Effectiveness of fosfomycin trometamol as oral step-down therapy for bacteraemic urinary tract infections due to MDR Escherichia coli: a post hoc analysis of the FOREST randomized tria

©2023 The Author(s). This manuscript version is made available under the CC-BY 4.0 license http://creativecommons.org/licenses/by/4.0/. This document is the Published, version of a Published Work that appeared in final form in Journal of Antimicrobial Chemotherapy. To access the final edited and published work see https://doi.org/10.1093/jac/dkad147Background: Fosfomycin is a potentially attractive option as step-down therapy for bacteraemic urinary tract infections (BUTI), but available data are scarce. Our objective was to compare the effectiveness and safety of fosfomycin trometamol and other oral drugs as step-down therapy in patients with BUTI due to MDR Escherichia coli (MDR-Ec). Methods: Participants in the FOREST trial (comparing IV fosfomycin with ceftriaxone or meropenem for BUTI caused by MDR-Ec in 22 Spanish hospitals from June 2014 to December 2018) who were stepped-down to oral fosfomycin (3 g q48h) or other drugs were included. The primary endpoint was clinical and microbiological cure (CMC) 5–7 days after finalization of treatment. A multivariate analysis was performed using logistic regression to estimate the association of oral step-down with fosfomycin with CMC adjusted for confounders. Results: Overall, 61 patients switched to oral fosfomycin trometamol and 47 to other drugs (cefuroxime axetil, 28; amoxicillin/clavulanic acid and trimethoprim/sulfamethoxazole, 7 each; ciprofloxacin, 5) were included. CMC was reached by 48/61 patients (78.7%) treated with fosfomycin trometamol and 38/47 (80.9%) with other drugs (difference, −2.2; 95% CI: −17.5 to 13.1; P = 0.38). Subgroup analyses provided similar results. Relapses occurred in 9/61 (15.0%) and 2/47 (4.3%) of patients, respectively (P = 0.03). The adjusted OR for CMC was 1.11 (95% CI: 0.42–3.29, P = 0.75). No relevant differences in adverse events were seen. Conclusions: Fosfomycin trometamol might be a reasonable option as step-down therapy in patients with BUTI due to MDR-Ec but the higher rate of relapses would need further assessment

Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections

IMPORTANCE The consumption of broad-spectrum drugs has increased as a consequence of the spread of multidrug-resistant (MDR) Escherichia coli. Finding alternatives for these infections is critical, for which some neglected drugs may be an option. OBJECTIVE To determine whether fosfomycin is noninferior to ceftriaxone or meropenem in the targeted treatment of bacteremic urinary tract infections (bUTIs) due to MDR E coli. DESIGN, SETTING, AND PARTICIPANTS This multicenter, randomized, pragmatic, open clinical trial was conducted at 22 Spanish hospitals from June 2014 to December 2018. Eligible participants were adult patients with bacteremic urinary tract infections due to MDR E coli; 161 of 1578 screened patients were randomized and followed up for 60 days. Data were analyzed in May 2021. INTERVENTIONS Patients were randomized 1 to 1 to receive intravenous fosfomycin disodium at 4 g every 6 hours (70 participants) or a comparator (ceftriaxone or meropenem if resistant; 73 participants) with the option to switch to oral fosfomycin trometamol for the fosfomycin group or an active oral drug or pa renteral ertapenem for the comparator group after 4 days. MAIN OUTCOMES AND MEASURES The primary outcome was clinical and microbiological cure (CMC) 5 to 7 days after finalization of treatment; a noninferiority margin of 7% was considered. RESULTS Among 143 patients in the modified intention-to-treat population (median [IQR] age, 72 [62-81] years; 73 [51.0%] women), 48 of 70 patients (68.6%) treated with fosfomycin and 57 of 73 patients (78.1%) treated with comparators reached CMC (risk difference, -9.4 percentage points; 1-sided 95% CI, -21.5 to infinity percentage points; P = .10). While clinical or microbiological failure occurred among 10 patients (14.3%) treated with fosfomycin and 14 patients (19.7%) treated with comparators (risk difference, -5.4 percentage points; 1-sided 95% CI. -infinity to 4.9; percentage points; P = .19), an increased rate of adverse event-related discontinuations occurred with fosfomycin vs comparators (6 discontinuations [8.5%] vs 0 discontinuations; P = .006). In an exploratory analysis among a subset of 38 patients who underwent rectal colonization studies, patients treated with fosfomycin acquired a new ceftriaxone-resistant or meropenem-resistant gram-negative bacteria at a decreased rate compared with patients treated with comparators (0 of 21 patients vs 4 of 17 patients [23.5%]; 1-sided P = .01). CONCLUSIONS AND RELEVANCE This study found that fosfomycin did not demonstrate noninferiority to comparators as targeted treatment of bUTI from MDR E coli; this was due to an increased rate of adverse event-related discontinuations. This finding suggests that fosfomycin may be considered for selected patients with these infections

Effectiveness of fosfomycin trometamol as oral step-down therapy for bacteraemic urinary tract infections due to MDR Escherichia coli: a post hoc analysis of the FOREST randomized trial

© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.[Background] Fosfomycin is a potentially attractive option as step-down therapy for bacteraemic urinary tract infections (BUTI), but available data are scarce. Our objective was to compare the effectiveness and safety of fosfomycin trometamol and other oral drugs as step-down therapy in patients with BUTI due to MDR Escherichia coli (MDR-Ec).[Methods] Participants in the FOREST trial (comparing IV fosfomycin with ceftriaxone or meropenem for BUTI caused by MDR-Ec in 22 Spanish hospitals from June 2014 to December 2018) who were stepped-down to oral fosfomycin (3 g q48h) or other drugs were included. The primary endpoint was clinical and microbiological cure (CMC) 5–7 days after finalization of treatment. A multivariate analysis was performed using logistic regression to estimate the association of oral step-down with fosfomycin with CMC adjusted for confounders.[Results] Overall, 61 patients switched to oral fosfomycin trometamol and 47 to other drugs (cefuroxime axetil, 28; amoxicillin/clavulanic acid and trimethoprim/sulfamethoxazole, 7 each; ciprofloxacin, 5) were included. CMC was reached by 48/61 patients (78.7%) treated with fosfomycin trometamol and 38/47 (80.9%) with other drugs (difference, −2.2; 95% CI: −17.5 to 13.1; P = 0.38). Subgroup analyses provided similar results. Relapses occurred in 9/61 (15.0%) and 2/47 (4.3%) of patients, respectively (P = 0.03). The adjusted OR for CMC was 1.11 (95% CI: 0.42–3.29, P = 0.75). No relevant differences in adverse events were seen.[Conclusions] Fosfomycin trometamol might be a reasonable option as step-down therapy in patients with BUTI due to MDR-Ec but the higher rate of relapses would need further assessment.This work was supported by Plan Nacional de I + D + i 2013–2016, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades, co-funded by European Development Regional Fund ‘A way to achieve Europe’, Operative Program Intelligence Growth 2014–2020, via the following grants: PI 13/01282; CIBERINFEC (CB21/13/00002; 00006; 00009; 00012; 00049; 00054; 00068; 00084; 00099); and Spanish Clinical Research and Clinical Trials Platform (SCReN, PT17/0017/0012).Peer reviewe

Risk factors for infections caused by carbapenem-resistant Enterobacterales: an international matched case-control-control study (EURECA)

Cases were patients with complicated urinary tract infection (cUTI), complicated intraabdominal (cIAI), pneumonia or bacteraemia from other sources (BSI-OS) due to CRE; control groups were patients with infection caused by carbapenem-susceptible Enterobacterales (CSE), and by non-infected patients, respectively. Matching criteria included type of infection for CSE group, ward and duration of hospital admission. Conditional logistic regression was used to identify risk factors. Findings Overall, 235 CRE case patients, 235 CSE controls and 705 non-infected controls were included. The CRE infections were cUTI (133, 56.7%), pneumonia (44, 18.7%), cIAI and BSI-OS (29, 12.3% each). Carbapenemase genes were found in 228 isolates: OXA-48/like, 112 (47.6%), KPC, 84 (35.7%), and metallo-beta-lactamases, 44 (18.7%); 13 produced two. The risk factors for CRE infection in both type of controls were (adjusted OR for CSE controls; 95% CI; p value) previous colonisation/infection by CRE (6.94; 2.74-15.53; <0.001), urinary catheter (1.78; 1.03-3.07; 0.038) and exposure to broad spectrum antibiotics, as categorical (2.20; 1.25-3.88; 0.006) and time-dependent (1.04 per day; 1.00-1.07; 0.014); chronic renal failure (2.81; 1.40-5.64; 0.004) and admission from home (0.44; 0.23-0.85; 0.014) were significant only for CSE controls. Subgroup analyses provided similar results. Interpretation The main risk factors for CRE infections in hospitals with high incidence included previous coloni-zation, urinary catheter and exposure to broad spectrum antibiotics

Risk factors for infections caused by carbapenem-resistant Enterobacterales: an international matched case-control-control study (EURECA)

© 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).[Background] Data on risk factors for carbapenem-resistant Enterobacterales (CRE) with wider applicability are needed to inform preventive measures and efficient design of randomised trials.[Methods] An international matched case-control-control study was performed in 50 hospitals with high CRE incidence from March 2016 to November 2018 to investigate different aspects of infections caused by CRE (NCT02709408). Cases were patients with complicated urinary tract infection (cUTI), complicated intraabdominal (cIAI), pneumonia or bacteraemia from other sources (BSI-OS) due to CRE; control groups were patients with infection caused by carbapenem-susceptible Enterobacterales (CSE), and by non-infected patients, respectively. Matching criteria included type of infection for CSE group, ward and duration of hospital admission. Conditional logistic regression was used to identify risk factors.[Findings] Overall, 235 CRE case patients, 235 CSE controls and 705 non-infected controls were included. The CRE infections were cUTI (133, 56.7%), pneumonia (44, 18.7%), cIAI and BSI-OS (29, 12.3% each). Carbapenemase genes were found in 228 isolates: OXA-48/like, 112 (47.6%), KPC, 84 (35.7%), and metallo-β-lactamases, 44 (18.7%); 13 produced two. The risk factors for CRE infection in both type of controls were (adjusted OR for CSE controls; 95% CI; p value) previous colonisation/infection by CRE (6.94; 2.74–15.53; <0.001), urinary catheter (1.78; 1.03–3.07; 0.038) and exposure to broad spectrum antibiotics, as categorical (2.20; 1.25–3.88; 0.006) and time-dependent (1.04 per day; 1.00–1.07; 0.014); chronic renal failure (2.81; 1.40–5.64; 0.004) and admission from home (0.44; 0.23–0.85; 0.014) were significant only for CSE controls. Subgroup analyses provided similar results.[Interpretation] The main risk factors for CRE infections in hospitals with high incidence included previous colonization, urinary catheter and exposure to broad spectrum antibiotics.The study was funded by the Innovative Medicines Initiative Joint Undertaking (https://www.imi.europa.eu/) under Grant Agreement No. 115620 (COMBACTE-CARE).Peer reviewe

Uso de los estados de cambio para el análisis del desplazamiento al centro educativo

Physical inactivity among children and adolescents is a global problem. Active commuting to and from school (ACS) is presented as a healthy alternative to promote physical activity in this population. The Transtheoretical Model of Change (TMC) is used to understand and promote behavioral change in relation to physical activity. The model is based on five stages: pre-contemplation, contemplation, preparation, action, and maintenance. The objective of the study was to analyze the relationship between the type of commuting and stages of change (SoC), taking into account sex and environment in which adolescents live. This study comprised a sample of 547 participants with a mean age of 15.99 years, who lived in urban, semi-urban, and rural areas. A questionnaire was used to identify the modes of transportation to/from the educational center and the SoC for active modes of commuting. Descriptive statistics and analyses of the differences among different environments with cross tables were used. There were no significant differences by sex in the mode of commuting to school. According to the priority mode of commuting, more than half of the participants (59.59%) traveled actively and 40.4% did so motorized. Significant relationships were found between the mode of commuting to the CE and the SoC, between the mode of commuting and the type of environment, and between the environment and the SoC. The main results allow us to conclude that active commuting among participating adolescents is related to the maintenance stage and, on the contrary, motorized transport is related to the pre-contemplation stage.La falta de actividad física en niños y adolescentes es un problema global. El desplazamiento activo al centro educativo (DACE) se presenta como una alternativa saludable para promover la actividad física en esta población. El Modelo Transteórico del Cambio (MTC) es utilizado para comprender y promover el cambio de comportamiento en relación a la actividad física. El modelo se basa en cinco etapas: precontemplación, contemplación, preparación, acción y mantenimiento. El objetivo del estudio fue analizar la relación entre el desplazamiento activo y los estados de cambio (EDC) teniendo en cuenta el sexo y el entorno en el que habitan los adolescentes. Este estudio contó con una muestra de 547 participantes con una edad media de 15,99 años, estos habitaban en áreas urbanas, semiurbanas y rurales. Se utilizó un cuestionario para la identificación de los modos de transporte al/desde el centro educativo y los EDC para el modo de desplazamiento activo. Se emplearon estadísticos descriptivos con tablas cruzadas para analizar las diferencias por entorno. No hubo diferencias significativas por sexo en el modo de desplazamiento. Según el modo de desplazamiento prioritario, más de la mitad de los participantes (59,59%) se desplazaban de forma activa y un 40,4% lo hacían de forma motorizada. Se hallaron relaciones significativas entre el modo de desplazamiento al CE y los EDC, entre el modo de desplazamiento y el tipo de entorno, y entre el entorno y los EDC. Los principales resultados permiten concluir que el transporte activo entre los adolescentes participantes se relaciona con el estado de mantenimiento y, por el contrario, el transporte motorizado se relaciona con el estado de precontemplación

Active commuting to school and the enviromental, social and lifestyle influences in spanish adolescentes: Paco y Paca (Pedal and walk to school, Pedal and walk home) Protocol study

Objetivos: Analizar los medios de desplazamiento escolar y las influencias del entorno físico y psicosocial (influencia familiar y otras influencias significativas como la de los iguales) así como la influencia de otros hábitos del estilo de vida (patrones de sueño, horas de pantallas y aspectos nutricionales) en el desplazamiento al/desde el centro educativo de adolescentes de Toledo, Granada, Sevilla y Valencia. El Proyecto PACOyPACA consiste en un estudio transversal. La muestra estuvo formada por estudiantes de 3º de Educación Secundaria Obligatoria (ESO) de 4 ciudades españolas (Toledo, Granada, Valencia y Sevilla) y por sus padres. Para garantizar la representatividad de la muestra, se seleccionaron aleatoriamente centros educativos atendiendo al nivel socioeconómico (NSE) y el índice de “caminabilidad” del vecindario en el que se ubican. El proyecto PACOyPACA servirá para adquirir conciencia sobre el estado actual del desplazamiento activo al centro educativo (DACE) en la adolescencia y los posibles factores que influyen sobre él. Estos conocimientos permitirán una mejor interpretación de la situación actual y será útil para el diseño y creación de estrategias con el fin de fomentar el DACE. Dichas estrategias permitirán la creación de una guía para impulsar iniciativas utilizando el centro educativo como punto clave de la acciónObjectives: To analyse the means of school commuting and the influences of the physical and psychosocial environment (family influence and other significant influences such as that of peers) as well as the influence of other lifestyle habits (sleep patterns, hours of screens and aspects nutrition) when commuting to/from school for adolescents in Toledo, Granada, Seville and Valencia. The PACOyPACA Project consists of a cross-sectional study. The sample consisted of 3rd year Compulsory Secondary Education (ESO) students from 4 Spanish cities (Toledo, Granada, Valencia, and Seville) and their parents. To guarantee the representativeness of the sample, schools were randomly selected based on the socioeconomic level (SES) and the "walkability" index of the neighbourhood in which they are located. The PACOyPACA project will serve to raise awareness about the current state of active commuting to school (ACS) in adolescence and the possible factors that influence it. This knowledge will allow a better interpretation of the current situation and will be useful for the design and creation of strategies in order to promote ACS. These strategies will allow the creation of a National guide to promote initiatives using schools as a key point of action

Lifestyle Behaviours Profile of Spanish Adolescents Who Actively Commute to School

The aim of this study was to study different ‘healthy profiles’ through the impact of multiple lifestyle behaviours (sleep patterns, screen time and quality diet) on active commuting to school (ACS) in adolescents. Sixteen secondary schools from four Spanish cities were randomly selected. All participants filled in an “Ad-Hoc” questionnaire to measure their mode of commuting and distance from home to school and their lifestyle behaviours. A multivariate logistic regression model was performed to analyse the main predictor variables of ACS. The final sample was 301 adolescents (50.2% girls; mean age ± SD: 14.9 ± 0.48 years). The percentage of ACS was 64.5%. Multiple logistic regressions showed: boys were more active commuters than girls [OR = 2.28 (CI 95%: 1.12–4.64); p = 0.02]; adolescents who lived farther had lower probability to ACS [OR = 0.74 (CI 95%: 0.69–0.80); p p = 0.04], while with each hour of sleep, the odds of ACS was reduced [OR = 0.51 (CI 95%: 0.30–0.89); p = 0.02]; higher odds were shown to ACS in adolescents who have more adherence to MD [OR = 1.16(CI 95%: 1.00–1.33); p = 0.05]; and habitual breakfast consumption was inversely associated with ACS [OR = 0.41 (CI: 95%: 0.18–0.96); p = 0.04]. ACS was associated with being a boy, living at a shorter distance to school, a daily sleep time ≥ 8 h and presented a higher adherence to MD

Guía PACO y PACA (Pedalea y Anda al COle y Pedalea y Anda a CAsa)

La guía está orientada al diseño de estrategias para promover ir y volver de los centros educativos andando o en bicicleta. Busca la promoción de actividad física a través del transporte activo en la comunidad educativa con una orientación hacia la mejora de la salud y la calidad de vida de la población. Su objetivo es dotar a los centros educativos y entidades locales de las herramientas necesarias para el diseño, creación, implementación y evaluación de proyectos de promoción de desplazamientos activos, saludables, seguros y sostenibles al centro educativo (como caminos escolares, cursos de conducción de bicicleta, organización de pedibús o ciclobús, etc.), a través de la elaboración de un plan de acción global integrado y mediante la creación de una red de apoyo, formada por todos los componentes que participan en el entorno educativo de nuestros jóvenes (familias, docentes, personal directivo de centros educativos, entidades locales y agentes sociales). De esta manera se pretende incorporar el transporte activo como parte del desplazamiento diario y facilitar la consecución de las recomendaciones de actividad física de forma sencilla y asequible e integradas en la vida diaria, para promover un estilo de vida saludable. Esta dirigida por tanto a los centros educativos y entidades locales que deseen poner en marcha una estrategia y/o plan para favorecer el transporte activo (caminar e ir en bici), seguro, saludable y sostenible al centro educativo, así como a todos aquellos agentes comprometidos con la actividad física y la promoción de la salud en el ámbito local. Los autores aconsejan que se lea la guía como un instrumento orientativo para aplicarlo de forma flexible en cada contexto particular y se entienda como un documento vivo, un “cuaderno de bitácora”, que pueda ser trabajado en las distintas instituciones, que se pueda compartir con la comunidad y con los distintos agentes, y así vertebrar un plan, programas o conjunto de acciones en el entorno educativo y local, con la suma de todos los recursos comunitarios disponibles