Efficacy and safety of a structured de-escalation from antipseudomonal ß-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial.

BACKGROUND: De-escalation from broad-spectrum to narrow-spectrum antibiotics is considered an important measure to reduce the selective pressure of antibiotics, but a scarcity of adequate evidence is a barrier to its implementation. We aimed to determine whether de-escalation from an antipseudomonal ß-lactam to a narrower-spectrum drug was non-inferior to continuing the antipseudomonal drug in patients with Enterobacterales bacteraemia. METHODS: An open-label, pragmatic, randomised trial was performed in 21 Spanish hospitals. Patients with bacteraemia caused by Enterobacterales susceptible to one of the de-escalation options and treated empirically with an antipseudomonal ß-lactam were eligible. Patients were randomly assigned (1:1; stratified by urinary source) to de-escalate to ampicillin, trimethoprim-sulfamethoxazole (urinary tract infections only), cefuroxime, cefotaxime or ceftriaxone, amoxicillin-clavulanic acid, ciprofloxacin, or ertapenem in that order according to susceptibility (de-escalation group), or to continue with the empiric antipseudomonal ß-lactam (control group). Oral switching was allowed in both groups. The primary outcome was clinical cure 3-5 days after end of treatment in the modified intention-to-treat (mITT) population, formed of patients who received at least one dose of study drug. Safety was assessed in all participants. Non-inferiority was declared when the lower bound of the 95% CI of the absolute difference in cure rate was above the -10% non-inferiority margin. This trial is registered with EudraCT (2015-004219-19) and ClinicalTrials.gov (NCT02795949) and is complete. FINDINGS: 2030 patients were screened between Oct 5, 2016, and Jan 23, 2020, of whom 171 were randomly assigned to the de-escalation group and 173 to the control group. 164 (50%) patients in the de-escalation group and 167 (50%) in the control group were included in the mITT population. 148 (90%) patients in the de-escalation group and 148 (89%) in the control group had clinical cure (risk difference 1·6 percentage points, 95% CI -5·0 to 8·2). The number of adverse events reported was 219 in the de-escalation group and 175 in the control group, of these, 53 (24%) in the de-escalation group and 56 (32%) in the control group were considered severe. Seven (5%) of 164 patients in the de-escalation group and nine (6%) of 167 patients in the control group died during the 60-day follow-up. There were no treatment-related deaths. INTERPRETATION: De-escalation from an antipseudomonal ß-lactam in Enterobacterales bacteraemia following a predefined rule was non-inferior to continuing the empiric antipseudomonal drug. These results support de-escalation in this setting. FUNDING: Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases; Spanish Clinical Research and Clinical Trials Platform, co-financed by the EU; European Development Regional Fund "A way to achieve Europe", Operative Program Intelligence Growth 2014-2020.

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.

Efficacy and safety of different antimicrobial DURATions for the treatment of Infections associated with Osteosynthesis Material implanted after long bone fractures (DURATIOM): Protocol for a randomized, pragmatic trial.

BACKGROUND: Infection associated with osteosynthesis material (IOM) is one of the most feared and challenging complications of trauma surgery and can cause significant functional loss, requiring multiple interventions and excessive consumption of antimicrobials. Evidence is needed about the best surgical procedure and the duration of antibiotic treatment according to the age of the implant or onset of infection symptoms, as it considers the biofilm formation and the state of fracture healing. There were not clinical trials evaluating the optimal duration of antibiotic therapy in IOM when implant is retained. Because there are antibiotics that have proven to be effective for the treatment of infection associated to implant, mainly in PJI, these antibiotics could be used in these infections. Investigating whether shorter duration of treatment is a priority in infectious diseases, as a way to reduce the exposure to antibiotics and help in controlling antimicrobial resistance and avoiding unnecessary adverse events and cost. We aim to describe the hypothesis, objectives, design, variables and procedures for a pragmatic randomized controlled trial comparing different durations of antibiotic treatment in IOM after long bone fractures treated with debridement and implant retention. METHODS AND DESIGN: This is a multicenter, open-label, non-inferiority, randomized, controlled, pragmatic phase 3 trial, comparing different durations of antibiotic treatment in IOM after long bone fractures treated with debridement and implant retention. Patients with microbiologically confirmed IOM will be included. Eligible patients are those older than 14 years, with early IOM (up to 2 weeks after the implant surgery) and delayed IOM (between 3 and 10 weeks after the implant surgery) with stabilized fracture and absence of bone exposure who sign the informed consent. Randomization will be 1:1 to receive a short-term antibiotic treatment (8 weeks in early IOM and 12 weeks in delayed IOM) or a long-term antibiotic treatment (12 weeks in early IOM or until fracture healing or implant removal in delayed IOM). The antibiotic treatment will be that used in routine practice by the specialist in infectious diseases. The primary outcome is the composited variable "cure" that includes clinical cure, radiological healing, and definitive soft tissue coverage, which will be evaluated in the test of cure at 12 months after the end of antibiotic therapy. Adverse events, resistance development during therapy and functional status will be collected. A total of 364 patients are needed to show a 10% non-inferiority margin, with 80% power and 5% one-sided significance level. DISCUSSION: If the hypothesis of non-inferiority of short vs. long antibiotic treatments is demonstrated, and the efficacy of antibiotics with less ecological impact in long treatments, the impact on reduction of bacterial resistance, toxicity and health costs will be observed. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT05294796) on Jan 26th 2022 and at the European Union Drug Regulating Authorities Clinical Trials (EUDRACT) (2021-003914-38) on Jul 16th 2021. The Sponsor Study Code is DURATIOM.

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).

Revisiting the epidemiology of bloodstream infections and healthcare-associated episodes: results from a multicentre prospective cohort in Spain (PRO-BAC Study).

The epidemiology of bloodstream infections (BSIs) is dynamic as it depends on microbiological, host and healthcare system factors. The aim of this study was to update the information regarding the epidemiology of BSIs in Spain considering the type of acquisition. An observational, prospective cohort study in 26 Spanish hospitals from October 2016 through March 2017 including all episodes of BSI in adults was performed. Bivariate analyses stratified by type of acquisition were performed. Multivariate analyses were performed by logistic regression. Overall, 6345 BSI episodes were included; 2510 (39.8%) were community-acquired (CA), 1661 (26.3%) were healthcare-associated (HCA) and 2056 (32.6%) hospital-acquired (HA). The 30-day mortality rates were 11.6%, 19.5% and 22.0%, respectively. The median age of patients was 71 years (interquartile range 60-81 years) and 3656 (58.3%; 95% confidence interval 57.1-59.6%) occurred in males. The proportions according to patient sex varied according to age strata. Escherichia coli (43.8%), Klebsiella spp. (8.9%), Staphylococcus aureus (8.9%) and coagulase-negative staphylococci (7.4%) were the most frequent pathogens. Multivariate analyses confirmed important differences between CA and HCA episodes, but also between HCA and HA episodes, in demographics, underlying conditions and aetiology. In conclusion, we have updated the epidemiological information regarding patients' profiles, underlying conditions, frequency of acquisition types and aetiological agents of BSI in Spain. HCA is confirmed as a distinct type of acquisition.

Liver manifestations in COVID-19 and the influence of pre-existing liver disease in the course of the infection.

INTRODUCTION: patients with advanced chronic liver disease (CLD) may be at an increased risk of a severe course due to cirrhosis-associated immune dysfunction. The aim of this study was to determine the prevalence of CLD in COVID-19 patients and to analyze the course of the infection, compared with patients with non-liver disease. MATERIALS AND METHODS: this was a retrospective single center study of all patients with a positive SARS-CoV-2 polymerase chain reaction (PCR) test from March 23rd to April 30th, 2020. Clinical and biochemical data of patients with and without CLD and COVID-19 were collected from the medical records. RESULT: four hundred and forty-seven patients with a SARS-CoV-2 positive PCR were included, 6.3 % had CLD; 69.7 % of patients with CLD were male, with a median age of 65.5 years and active alcohol consumption and smoking; 75 % had non-advanced liver fibrosis and most had non-alcoholic fatty liver disease (NAFLD). The hospital admission rate (92.9 % vs 47.7 %, p < 0.001), concomitant comorbidities (diabetes 38.5 vs 16.5 %, p = 0.011; obesity 30.8 vs 8.5 %, p = 0.033; cancer 23.1 vs 5 %, p = 0.027; and chronic obstructive pulmonary disease (COPD) 19.2 vs 9 %, p = 0.009) and concomitant antibiotics treatment (19.3 vs 5 %, p = 0.018) were higher in patients with CLD than in those without CLD. In-patient hospital mortality rates were similar in both groups (30.8 vs 19.6 %, p = 0.289). The presence of CLD was not associated with mortality (OR = 1.06; 95 % CI = 0.35-3.18; p = 0.924). However, patients with CLD and COVID-19 who were male, obese or under concomitant antibiotic treatment had the highest risk of mortality according to the univariate analysis. CONCLUSION: patients with CLD had a higher risk of hospital admission, with worse outcomes during the COVID-19 infection associated to other concomitant comorbidities and a suspicion of bacterial co-infection.

Targeted simplification versus antipseudomonal broad-spectrum beta-lactams in patients with bloodstream infections due to Enterobacteriaceae (SIMPLIFY): a study protocol for a multicentre, open-label, phase III randomised, controlled, non-inferiority clinical trial.

INTRODUCTION: Within the context of antimicrobial stewardship programmes, de-escalation of antimicrobial therapy is one of the proposed strategies for reducing the unnecessary use of broad-spectrum antibiotics (BSA). The empirical treatment of nosocomial and some healthcare-associated bloodstream infections (BSI) frequently includes a beta-lactam with antipseudomonal activity as monotherapy or in combination with other drugs, so there is a great opportunity to optimise the empirical therapy based on microbiological data. De-escalation is assumed as standard of care for experts in infectious diseases. However, it is less frequent than it would desirable. METHODS AND ANALYSIS: The SIMPLIFY trial is a multicentre, open-label, non-inferiority phase III randomised controlled clinical trial, designed as a pragmatic 'real-practice' trial. The aim of this trial is to demonstrate the non-inferiority of de-escalation from an empirical beta-lactam with antipseudomonal activity to a targeted narrow-spectrum antimicrobial in patients with BSI due to Enterobacteriaceae. The primary outcome is clinical cure, which will be assessed at the test of cure visit. It will be conducted at 19 Spanish public and university hospitals. ETHICS AND DISSEMINATION: Each participating centre has obtained the approval of the ethics review committee, the agreement of the directors of the institutions and authorisation from the Spanish Regulatory Agency (Agencia Española del Medicamento y Productos Sanitarios). Data will be presented at international conferences and published in peer-reviewed journals. DISCUSSION: Strategies to reduce the use of BSA should be a priority. Most of the studies that support de-escalation are observational, retrospective and heterogeneous. A recent Cochrane review stated that well-designed clinical trials should be conducted to assess the safety and efficacy of de-escalation. TRIAL REGISTRATION NUMBER: The European Union Clinical Trials Register: EudraCT number 2015-004219-19. Clinical trials.gov: NCT02795949. Protocol version: V.2.0, dated 16 May 2016. All items from the WHO Trial Registration Data Set are included in the registry.

EUropean prospective cohort study on Enterobacteriaceae showing REsistance to CArbapenems (EURECA): a protocol of a European multicentre observational study.

INTRODUCTION: The rapid worldwide spread of carbapenem-resistant Enterobacteriaceae (CRE) constitutes a major challenge. The aim of the EUropean prospective cohort study on Enterobacteriaceae showing REsistance to CArbapenems (EURECA), which is part of the Innovative Medicines Initiative Joint Undertaking (IMI JU) funded COMBACTE-CARE project, is to investigate risk factors for and outcome determinants of CRE infections to inform randomised clinical trial designs and to provide a historical cohort that could eventually be used for future comparisons with new drugs targeting CRE. METHODS: A multicentre (50 sites), multinational (11 European countries), analytical observational project was designed, comprising 3 studies. The aims of study 1 (a prospective cohort study) include characterising the features, clinical management and outcomes of hospitalised patients with intra-abdominal infection, pneumonia, complicated urinary tract infections and bloodstream infections caused by CRE (202 patients in each group). The main outcomes will be 30-day all-cause mortality and clinical response. Study 2 (a nested case-control study) will identify the risk factors for target infections caused by CRE; 248 selected patients from study 1 will be matched with patients with carbapenem-susceptible Enterobacteriaceae (1:1) and with hospitalised patients (1:3) and will provide a historical cohort of patients with CRE infections. Study 3 (a matched cohort study) will follow patients in study 2 in order to assess mortality, length of stay and hospital costs associated with CRE. All patients will be followed for 30 days. Different, up-to-date statistical methods will be applied to come to unbiased estimates for all 3 studies. ETHICS AND DISSEMINATION: Before-study sites will be initiated, approval will be sought from appropriate regulatory agencies and local Ethics Committees of Research or Institutional Review Boards (IRBs) to conduct the study in accordance with regulatory requirements. This is an observational study and therefore no intervention in the diagnosis, management or treatment of the patients will be required on behalf of the investigation. Any formal presentation or publication of data collected from this study will be considered as a joint publication by the participating physician(s) and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE) for authorship. TRIAL REGISTRATION NUMBER: NCT02709408.

The use of ertapenem for the treatment of community-acquired pneumonia in routine hospital practice: a matched cohort study / Uso de ertapenem en la neumonía adquirida en la comunidad en la práctica clínica diaria: estudio de cohortes pareadas

Background. The clinical response to ertapenem in community-acquired pneumonia (CAP) at the setting of routine hospital practice has been scarcely evaluated. Methods. We retrospectively compared CAP cases treated with ertapenem or with other standard antimicrobials (controls) at a tertiary 1,434-bed center from 2005 to 2014. Results. Out of 6,145 patients hospitalized with CAP, 64 (1%) ertapenem-treated and 128 controls were studied (PSI IV-V 72%, mean age 73 years.). A significant higher proportion of bedridden patients (41% vs. 21%), residence in nursing homes (19% vs. 7%), previous use of antibiotics (39% vs. 29%) and necrotizing (13% vs. 1%) or complicated (36% vs. 19%) pneumonia, was observed in the ertapenem vs. non-ertapenem patients. Initial treatment with ertapenem was independently associated with an earlier resolution of signs of infection. In patients aged 65 or older the independent risks factors for mortality were: PSI score (7.0, 95%CI 1.8-27.7), bedridden status (4.6, 95%CI 1.1-20.9) and Health Care Associated Pneumonia (HCAP) (4.6, 95%CI 1.3-16.5). First-line treatment with ertapenem was an independent protector factor in this subgroup of patients (0.1, 95%CI 0.1-0.7). Conclusions. Ertapenem showed a superior clinical response in frail elderly patients with complicated community- acquired pneumonia, and it may be considered as a firstline therapeutic regimen in this setting (AU)

Introducción. La respuesta clínica a ertapenem en la neumonía adquirida en la comunidad (NAC) en el contexto de la práctica clínica diaria ha sido evaluada de forma insuficiente. Material y Métodos. Estudio retrospectivo, comparativo de pacientes con NAC tratados con ertapenem o con otros antimicrobianos en un hospital terciario de 1.434 camas en el período 2005-2014. Resultados. De los 6.145 pacientes hospitalizados con NAC, 64 (1%) tratados con ertapenem y 128 controles fueron incluidos en el estudio (PSI IV-V 72%, edad media 73 años). Se observó una proporción significativamente mayor de pacientes encamados (41% vs. 21%), institucionalizados (19% vs. 7%), con antibioterapia previa (39% vs. 29%) y con neumonías necrotizantes (13% vs. 1%) o complicadas (36% vs. 19%) en el grupo de ertapenem vs. no-ertapenem. El tratamiento inicial con ertapenem se asoció de forma independiente con una resolución más temprana de los signos de infección. En el subgrupo de pacientes con 65 años o más, los factores independientes de riesgo de mortalidad fueron: PSI score (7,0 IC95% 1,8-27,7), encamamiento (4,6 IC95% 1,1-20,9) y la Neumonía Asociada a Cuidados Sanitarios (NACS) (4,6 IC95% 1,3-16,5). El tratamiento en primera línea con ertapenem fue un factor protector independiente en este grupo de pacientes (0,1 IC95% 0,1-0,7). Conclusiones. El tratamiento con ertapenem se asoció a una respuesta clínica superior en el paciente anciano frágil con NAC complicada y se podría considerar como un régimen terapéutico de primera línea en este contexto (AU)