Journal Article

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

Jiménez Aguilar, Patricia, Moreno-Mellado, Elisa, Bravo-Ferrer, José María, Fernández Ávila, María Luisa, Díaz-López, María Dolores, Rodríguez-Baño, Jesús, Bilbao del Olmo, Idoia, Romero Gómez, María, Fariñas, María Carmen, Paño, José Ramón, López-Cortés, Luis Eduardo, Goenaga-Sánchez, Miguel Ángel, Castón, Juan José, de las Cuevas, Carmen, López Soria, Leyre Mónica, Giner Oncina, Livia, Delgado-Valverde, Mercedes, Martínez Lamas, Lucía, Retamar-Gentil, Pilar, Rúa Gómez, Marta, Rodríguez, Juan Carlos, Martín-Aspas, Andrés, Cuervo, Guillermo, Cano, Ángela, López Mato, Pablo, Reguero, José María, Leiva-León, José, Ruiz de Alegría-Puig, Carlos, Guio Carrión, Laura, Gómez-Ruiz de Arbulo, Marta, Sáez-Bejar, Carmen, Yuste, José Ramón, Arnaiz de las Revillas, Francisco, Rufián, Manuel Recio, Romero Palacios, Alberto, Ibarguren Pinilla, Maialen, Torres Beceiro, Isabel, Bou, Germán, Xercavins-Valls, Mariona, Dietl, Beatriz, Argüelles Curto, Adrián, Capón González, Patricia, Anza, Diego Vicente, Nieto Aranda, Javier, Borreguero, Irene, Pérez Cortés, Salvador, del Carmen Martínez-Rubio,

2024

Overview

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 β-lactam to a narrower-spectrum drug was non-inferior to continuing the antipseudomonal drug in patients with Enterobacterales bacteraemia. 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 β-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 β-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. 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. De-escalation from an antipseudomonal β-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. 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.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Amides / Amoxicillin / Ampicillin / Anti-Bacterial Agents - adverse effects / Antibiotics / Antimicrobial agents / Bacteremia / Bacteremia - drug therapy / beta-Lactams - adverse effects / Case reports / Cefotaxime / Ceftriaxone / Cefuroxime / Ciprofloxacin / Clavulanic acid / Clinical medicine / Clinical trials / Drugs / Enterobacterales / Ertapenem / Health services / Humans / Infectious diseases / Labels / Lower bounds / Microorganisms / Mortality / Nosocomial infections / Patients / Penicillin / Regional development / Safety / Sulfamethoxazole / Systematic review / Treatment Outcome / Trimethoprim / Urinary tract / Urogenital system / β-Lactam antibiotics