Association of microbiological factors with mortality in Escherichia coli bacteraemia presenting with sepsis/septic shock: A prospective cohort study.

OBJECTIVES: This study aimed to determine the association of E. coli microbiological factors with 30-day mortality in BSI patients presenting with a dysregulated response to infection (i.e., sepsis or septic shock). METHODS: Whole genome sequencing was performed on 224 E. coli isolates of patients with sepsis/septic shock, from 22 Spanish hospitals. Phylogroup, sequence type, virulence, antibiotic resistance and pathogenicity islands were assessed. A multivariable model for 30-day mortality including clinical and epidemiological variables was built, to which microbiological variables were hierarchically added. The predictive capacity of the models was estimated by the area under the receiver operating characteristic curve (AUROC) with 95% confidence intervals (CI). RESULTS: Mortality at day 30 was 31% (69 patients). The clinical model for mortality included (adjusted OR; 95% CI) age (1.04; 1.02-1.07), Charlson index ≥3 (1.78; 0.95-3.32), urinary BSI source (0.30; 0.16-0.57) and active empirical treatment (0.36; 0.11-1.14) with an AUROC of 0.73 (95% CI, 0.67-0.80). Addition of microbiological factors selected clone ST95 (3.64; 0.94-14.04), eilA gene (2.62; 1.14-6.02) and astA gene (2.39; 0.87-6.59) as associated with mortality, with an AUROC of 0.76 (0.69-0.82). CONCLUSIONS: Despite having a modest overall contribution, some microbiological factors were associated with increased odds of death and would deserve being studied as potential therapeutic or preventive targets.

Whole-genome characterisation of Escherichia coli isolates from patients with bacteraemia presenting with sepsis or septic shock in Spain: a multicentre cross-sectional study.

BACKGROUND: Escherichia coli is the most frequent cause of bloodstream infections (BSIs). About one-third of patients with BSIs due to E coli develop sepsis or shock. The objective of this study is to characterise the microbiological features of E coli blood isolates causing sepsis or septic shock to provide exploratory information for future diagnostic, preventive, or therapeutic interventions. METHODS: E coli blood isolates from a multicentre cross-sectional study of patients older than 14 years presenting with sepsis or septic shock (according to the Third International Consensus Definitions for Sepsis and Septic Shock criteria) from hospitals in Spain between Oct 4, 2016, and Oct 15, 2017, were studied by whole-genome sequencing. Phylogroups, sequence types (STs), serotype, FimH types, antimicrobial resistance (AMR) genes, pathogenicity islands, and virulence factors were identified. Susceptibility testing was performed by broth microdilution. The main outcome of this study was the characterisation of the E coli blood isolates in terms of population structure by phylogroups, groups (group 1: phylogroups B2, F, and G; group 2: A, B1, and C; group 3: D), and STs and distribution by geographical location and bloodstream infection source. Other outcomes were virulence score and prevalence of virulence-associated genes, pathogenicity islands, AMR, and AMR-associated genes. Frequencies were compared using χ² or Fisher's exact tests, and continuous variables using the Mann-Whitney test, with Bonferroni correction for multiple comparisons. FINDINGS: We analysed 224 isolates: 140 isolates (63%) were included in phylogenetic group 1, 52 (23%) in group 2, and 32 (14%) in group 3. 85 STs were identified, with four comprising 44% (n=98) of the isolates: ST131 (38 [17%]), ST73 (25 [11%]), ST69 (23 [10%]), and ST95 (12 [5%]). No significant differences in phylogroup or ST distribution were found according to geographical areas or source of bloodstream infection, except for ST95, which was more frequent in urinary tract infections than in other sources (11 [9%] of 116 vs 1 [1%] of 108, p=0·0045). Median virulence score was higher in group 1 (median 25·0 [IQR 20·5-29·0) than in group 2 (median 14·5 [9·0-20·0]; p<0·0001) and group 3 (median 21 [16·5-23·0]; p<0·0001); prevalence of several pathogenicity islands was higher in group 1. No significant differences were found between phylogenetic groups in proportions of resistance to antibiotics. ST73 had higher median virulence score (32 [IQR 29-35]) than the other predominant clones (median range 21-28). Some virulence genes and pathogenicity islands were significantly associated with each ST. ST131 isolates had higher prevalence of AMR and a higher proportion of AMR genes, notably blaCTX-M-15 and blaOXA-1. INTERPRETATION: In this exploratory study, the population structure of E coli causing sepsis or shock was similar to previous studies that included all bacteraemic isolates. Virulence genes, pathogenicity islands, and AMR genes were not randomly distributed among phylogroups or STs. These results provide a comprehensive characterisation of invasive E coli isolates causing severe response syndrome. Future studies are required to determine the contribution of these microbiological factors to severe clinical presentation and worse outcomes in patients with E coli bloodstream infection. FUNDING: Instituto de Salud Carlos III.

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.

Host genetic variants associated with susceptibility and severity of pneumococcal pneumonia in adult patients.

BACKGROUND: Pneumococcal community-acquired pneumonia (P-CAP) is a major cause of morbidity and hospitalization. Several host genetics factors influencing risk of pneumococcal disease have been identified, with less information about its association with P-CAP. The aim of the study was to assess the influence of single nucleotide polymorphisms (SNP) within key genes involved in the innate immune response on the susceptibility to P-CAP and to study whether these polymorphic variants were associated with the severity and outcome of the episodes in a cohort of adult Caucasian patients. METHODS: Seventeen SNPs from 7 genes (IL-R1, IL-4, IL-10, IL-12B, NFKBIA, NFKBIE, NFKBIZ) were analyzed. For susceptibility, a case-control study including a cohort of 57 adult with P-CAP, and 280 ethnically matched controls was performed. Genetic influence on clinical severity and outcome was evaluated in a prospective observational study including all consecutive adult P-CAP patients from November 2015 to May 2017. RESULTS: The NFKBIA polymorphism rs696 and a haplotype combination were associated with susceptibility to P-CAP (OR = 0.62, p = 0.005 and OR = 0.63, p = 0.008, respectively). The SNP IL4 rs2227284 was associated with severe P-CAP (OR = 2.17, p = 0.04). IL-R1 (rs3917267) and IL-10 (rs3024509) variants were related with respiratory failure (OR = 3.31, p = 0.001 and OR = 0.18, p = 0.003, respectively) as well as several haplotype combinations in NFKBIA, NFKBIZ, IL-R1 and IL-10 (p = 0,02, p = 0,01, p = 0,001, p = 0,03, respectively). CURB-65 values were associated with the IL-10 rs3024509 variant (beta = - 0.4, p = 0.04), and with haplotype combinations of NFKBIZ and IL-10 (p = 0.05, p = 0.04, respectively). Genetic variants in IL-10 (rs3024509) and in IL-12B (rs730691) were associated with PSI values (beta = - 0.54, p = 0.01, and beta = - 0.28, p = 0.04, respectively), as were allelic combinations in IL-R1 (p = 0.02) and IL-10 (p = 0.01). Finally, several polymorphisms in the IL-R1 gene (rs13020778, rs2160227, & rs3917267) were associated with the time elapsed until clinical stability (beta = - 0.83, p = 0.03; beta = - 1, p = 0.02 and beta = 1.07, p = 0.008, respectively). CONCLUSIONS: A genetic variant in NFKBIA was associated with susceptibility to P-CAP in adult Caucasian patients and genetic variants from key cytokines of the innate immune response (Il-4, IL-10, IL-R1 and IL-12B) and NF-κB inhibitors were associated with different phenotypes of severe P-CAP. If validated, these SNPs may help to identify people at risk of P-CAP or severe P-CAP on which preventive measures could be applied.

Contemporary use of cefazolin for MSSA infective endocarditis: analysis of a national prospective cohort.

OBJECTIVES: This study aimed to assess the real use of cefazolin for methicillin-susceptible Staphylococcus aureus (MSSA) infective endocarditis (IE) in the Spanish National Endocarditis Database (GAMES) and to compare it with antistaphylococcal penicillin (ASP). METHODS: Prospective cohort study with retrospective analysis of a cohort of MSSA IE treated with cloxacillin and/or cefazolin. Outcomes assessed were relapse; intra-hospital, overall, and endocarditis-related mortality; and adverse events. Risk of renal toxicity with each treatment was evaluated separately. RESULTS: We included 631 IE episodes caused by MSSA treated with cloxacillin and/or cefazolin. Antibiotic treatment was cloxacillin, cefazolin, or both in 537 (85%), 57 (9%), and 37 (6%) episodes, respectively. Patients treated with cefazolin had significantly higher rates of comorbidities (median Charlson Index 7, P <0.01) and previous renal failure (57.9%, P <0.01). Patients treated with cloxacillin presented higher rates of septic shock (25%, P = 0.033) and new-onset or worsening renal failure (47.3%, P = 0.024) with significantly higher rates of in-hospital mortality (38.5%, P = 0.017). One-year IE-related mortality and rate of relapses were similar between treatment groups. None of the treatments were identified as risk or protective factors. CONCLUSION: Our results suggest that cefazolin is a valuable option for the treatment of MSSA IE, without differences in 1-year mortality or relapses compared with cloxacillin, and might be considered equally effective.

Cloxacillin plus fosfomycin versus cloxacillin alone for methicillin-susceptible Staphylococcus aureus bacteremia: a randomized trial.

Treatment failure occurs in about 25% of patients with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. We assessed whether cloxacillin plus fosfomycin achieves better treatment success than cloxacillin alone in hospitalized adults with MSSA bacteremia. We conducted a multicenter, open-label, phase III-IV superiority randomized clinical trial. We randomly assigned patients (1:1) to receive 2 g of intravenous cloxacillin alone every 4 h or with 3 g of intravenous fosfomycin every 6 h for the initial 7 days. The primary endpoint was treatment success at day 7, a composite endpoint with the following criteria: patient alive, stable or with improved quick Sequential Organ Failure Assessment score, afebrile and with negative blood cultures for MSSA, adjudicated by an independent committee blinded to treatment allocation. We randomized 215 patients, of whom 105 received cloxacillin plus fosfomycin and 110 received cloxacillin alone. We analyzed the primary endpoint with the intention-to-treat approach in 214 patients who received at least 1 day of treatment. Treatment success at day 7 after randomization was achieved in 83 (79.8%) of 104 patients receiving combination treatment versus 82 (74.5%) of 110 patients receiving monotherapy (risk difference 5.3%; 95% confidence interval (CI), -5.95-16.48). Secondary endpoints, including mortality and adverse events, were similar in the two groups except for persistent bacteremia at day 3, which was less common in the combination arm. In a prespecified interim analysis, the independent committee recommended stopping recruitment for futility prior to meeting the planned randomization of 366 patients. Cloxacillin plus fosfomycin did not achieve better treatment success at day 7 of therapy than cloxacillin alone in MSSA bacteremia. Further trials should consider the intrinsic heterogeneity of the infection by using a more personalized approach. ClinicalTrials.gov registration: NCT03959345 .

Reducing the duration of antibiotic therapy in surgical patients through a specific nationwide antimicrobial stewardship program. A prospective, interventional cohort study.

BACKGROUND: Guidelines recommend 5-7 days of antibiotic treatment in patients with surgical infection and adequate source control. This nationwide stewardship intervention aimed to reduce the duration of treatments in surgical patients to <7 days. METHODS: Prospective cohort study evaluating surgical patients receiving antibiotics ≥7 days in 32 hospitals. Indication for treatment, quality of source control, type of recommendations issued, and adherence to the recommendations were analysed. Temporal trends in the percentages of patients with treatment >7 days were evaluated using a linear regression model and Pearson's correlation coefficients. RESULTS: A total of 32 499 patients were included. Of these, 13.7% had treatments ≥7 days. In all, 3912 stewardship interventions were performed, primarily in general surgery (90.7%) and urology (8.1%). The main types of infection were intra-abdominal (73.4%), skin/soft tissues (9.8%) and urinary (9.2%). The septic focus was considered controlled in 59.9% of cases. Out of 5458 antibiotic prescriptions, the most frequently analysed drugs were piperacillin/tazobactam (21.7%), metronidazole (11.2%), amoxicillin/clavulanate (10.3%), meropenem (10.7%), ceftriaxone (9.3%) and ciprofloxacin (6.7%). The main recommendations issued were: treatment discontinuation (35.0%), maintenance (40.0%) or de-escalation (15.5%), and the overall adherence rate was 91.5%. With adequate source control, the most frequent recommendation was to terminate treatment (51.2%). Throughout the study period, a significant decrease in the percentage of prolonged treatments was observed (Pc=-0.69;P < 0.001). CONCLUSIONS: This stewardship programme reduced the duration of treatments in surgical departments. Preference was given to general surgery services, intra-abdominal infection, and beta-lactam antibiotics, including carbapenems. Adherence to the issued recommendations was high.

EN-DALBACEN 2.0 Cohort: real-life study of dalbavancin as sequential/consolidation therapy in patients with infective endocarditis due to Gram-positive cocci.

OBJECTIVES: Infective endocarditis (IE) has high mortality and morbidity and requires long hospital stays to deliver the antibiotic treatment recommended in clinical practice guidelines. We aimed to analyse the health outcomes of the use of dalbavancin (DBV) in the consolidation treatment of IEs caused by Gram-positive cocci and to perform a pharmacoeconomic study. MATERIALS AND METHODS: This observational, retrospective, Spanish multicentre study in patients with IE who received DBV as part of antibiotic treatment in consolidation phase were followed for at least 12 months. The study was approved by the Provincial Committee of the coordinating centre. RESULTS: The study included 124 subjects, 70.2% male, with a mean age of 67.4 years and median Charlson index of 4 (interquartile range: 2.5-6). Criteria for definite IE were met by 91.1%. Coagulase-negative staphylococci (38.8%), Staphylococcus aureus (22.6%), Enterococcus faecalis (19.4%), and Streptococcus Spp. (9.7%) were isolated more frequently, all susceptible to vancomycin. Before DVB administration, 91.2% had undergone surgery; 60.5% had received a second regimen for 24.5 d (16.6-56); and 20.2% had received a third regimen for 14.5 d (12-19.5). DBV was administered to facilitate discharge in 95.2% of cases. At 12 months, the effectiveness was of 95.9%, and there was 0.8% loss to follow-up, 0.8% IE-related death, and 3.2% relapse. Adverse events were recorded in 3.2%. The hospital stay was reduced by 14 d, and there was a mean savings of 5548.57 €/patient vs. conventional treatments. CONCLUSION: DBV is highly effective, safe, and cost-effective as consolidation therapy in patients with IE by Gram-positive cocci, with few adverse events.

Evaluation of Plasma Lipocalin-2 as a Predictor of Etiology and Severity in Adult Patients with Community-Acquired Pneumonia.

The aim of this study was to evaluate the diagnostic performance of plasma Lipocalin-2 (LCN2) concentration in adult patients with community-acquired pneumonia (CAP) to determine its etiology, severity and prognosis. A prospective observational study involving adults with CAP from November 2015 to May 2017 was conducted. Plasma LCN2 concentration was measured upon admission by a modified enzyme immunoassay coupled with chemiluminescence (Architect, Abbott Laboratories). The diagnostic performance of LCN2, C-reactive protein (CRP) and white blood cell to predict bacterial CAP was assessed. A total of 130 patients with CAP were included: 71 (54.6%) bacterial CAP, 42 (32.3%) unknown origin CAP and 17 (13.1%) viral CAP. LCN2 was higher in bacterial CAP than in non-bacterial CAP (122.0 vs. 89.7 ng/mL, respectively) (p = 0.03) with a limited ability to distinguish bacterial and non-bacterial CAP (AUROC: 0.62 [95% CI 0.52-0.72]). The LCN2 cutoff ≥ 204 ng/mL predicted the presence of pneumococcal bacteremia with an AUROC of 0.74 (sensitivity 70%, specificity 79.1%). Regarding severity, as defined by CURB-65 and PSI scores, there was a significant linear trend in the mean concentration of LCN2, exhibiting a shift from the low-risk to the intermediate-risk and high-risk group (p < 0.001 and 0.001, respectively). LCN2 concentration was associated with severity in adult patients with CAP. However, its utility as a biomarker to discriminate viral and bacterial etiology in CAP is limited.

The hidden side of infective endocarditis: Diagnostic and management of 500 consecutive cases in noncardiac surgery centers (2009-2018).

BACKGROUND: We aimed to describe infective endocarditis cases from noncardiac surgery centers, as current knowledge on infective endocarditis is derived mostly from cardiac surgery hospitals. METHODS: An observational retrospective study (2009-2018) was conducted in 9 noncardiac surgery hospitals in Central Catalonia. All adult patients diagnosed with definitive infective endocarditis were included. Transferred and nontransferred cohorts were compared, and a logistic regression model was used to ascertain the prognostic factors. RESULTS: Overall, 502 infective endocarditis episodes were included: 183 (36.5%) were transferred to the cardiac surgery center, whereas 319 were not, with (18.7%) and without (45%) surgical indications. Cardiac surgery was performed in 83% of transferred patients. In-hospital (14% vs 23%) and 1-year (20% vs 35%) mortality rates were significantly lower in transferred patients (P < .001). Among the patients not undergoing cardiac surgery despite an indication, 55 (54%) died within 1 year. The multivariate analysis identified the following independent predictive factors for in-hospital mortality: Staphylococcus aureus infective endocarditis (odds ratio: 1.93 [1.08, 3.47]), heart failure (odds ratio: 3.87 [2.28, 6.57]), central nervous system embolism (odds ratio: 2.95 [1.41, 5.14]), and Charlson score (odds ratio: 1.19 [1.09, 1.30]), whereas community acquisition (odds ratio: 0.52 [0.29, 0.93]), cardiac surgery (odds ratio: 0.42 [0.20, 0.87]), but not transfer (odds ratio: 1.23 [0.84, 3.95]) were identified as protective factors. One-year mortality was associated with S. aureus infective endocarditis (odds ratio: 1.82 [1.04, 3.18]), heart failure (odds ratio: 3.74 [2.27, 6.16]), and Charlson score (odds ratio: 1.23 [1.13, 1.33]), whereas cardiac surgery (odds ratio: 0.41 [0.21, 0.79]) was identified as a protective factor. CONCLUSION: Patients not transferred to a referral cardiac surgery center have a worse prognosis compared to those ultimately transferred, as cardiac surgery is associated with lower mortality rates.

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.

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.

Changing Trends in the Global Consumption of Treatments Used in Hospitalized Patients for COVID-19: A Time Series Multicentre Study.

AIM: To analyze trends in the prescription of COVID-19 treatments for hospitalized patients during the pandemic. METHODS: Multicenter, ecological, time-series study of aggregate data for all adult patients with COVID-19 treated in five acute-care hospitals in Barcelona, Spain, between March 2020 and May 2021. Trends in the monthly prevalence of drugs used against COVID-19 were analyzed by the Mantel-Haenszel test. RESULTS: The participating hospitals admitted 22,277 patients with COVID-19 during the study period, reporting an overall mortality of 10.8%. In the first months of the pandemic, lopinavir/ritonavir and hydroxychloroquine were the most frequently used antivirals, but these fell into disuse and were replaced by remdesivir in July 2020. By contrast, the trend in tocilizumab use varied, first peaking in April and May 2020, declining until January 2021, and showing a discrete upward trend thereafter. Regarding corticosteroid use, we observed a notable upward trend in the use of dexamethasone 6 mg per day from July 2020. Finally, there was a high prevalence of antibiotics use, especially azithromycin, in the first three months, but this decreased thereafter. CONCLUSIONS: Treatment for patients hospitalized with COVID-19 evolved with the changing scientific evidence during the pandemic. Initially, multiple drugs were empirically used that subsequently could not demonstrate clinical benefit. In future pandemics, stakeholders should strive to promote the early implementation of adaptive randomized clinical trials.

Risk factors associated with inappropriate empirical antimicrobial treatment in bloodstream infections. A cohort study.

Introduction: Bloodstream infections (BSI) are a major cause of mortality all over the world. Inappropriate empirical antimicrobial treatment (i-EAT) impact on mortality has been largely reported. However, information on related factors for the election of i-EAT in the treatment of BSI in adults is lacking. The aim of the study was the identification of risk-factors associated with the use of i-EAT in BSI. Methods: A retrospective, observational cohort study, from a prospective database was conducted in a 400-bed acute-care teaching hospital including all BSI episodes in adult patients between January and December 2018. The main outcome variable was EAT appropriation. Multivariate analysis using logistic regression was performed. Results: 599 BSI episodes were included, 146 (24%) received i-EAT. Male gender, nosocomial and healthcare-associated acquisition of infection, a high Charlson Comorbidity Index (CCI) score and the isolation of multidrug resistant (MDR) microorganisms were more frequent in the i-EAT group. Adequation to local guidelines' recommendations on EAT resulted in 91% of appropriate empirical antimicrobial treatment (a-EAT). Patients receiving i-EAT presented higher mortality rates at day 14 and 30 when compared to patients with a-EAT (14% vs. 6%, p = 0.002 and 22% vs. 9%, p < 0.001 respectively). In the multivariate analysis, a CCI score ≥3 (OR 1.90 (95% CI 1.16-3.12) p = 0.01) and the isolation of a multidrug resistant (MDR) microorganism (OR 3.79 (95% CI 2.28-6.30), p < 0.001) were found as independent risk factors for i-EAT. In contrast, female gender (OR 0.59 (95% CI 0.35-0.98), p = 0.04), a correct identification of clinical syndrome prior to antibiotics administration (OR 0.26 (95% CI 0.16-0.44), p < 0.001) and adherence to local guidelines (OR 0.22 (95% CI 0.13-0.38), p < 0.001) were identified as protective factors against i-EAT. Conclusion: One quarter of BSI episodes received i-EAT. Some of the i-EAT related factors were unmodifiable (male gender, CCI score ≥3 and isolation of a MDR microorganism) but others (incorrect identification of clinical syndrome before starting EAT or the use of local guidelines for EAT) could be addressed to optimize the use of antimicrobials.

Conventional Hospitalization versus Sequential Outpatient Parenteral Antibiotic Therapy for Staphylococcus aureus Bacteremia: Post-Hoc Analysis of a Multicenter Observational Cohort.

It is not known whether sequential outpatient parenteral antimicrobial (OPAT) is as safe and effective as conventional hospitalization in patients with S. aureus bacteremia (SAB). A post-hoc analysis of the comparative effectiveness of conventional hospitalization versus sequential OPAT was performed in two prospective Spanish cohorts of patients with S. aureus bacteremia. The PROBAC cohort is a national, multicenter, prospective observational cohort of patients diagnosed in 22 Spanish hospitals between October 2016 and March 2017. The DOMUS OPAT cohort is a prospective observational cohort including patients from two university hospitals in Seville, Spain from 2012 to 2021. Multivariate regression was performed, including a propensity score (PS) for receiving OPAT, stratified analysis according to PS quartiles, and matched pair analyses based on PS. Four hundred and thirteen patients were included in the analysis: 150 in sequential OPAT and 263 in the full hospitalization therapy group. In multivariate analysis, including PS and center effect as covariates, 60-day treatment failure was lower in the OPAT group than in the full hospitalization group (p < 0.001; OR 0.275, 95%CI 0.129−0.584). In the PS-based matched analyses, sequential treatment under OPAT was not associated with higher 60-day treatment failure (p = 0.253; adjusted OR 0.660; % CI 0.324−1.345). OPAT is a safe and effective alternative to conventional in-patient therapy for completion of treatment in well-selected patients with SAB, mainly those associated with a low-risk source and without end-stage kidney disease.

Multivalvular Endocarditis: A Rare Condition with Poor Prognosis.

Background. Infective endocarditis (IE) is a severe condition. Our aim was to describe the profile and prognosis of patients with multivalvular infective endocarditis (MIE) and compare them to single-valve IE (SIE). Methods. We used a retrospective analysis of the Spanish IE Registry (2008−2020). Results. From 4064 definite cases of valvular IE, 577 (14.2%) had MIE. In patients with MIE, the most common locations were mitral (552, 95.7%) and aortic (550, 95.3%), with mitral-aortic involvement present in 507 patients (87.9%). The most common etiologies were S. viridans (192, 33.3%) and S. aureus (113, 19.6%). MIE involved only native valves in 450 patients (78.0%). Compared with patients with SIE, patients with MIE had a similar age (69 vs. 67 years, respectively, p = 0.27) and similar baseline characteristics, but were more frequently men (67.1% vs. 72.9%, p = 0.005) and had a higher incidence of intracardiac complications (36.2% vs. 50.4%, p < 0.001), heart failure (42.7% vs. 52.9%, p < 0.001), surgical indication (67.7 vs. 85.1%, p < 0.001), surgery (46.3% vs. 56.3%), and in-hospital mortality (26.9% vs. 34.3%, p < 0.001). MIE was an independent predictor of in-hospital mortality (odds ratio (OR) 1.3, 95% confidence interval (CI) 1.1−1.7, p = 0.004) but did not have an independent association with 1-year mortality (OR 1.1, 95% CI 0.9−1.4, p = 0.43). Conclusions. About one-seventh of the valvular IE patients had MIE, mainly due to mitral-aortic involvement. MIE is associated with a poor in-hospital prognosis. An early diagnosis and treatment of IE might avoid its spread to a second valve.

Pseudomonas aeruginosa Community-Onset Bloodstream Infections: Characterization, Diagnostic Predictors, and Predictive Score Development-Results from the PRO-BAC Cohort.

Community-onset bloodstream infections (CO-BSI) caused by gram-negative bacilli are common and associated with significant mortality; those caused by Pseudomonas aeruginosa are associated with worse prognosis and higher rates of inadequateempirical antibiotic treatment. The aims of this study were to describe the characteristics of patients with CO-BSI caused by P. aeruginosa, to identify predictors, and to develop a predictive score for P. aeruginosa CO-BSI. Materials/methods: PROBAC is a prospective cohort including patients >14 years with BSI from 26 Spanish hospitals between October 2016 and May 2017. Patients with monomicrobial P. aeruginosa CO-BSI and monomicrobial Enterobacterales CO-BSI were included. Variables of interest were collected. Independent predictors of Pseudomonas aeruginosa CO-BSI were identified by logistic regression and a prediction score was developed. Results: A total of 78patients with P. aeruginosa CO-BSI and 2572 with Enterobacterales CO-BSI were included. Patients with P. aeruginosa had a median age of 70 years (IQR 60−79), 68.8% were male, median Charlson score was 5 (IQR 3−7), and 30-daymortality was 18.5%. Multivariate analysis identified the following predictors of CO-BSI-PA [adjusted OR (95% CI)]: male gender [1.89 (1.14−3.12)], haematological malignancy [2.45 (1.20−4.99)], obstructive uropathy [2.86 (1.13−3.02)], source of infection other than urinary tract, biliary tract or intra-abdominal [6.69 (4.10−10.92)] and healthcare-associated BSI [1.85 (1.13−3.02)]. Anindex predictive of CO-BSI-PA was developed; scores ≥ 3.5 showed a negative predictive value of 89% and an area under the receiver operator curve (ROC) of 0.66. Conclusions: We did not find a good predictive score of P. aeruginosa CO-BSI due to its relatively low incidence in the overall population. Our model includes variables that are easy to collect in real clinical practice and could be useful to detect patients with very low risk of P. aeruginosa CO-BSI.

Novel genes and sex differences in COVID-19 severity.

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Risk Factors and Predictive Score for Bacteremic Biliary Tract Infections Due to Enterococcus faecalis and Enterococcus faecium: a Multicenter Cohort Study from the PROBAC Project.

Biliary-tract bloodstream infections (BT-BSI) caused by Enterococcus faecalis and E. faecium are associated with inappropriate empirical treatment and worse outcomes compared to other etiologies. The objective of this study was to investigate the risk factors for enterococcal BT-BSI. Patients with BT-BSI from the PROBAC cohort, including consecutive patients with BSI in 26 Spanish hospitals between October 2016 and March 2017, were selected; episodes caused by E. faecalis or E. faecium and other causes were compared. Independent predictors for enterococci were identified by logistic regression, and a predictive score was developed. Eight hundred fifty episodes of BT-BSI were included; 73 (8.5%) were due to target Enterococcus spp. (48 [66%] were E. faecium and 25 [34%] E. faecalis). By multivariate analysis, the variables independently associated with Enterococcus spp. were (OR; 95% confidence interval): cholangiocarcinoma (4.48;1.32 to 15.25), hospital acquisition (3.58;2.11 to 6.07), use of carbapenems in the previous month (3.35;1.45 to 7.78), biliary prosthesis (2.19;1.24 to 3.90), and moderate or severe chronic kidney disease (1.55;1.07 to 2.26). The AUC of the model was 0.74 [95% CI0.67 to 0.80]. A score was developed, with 7, 6, 5, 4, and 2 points for these variables, respectively, with a negative predictive value of 95% for a score ≤ 6. A model, including cholangiocarcinoma, biliary prosthesis, hospital acquisition, previous carbapenems, and chronic kidney disease showed moderate prediction ability for enterococcal BT-BSI. Although the score will need to be validated, this information may be useful for deciding empirical therapy in biliary tract infections when bacteremia is suspected. IMPORTANCE Biliary tract infections are frequent, and a significant cause of morbidity and mortality. Bacteremia is common in these infections, particularly in the elderly and patients with cancer. Inappropriate empirical treatment has been associated with increased risk of mortality in bacteremic cholangitis, and the probability of receiving inactive empirical treatment is higher in episodes caused by enterococci. This is because many of the antimicrobial agents recommended in guidelines for biliary tract infections lack activity against these organisms. To the best of our knowledge, this is the first study analyzing the predictive factors for enterococcal BT-BSI and deriving a predictive score.

Risk of cardiac device-related infection in patients with late-onset bloodstream infection. Analysis on a National Cohort.

OBJECTIVES: To determine the incidence of cardiac device-related infection (CDRI) among patients with cardiac device (CD) during late-onset bloodstream infection (BSI) and to identify the risk factors associated with CDRI. METHODS: Patients with a CD (cardiac implantable electronic devices -CIED- and/or prosthetic heart valve -PHV-) and late-onset-BSI (>1 year after the CD implantation/last manipulation) were selected from the PROBAC project, a prospective, observational cohort study including adult patients with bacteraemia consecutively admitted to 26 Spanish hospitals from October 2016 to March 2017. Multivariate analyses using logistic regression were performed to identify the risk factors associated with CDRI. RESULTS: 317 BSI from patients carrying a CD were registered, 187 (56.2%) were late-onset-BSI. A total of 40 (21.4%) CDRI were identified during late-onset-BSI. The CDRI cumulative incidence in Gram-positive-BSI was 41.8% (38/91), with S. aureus, Enterococcus spp. and viridans streptococci showing the greatest percentages: 40% (12/30), 42% (11/26) and 75% (6/8), respectively. Independent predictors of CDRI were an unknown source of infection (OR: 2.88 [CI 95%:1.18-7.06], p = 0.02), Gram-positive-aetiology (23.1 [5.23-102.1], p < 0.001) and persistent bacteraemia (4.81 [1.21-19], p = 0.03). In an exploratory analysis, S. aureus (3.99 [1.37-11.65], p = 0.011), Enterococcus spp. (5.21 [1.76-15.4], p = 0.003) and viridans streptococci (28.7 [4.71-173.5], p < 0.001) aetiology were also found to be risk factors for CDRI. CONCLUSIONS: CDRI during late-onset-BSI is a frequent phenomenon. Risk of CDRI differs among species, happening in almost half of the Gram-positive-BSI. An unknown source of the primary infection, Gram-positive-aetiology -especially S. aureus, Enterococcus spp. and viridans streptococci-, and persistent bacteraemia were identified as risk factors for CDRI.