Attributable mortality of infections caused by carbapenem-resistant Enterobacterales: results from a prospective, multinational case-control-control matched cohorts study (EURECA).

OBJECTIVES: To assess the mortality attributable to infections caused by carbapenem-resistant Enterobacterales (CRE) and to investigate the effect of clinical management on differences in observed outcomes in a multinational matched cohort study. METHODS: A prospective matched-cohorts study (NCT02709408) was performed in 50 European hospitals from March 2016 to November 2018. The main outcome was 30-day mortality with an active post-discharge follow-up when applied. The CRE cohort included patients with complicated urinary tract infections, complicated intra-abdominal infections, pneumonia, or bacteraemia from other sources because of CRE. Two control cohorts were selected: patients with infection caused by carbapenem-susceptible Enterobacterales (CSE) and patients without infection. Matching criteria included type of infection for the CSE group, hospital ward of CRE detection, and duration of hospital admission up to CRE detection. Multivariable and stratified Cox regression was applied. RESULTS: The cohorts included 235 patients with CRE infection, 235 patients with CSE infection, and 705 non-infected patients. The 30-day mortality (95% CI) was 23.8% (18.8-29.6), 10.6% (7.2-15.2), and 8.4% (6.5-10.6), respectively. The difference in 30-day mortality rates between patients with CRE infection when compared with patients with CSE infection was 13.2% (95% CI, 6.3-20.0), (HR, 2.57; 95% CI, 1.55-4.26; p < 0.001), and 15.4% (95% CI, 10.5-20.2) when compared with non-infected patients (HR, 3.85; 95% CI, 2.57-5.77; p < 0.001). The population attributable fraction for 30-day mortality for CRE vs. CSE was 19.28%, and for CRE vs. non-infected patients was 9.61%. After adjustment for baseline variables, the HRs for mortality were 1.87 (95% CI, 0.99-3.50; p 0.06) and 3.65 (95% CI, 2.29-5.82; p < 0.001), respectively. However, when treatment-related time-dependent variables were added, the HR of CRE vs. CSE reduced to 1.44 (95% CI, 0.78-2.67; p 0.24). DISCUSSION: CRE infections are associated with significant attributable mortality and increased adjusted hazard of mortality when compared with CSE infections or patients without infection. Underlying patient characteristics and a delay in appropriate treatment play an important role in the CRE mortality.

Digital adaptation of group activities in an outpatient center of a children´s hospital: Adolescent participants' experiences. / Adaptación telemática de las actividades grupales de un hospital de día infanto-juvenil: experiencias de participantes adolescentes.

Introduction: Outpatient centers offer specialized care to users with severe psychiatric disorders. The usual group activities of outpatient centers have been shown to be effective in the child and adolescent population. There are significant access limitations to these services and one way to expand coverage is through digital care. However, there are no studies on digital outpatient care services in Chile. The present study is part of the preparatory phase of a future randomized clinical trial to investigate the effectiveness of digital adaptation of outpatient centers interventions. Objectives: To explore the experience and subjective perception of the pilot intervention participants by identifying central themes, and to evaluate the participant's satisfaction regarding the intervention. Methods: Of the 13 users of the digital group activities, 10 participated in this study. Semi-structured interviews and satisfaction surveys were conducted between August 2020 and January 2021. The interviews were evaluated using content analysis and the surveys were conducted using descriptive statistics. Conclusions and Results: Participants were particularly appreciative of positive social interactions (with peers and therapists). There is a general perception of having improved socioemotional skills and mood. The digital implementation was satisfactory for most participants, who suggested adding activities that promote deeper interactions with their peers. The core elements of this intervention would be the perception of social support (a possible therapeutic mechanism), along with the feeling of improved social skills and mood (possible main outcome).

Introducción: Los hospitales de día ofrecen atención especializada a usuarios con patologías psiquiátricas graves. Las actividades grupales habituales del hospital de día han demostrado efectividad en población infanto-juvenil. Existen importantes limitaciones de acceso a estos servicios y una forma de ampliar la cobertura es a través de la atención telemática. Sin embargo, no existen estudios sobre atención telemática de hospital de día en Chile. El presente estudio es parte de la fase preparatoria de un futuro ensayo clínico aleatorizado para investigar la efectividad de la adaptación telemática de las intervenciones de un hospital de día. Objetivos: Explorar la percepción y experiencia subjetiva de los participantes de la versión piloto de dicha intervención identificando temáticas centrales, y evaluar la satisfacción de los participantes con la intervención. Métodos: De los 13 usuarios de las actividades grupales telemáticas, 10 participaron en este estudio. Se realizaron entrevistas semi-estructuradas y encuestas de satisfacción entre agosto de 2020 y enero de 2021. Las entrevistas fueron evaluadas utilizando análisis de contenido y las encuestas se realizaron con estadísticas descriptivas. Resultados: Se aprecia una especial valoración de los participantes por las interacciones sociales positivas (con pares y terapeutas). Aparece una percepción general de haber mejorado en habilidades socioemocionales y estado de ánimo. La implementación telemática resultó satisfactoria para la mayoría de los participantes, quienes proponen agregar actividades que promuevan interacciones más profundas con sus pares. Conclusiones: Los elementos centrales de esta intervención serían la percepción de apoyo social (posible mecanismo terapéutico), junto con la sensación de mejorar las habilidades sociales y el estado de ánimo (posible resultado principal).

Memory SARS-CoV-2 T-cell response in convalescent COVID-19 patients with undetectable specific IgG antibodies: a comparative study.

Background: During the COVID-19 pandemic, a variable percentage of patients with SARS-CoV-2 infection failed to elicit humoral response. This study investigates whether patients with undetectable SARS-CoV-2 IgG are able to generate SARS-CoV-2 memory T cells with proliferative capacity upon stimulation. Methods: This cross-sectional study was conducted with convalescent COVID-19 patients, diagnosed with a positive real-time PCR (RT-PCR) from nasal and pharyngeal swab specimens. COVID-19 patients were enrolled ≥3 months after the last PCR positive. Proliferative T-cell response after whole blood stimulation was assessed using the FASCIA assay. Results: A total of 119 participants (86 PCR-confirmed COVID-19 patients and 33 healthy controls) were randomly filtered from an initial cohort. Of these 86 patients, 59 had detectable (seropositive) and 27 had undetectable (seronegative) SARS-CoV-2 IgG. Seropositive patients were subclassified as asymptomatic/mild or severe according to the oxygen supplementation requirement. SARS-CoV-2 CD3+ and CD4+ T cells showed significantly lower proliferative response in seronegative than in seropositive patients. The ROC curve analysis indicated that ≥ 5 CD4+ blasts/µL of blood defined a "positive SARS-CoV-2 T cell response". According to this cut-off, 93.2% of seropositive patients had a positive T-cell response compared to 50% of seronegative patients and 20% of negative controls (chi-square; p < 0.001). Conclusions: This proliferative assay is useful not only to discriminate convalescent patients from negative controls, but also to distinguish seropositive patients from those with undetectable SARS-CoV-2 IgG antibodies. Memory T cells in seronegative patients are able to respond to SARSCoV-2 peptides, although at a lower magnitude than seropositive patients.

Adaptación telemática de las actividades grupales de un hospital de día infanto-juvenil: experiencias de participantes adolescentes / Digital adaptation of group activities in an outpatient center of a children´s hospital: Adolescent participants' experiences

Introducción Los hospitales de día ofrecen atención especializada a usuarios con patologías psiquiátricas graves. Las actividades grupales habituales del hospital de día han demostrado efectividad en población infanto-juvenil. Existen importantes limitaciones de acceso a estos servicios y una forma de ampliar la cobertura es a través de la atención telemática. Sin embargo, no existen estudios sobre atención telemática de hospital de día en Chile. El presente estudio es parte de la fase preparatoria de un futuro ensayo clínico aleatorizado para investigar la efectividad de la adaptación telemática de las intervenciones de un hospital de día. Objetivos Explorar la percepción y experiencia subjetiva de los participantes de la versión piloto de dicha intervención identificando temáticas centrales, y evaluar la satisfacción de los participantes con la intervención. Métodos De los 13 usuarios de las actividades grupales telemáticas, 10 participaron en este estudio. Se realizaron entrevistas semi-estructuradas y encuestas de satisfacción entre agosto de 2020 y enero de 2021. Las entrevistas fueron evaluadas utilizando análisis de contenido y las encuestas se realizaron con estadísticas descriptivas. Resultados Se aprecia una especial valoración de los participantes por las interacciones sociales positivas (con pares y terapeutas). Aparece una percepción general de haber mejorado en habilidades socioemocionales y estado de ánimo. La implementación telemática resultó satisfactoria para la mayoría de los participantes, quienes proponen agregar actividades que promuevan interacciones más profundas con sus pares. Conclusiones Los elementos centrales de esta intervención serían la percepción de apoyo social (posible mecanismo terapéutico), junto con la sensación de mejorar las habilidades sociales y el estado de ánimo (posible resultado principal).

Introduction Outpatient centers offer specialized care to users with severe psychiatric disorders. The usual group activities of outpatient centers have been shown to be effective in the child and adolescent population. There are significant access limitations to these services and one way to expand coverage is through digital care. However, there are no studies on digital outpatient care services in Chile. The present study is part of the preparatory phase of a future randomized clinical trial to investigate the effectiveness of digital adaptation of outpatient centers interventions. Objectives To explore the experience and subjective perception of the pilot intervention participants by identifying central themes, and to evaluate the participant's satisfaction regarding the intervention. Methods Of the 13 users of the digital group activities, 10 participated in this study. Semi-structured interviews and satisfaction surveys were conducted between August 2020 and January 2021. The interviews were evaluated using content analysis and the surveys were conducted using descriptive statistics. Conclusions Results Participants were particularly appreciative of positive social interactions (with peers and therapists). There is a general perception of having improved socioemotional skills and mood. The digital implementation was satisfactory for most participants, who suggested adding activities that promote deeper interactions with their peers. The core elements of this intervention would be the perception of social support (a possible therapeutic mechanism), along with the feeling of improved social skills and mood (possible main outcome).

Criminal recidivism in Colombian juvenile offenders: Related risk and protective factors / Reincidencia delictiva en adolescentes colombianos: factores de riesgo y protectores relacionados

Abstract Research with adolescent offenders is concerned with identifying risk and protective factors that influence recidivism and desistance from crime. A quantitative and cross-sectional investigation designed to examine the influence of risk and protective factors on recidivism in Colombian adolescents is presented. In seven regions of Colombia, a convenience sample was obtained, and 646 adolescents aged 14 to 19 years (M = 17.08; SD: 1.23; 15 % girls) belonging to the Sistema de Responsabilidad Penal para Adolescentes (SRPA) participated. The Communities That Care Youth Survey (CTC-YS) was used for the evaluation. It evaluated a broad set of risk and protective factors identified through the community, school, family, peer group, individual conditions, and behavioral outcomes, including drug use, antisocial behavior, and delinquency. Descriptive analyses were conducted, and all CTC-YS factors were correlated with antisocial behavior. The results show varying degrees of relationship between the factors assessed and antisocial behavior. Binary logistic regression was used to determine which risk and protective factors influence recidivism. It was noted that favorable parental attitudes towards drug use and antisocial behavior, early onset of drug use, low school engagement, and interaction with antisocial peers increases the probability of recidivism. Recidivism was identified as being affected by, among other factors, favorable parental attitudes toward drug use and antisocial behavior, early onset of drug use, and low school engagement. It was also observed that beliefs in a moral order, opportunities for prosocial school participation and lower drug use frequency reduce the probability of recidivism. According to the results, the factors that influence criminal recidivism are multiple, and social, family, school, and individual factors need to be addressed. The need to intervene in attitudes favorable to antisocial behavior on the part of parents, strengthen school services, and carry out treatment for drug use to favor the reduction of recidivism in Colombian adolescents is discussed.

Resumen La investigación con adolescentes ofensores busca identificar los factores de riesgo y de protección que afectan a la reincidencia y al desistimiento. Esta información es útil para desarrollar programas de prevención de la conducta antisocial y facilita los procesos de intervención que favorecen la reinserción social. Desde el punto de vista legal, la reincidencia es la participación de un individuo en nuevos actos delictivos, que conduce a una nueva condena, después de haber sido judicializado por un delito anterior. El desistimiento, en cambio, es la interrupción de la conducta antisocial y se caracteriza por la reinserción social exitosa y el ajuste a las normas de la comunidad. Se han identificado factores sociales, familiares, escolares, relacionales e individuales que afectan a la reincidencia y al desistimiento. Se presenta una investigación cuantitativa que utilizó una medición de corte transversal, diseñada para examinar la influencia de los factores de riesgo y protección en la reincidencia de los adolescentes colombianos. Se realizó un muestreo por disponibilidad y conveniencia en instituciones de siete departamentos o regiones geográficas de Colombia. Los participantes fueron 646 adolescentes de entre 14 y 19 años (M = 17.08; DT: 1.23; 15 % chicas). Todos ellos estaban judicializados y cumpliendo sus sanciones legales en el Sistema de Responsabilidad Penal para Adolescentes (SRPA). Para la evaluación se utilizó la encuesta Communities That Care Youth Survey (CTC-YS). Se trata de un instrumento de 135 ítems diseñado para medir un amplio conjunto de factores de riesgo y de protección identificados a través de las condiciones de la comunidad, la escuela, la familia, el grupo de pares y el individuo, así como los resultados conductuales, que incluyen el uso de drogas, la violencia, el comportamiento antisocial y la delincuencia. El instrumento mostró buena fiabilidad en este estudio. La reincidencia se evaluó con criterios legales, es decir, se tuvieron en cuenta el número de condenas oficiales. Para ello se revisaron los expedientes de los participantes y se los cruzó con la información reportada por los profesionales que atendían los centros y el autoinforme de los participantes. Se obtuvo la aprobación del comité de ética y permiso del gobierno a través del Instituto Colombiano de Bienestar Familiar -ICBF- (Autorización E-2016-660327-0111). Los consentimientos informados fueron firmados por los defensores, los directores de los centros de atención, los padres de los adolescentes y por cada uno de los participantes. Una vez finalizada la investigación, se socializaron los resultados a través de grupos focales con los interesados, incluidos los adolescentes. Se realizaron análisis descriptivos con los datos y se correlacionaron todos los factores del CTC-YS con la variable conducta antisocial y delictiva provista por el mismo instrumento. Luego se realizó una regresión logística binaria para determinar qué factores de riesgo y protección influyen en la reincidencia. Se observaron diferentes grados de relación entre los factores evaluados y la conducta antisocial-delictiva. Los resultados indican que la reincidencia se ve afectada, entre otros factores, por las actitudes favorables de los padres hacia el uso de drogas y la conducta antisocial, el inicio temprano del consumo de drogas y el bajo compromiso escolar. Las creencias en un orden moral y las oportunidades por la participación escolar prosocial y la menor frecuencia de uso de drogas muestran disminución en la probabilidad de reincidencia. Según los resultados, los factores que influyen en la reincidencia delictiva son múltiples y requieren la intervención de las condiciones sociales, familiares, escolares e individuales. Se discute la necesidad de intervenir en las actitudes favorables a la conducta delictiva por parte de los padres, fortalecer los servicios escolares, realizar tratamiento para abandonar el uso de drogas y desarrollar modelos de intervención que cuenten con evidencias de eficacia para ayudar a reducir la reincidencia en los adolescentes colombianos.

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

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-ß-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. Funding: The study was funded by the Innovative Medicines Initiative Joint Undertaking (https://www.imi.europa.eu/) under Grant Agreement No. 115620 (COMBACTE-CARE).

Outcomes of octogenarians and nonagenarians with Pseudomonas aeruginosa bacteremia: a multicenter retrospective study.

BACKGROUND: P. aeruginosa bacteremia is a common and severe infection carrying high mortality in older adults. We aimed to evaluate outcomes of P. aeruginosa bacteremia among old adults (≥ 80 years). METHODS: We included the 464/2394 (19%) older adults from a retrospective multinational (9 countries, 25 centers) cohort study of individuals hospitalized with P. aeruginosa bacteremia. Bivariate and multivariable logistic regression models were used to evaluate risk factors for 30-day mortality among older adults. RESULTS: Among 464 adults aged ≥ 80 years, the mean age was 84.61 (SD 3.98) years, and 274 (59%) were men. Compared to younger patients, ≥ 80 years adults had lower Charlson score; were less likely to have nosocomial acquisition; and more likely to have urinary source. Thirty-day mortality was 30%, versus 27% among patients 65-79 years (n = 894) and 25% among patients < 65 years (n = 1036). Multivariate analysis for predictors of mortality among patients ≥ 80 years, demonstrated higher SOFA score (odds ratio [OR] 1.36, 95% confidence interval [CI] 1.23-1.51, p < 0.001), corticosteroid therapy (OR 3.15, 95% CI: 1.24-8.01, p = 0.016) and hospital acquired P. aeruginosa bacteremia (OR 2.30, 95% CI: 1.33-3.98, p = 0.003) as predictors. Appropriate empirical therapy within 24 h, type of definitive anti-pseudomonal drug, and type of regimen (monotherapy or combination) were not associated with 30-day mortality. CONCLUSIONS: In older adults with P. aeruginosa bacteremia, background conditions, place of acquisition, and disease severity are associated with mortality, rather than the antimicrobial regimen. In this regard, preventive efforts and early diagnosis before organ failure develops might be beneficial for improving outcomes.

Prognostic Significance of the Relative Load of KPC-Producing Klebsiella pneumoniae within the Intestinal Microbiota in a Prospective Cohort of Colonized Patients.

Increased relative bacterial load of KPC-producing Klebsiella pneumoniae (KPC-KP) within the intestinal microbiota has been associated with KPC-KP bacteremia. Prospective observational study of KPC-KP adult carriers with a hospital admission at recruitment or within the three prior months (January 2018 to February 2019). A qPCR-based assay was developed to measure the relative load of KPC-KP in rectal swabs (RLKPC, proportion of blaKPC relative to 16S rRNA gene copy number). We generated Fine-Gray competing risk and Cox regression models for survival analysis of all-site KPC-KP infection and all-cause mortality, respectively, at 90 and 30 days. The median RLKPC at baseline among 80 KPC-KP adult carriers was 0.28% (range 0.001% to 2.70%). Giannella Risk Score (GRS) was independently associated with 90-day and 30-day all-site infection (adjusted subdistribution hazard ratio [aHR] 1.23, 95% CI = 1.15 to 1.32, P < 0.001). RLKPC (adjusted hazard ratio [aHR] 1.04, 95% CI = 1.01 to 1.07, P = 0.008) and age (aHR 1.05, 95% CI = 1.01 to 1.10, P = 0.008) were independent predictors of 90-day all-cause mortality in a Cox model stratified by length of hospital stay (LOHS) ≥20 days. An adjusted Cox model for 30-day all-cause mortality, stratified by LOHS ≥14 days, included RLKPC (aHR 1.03, 95% CI = 1.00 to 1.06, P = 0.027), age (aHR 1.10, 95% CI = 1.03 to 1.18, P = 0.004), and severe KPC-KP infection (INCREMENT-CPE score >7, aHR 2.96, 95% CI = 0.97 to 9.07, P = 0.057). KPC-KP relative intestinal load was independently associated with all-cause mortality in our clinical setting, after adjusting for age and severe KPC-KP infection. Our study confirms the utility of GRS to predict infection risk in patients colonized by KPC-KP. IMPORTANCE The rapid dissemination of carbapenemase-producing Enterobacterales represents a global public health threat. Increased relative load of KPC-producing Klebsiella pneumoniae (KPC-KP) within the intestinal microbiota has been associated with an increased risk of bloodstream infection by KPC-KP. We developed a qPCR assay for quantification of the relative KPC-KP intestinal load (RLKPC) in 80 colonized patients and examined its association with subsequent all-site KPC-KP infection and all-cause mortality within 90 days. Giannella Risk Score, which predicts infection risk in colonized patients, was independently associated with the development of all-site KPC-KP infection. RLKPC was not associated with all-site KPC-KP infection, possibly reflecting the large heterogeneity in patient clinical conditions and infection types. RLKPC was an independent predictor of all-cause mortality within 90 and 30 days in our clinical setting. We hypothesize that KPC-KP load may behave as a surrogate marker for the severity of the patient's clinical condition.

Duration of Treatment for Pseudomonas aeruginosa Bacteremia: a Retrospective Study.

INTRODUCTION: There is no consensus regarding optimal duration of antibiotic therapy for Pseudomonas aeruginosa bacteremia. We aimed to evaluate the impact of short antibiotic course. METHODS: We present a retrospective multicenter study including patients with P. aeruginosa bacteremia during 2009-2015. We evaluated outcomes of patients treated with short (6-10 days) versus long (11-15 days) antibiotic courses. The primary outcome was a composite of 30-day mortality or bacteremia recurrence and/or persistence. Univariate and inverse probability treatment-weighted (IPTW) adjusted multivariate analysis for the primary outcome was performed. To avoid immortal time bias, the landmark method was used. RESULTS: We included 657 patients; 273 received a short antibiotic course and 384 a long course. There was no significant difference in baseline characteristics of patients. The composite primary outcome occurred in 61/384 patients in the long-treatment group (16%) versus 32/273 in the short-treatment group (12%) (p = 0.131). Mortality accounted for 41/384 (11%) versus 25/273 (9%) of cases, respectively. Length of hospital stay was significantly shorter in the short group [median 13 days, interquartile range (IQR) 9-21 days, versus median 15 days, IQR 11-26 days, p = 0.002]. Ten patients in the long group discontinued antibiotic therapy owing to adverse events, compared with none in the short group. On univariate and multivariate analyses, duration of therapy was not associated with the primary outcome. CONCLUSIONS: In this retrospective study, 6-10 days of antibiotic course for P. aeruginosa bacteremia were as effective as longer courses in terms of survival and recurrence. Shorter therapy was associated with reduced length of stay and less drug discontinuation.

Proof­of­concept study to quantify changes in intestinal loads of KPC-producing Klebsiella pneumoniae in colonised patients following selective digestive decontamination with oral gentamicin.

OBJECTIVES: To monitor quantitatively the extent of intestinal colonisation by KPC-producing Klebsiella pneumoniae (KPC-Kp) in colonised patients who receive selective digestive decontamination (SDD) with oral gentamicin. METHODS: We developed a real-time quantitative PCR (qPCR) method for determination of the relative load of blaKPC (RLKPC) within the gut microbiota. Clinical validation was performed using a culture method as the gold standard and receiver operating curve (ROC) analysis. Fifteen patients were observationally and prospectively followed for one year. Clinical, microbiological variables and rectal swab samples were collected at 0 (baseline), 14 and 30 days and monthly thereafter. RESULTS: Clinical validation performed on 111 rectal swab samples demonstrated that the PCR method detected 17% more positives than the culture method. ROC curve analysis documented excellent agreement between both methods (area under the curve, 0.96; 95% confidence interval 0.93-0.99). The RLKPC decreased in 6/15 (40%) and 7/12 (58.3%) patients on days 14 and 30, respectively. Persistent eradication was observed in 2/12 (16.7%), 3/9 (33.3%), 4/8 (50%) and 7/8 (87.5%) patients at 1, 3, 6 and 12 months, respectively, with a median time of 150 days (range 30-270) to persistent eradication. Gentamicin-resistant KPC-Kp isolates were identified in 4/15 (26.7%) patients. The rates of infections (57.1% vs. 12.5%, P = 0.119) and deaths (71.4% vs. 0%, P = 0.007) were higher among patients with high baseline RLKPC. CONCLUSION: Following SDD, a rapid reduction on intestinal load is observed when the colonising KPC-Kp isolate is susceptible to gentamicin; however, persistent eradication at the end of SDD is low. Intestinal carriage of KPC-Kp persists after three months in about one third of patients.

Randomised, double-blind, placebo-controlled, phase 2, superiority trial to demonstrate the effectiveness of faecal microbiota transplantation for selective intestinal decolonisation of patients colonised by carbapenemase-producing Klebsiella pneumoniae (KAPEDIS).

INTRODUCTION: Infections caused by carbapenemase-producing Enterobacterales are frequent and associated with high rates of mortality. Intestinal carriers are at increased risk of infection by these microorganisms. Decolonisation strategies with antibiotics have not obtained conclusive results. Faecal microbiota transplantation (FMT) could be an effective and safe strategy to decolonise intestinal carriers of KPC-producing Klebsiella pneumoniae (KPC-Kp) but this hypothesis needs evaluation in appropriate clinical trials. METHODS AND ANALYSIS: The KAPEDIS trial is a single-centre, randomised, double-blind, placebo-controlled, phase 2, superiority clinical trial of FMT for eradication of intestinal colonisation by KPC-Kp. One hundred and twenty patients with rectal colonisation by KPC-Kp will be randomised 1:1 to receive encapsulated lyophilised FMT or placebo. The primary outcome is KPC-Kp eradication at 30 days. Secondary outcomes are: (1) frequency of adverse events; (2) changes in KPC-Kp relative load within the intestinal microbiota at 7, 30 and 90 days, estimated by real-time quantitative PCR analysis of rectal swab samples and (3) rates of persistent eradication, KPC-Kp infection and crude mortality at 90 days. Participants will be monitored for adverse effects throughout the intervention. ETHICS AND DISSEMINATION: Ethical approval was obtained from Reina Sofía University Hospital Institutional Review Board (approval reference number: 2019-003808-13). Trial results will be published in peer-reviewed journals and disseminated at national and international conferences. TRIAL REGISTRATION NUMBER: NCT04760665.

Association between Timing of Colonization and Risk of Developing Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae Infection in Hospitalized Patients.

Colonization by KPC-producing Klebsiella pneumoniae (KPC-Kp) is associated with the risk of developing KPC-Kp infection. The impact of the time elapsed since a patient becomes colonized on this risk is not well known. An observational, prospective, longitudinal cohort study of colonized patients undergoing active rectal culture screening to rule out KPC-Kp colonization (July 2012 to November 2017). Patients with a positive culture at inclusion (colonized at start of follow-up) and those with a negative culture at inclusion who became colonized within 90 days (colonized during follow-up) were included in the analysis. CART analysis was used to dichotomize variables according to their association with infection. Kaplan-Meier infection-free survival curves and the log-rank test were used for group comparisons. Logistic regression was used to identify variables associated with KPC-Kp infection. Among 1310 patients included, 166 were colonized at the end of follow-up. Forty-seven out of 118 patients colonized at start of follow-up developed infection (39.8%) versus 31 out of 48 patients colonized during follow-up (64.6%; P = 0.006). Variables associated with KPC-Kp infection in the logistic regression analysis were: colonization detection during follow-up (OR, 2.74; 95% CI, 1.07 to 7.04; P = 0.03), Giannella risk score (OR, 1.51; 95% CI, 1.32 to 1.73; P < 0.001), high-risk ward (OR, 4.77; 95% CI, 1.61 to 14.10; P = 0.005) and urological manipulation after admission (OR, 3.69; 95% CI, 1.08 to 12.60; P = 0.04). In 25 out of 31 patients (80.6%) colonized during follow-up who developed KPC-Kp infection, infection appeared within 15 days after colonization. The risk of KPC-Kp infection was higher when colonization is recently acquired during hospitalization. In this prospective study, we concluded that the timing of colonization was a factor to assess when considering empirical treatment for suspected KPC-Kp infection and prophylaxis or infection control. IMPORTANCE In this study, it was confirmed that patients who became colonized during hospitalization had a higher risk of developing KPC-Kp infection than hospitalized patients who were already colonized at the start of follow-up. Besides, the risk of infection in the group of patients who became colonized during follow-up was greater in the first weeks immediately after colonization was confirmed. Our findings support the need for designing preventive strategies for patients at the highest risk of infection development, including those admitted in high-risk hospital wards and those undergoing urological procedures.

Factors associated with recruitment success in the phase 2a study of aztreonam-avibactam development programme: a descriptive qualitative analysis among sites in Spain.

OBJECTIVE: Successful clinical trials are subject to recruitment. Recently, the REJUVENATE trial, a prospective phase 2a open-label, single-arm interventional clinical trial conducted within the Innovative Medicines Initiative-supported Combatting Bacterial Resistance in Europe-Carbapenem Resistance project, was published, with 85% of the recruitment performed in Spain. We analysed the recruitment success in this trial by establishing a model of recruitment practice. METHODS: A descriptive qualitative study was performed from May 2016 to October 2017 at 10 participating Spanish centres. Data were extracted from: (1) feasibility questionnaires to assess the centre's potential for patient enrolment; (2) delegation of responsibility records; (3) pre-screening records including an anonymised list of potentially eligible and (4) screening and enrolment records. A descriptive analysis of the features was performed by the participating centre. Pearson's and Spearman's correlation coefficients were calculated to determine factors of recruitment success. RESULTS: The highest recruitment rate was observed in Hospitals 3 and 6 (58.8 and 47.0 patients per month, respectively). All the study teams were multidisciplinary with a median of 15 members (range: 7-22). Only Hospitals 3, 5 and 6 had dedicated nursing staff appointed exclusively to this study. Moreover, in those three hospitals and in Hospital 9, the study coordinator performed exclusive functions as a research planner, and did not assume these functions for the other hospitals. The univariate analysis showed a significant association between recruitment success and months of recruitment (p=0.024), number of staff (p<0.001), higher number of pharmacists (p=0.005), infectious disease specialists (p<0.001), the presence of microbiologist in the research team (p=0.018) and specifically dedicated nursing staff (p=0.036). CONCLUSIONS: The existence of broad multidisciplinary teams with staff dedicated exclusively to the study as well as the implementation of a well-designed local patient assessment strategy were the essential optimisation factors for recruitment success in Spain. TRIAL REGISTRATION NUMBER: NCT02655419; EudraCT 2015-002726-39; analysis of pre-screened patients.

Impact of ceftazidime/avibactam versus best available therapy on mortality from infections caused by carbapenemase-producing Enterobacterales (CAVICOR study).

BACKGROUND: Infections caused by carbapenemase-producing Enterobacterales (CPE) are not well represented in pivotal trials with ceftazidime/avibactam. The best strategy for the treatment of these infections is unknown. METHODS: We conducted a multicentre retrospective observational study of patients who received ≥48 h of ceftazidime/avibactam or best available therapy (BAT) for documented CPE infections. The primary outcome was 30 day crude mortality. Secondary outcomes were 21 day clinical response and microbiological response. A multivariate logistic regression model was used to identify factors predictive of 30 day crude mortality. A propensity score to receive treatment with ceftazidime/avibactam was used as a covariate in the analysis. RESULTS: The cohort included 339 patients with CPE infections. Ceftazidime/avibactam treatment was used in 189 (55.8%) patients and 150 (44.2%) received BAT at a median of 2 days after diagnosis of infection. In multivariate analysis, ceftazidime/avibactam treatment was associated with survival (OR 0.41, 95% CI 0.20-0.80; P = 0.01), whereas INCREMENT-CPE scores of >7 points (OR 2.57, 95% CI 1.18-1.5.58; P = 0.01) and SOFA score (OR 1.20, 95% CI 1.08-1.34; P = 0.001) were associated with higher mortality. In patients with INCREMENT-CPE scores of >7 points, ceftazidime/avibactam treatment was associated with lower mortality compared with BAT (16/73, 21.9% versus 23/49, 46.9%; P = 0.004). Ceftazidime/avibactam was also an independent factor of 21 day clinical response (OR 2.43, 95% CI 1.16-5.12; P = 0.02) and microbiological eradication (OR 0.40, 95% CI 0.18-0.85; P = 0.02). CONCLUSIONS: Ceftazidime/avibactam is an effective alternative for the treatment of CPE infections, especially in patients with INCREMENT-CPE scores of >7 points. A randomized controlled trial should confirm these findings.

Immunoguided Discontinuation of Prophylaxis for Cytomegalovirus Disease in Kidney Transplant Recipients Treated With Antithymocyte Globulin: A Randomized Clinical Trial.

BACKGROUND: Antiviral prophylaxis is recommended in cytomegalovirus (CMV)-seropositive kidney transplant (KT) recipients receiving antithymocyte globulin (ATG) as induction. An alternative strategy of premature discontinuation of prophylaxis after CMV-specific cell-mediated immunity (CMV-CMI) recovery (immunoguided prevention) has not been studied. Our aim was to determine whether it is effective and safe to discontinue prophylaxis when CMV-CMI is detected and to continue with preemptive therapy. METHODS: In this open-label, noninferiority clinical trial, patients were randomized 1:1 to follow an immunoguided strategy, receiving prophylaxis until CMV-CMI recovery or to receive fixed-duration prophylaxis until day 90. After prophylaxis, preemptive therapy (valganciclovir 900 mg twice daily) was indicated in both arms until month 6. The primary and secondary outcomes were incidence of CMV disease and replication, respectively, within the first 12 months. Desirability of outcome ranking (DOOR) assessed 2 deleterious events (CMV disease/replication and neutropenia). RESULTS: A total of 150 CMV-seropositive KT recipients were randomly assigned. There was no difference in the incidence of CMV disease (0% vs 2.7%; P = .149) and replication (17.1% vs 13.5%; log-rank test, P = .422) between both arms. Incidence of neutropenia was lower in the immunoguided arm (9.2% vs 37.8%; odds ratio, 6.0; P < .001). A total of 66.1% of patients in the immunoguided arm showed a better DOOR, indicating a greater likelihood of a better outcome. CONCLUSIONS: Prophylaxis can be prematurely discontinued in CMV-seropositive KT patients receiving ATG when CMV-CMI is recovered since no significant increase in the incidence of CMV replication or disease is observed. CLINICAL TRIALS REGISTRATION: NCT03123627.

Association between rectal colonisation by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae and mortality: a prospective, observational study.

OBJECTIVES: We evaluated the association of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) rectal colonisation with crude mortality and whether this association is independent of the risk of KPC-Kp infection. METHODS: This was a prospective cohort study of patients followed-up 90 days after a study of rectal colonisation. Cox regression was used to study the variables associated with crude mortality. Sensitivity analyses for 90-day crude mortality in different subcohorts were performed. RESULTS: A total of 1244 patients (1078 non-colonised and 166 colonised) were included. None of the non-colonised patients and 78 (47.0%) of the colonised patients developed KPC-Kp infection. The 90-day crude mortality was 18.0% (194/1078) in non-colonised patients and 41.6% (69/166) in colonised patients. Rectal colonisation was not associated with crude mortality [hazard ratio (HR) = 1.03, 95% confidence interval (CI) 0.69-1.54; P = 0.85] when the model was adjusted for severe KPC-Kp infection [INCREMENT-CPE score (ICS) > 7]. KPC-Kp infection with ICS > 7 was associated with an increased risk of all-cause mortality (HR = 2.21, 95% CI 1.35-3.63; P = 0.002). In the sensitivity analyses, KPC-Kp colonisation was not associated with mortality in any of the analysed subcohorts, including patients who did not develop KPC-Kp infection (HR = 0.93, 95% CI 0.60-1.43; P = 0.74). CONCLUSION: KPC-Kp rectal colonisation was not associated with crude mortality. Mortality increased when colonised patients developed severe KPC-Kp infection (ICS > 7). Rectal colonisation was a necessary although insufficient condition to die from a KPC-Kp infection.

Seven-versus 14-day course of antibiotics for the treatment of bloodstream infections by Enterobacterales: a randomized, controlled trial.

OBJECTIVE: To prove that 7-day courses of antibiotics for bloodstream infections caused by members of the Enterobacterales (eBSIs) allow a reduction in patients' exposure to antibiotics while achieving clinical outcomes similar to those of 14-day schemes. METHODS: A randomized trial was performed. Adult patients developing eBSI with appropriate source control were assigned to 7 or 14 days of treatment, and followed 28 days after treatment cessation; treatments could be resumed whenever necessary. The primary endpoint was days of treatment at the end of follow-up. Clinical outcomes included clinical cure, relapse of eBSI and relapse of fever. A superiority margin of 3 days was set for the primary endpoint, and a non-inferiority margin of 10% was set for clinical outcomes. Efficacy and safety were assessed together with a DOOR/RADAR (desirability of outcome ranking and response adjusted for duration of antibiotic risk) analysis. RESULTS: 248 patients were assigned to 7 (n = 119) or 14 (n = 129) days of treatment. In the intention-to-treat analysis, median days of treatment at the end of follow-up were 7 and 14 days (difference 7, 95%CI 7-7). The non-inferiority margin was also met for clinical outcomes, except for relapse of fever (-0.2%, 95%CI -10.4 to 10.1). The DOOR/RADAR showed that 7-day schemes had a 77.7% probability of achieving better results than 14-day treatments. CONCLUSIONS: 7-day schemes allowed a reduction in antibiotic exposure of patients with eBSI while achieving outcomes similar to those of 14-day schemes. The possibility of relapsing fever in a limited number of patients, without relevance to final outcomes, may not be excluded, but was overcome by the benefits of shortening treatments.

Day hospital during COVID-19 pandemic: adolescents experiences of telematic group interventions / Hospital de día en contexto de pandemia por COVID-19: experiencias de adolescentes asistiendo a intervenciones grupales telemáticas

Objective: To explore the experience of adolescent users of the day hospital who were part of the telematic adaptation of the usual group interventions of the day hospital. Background: Day Hospitals are specialized outpatient facilities whose objective is to stabilize the user through intensive treatment while remaining in their family or community. In Chile, there are not enough day hospitals. One way of expanding the coverage is telematic care, which also is adapted to the COVID-19 pandemic restrictions.  However, there are no studies on telematic day hospital services in Chile. Material and Methods: ten users participated in the study (out of 13 users of the intervention). We conducted semi-structured interviews and self-administered surveys between August 2020 and January 2021. Content Analysis was used to analyze the interviews, and the surveys were analyzed with descriptive statistics. Results: Positive social interactions were particularly valued by the participants (with both peers and therapists). There is a general perception of having improved socioemotional skills and mood. Telematic implementation was considered satisfactory by most participants, and they proposed incorporating more activities to promote deeper interactions with their peers. Conclusion: The core elements of this intervention would be the perception of social support (a possible therapeutic mechanism) and the feeling of having improved social skills and mood (possible primary outcome).

Objetivo: explorar la experiencia de adolescentes usuarios del hospital de día que fueron parte de la adaptación telemática de las intervenciones grupales habituales de dicho hospital. Antecedente teóricos: los Hospitales de Día (HDD) son puntos de atención de hospitalización diurna y especializada cuyo objetivo es alcanzar la estabilización del usuario/a por medio de un tratamiento intensivo permaneciendo en su familia o comunidad. Los HDD en Chile son insuficientes. Una forma de ampliar la cobertura es la atención telemática, la que además se adapta a las limitaciones impuestas por la pandemia por COVID-19.  Sin embargo, no existen estudios sobre atención telemática de HDD en Chile. Material y Métodos: de los 13 usuarios de la intervención, 10 participaron en este estudio. Se realizaron entrevistas semi-estructuradas y encuestas autoaplicadas entre agosto 2020 y enero 2021.  Las entrevistas fueron analizadas utilizando Análisis de Contenido y las encuestas se analizaron con estadísticas descriptivas. Resultados: se aprecia una especial valoración de los/las participantes por las interacciones sociales positivas (con pares y terapeutas). Aparece una percepción general de haber mejorado en habilidades socioemocionales y estado de ánimo. La implementación telemática resultó satisfactoria para la mayoría de los participantes quienes proponen agregar actividades que promuevan interacciones más profundas con sus pares. Conclusión: los elementos centrales de esta intervención serían la percepción de apoyo social (posible mecanismo terapéutico) y la sensación de mejorar las habilidades sociales y el estado de ánimo (posible resultado principal).

Impact of an Antimicrobial Stewardship Program on the Incidence of Carbapenem Resistant Gram-Negative Bacilli: An Interrupted Time-Series Analysis.

Carbapenem-resistant Gram-negative bacilli (CR-GNB) are a critical public health threat, and carbapenem use contributes to their spread. Antimicrobial stewardship programs (ASPs) have proven successful in reducing antimicrobial use. However, evidence on the impact of carbapenem resistance remains unclear. We evaluated the impact of a multifaceted ASP on carbapenem use and incidence of CR-GNB in a high-endemic hospital. An interrupted time-series analysis was conducted one year before and two years after starting the ASP to assess carbapenem consumption, CR-GNB incidence, death rates of sentinel events, and other variables potentially related to CR-GNB incidence. An intense reduction in carbapenem consumption occurred after starting the intervention and was sustained two years later (relative effect -83.51%; 95% CI -87.23 to -79.79). The incidence density of CR-GNB decreased by -0.915 cases per 1000 occupied bed days (95% CI -1.743 to -0.087). This effect was especially marked in CR-Klebsiella pneumoniae and CR-Escherichia coli, reversing the pre-intervention upward trend and leading to a relative reduction of -91.15% (95% CI -105.53 to -76.76) and -89.93% (95% CI -107.03 to -72.83), respectively, two years after starting the program. Death rates did not change. This ASP contributed to decreasing CR-GNB incidence through a sustained reduction in antibiotic use without increasing mortality rates.

Combination versus monotherapy as definitive treatment for Pseudomonas aeruginosa bacteraemia: a multicentre retrospective observational cohort study.

BACKGROUND: Pseudomonas aeruginosa bacteraemia is a common and serious infection. No consensus exists regarding whether definitive combination therapy is superior to monotherapy. We aimed to evaluate the impact of combination therapy on mortality. METHODS: This was a multicentre retrospective study (nine countries, 25 centres), including 1277 patients with P. aeruginosa bacteraemia during 2009-15. We evaluated the association between ß-lactam plus aminoglycoside or quinolone combination therapy versus ß-lactam monotherapy and mortality. The primary outcome was 30 day all-cause mortality. Univariate and multivariate Cox regression analyses were conducted, introducing combination as a time-dependent variable. Propensity score was conducted to adjust for confounding for choosing combination therapy over monotherapy. RESULTS: Of 1119 patients included, 843 received definitive monotherapy and 276 received combination therapy (59% aminoglycoside and 41% quinolone). Mortality at 30 days was 16.9% (189/1119) and was similar between combination (45/276; 16.3%) and monotherapy (144/843; 17.1%) groups (P = 0.765). In multivariate Cox regression, combination therapy was not associated with reduced mortality (HR 0.98, 95% CI 0.64-1.53). No advantage in terms of clinical failure, microbiological failure or recurrent/persistent bacteraemia was demonstrated using combination therapy. Likewise, adverse events and resistance development were similar for the two regimens. CONCLUSIONS: In this retrospective cohort, no mortality advantage was demonstrated using combination therapy over monotherapy for P. aeruginosa bacteraemia. Combination therapy did not improve clinical or microbiological failure rates, nor affect adverse events or resistance development. Our finding of no benefit with combination therapy needs confirmation in well-designed randomized controlled trials.