Introduction: Alternatives to carbapenems are needed in the treatment of third-generation cephalosporin-resistant Enterobacterales (3GCR-E). Temocillin is a suitable candidate, but comparative randomised studies are lacking. The objective is to investigate if temocillin is non-inferior to carbapenems in the targeted treatment of bacteraemia due to 3GCR-E. Methods and analysis: Multicentre, open-label, randomised, controlled, pragmatic phase 3 trial. Patients with bacteraemia due to 3GCR-E will be randomised to receive intravenously temocillin (2 g three times a day) or carbapenem (meropenem 1 g three times a day or ertapenem 1 g once daily). The primary endpoint will be clinical success 7–10 days after end of treatment with no recurrence or death at day 28. Adverse events will be collected; serum levels of temocillin will be investigated in a subset of patients. For a 10% non-inferiority margin, 334 patients will be included (167 in each study arm). For the primary analysis, the absolute difference with one-sided 95% CI in the proportion of patients reaching the primary endpoint will be compared in the modified intention-to-treat population. Ethics and dissemination: The study started after approval of the Spanish Regulatory Agency and the reference institutional review board. Data will be published in peer-reviewed journals. Trial registration number: NCT04478721.

Introduction: Enterococcus spp is responsible for 8%–15% of total bacteraemias with an associated global mortality around 23%–30%. Regarding the clinical management of enterococcal bacteraemia, the evidence on the duration of antibiotic treatment is scarce and the studies do not discriminate between complicated and uncomplicated bacteraemia. Methods: The INTENSE study is a multicentre, open-label, randomised, pragmatic, phase-IV clinical trial to demonstrate the non-inferiority of a 7-day vs 14-day course for the treatment of uncomplicated enterococcal bacteraemia and incorporating the early switching to oral antibiotics when feasible. The primary efficacy endpoint is the clinical cure at day 30±2 after the end of the treatment. Secondary endpoints will include the rate of relapse or infective endocarditis, length of stay, duration of intravenous therapy, Clostridioides difficile infection and the evaluation of the safety of both treatment arms through the recording and analysis of adverse events. For a 6% non-inferiority margin and considering a 5% withdrawal rate, 284 patients will be included. Analysis: The difference in proportions with one-sided 95% CIs will be calculated for the clinical cure rate using the control group as reference. For secondary categorical endpoints, a similar analysis will be performed and Mann-Whitney U-test will be used to compare median values of quantitative variables. A superiority analysis applying the response adjusted for days of antibiotic risk will be performed if there were incidents in recruitment; will allow obtaining results with 194 patients recruited. Ethics and dissemination: The study has obtained the authorisation from the Spanish Regulatory Authority, the approval of the ethics committee and the agreement of the directors of each centre. Data will be published in peer-reviewed journals. Trial registration number: NCT05394298 .

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.

Objectives: For 475 ESBL-producing Escherichia coli (ESBL-Ec), and 171 ESBL-producing Klebsiella pneumoniae (ESBL-Kp) collected from human carriers, the human-polluted (hp)-environment, and food: (i) to compare the antimicrobial resistance gene (ARG) content, and (ii) to assess clonal relationships between human and non-human isolates. Methods: Two prospective multicentre cohorts were assessed: colonised hospitalised index-subjects and household contacts, and long-term care facility (LTCF) residents. Additionally, linked hp-environment and food samples were collected. Presence of ARGs were assessed using pairwise comparisons and proportional similarity index (PSI). Clonal relationships were assessed using cgMLST distance visualisations and maximum likelihood phylogeny. Results: ESBL-Ec and ESBL-Kp co-occurred in 14/65 households, 3/6 LTCFs, and in 33/202 of ESBL-positive participants. Thirty-nine percent of detected ARG types were found in both species (36/93). Frequencies of beta-lactamase, ESBL, aminoglycoside, and sulfonamide ARG types from human ESBL-Ec and ESBL-Kp overlapped considerably: PSIs 0.59-0.75, and were equal or higher compared to the overlap between ESBL-Ec from humans and food isolates: PSIs 0.33-0.72. Isolates from humans and the hp-environment were frequently clonally related, indicating human contamination of the environment. Links with food isolates were observed less frequently. For ESBL-Ec both interregional and regional clonal dissemination were observed, while for ESBL-Kp clonal dissemination was mainly regional. Conclusions: ESBL-Ec and ESBL-Kp from human carriage showed considerable overlap in ARG content. Furthermore, clonal links were observed frequently between humans and hp-environment, and with lower frequency between humans and food. These findings are consistent with human-to-human transmission as an important driver of ARG spread in humans.