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.Instituto de Salud Carlos III (ISCIII): PI15/00439, integrado en el Plan Nacional de I+D+i 2013-2016 y cofinanciado por la Unión Europea (ERDF/ESF, “Investing in your future”)

Temocillin versus meropenem for the targeted treatment of bacteraemia due to third-generation cephalosporin-resistant Enterobacterales (ASTARTÉ): protocol for a randomised, pragmatic trial

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.Instituto de Salud Carlos III ICI19/00093Ministerio de Economía, Industria y Competitividad y Fondos FEDER RD16/0016/0001, 0002, 0004, 0008, 0009, 0010, 0011, 0013, 001

Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections A Randomized Clinical Trial

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

Statistical analysis plan. Study protocol for a randomized clinical trial to assess 7 versus 14-days of treatment for Pseudomonas aeruginosa bloodstream infections (SHORTEN-2 trial)

Efficacy and safety of 7 versus 14 days of antibiotic treatment for Pseudomonas aeruginosa bacteraemia: a multicentre, randomized clinical trial (SHORTEN-2) with a DOOR/RADAR analysis.Peer reviewe

Full-length study protocol (Spanish). Study protocol for a randomized clinical trial to assess 7 versus 14-days of treatment for Pseudomonas aeruginosa bloodstream infections (SHORTEN-2 trial)

Eficacia y seguridad de 7 versus 14 días de tratamiento antibiótico para la bacteriemia producida por Pseudomonas aeruginosa: un ensayo clínico multicéntrico, aleatorizado (SHORTEN-2) con un análisis DOOR/RADAR.Peer reviewe

List of participating centers. Study protocol for a randomized clinical trial to assess 7 versus 14-days of treatment for Pseudomonas aeruginosa bloodstream infections (SHORTEN-2 trial)

S1 File. List of participating centers.Peer reviewe

Full-length study protocol (English). Study protocol for a randomized clinical trial to assess 7 versus 14-days of treatment for Pseudomonas aeruginosa bloodstream infections (SHORTEN-2 trial)

Efficacy and safety of 7 versus 14 days of antibiotic treatment for Pseudomonas aeruginosa bacteraemia: a multicentre, randomized clinical trial (SHORTEN-2) with a DOOR/RADAR analysis.Peer reviewe

Results of the survey among participating centers regarding diagnostic and clinical routines for the management of BSI-PA

S4 File. Results of the survey among participating centers regarding diagnostic and clinical routines for the management of BSI-PAPeer reviewe

Definitions for main trial variables. Study protocol for a randomized clinical trial to assess 7 versus 14-days of treatment for Pseudomonas aeruginosa bloodstream infections (SHORTEN-2 trial)

S2 File. Definitions for main trial variables.Peer reviewe

Efficacy and safety of a booster dose of influenza vaccination in solid organ transplant recipients, TRANSGRIPE 1-2: study protocol for a multicenter, randomized, controlled clinical trial

BACKGROUND: Despite administration of annual influenza vaccination, influenza-associated complications in transplant recipients continue to be an important cause of hospitalization and death. Although influenza vaccination has been proven to be the most effective measure to reduce influenza infection after transplantation, transplant recipients are still vulnerable to influenza infections, with lower serological responses to vaccination compared to the general population. In order to assess the efficacy and safety of an alternative immunization scheme for solid organ transplant recipients, the TRANSGRIPE1-2 Study Group aimed to test a booster dose administration 5 weeks after the standard vaccination. The primary objective of this trial was to compare short-term and long-term neutralizing antibody immunogenicity of a booster dose of influenza vaccination to the standard single-dose immunization scheme. Secondary objectives included the evaluation of the efficacy and/or safety, cellular immune response, incidence of influenza infection, graft rejection, retransplant and mortality rates. METHODS/DESIGN: This phase III, randomized, controlled, open-label clinical trial was conducted between October 2012 and December 2013 in 12 Spanish public referral hospitals. Solid organ transplant recipients (liver, kidney, heart or lung), older than 16 years of age more than 30 days after transplantation were eligible to participate. Patients (N = 514) were stratified 1:1 by center, type of organ and time after transplantation and who either received the standard single dose (n = 257) or were treated according to a novel influenza vaccination schedule comprising the administration of a booster dose 5 weeks after standard vaccination (n = 254). Seroconversion rates were measured as a determinant of protection against influenza (main outcome). Efficacy and safety outcomes were followed until 1 year after influenza vaccination with assessment of short-term (0, 5, 10 and 15 weeks) and long-term (12 months) results. Intention-to-treat, per-protocol and safety analyses will be performed. DISCUSSION: This trial will increase knowledge about the safety and efficacy of a booster dose of influenza vaccine in solid organ transplant recipients. At the time the manuscript was submitted for publication, trial recruitment was closed with a total of 499 participants included during a 2-month period (within the seasonal influenza vaccination campaign). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01761435 (registered 13 December 2012). EudraCT Identifier: 2011-003243-21 (registered 4 July 2011)