Scientific publications
Efficacy and safety of a structured de-escalation from antipseudomonal β-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY). Scientific Publication
Luis Eduardo López-Cortés 1 , Mercedes Delgado-Valverde 2 , Elisa Moreno-Mellado 2 , Josune Goikoetxea Aguirre 3 , Laura Guio Carrión 3 , María José Blanco Vidal 3 , Leyre Mónica López Soria 4 , María Teresa Pérez-Rodríguez 5 , Lucía Martínez Lamas 6 , Francisco Arnaiz de Las Revillas 7 , Carlos Armiñanzas 7 , Carlos Ruiz de Alegría-Puig 8 , Patricia Jiménez Aguilar 9 , María Del Carmen Martínez-Rubio 10 , Carmen Sáez-Bejar 11 , Carmen de Las Cuevas 12 , Andrés Martín-Aspas 13 , Fátima Galán 14 , José Ramón Yuste 15 , José Leiva-León 16 , Germán Bou 17 , Patricia Capón González 18 , Lucía Boix-Palop 19 , Mariona Xercavins-Valls 20 , Miguel Ángel Goenaga-Sánchez 21 , Diego Vicente Anza 22 , Juan José Castón 23 , Manuel Recio Rufián 23 , Esperanza Merino 24 , Juan Carlos Rodríguez 25 , Belén Loeches 26 , Guillermo Cuervo 27 , José Manuel Guerra Laso 28 , Antonio Plata 29 , Salvador Pérez Cortés 30 , Pablo López Mato 31 , José Luis Sierra Monzón 32 , Clara Rosso-Fernández 33 , José María Bravo-Ferrer 2 , Pilar Retamar-Gentil 2 , Jesús Rodríguez-Baño 2 ; SIMPLIFY study group
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 β-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 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.
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 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.
CITATION Lancet Infect Dis. 2024 Jan 9:S1473-3099(23)00686-2. doi: 10.1016/S1473-3099(23)00686-2
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