (PDT) attainment in critically ill patients. This is a secondary analysis of the DOLPHIN trial, a multicentre, open-label, randomised controlled trial. Patients with a PCT value available at day 1 (T1), day 3 (T3), or day 5 (T5) after randomisation were included. The primary outcome was the absolute difference in PCT concentration at T1, T3, and T5 between the MIPD and the standard dosing group. In total, 662 PCT concentrations from 351 critically ill patients were analysed. There was no statistically significant difference in PCT concentration between the trial arms at T1, T3, or T5. The median PCT concentration was highest in patients who exceeded 10× PDT at T1 [13.15 ng/mL (IQR 5.43–22.75)]. In 28-day non-survivors and in patients that exceeded PDT at T1, PCT decreased significantly between T1 and T3, but plateaued between T3 and T5. PCT concentrations were not significantly different between patients receiving antibiotic treatment with or without MIPD guidance. The potential of PCT to guide antibiotic dosing merits further investigation.

The lateral flow assay (LFA) is an ideal technology for at-home medical diagnostic tests due to its ease of use, cost-effectiveness, and rapid results. Despite these advantages, only few LFAs, such as the pregnancy and COVID-19 tests, have been translated from the laboratory to the homes of patients. To date, the medical applicability of LFAs is limited by the fact that they only provide yes/no answers unless combined with optical readers that are too expensive for at-home applications. Furthermore, LFAs are unable to compete with the state-of-the-art technologies in centralized laboratories in terms of detection limits. To address those shortcomings, we have developed an electrochemical readout procedure to enable quantitative and sensitive LFAs. This technique is based on a voltage-triggered in-situ dissolution of gold nanoparticles, the conventional label used to visualize target-specific signals on the test line in LFAs. Following the dissolution, the amount of gold is measured by electroplating onto an electrode and subsequent electrochemical quantification of the deposited gold. The measured current has a low noise, which achieves superior detection limits compared to optical techniques where background light scattering is limiting the readout performance. In addition, the hardware for the readout was developed to demonstrate translatability towards low-cost electronics.

Background: Acute kidney injury (AKI) as a result of iodinated contrast media (CM) has been linked to CM-induced renal ischemia and toxic effects on endothelial cells (EC). The recombinant human C1 inhibitor (rhC1INH) has been shown to influence EC activation. Methods: Secondary analysis of 74/77 (96%) participants of a double-blind, randomized, and placebo-controlled study that assessed the effect of rhC1INH on AKI. E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM-1), and CC-chemokin-ligand-5 (CCL5) were determined in frozen blood samples over 48 h and analyzed according to the treatment group and renal outcomes. Results: The mean age was 76.7 years, and 37 patients each received rhC1INH and placebo, respectively. In the entire study population, minor differences in median EC activation markers/CCL5 concentrations during the first 48 h compared to baseline were observed (e.g., E-selectin 27.5 ng/mL at baseline vs. 29.7 ng/mL on day 1, CCL5: 17.7 ng/mL at baseline vs. 32.2 ng/mL on day 2). Absolute changes in ICAM-1/E-selectin concentrations correlated with a higher peak change in urinary NGAL concentrations. However, AKI was not associated with significant changes in EC markers/CCL5. Last, no significant differences in serum concentrations of EC activation markers/CCL5 were evident between the placebo and the rhC1INH group. Conclusions: CM administration during coronary angiography only mildly activated ECs within the first 48 h, which does not explain subsequent AKI. The administration of rhC1INH was not associated with a reduction of EC activation or CCL5.