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
Copyright © 2024 Elsevier Ltd. All rights reserved..
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.
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.
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E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
The Lancet. Infectious diseases - 24(2024), 4 vom: 01. März, Seite 375-385 |
| Sprache: |
Englisch |
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| Themen: |
75J73V1629 |
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| Anmerkungen: |
Date Completed 25.03.2024 Date Revised 25.03.2024 published: Print-Electronic ClinicalTrials.gov: NCT02795949 Citation Status MEDLINE |
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| doi: |
10.1016/S1473-3099(23)00686-2 |
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| PPN (Katalog-ID): |
NLM367063190 |
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| 100 | 1 | |a López-Cortés, Luis Eduardo |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Efficacy and safety of a structured de-escalation from antipseudomonal β-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY) |b an open-label, multicentre, randomised trial |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT02795949 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 Elsevier Ltd. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Galán, Fátima |e verfasserin |4 aut | |
| 700 | 1 | |a Yuste, José Ramón |e verfasserin |4 aut | |
| 700 | 1 | |a Leiva-León, José |e verfasserin |4 aut | |
| 700 | 1 | |a Bou, Germán |e verfasserin |4 aut | |
| 700 | 1 | |a Capón González, Patricia |e verfasserin |4 aut | |
| 700 | 1 | |a Boix-Palop, Lucía |e verfasserin |4 aut | |
| 700 | 1 | |a Xercavins-Valls, Mariona |e verfasserin |4 aut | |
| 700 | 1 | |a Goenaga-Sánchez, Miguel Ángel |e verfasserin |4 aut | |
| 700 | 1 | |a Anza, Diego Vicente |e verfasserin |4 aut | |
| 700 | 1 | |a Castón, Juan José |e verfasserin |4 aut | |
| 700 | 1 | |a Rufián, Manuel Recio |e verfasserin |4 aut | |
| 700 | 1 | |a Merino, Esperanza |e verfasserin |4 aut | |
| 700 | 1 | |a Rodríguez, Juan Carlos |e verfasserin |4 aut | |
| 700 | 1 | |a Loeches, Belén |e verfasserin |4 aut | |
| 700 | 1 | |a Cuervo, Guillermo |e verfasserin |4 aut | |
| 700 | 1 | |a Guerra Laso, José Manuel |e verfasserin |4 aut | |
| 700 | 1 | |a Plata, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Pérez Cortés, Salvador |e verfasserin |4 aut | |
| 700 | 1 | |a López Mato, Pablo |e verfasserin |4 aut | |
| 700 | 1 | |a Sierra Monzón, José Luis |e verfasserin |4 aut | |
| 700 | 1 | |a Rosso-Fernández, Clara |e verfasserin |4 aut | |
| 700 | 1 | |a Bravo-Ferrer, José María |e verfasserin |4 aut | |
| 700 | 1 | |a Retamar-Gentil, Pilar |e verfasserin |4 aut | |
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| 700 | 1 | |a Nieto Aranda, Javier |e investigator |4 oth | |
| 700 | 1 | |a Sousa Domínguez, Adrián |e investigator |4 oth | |
| 700 | 1 | |a González-Rico, Claudia |e investigator |4 oth | |
| 700 | 1 | |a Fariñas, María Carmen |e investigator |4 oth | |
| 700 | 1 | |a Fernández Ávila, María Luisa |e investigator |4 oth | |
| 700 | 1 | |a Romero Palacios, Alberto |e investigator |4 oth | |
| 700 | 1 | |a Guerrero Sánchez, Francisca María |e investigator |4 oth | |
| 700 | 1 | |a Rúa Gómez, Marta |e investigator |4 oth | |
| 700 | 1 | |a Bilbao Del Olmo, Idoia |e investigator |4 oth | |
| 700 | 1 | |a Calbo, Esther |e investigator |4 oth | |
| 700 | 1 | |a Dietl, Beatriz |e investigator |4 oth | |
| 700 | 1 | |a Ibarguren Pinilla, Maialen |e investigator |4 oth | |
| 700 | 1 | |a Gómez-Ruiz de Arbulo, Marta |e investigator |4 oth | |
| 700 | 1 | |a Torres Beceiro, Isabel |e investigator |4 oth | |
| 700 | 1 | |a Machuca, Isabel |e investigator |4 oth | |
| 700 | 1 | |a Cano, Ángela |e investigator |4 oth | |
| 700 | 1 | |a Giner Oncina, Livia |e investigator |4 oth | |
| 700 | 1 | |a Pinargote Celorio, Héctor |e investigator |4 oth | |
| 700 | 1 | |a Cendejas, Emilio |e investigator |4 oth | |
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| 700 | 1 | |a Díaz-López, María Dolores |e investigator |4 oth | |
| 700 | 1 | |a Paño, José Ramón |e investigator |4 oth | |
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