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Multicentre, randomised, open-label, phase IV-III study to evaluate the efficacy of cloxacillin plus fosfomycin versus cloxacillin alone in adult patients with methicillin-susceptible Staphylococcus aureus bacteraemia: study protocol for the SAFO trial.
Grillo, Sara; Cuervo, Guillermo; Carratala, Jordi; San-Juan, Rafael; Aguado, Jose M; Morata, Laura; Gomez-Zorrilla, Silvia; López-Contreras, Joaquín; Gasch, Oriol; Gomila-Grange, Aina; Iftimie, Simona; Garcia-Pardo, Graciano; Calbo, Esther; Boix-Palop, Lucía; Oriol, Isabel; Jover-Sáenz, Alfredo; López-Cortés, Luis Eduardo; Euba, Gorane; Aguirregabiria, Malen; Garcia-Pais, Maria Jose; Gioia, Francesca; Paño, Jose Ramón; Pedro-Botet, Maria Luisa; Benítez, Rosa Maria; Pérez-Rodríguez, Maria Teresa; Meije, Yolanda; Loeches-Yagüe, Maria Belén; Horna, Gertrudis; Berbel, Damaris; Domínguez, Maria Ángeles; Padullés, Ariadna; Cobo, Sara; Hereu, Pilar; Videla, Sebastian; Tebe, Cristian; Pallarés, Natàlia; Miro, Josep M; Pujol, Miquel.
  • Grillo S; Department of Infectious Diseases, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Spain.
  • Cuervo G; Bellvitge Institute for Biomedical Research, IDIBELL, Barcelona, Spain.
  • Carratala J; Department of Infectious Diseases, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Spain guillermo.cuervo@bellvitgehospital.cat.
  • San-Juan R; Bellvitge Institute for Biomedical Research, IDIBELL, Barcelona, Spain.
  • Aguado JM; Department of Infectious Diseases, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Spain.
  • Morata L; University of Barcelona, Barcelona, Spain.
  • Gomez-Zorrilla S; Department of Infectious Diseases, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • López-Contreras J; Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain.
  • Gasch O; Department of Infectious Diseases, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • Gomila-Grange A; Complutense University of Madrid, Madrid, Spain.
  • Iftimie S; Department of Infectious Diseases, Hospital Clinic de Barcelona, Barcelona, Spain.
  • Garcia-Pardo G; Institut d'Investigacions Biomèdiques August Pi i Sunyer, IDIBAPS, Barcelona, Spain.
  • Calbo E; Department of Infectious Diseases, Consorci Parc de Salut MAR de Barcelona, Barcelona, Spain.
  • Boix-Palop L; Institut de Recerca Hospital del Mar, IMIM, Barcelona, Spain.
  • Oriol I; Department of Infectious diseases, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
  • Jover-Sáenz A; Institut d'Investigació Biomèdica Sant Pau IIB Sant Pau, Barcelona, Spain.
  • López-Cortés LE; Infectious Diseases Department, Consorcio Corporacion Sanitaria Parc Tauli, Sabadell, Spain.
  • Euba G; Institut d'Investigació i Innovació Parc Taulí, I3PT, Sabadell, Spain.
  • Aguirregabiria M; Institut d'Investigació i Innovació Parc Taulí, I3PT, Sabadell, Spain.
  • Garcia-Pais MJ; Consorcio Corporación Sanitaria Parc Taulí, Sabadell, Spain.
  • Gioia F; Department of Infection and Immunity, Hospital Universitari Sant Joan de Reus, Reus, Spain.
  • Paño JR; Departament of Preventive Medicine, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain.
  • Pedro-Botet ML; Infectious Diseases Unit, Hospital Universitari MutuaTerrassa, Terrassa, Spain.
  • Benítez RM; Fundació per la Docència i Recerca MútuaTerrassa, Terrassa, Spain.
  • Pérez-Rodríguez MT; Infectious Diseases Unit, Hospital Universitari MutuaTerrassa, Terrassa, Spain.
  • Meije Y; Fundació per la Docència i Recerca MútuaTerrassa, Terrassa, Spain.
  • Loeches-Yagüe MB; Department of Internal Medicine, Hospital de Sant Joan Despi Moises Broggi, Sant Joan Despi, Spain.
  • Horna G; Territorial Unit of Nosocomial Infection, Hospital Universitari Arnau de Vilanova, Lleida, Spain.
  • Berbel D; Institut de Recerca Biomèdica de Lleida, IRBLLEIDA, Lleida, Spain.
  • Domínguez MÁ; Department of Infectious diseases, Hospital Universitario Virgen Macarena, Seville, Spain.
  • Padullés A; Instituto de Biomedicina de Sevilla, Sevilla, Spain.
  • Cobo S; Department of Infectious Diseases, Hospital Universitario Cruces, Barakaldo, Spain.
  • Hereu P; Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.
  • Videla S; Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.
  • Tebe C; Microbiology Department, Hospital Universitario Cruces, Barakaldo, Spain.
  • Pallarés N; Internal Medicine, Hospital Universitario Lucus Augusti, Lugo, Spain.
  • Miro JM; Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain.
  • Pujol M; Department of Infectious diseases, Hospital Universitario Ramon y Cajal, Madrid, Spain.
BMJ Open ; 11(8): e051208, 2021 08 05.
Article in English | MEDLINE | ID: covidwho-1346066
ABSTRACT

INTRODUCTION:

Methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a frequent condition, with high mortality rates. There is a growing interest in identifying new therapeutic regimens able to reduce therapeutic failure and mortality observed with the standard of care of beta-lactam monotherapy. In vitro and small-scale studies have found synergy between cloxacillin and fosfomycin against S. aureus. Our aim is to test the hypothesis that cloxacillin plus fosfomycin achieves higher treatment success than cloxacillin alone in patients with MSSA bacteraemia.

METHODS:

We will perform a superiority, randomised, open-label, phase IV-III, two-armed parallel group (11) clinical trial at 20 Spanish tertiary hospitals. Adults (≥18 years) with isolation of MSSA from at least one blood culture ≤72 hours before inclusion with evidence of infection, will be randomly allocated to receive either cloxacillin 2 g/4-hour intravenous plus fosfomycin 3 g/6-hour intravenous or cloxacillin 2 g/4-hour intravenous alone for 7 days. After the first week, sequential treatment and total duration of antibiotic therapy will be determined according to clinical criteria by the attending physician.Primary endpoints (1) Treatment success at day 7, a composite endpoint comprising all the following criteria patient alive, stable or with improved quick-Sequential Organ Failure Assessment score, afebrile and with negative blood cultures for MSSA at day 7. (2) Treatment success at test of cure (TOC) visit patient alive and no isolation of MSSA in blood culture or at another sterile site from day 8 until TOC (12 weeks after randomisation).We assume a rate of treatment success of 74% in the cloxacillin group. Accepting alpha risk of 0.05 and beta risk of 0.2 in a two-sided test, 183 subjects will be required in each of the control and experimental groups to obtain statistically significant difference of 12% (considered clinically significant). ETHICS AND DISSEMINATION Ethical approval has been obtained from the Ethics Committee of Bellvitge University Hospital (AC069/18) and from the Spanish Medicines and Healthcare Product Regulatory Agency (AEMPS, AC069/18), and is valid for all participating centres under existing Spanish legislation. The results will be presented at international meetings and will be made available to patients and funders. TRIAL REGISTRATION NUMBER The protocol has been approved by AEMPS with the Trial Registration Number EudraCT 2018-001207-37. ClinicalTrials.gov Identifier NCT03959345; Pre-results.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Staphylococcal Infections / Bacteremia / Fosfomycin Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Limits: Adult / Humans Language: English Journal: BMJ Open Year: 2021 Document Type: Article Affiliation country: Bmjopen-2021-051208

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Staphylococcal Infections / Bacteremia / Fosfomycin Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Limits: Adult / Humans Language: English Journal: BMJ Open Year: 2021 Document Type: Article Affiliation country: Bmjopen-2021-051208