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BACKGROUND: Oral treatment alternatives for febrile urinary tract infections are limited in the era of increasing antimicrobial resistance. We aim to evaluate if the combination of pivmecillinam and amoxicillin/clavulanic acid is non-inferior to current alternatives for step-down therapy in adult patients with febrile urinary tract infection. METHODS: We plan to perform an investigator-initiated non-inferiority trial. Adult hospitalised patients treated with 1-5 days of intravenous antibiotics for acute febrile urinary tract infection caused by extended spectrum beta-lactamase (ESBL) producing Enterobacterales will be randomised 1:1 to either control (7-10 days of either oral ciprofloxacin 500 mg twice daily or oral trimethoprim-sulfamethoxazole 800 mg/160 mg twice daily or intravenous ertapenem 1 g once daily, depending on sex, drug allergy, glomerular filtration rate and susceptibility testing) or intervention (10 days of pivmecillinam 400 mg three times daily and amoxicillin/clavulanic acid 500/125 mg three times daily). The primary outcome will be clinical cure 10 days (+/- 2 days) after antibiotic treatment completion. Clinical cure is defined as being alive with absence of fever and return to non-infected baseline of urinary tract symptoms without additional antibiotic treatment or re-hospitalisation (for urinary tract infection) based on a centralised allocation-blinded structured telephone interview. We plan to recruit 330 patients to achieve 90% power based on a sample size simulation analysis using a two-group comparison, one-sided alpha of 2.5%, an absolute non-inferiority margin of 10% and expecting 93% clinical cure rate and 10% loss to follow-up. The primary endpoint will be analysed using generalised estimated equations and reported as risk difference for both intention-to-treat and per protocol populations. Patients are planned to be recruited from at least 10 centres in Sweden from 2023 to 2026. DISCUSSION: If the combination of pivmecillinam and amoxicillin/clavulanic acid is found to be non-inferior to the control drugs there are potential benefits in terms of tolerability, frequency of interactions, outpatient treatment, side effects, nosocomial infections and drive for further antimicrobial resistance compared to existing drugs. TRIAL REGISTRATION: NCT05224401. Registered on February 4, 2022.

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Background and Aims: Transient elastography (TE) has largely replaced liver biopsy to evaluate fibrosis stage and cirrhosis in chronic hepatitis C. Previous studies have reported excellent reliability of TE but agreement metrics have not been reported. This study aimed to assess interrater agreement and reliability of repeated TE measurements. Methods: Two operators performed TE independently, directly after each other. The primary outcome was disagreement, defined as a difference in TE results between operators of ≥33%, as well as the smallest detectable change, SDC95 (i.e., the difference between measurements needed to state with 95% certainty that there is a difference in underlying stiffness). Secondary outcomes included reliability, measured as intraclass correlation (ICC), and patient and examination characteristics associated with the agreement. Results: In total, 65 patients were included, with a mean liver stiffness of 9.7 kPa. Of these, 21 (32%) had a disagreement in TE results of ≥33% between the two operators. The SDC95 on the log scale was 1.97, indicating that an almost twofold increase or decrease in liver stiffness would be required to confidently represent a change in the underlying fibrosis. Reliability, estimated using the ICC, was acceptable at 0.86. In a post hoc analysis, fasting less than 5 h before TE was associated with a higher degree of disagreement (48% vs. 19%, p = 0.03). Conclusions: In our clinical setting, interrater agreement in directly repeated TE measurements was surprisingly low. It is essential to further investigate the reliability and agreement of TE to determine its validity and usefulness.

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BACKGROUND: The aim of this study was to provide a descriptive account of carbapenem resistance and risk factors for mortality from invasive Acinetobacter infections in the south of Sweden. METHODS: Blood isolates with growth of Acinetobacter species between 2010 and 2019 in Skåne county were subtyped using MALDI-TOF and subjected to susceptibility testing against clinically relevant antibiotics. Association between risk factors and 30-day mortality were analysed in univariate and multivariate logistic regression models. RESULTS: There were 179 bacteraemia episodes in 176 patients included in the study. The 30-day all-cause mortality was 16%. In all, two percent of Acinetobacter strains were carbapenem resistant. Independent risk factors associated with 30-day mortality in the multivariate regression model were Acinetobacter growth in all blood cultures drawn at the day of bacteraemia onset (OR 5.0, 95% CI: 1.8 to 13.7, p= 0.002), baseline functional capacity (1-4 points, OR 2.0, 95% CI: 1.2 to 3.4, p= 0.010) and correct empiric antibiotics at time of culture (OR 3.5 95% CI: 1.0 to 11.8, p= 0.045). CONCLUSION: This study on Acinetobacter bacteraemia in South Sweden found low 30-day mortality and low carbapenem-resistance rates compared to previous international studies which may be due to a higher rate of contaminant findings.

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BACKGROUND: Transrectal prostate biopsy (TRbx) transfers colonic bacteria into prostatic tissue, potentially causing infectious complications, including sepsis. Our objective was to determine whether biopsy needle shape, surface properties and sampling mechanism affect the number of bacteria transferred through the colon wall, and evaluate a novel needle with improved properties. METHODS: The standard Tru-Cut biopsy needle used today was evaluated for mechanisms of bacterial transfer in a pilot study. A novel Tru-Cut needle (Forsvall needle prototype) was developed. TRbx was simulated using human colons ex-vivo. Four subtypes of the prototype needle were compared with a standard Tru-Cut needle (BARD 18 G). Prototype and standard needles were used to puncture 4 different colon specimens in 10 randomized sites per colon. Needles were submerged into culture media to capture translocated bacteria. The media was cultured on blood agar and then the total amount of transferred bacteria was calculated for each needle. The primary outcome measure was the percent reduction of bacteria translocated by the prototype needles relative to the standard needle. Secondary outcome measures were the effects of tip design and coating on the percent reduction of translocated bacteria. RESULTS: Prototype needles reduced the number of translocated bacteria by, on average, 96.0% (95% confidence interval 93.0-97.7%; p < 0.001) relative to the standard needle. This percent reduction was not significantly affected by prototype needle tip style or surface coating. CONCLUSIONS: The Forsvall needle significantly reduces colonic bacterial translocation, suggesting that it could reduce infectious complications in prostate biopsy. A clinical trial has been initiated.

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BACKGROUND: Patients with COVID-19 and hypoxaemia despite conventional low-flow oxygen therapy are often treated with high-flow nasal cannula (HFNC) in line with international guidelines. Oxygen delivery by helmet continuous positive airway pressure (CPAP) is a feasible option that enables a higher positive end-expiratory pressure (PEEP) and may theoretically reduce the need for intubation compared to HFNC but direct comparative evidence is lacking. METHODS: We plan to perform an investigator-initiated, pragmatic, randomised trial at an intermediate-level COVID-19 cohort ward in Helsingborg Hospital, southern Sweden. We have estimated a required sample size of 120 patients randomised 1:1 to HFNC or Helmet CPAP to achieve 90% power to detect superiority at a 0.05 significance level regarding the primary outcome of ventilator free days (VFD) within 28 days using a Mann-Whitney U test. Patient recruitment is planned to being June 2020 and be completed in the first half of 2021. DISCUSSION: We hypothesise that the use of Helmet CPAP will reduce the need for invasive mechanical ventilation compared to the use of HFNC without having a negative effect on survival. This could have important implications during the current COVID-19 epidemic. TRIAL REGISTRATION: ClinicalTrials.gov NCT04395807 . Registered on 20 May 2020.

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BACKGROUND: Heparin-binding protein (HBP) is a neutrophil-derived pro-inflammatory protein, an inducer of endothelial dysfunction and vascular permeability and a promising prognostic biomarker in sepsis. This exploratory study aims to describe the kinetics of plasma HBP during septic shock and investigate an association between repeated measures of HBP concentration and cardiovascular organ dysfunction severity. METHODS: We included patients at or above 18 years with suspected septic shock on admission to the intensive care unit (ICU) during 2014 and 2016 to 2018. Plasma samples were collected from ICU admission and every 4 h for 72 h or until death or ICU discharge and batch analysed for HBP. Mean arterial blood pressure (MAP) and noradrenaline dose (NA dose) were recorded at each sampling time point, and systemic vascular resistance index (SVRI) was recorded when available from non-invasive monitoring. The association between HBP, NA dose, MAP and SVRI was assessed respectively using mixed-effects linear regression models. Procalcitonin (PCT) was used as a comparator. RESULTS: A total of 24 patients were included. The kinetics of plasma HBP was highly variable over time, with occasional >2-fold increases and decreases in between 4-h measurements. Every 100 ng/mL increase in HBP corresponded to a 30% increase in NA dose in a crude model (95% CI 3 to 60%, p = 0.03, nobs = 340), a 1.4-mmHg decrease in MAP in an adjusted model (95% CI - 1 to - 2.3 mmHg, p = 0.04) or a 99 dyne s cm-5 m-2 decrease in SVRI in another adjusted model (95% CI - 36 to - 162, p = 0.002, npat = 13). PCT had a stronger association to NA dose than HBP in a crude model but was not significantly associated to NA dose, MAP or SVRI in any time-adjusted model. CONCLUSIONS: Plasma HBP displayed a highly variable kinetic pattern during septic shock and was significantly associated to cardiovascular organ dysfunction severity over time.

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BACKGROUND: To allow early identification of patients at risk of sepsis in the emergency department (ED), a variety of risk stratification scores and/or triage systems are used. The first aim of this study was to develop a risk stratification score for sepsis based upon vital signs and biomarkers using a statistical approach. Second, we aimed to validate the Rapid Emergency Triage and Treatment System (RETTS) for sepsis. RETTS combines vital signs with symptoms for risk stratification. METHODS: We retrospectively analysed data from two prospective, observational, multicentre cohorts of patients from studies of biomarkers in ED. A candidate risk stratification score called Sepsis Heparin-binding protein-based Early Warning Score (SHEWS) was constructed using the Least Absolute Shrinkage and Selector Operator (LASSO) method. SHEWS and RETTS were compared to National Early Warning Score 2 (NEWS2) for infection-related organ dysfunction, intensive care or death within the first 72h after admission (i.e. sepsis). RESULTS: 506 patients with a diagnosed infection constituted cohort A, in which SHEWS was derived and RETTS was validated. 435 patients constituted cohort B of whom 184 had a diagnosed infection where both scores were validated. In both cohorts (A and B), AUC for infection-related organ dysfunction, intensive care or death was higher for NEWS2, 0.80 (95% CI 0.76-0.84) and 0.69 (95% CI 0.63-0.74), than RETTS, 0.74 (95% CI 0.70-0.79) and 0.55 (95% CI 0.49-0.60), p = 0.05 and p <0.01, respectively. SHEWS had the highest AUC, 0.73 (95% CI 0.68-0.79) p = 0.32 in cohort B. CONCLUSIONS: Even with a statistical approach, we could not construct better risk stratification scores for sepsis than NEWS2. RETTS was inferior to NEWS2 for screening for sepsis.

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Early administration of antibiotics is associated with better survival in sepsis, thus screening and early detection for sepsis is of clinical importance. Current risk stratification scores used for bedside detection of sepsis, for example Quick Sequential Organ Failure Assessment (qSOFA) and National Early Warning Score 2 (NEWS2), are primarily validated for death and intensive care. The primary aim of this study was to compare the diagnostic accuracy of qSOFA and NEWS2 for a composite outcome of sepsis with organ dysfunction, infection-related mortality within <72 h, or intensive care due to an infection. Retrospective analysis of data from two prospective, observational, multicentre, convenience trials of sepsis biomarkers at emergency departments were performed. Cohort A consisted of 526 patients with a diagnosed infection, 288 with the composite outcome. Cohort B consisted of 645 patients, of whom 269 had a diagnosed infection and 191 experienced the composite outcome. In Cohort A and B, NEWS2 had significantly higher area under receiver operating characteristic curve (AUC), 0.80 (95% CI 0.75-0.83) and 0.70 (95% CI 0.65-0.74), than qSOFA, AUC 0.70 (95% CI 0.66-0.75) and 0.62 (95% CI 0.57-0.67) p < 0.01 and, p = 0.02, respectively for the composite outcome. NEWS2 was superior to qSOFA for screening for sepsis with organ dysfunction, infection-related mortality or intensive care due to an infection both among infected patients and among undifferentiated patients at emergency departments.

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OBJECTIVE: Rapid and early detection of patients at risk to develop sepsis remains demanding. Heparin-binding protein (HBP) has previously demonstrated good prognostic properties in detecting organ dysfunction among patients with suspected infections. This study aimed to evaluate the plasma levels of HBP as a prognostic biomarker for infection-induced organ dysfunction among patients seeking medical attention at the emergency department. DESIGN: Prospective, international multicenter, convenience sample study. SETTING: Four general emergency departments at academic centers in Sweden, Switzerland, and Canada. PATIENTS: All emergency encounters among adults where one of the following criteria were fulfilled: respiratory rate >25 breaths per minute; heart rate >120 beats per minute; altered mental status; systolic blood pressure <100 mm Hg; oxygen saturation <90% without oxygen; oxygen saturation <93% with oxygen; reported oxygen saturation <90%. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: A total of 524 emergency department patients were prospectively enrolled, of these 236 (45%) were eventually adjudicated to have a noninfectious disease. Three hundred forty-seven patients (66%) had or developed organ dysfunction within 72 h, 54 patients (10%) were admitted to an intensive care unit, and 23 patients (4%) died within 72 h. For the primary outcome, detection of infected-related organ dysfunction within 72 h, the area under the receiver operating curve (AUC) for HBP was 0.73 (95% CI 0.68-0.78) among all patients and 0.82 (95% CI 0.76-0.87) among patients confidently adjudicated to either infection or no infection. Against the secondary outcome, infection leading to admittance to the ICU, death or a persistent high SOFA-score due to an infection (SOFA-score ≥5 at 12-24 h) HBP had an AUC of 0.87 (95% CI 0.79-0.95) among all patients and 0.88 (95% CI 0.77-0.99) among patients confidently adjudicated to either infection or noninfection. CONCLUSIONS: Among patients at the emergency department, HBP demonstrated good prognostic and discriminatory properties in detecting the most severely ill patients with infection.

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BACKGROUND: Sepsis-related acute kidney injury (AKI) accounts for major morbidity and mortality among the critically ill. Heparin-binding protein (HBP) is a promising biomarker in predicting development and prognosis of severe sepsis and septic shock that has recently been proposed to be involved in the pathophysiology of AKI. The objective of this study was to investigate the added predictive value of measuring plasma HBP on admission to the intensive care unit (ICU) regarding the development of septic AKI. METHODS: We included 601 patients with severe sepsis or septic shock from the prospective, observational FINNAKI study conducted in seventeen Finnish ICUs during a 5-month period (1 September 2011-1 February 2012). The main outcome measure was the development of KDIGO AKI stages 2-3 from 12 h after admission up to 5 days. Statistical analysis for the primary endpoint included construction of a clinical risk model, area under the receiver operating curve (ROC area), category-free net reclassification index (cfNRI) and integrated discrimination improvement (IDI) with 95% confidence intervals (95% CI). RESULTS: Out of 511 eligible patients, 101 (20%) reached the primary endpoint. The addition of plasma HBP to a clinical risk model significantly increased ROC area (0.82 vs. 0.78, p = 0.03) and risk classification scores: cfNRI 62.0% (95% CI 40.5-82.4%) and IDI 0.053 (95% CI 0.029-0.075). CONCLUSIONS: Plasma HBP adds predictive value to known clinical risk factors in septic AKI. Further studies are warranted to compare the predictive performance of plasma HBP to other novel AKI biomarkers.