Efficacy of extended infusion of β-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients : Protocol for a randomised, multicentre, open-label, superiority clinical trial (BEATLE)

Altres ajuts: The BEATLE study is a non-commercial, investigator-driven clinical trial funded by the Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0005; RD16/0016/0010) The Spanish Clinical Research Network (SCReN) provides clinical trial data monitoring and oversees pharmacovigilance (PT17/0017/0010).Background: Febrile neutropaenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal β-lactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimised administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematological patients with FN. Methods: A randomised, multicentre, open-label, superiority clinical trial will be performed. Patients with haematological malignancies undergoing chemotherapy or haematopoietic stem-cell transplant and who have FN and receive empirical antibiotic therapy with cefepime, piperacillin-tazobactam or meropenem will be randomised (1:1) to receive the antibiotic by EI (during half the time of the dosing interval) in the study group, or by II (30 min) in the control group. The primary endpoint will be clinical efficacy, defined as defervescence without modifying the antibiotic treatment administered within the first 5 days of therapy. The primary endpoint will be analysed in the intention-to-treat population. The secondary endpoints will be pharmacokinetic/pharmacodynamic (PK/PD) target achievement, bacteraemia clearance, decrease in C-reactive protein, overall (30-day) case-fatality rate, adverse events and development of a population PK model of the BLA studied. Discussion: Data on the usefulness of BLA administration in patients with FN are scant. Only three clinical studies addressing this issue have been published thus far, with contradictory results. Moreover, these studies had some methodological flaws that limit the interpretation of their findings. If this randomised, multicentre, phase IV, open-label, superiority clinical trial validates the hypothesis that the administration of BLA is clinically more effective by EI than by II in haematological patients with FN, then the daily routine management of these high-risk patients could be changed to improve their outcomes. Trial registration: European Clinical Trials Database: EudraCT 2018-001476-37. ClinicalTrials.gov, ID: NCT04233996

Efficacy of extended infusion of beta-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients: protocol for a randomised, multicentre, open-label, superiority clinical trial (BEATLE)

Background: Febrile neutropaenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal beta-lactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimised administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematological patients with FN. Methods: A randomised, multicentre, open-label, superiority clinical trial will be performed. Patients with haematological malignancies undergoing chemotherapy or haematopoietic stem-cell transplant and who have FN and receive empirical antibiotic therapy with cefepime, piperacillin-tazobactam or meropenem will be randomised (1:1) to receive the antibiotic by EI (during half the time of the dosing interval) in the study group, or by II (30 min) in the control group. The primary endpoint will be clinical efficacy, defined as defervescence without modifying the antibiotic treatment administered within the first 5 days of therapy. The primary endpoint will be analysed in the intention-to-treat population. The secondary endpoints will be pharmacokinetic/pharmacodynamic (PK/PD) target achievement, bacteraemia clearance, decrease in C-reactive protein, overall (30-day) case-fatality rate, adverse events and development of a population PK model of the BLA studied. Discussion: Data on the usefulness of BLA administration in patients with FN are scant. Only three clinical studies addressing this issue have been published thus far, with contradictory results. Moreover, these studies had some methodological flaws that limit the interpretation of their findings. If this randomised, multicentre, phase IV, open-label, superiority clinical trial validates the hypothesis that the administration of BLA is clinically more effective by EI than by II in haematological patients with FN, then the daily routine management of these high-risk patients could be changed to improve their outcomes

Clinical efficacy of β-lactam/β-lactamase inhibitor combinations for the treatment of bloodstream infection due to extended-spectrum β-lactamase-producing Enterobacteriaceae in haematological patients with neutropaenia: a study protocol for a retrospective observational study (BICAR)

Introduction: Bloodstream infection (BSI) due to extended-spectrum β-lactamase-producing Gram-negative bacilli (ESBL-GNB) is increasing at an alarming pace worldwide. Although β-lactam/β-lactamase inhibitor (BLBLI) combinations have been suggested as an alternative to carbapenems for the treatment of BSI due to these resistant organisms in the general population, their usefulness for the treatment of BSI due to ESBL-GNB in haematological patients with neutropaenia is yet to be elucidated. The aim of the BICAR study is to compare the efficacy of BLBLI combinations with that of carbapenems for the treatment of BSI due to an ESBL-GNB in this population. Methods and analysis: A multinational, multicentre, observational retrospective study. Episodes of BSI due to ESBL-GNB occurring in haematological patients and haematopoietic stem cell transplant recipients with neutropaenia from 1 January 2006 to 31 March 2015 will be analysed. The primary end point will be case-fatality rate within 30 days of onset of BSI. The secondary end points will be 7-day and 14-day case-fatality rates, microbiological failure, colonisation/infection by resistant bacteria, superinfection, intensive care unit admission and development of adverse events. Sample size: The number of expected episodes of BSI due to ESBL-GNB in the participant centres will be 260 with a ratio of control to experimental participants of 2. Ethics and dissemination: The protocol of the study was approved at the first site by the Research Ethics Committee (REC) of Hospital Universitari de Bellvitge. Approval will be also sought from all relevant RECs. Any formal presentation or publication of data from this study will be considered as a joint publication by the participating investigators and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE). The study has been endorsed by the European Study Group for Bloodstream Infection and Sepsis (ESGBIS) and the European Study Group for Infections in Compromised Hosts (ESGICH)

Income level and regional policies, underlying factors associated with unwarranted variations in conservative breast cancer surgery in Spain

<p>Abstract</p> <p>Background</p> <p>Geographical variations in medical practice are expected to be small when the evidence about the effectiveness and safety of a particular technology is abundant. This would be the case of the prescription of conservative surgery in breast cancer patients. In these cases, when variation is larger than expected by need, socioeconomic factors have been argued as an explanation. Objectives: Using an ecologic design, our study aims at describing the variability in the use of surgical conservative versus non-conservative treatment. Additionally, it seeks to establish whether the socioeconomic status of the healthcare area influences the use of one or the other technique.</p> <p>Methods</p> <p>81,868 mastectomies performed between 2002 and 2006 in 180 healthcare areas were studied. Standardized utilization rates of breast cancer conservative (CS) and non-conservative (NCS) procedures were estimated as well as the variation among areas, using small area statistics. Concentration curves and dominance tests were estimated to determine the impact of income and instruction levels in the healthcare area on surgery rates. Multilevel analyses were performed to determine the influence of regional policies.</p> <p>Results</p> <p>Variation in the use of CS was massive (4-fold factor between the highest and the lowest rate) and larger than in the case of NCS (2-fold), whichever the age group. Healthcare areas with higher economic and instruction levels showed highest rates of CS, regardless of the age group, while areas with lower economic and educational levels yielded higher rates of NCS interventions. Living in a particular Autonomous Community (AC), explained a substantial part of the CS residual variance (up to a 60.5% in women 50 to 70).</p> <p>Conclusion</p> <p>The place where a woman lives -income level and regional policies- explain the unexpectedly high variation found in utilization rates of conservative breast cancer surgery.</p

Riesgo de fractura en la cohorte FRODOS. Estudio comparativo de la aplicación del modelo FRAX® español, francés, inglés y sueco

Fundamento y objetivos: Los estudios sobre validación del FRAX® en España muestran una infravaloración del riesgo de fracturas osteoporóticas principales (FOP) y predicciones más ajustadas para las fracturas femorales (FF). Se ha sugerido que este algoritmo podría mejorarse con datos más concretos de la epidemiología de las fracturas en España. Los objetivos de este trabajo fueron describir el riesgo basal de fracturas según el modelo español FRAX® en las participantes de la cohorte FRODOS y comparar estos datos con la aplicación de otros modelos europeos FRAX® en la misma cohorte.Métodos: Estudio observacional en una cohorte poblacional de 2.968 mujeres postmenopáusicas (59-70 años); se utilizó la versión online desktop de FRAX® para múltiples entradas de datos para calcular los riesgos de FOP y FF a 10 años aplicando los modelos español, francés, inglés y sueco en la misma cohorte.Resultados: El riesgo más bajo correspondió al modelo español: FF: 1,22% (36 fracturas esperadas) y FOP: 5,28% (n=197), mientras que el riesgo más alto fue el del modelo sueco: FF: 3,15% y FOP 13,51% (n=401). Los modelos de Francia y el Reino Unido presentaron valores intermedios. Conclusión: En una cohorte española de 2.968 mujeres postmenopáusicas el riesgo porcentual de fracturas esperadas a 10 años se incrementa con un gradiente de latitud sur-norte al aplicar diferentes modelos FRAX® europeos. Los resultados de incidencia de fracturas en la cohorte FRODOS previsto para los próximos años, confirmarán o no la utilidad del presente análisis

Riesgo de fractura en la cohorte FRODOS. Estudio comparativo de la aplicación del modelo FRAX® español, francés, inglés y sueco.

Background and objectives: Studies on the validation of FRAX® in Spain show an underestimation of the risk of principal osteoporotic fractures (POFs) and more accurate predictions for femoral fractures (FF). It has been suggested that this algorithm may be improved with more specific data on the epidemiology of these fractures in Spain. The objectives of this work were to describe the baseline risk of fractures according to the Spanish FRAX® model in the participants of the FRODOS cohort, and to compare these data with the application of other European models of FRAX® in the same cohort. Methods: Observational study in a population cohort of 2,968 postmenopausal women (59-70 years of age). The online desktop version of FRAX® was used for multiple data entries to calculate the risk of POFs and FFs at 10 years using the Spanish, French, British and Swedish models in the same cohort. Results: The lowest risk corresponded to the Spanish model: FF: 1.22% (36 expected fractures) and POF: 5.28% (n=197), while the highest risk was for the Swedish model: FF: 3.15% and POF 13.51% (n=401). The models for France and the United Kingdom had intermediate values. Conclusion: In a Spanish cohort of 2,968 postmenopausal women the percentage risk of expected fractures at 10 years increased following a south-north latitude gradient when different European FRAX® models were applied. The results for the incidence of fractures on the FRODOS cohort predicted for the coming years will confirm, or not, the usefulness of this analysis.Fundamento y objetivos: Los estudios sobre validación del FRAX® en España muestran una infravaloración del riesgo de fracturas osteoporóticas principales (FOP) y predicciones más ajustadas para las fracturas femorales (FF). Se ha sugerido que este algoritmo podría mejorarse con datos más concretos de la epidemiología de las fracturas en España. Los objetivos de este trabajo fueron describir el riesgo basal de fracturas según el modelo español FRAX® en las participantes de la cohorte FRODOS y comparar estos datos con la aplicación de otros modelos europeos FRAX® en la misma cohorte. Métodos: Estudio observacional en una cohorte poblacional de 2.968 mujeres postmenopáusicas (59-70 años); se utilizó la versión online desktop de FRAX® para múltiples entradas de datos para calcular los riesgos de FOP y FF a 10 años aplicando los modelos español, francés, inglés y sueco en la misma cohorte. Resultados: El riesgo más bajo correspondió al modelo español: FF: 1,22% (36 fracturas esperadas) y FOP: 5,28% (n=197), mientras que el riesgo más alto fue el del modelo sueco: FF: 3,15% y FOP 13,51% (n=401). Los modelos de Francia y el Reino Unido presentaron valores intermedios. Conclusión: En una cohorte española de 2.968 mujeres postmenopáusicas el riesgo porcentual de fracturas esperadas a 10 años se incrementa con un gradiente de latitud sur-norte al aplicar diferentes modelos FRAX® europeos. Los resultados de incidencia de fracturas en la cohorte FRODOS previsto para los próximos años, confirmarán o no la utilidad del presente análisis

Large scale purification of presynaptic plasma membranes from Torpedo marmorata electric organ

The presynaptic plasma membrane (PSPM) of cholinergic nerve terminals was purified from Torpedo electric organ using a large-scale procedure. Up to 500 g of frozen electric organ were fractioned in a single run, leading to the isolation of greater than 100 mg of PSPM proteins. The purity of the fraction is similar to that of the synaptosomal plasma membrane obtained after subfractionation of Torpedo synaptosomes as judged by its membrane-bound acetylcholinesterase activity, the number of Glycera convoluta neurotoxin binding sites, and the binding of two monoclonal antibodies directed against PSPM. The specificity of these antibodies for the PSPM is demonstrated by immunofluorescence microscopy

Large scale purification of presynaptic plasma membranes from Torpedo marmorata electric organ

The presynaptic plasma membrane (PSPM) of cholinergic nerve terminals was purified from Torpedo electric organ using a large-scale procedure. Up to 500 g of frozen electric organ were fractioned in a single run, leading to the isolation of greater than 100 mg of PSPM proteins. The purity of the fraction is similar to that of the synaptosomal plasma membrane obtained after subfractionation of Torpedo synaptosomes as judged by its membrane-bound acetylcholinesterase activity, the number of Glycera convoluta neurotoxin binding sites, and the binding of two monoclonal antibodies directed against PSPM. The specificity of these antibodies for the PSPM is demonstrated by immunofluorescence microscopy