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Abstract
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.
Trial registration number The European Union Clinical Trials Register: EudraCT number 2015-004219-19. Clinical trials.gov: NCT02795949. Protocol version: V.2.0, dated 16 May 2016. All items from the WHO Trial Registration Data Set are included in the registry.
- De-escalation
- Enterobacteriaceae
- bloodstream infection
- broad-spectrum antibiotics
- antimicrobial stewardship
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Footnotes
Contributors JR-B and LEL-C were responsible for formulating the overall research questions and for the methodological design of the study. CR-F, BA and LL-A collaborated in the submission of the project for the Spanish funding and collaborated in the methodological aspects of the study. JR-B is the coordinating investigator and leader of the coordination team. CR-F is responsible for the CTU. MN-N collaborated with writing of the manuscript and with the pharmacovigilance design, and JB-F, PR-G and CL collaborated in the organisation of the study. MD contributed in all the microbiological details of the study. JR-B and LEL-C participated in its design and supervised the project. All authors read and approved the final manuscript.
Funding Fundación Pública Andaluza para la Gestión de la Investigación enSalud de Sevilla (FISEVI), Contact: claram.rosso.sspa@juntadeandalucia.es. This project is a non-commercial, investigator-driven clinical trial, funded through public competitive call by the Instituto de Salud Carlos III (ISCIII), document number: PI15/00439, funded by Instituto de Salud Carlos III, integrated in the national I+D+i 2013-2016 and co-funded by European Union (ERDF/ESF, “Investing in your future”). This study is supported by the Spanish Clinical Research Network and funded by ISCII: study number 16.001.
Disclaimer The sponsor and funders of the study had no role in the study design or in manuscript development.
Competing interests None declared.
Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.
Ethics approval Spanish Regulatory Agency.
Provenance and peer review Not commissioned; externally peer reviewed.
Collaborators P Aguilar, IJ de la Calle and A Romero (Hospital Universitario Puerto Real, Cádiz); E Merino, V Boix, L Giner, JC Rodríguez and A Gimeno (Hospital Universitario de Alicante); F Guerrero-Sánchez, A Martín-Aspas and F Galán-Sánchez (Hospital Universitario Puerta del Mar, Cádiz); D Diez, V Pérez-Carral and MI Paz (Complexo Hospitalario Universitario de Ourense); C Fariñas, C Armiñanzas, C González and C Ruiz de Alegría-Puig (Hospital Universitario Marqués de Valdecilla, Santander); L Gómez, E Calbo and M Xercavins-Valls (Hospital Universitario Mutua Terrassa, Terrassa); F García-Colchero and M Chávez (Hospital San Juan de Dios, Sevilla); J Goikoetxea-Agirre, M Montejo and L López (Hospital Universitario de Cruces, Barakaldo); G Bou and I Torres (Hospital Universitario A Coruña); S Pérez-Cortés and MD López-Prieto (Hospital Universitario de Jerez); B Loeches and M Romero (Hospital Universitario La Paz, Madrid); M Ibarguren, MA Goenaga-Sánchez and JM García-Arenzana (Hospital Universitario Donostia); JR Yuste and J Leiva-León (Clínica Universitaria de Navarra); A Salas-Aparicio and C de las Cuevas (Hospital Universitario La Princesa, Madrid); JM Guerra-Laso and I Fernández-Natal (Complejo Asistencial Universitario de León); MT Pérez and F Vasallo (Xerencia de Xestión Integrada de Vigo); G Cuervo and C Ardanuy (Hospital Universitario de Bellvitge); JR Paño and S Salvo (Hospital Clínico Universitario Lozano Blesa, Zaragoza); ML Martín-Pena and E Ruiz de Gospegui (Hospital Universitario Son Espases); M del Barrio, S Sadyrbaeva, M Coronel-Janeiro, MP Alarcón-González and A González-Herrero (Hospital Universitario Virgen Macarena).