Efficacy of Cloxacillin and Fosfomycin Combination Versus Cloxacillin Monotherapy in Patients With MSSA Bacteremia

NCT03959345 | Terminated Phase 4

• 1 other identifier: 2018-001207-37
• Study Type: interventional
• Target: 215
• Locations: 1 country
• Sites: 17

Brief Summary

Background: Despite management improvement in lasts years, S.aureus bacteremia leads to high morbidity and mortality. For over 50 years, methicillin-susceptible S.aureus (MSSA) bacteremia standard treatment was cloxacillin. Previous studies using different therapies and combination treatment fall to improve survival in these patients. Aim: to demonstrate the efficacy of the cloxacillin and fosfomycin combination administered during the first week of treatment, compared with cloxacillin monotherapy in patients with MSSA bacteremia in treatment success. Methods: A multicentre, superiority, open-label, randomized, phase IV-III, two-armed parallel (1:1) groups clinical trial. Adult patients with MSSA bacteremia will be randomized to Combination therapy group: patients will receive intravenous cloxacillin 2g/4h and fosfomycin 3 g/6h for the duration of 7 days treatment, or Standard therapy group: patients will receive intravenous cloxacillin 2g/4h for the duration of 7 days IV treatment. After the first week, antibiotic treatment and duration will be decided by responsible clinician following clinical practice. The primary endpoint is the treatment success measured at day 7 of treatment; a composite endpoint defined by all of the following criteria met after randomization: patient alive at day 7 AND stable or improved quick SOFA score (compared with baseline) at day 7 AND fever resolved at day 7 AND negative blood cultures for S. aureus at day 7. In case of achieving statistical differences in the primary endpoint, investigators will perform a hierarchical analysis of the treatment success at Test of Cure visit (TOC, 12 weeks after randomization), defined by the presence of all of the following: patient alive at TOC AND no evidence of microbiological treatment failure defined as isolation of S. aureus from blood culture or other sterile site from day 8 after randomization until TOC. Investigators have assumed a 74% of treatment success in monotherapy group. Accepting an alpha risk of 0.05 and a beta risk of 0.2 in a two-sided test, 183 subjects are necessary in first group and 183 in the second to find a statistically significant difference of 12%. It has been anticipated a drop-out rate of 5%. Discussion: Randomized studies assessing efficacy of different treatment in MSSA bacteremia are lacking. This study could help to improve knowledge about MSSA bacteremia and whether combined treatment with cloxacillin and fosfomycin could improve outcomes compared with standard treatment.

Conditions

Methicillin Susceptible Staphylococcus Aureus Septicemia

Outcome Measures

Primary Outcomes (2)

• Treatment success at day 7

  Composite endpoint defined by all of the following criteria met after randomization: patient alive at day 7 AND stable or improved quick SOFA score (compared with baseline) at day 7 AND fever resolved at day 7 AND negative blood cultures for S. aureus at day 7.

  Day 7 after randomization.

• Treatment success at TOC

  In case of achieving statistical differences in the primary endpoint, we will perform a hierarchical analysis of the treatment success at Test of Cure visit (TOC, 12 weeks after randomisation). Treatment success at TOC visit, defined by presence of all of the following: * Patient alive at TOC; * No isolation of MSSA in blood culture or in another sterile site from day 8 until TOC.

  12 weeks after randomization

Study Arms (2)

Combination therapy group

EXPERIMENTAL

intravenous cloxacillin 2g/4h and fosfomycin 3 g/6h for the duration of 7 days treatment

Drug: Combination therapy group

Standard therapy group

ACTIVE COMPARATOR

intravenous cloxacillin 2g/4h for the duration of 7 days IV treatment

Drug: Standard therapy group

Interventions

Combination therapy group DRUG

Adult patients with MSSA bacteraemia will be randomized to Combination therapy group: patients will receive intravenous cloxacillin 2g/4h and fosfomycin 3 g/6h for the duration of 7 days treatment. After the first week, antibiotic treatment and duration will be decided by responsible clinician following clinical practice.

Combination therapy group

Standard therapy group DRUG

Adult patients with MSSA bacteraemia will be randomized to Standard therapy group: patients will receive intravenous cloxacillin 2g/4h for the duration of 7 days IV treatment. After the first week, antibiotic treatment and duration will be decided by responsible clinician following clinical practice.

Standard therapy group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects, aged ≥ 18 years;
• MSSA bacteraemia: ≥ 1 positive blood culture(s) for MSSA in the first 72 h up to randomisation in patients with clinical suspicion of infection;
• Written informed consent of the participant or the legal representative.

You may not qualify if:

• Severe clinical status with expected death \<48h.
• Severe hepatic cirrhosis (Child-Pugh C).
• Moderate-severe cardiac chronic failure (NYHA III-IV).
• Prosthetic endocarditis (need for concomitant antibiotic therapy active against S. aureus together with the study antibiotics for the first 7 days of the study).
• No pre-existing evidence of S. aureus fosfomycin non-susceptibility.
• Known hypersensitivity to cloxacillin or fosfomycin.
• Polymicrobial bacteraemia with more than one microorganism in blood cultures.
• Miastenia gravis.
• Participation in another clinical trial.
• Previous participation in the present clinical trial.
• Acute SARS-CoV2 infection.

Sponsors & Collaborators

• Miquel Pujol: lead
• Institut d'Investigació Biomèdica de Bellvitge: collaborator
• Instituto de Salud Carlos III: collaborator

Study Sites (17)

Hospital Universitari Germans Trias i Pujol

Badalona, Barcelona, Spain

Location

Hospital Sant Joan Despí Moisés Broggi

Sant Joan Despí, Barcelona, Spain

Location

University Hospital Cruces

Barakaldo, Spain

Location

Bellvitge University Hospital

Barcelona, Spain

Location

Hospital del Mar

Barcelona, Spain

Location

University Hospital Clínic de Barcelona

Barcelona, Spain

Location

University Hospital Santa Creu i Sant Pau

Barcelona, Spain

Location

University Hospital Arnau de Vilanova

Lleida, Spain

Location

University Hospital Lucus Agustí

Lugo, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, Spain

Location

University Hospital 12 de Octubre

Madrid, Spain

Location

University Hospital Sant Joan

Reus, Spain

Location

Corporació Sanitària Parc Taulí

Sabadell, Spain

Location

University Hospital Virgen Macarena

Seville, Spain

Location

University Hospital Joan XXIII

Tarragona, Spain

Location

University Hospital Mùtua de Terrassa

Terrassa, Spain

Location

Hospital Clínico Lozano Blesa

Zaragoza, Spain

Location

Related Publications (11)

• Bergin SP, Holland TL, Fowler VG Jr, Tong SYC. Bacteremia, Sepsis, and Infective Endocarditis Associated with Staphylococcus aureus. Curr Top Microbiol Immunol. 2017;409:263-296. doi: 10.1007/82_2015_5001.

  PMID: 26659121 BACKGROUND

• van Hal SJ, Jensen SO, Vaska VL, Espedido BA, Paterson DL, Gosbell IB. Predictors of mortality in Staphylococcus aureus Bacteremia. Clin Microbiol Rev. 2012 Apr;25(2):362-86. doi: 10.1128/CMR.05022-11.

  PMID: 22491776 BACKGROUND

• Gasch O, Camoez M, Dominguez MA, Padilla B, Pintado V, Almirante B, Molina J, Lopez-Medrano F, Ruiz E, Martinez JA, Bereciartua E, Rodriguez-Lopez F, Fernandez-Mazarrasa C, Goenaga MA, Benito N, Rodriguez-Bano J, Espejo E, Pujol M; REIPI/GEIH Study Groups. Predictive factors for mortality in patients with methicillin-resistant Staphylococcus aureus bloodstream infection: impact on outcome of host, microorganism and therapy. Clin Microbiol Infect. 2013 Nov;19(11):1049-57. doi: 10.1111/1469-0691.12108. Epub 2013 Jan 17.

  PMID: 23331461 BACKGROUND

• Minejima E, Mai N, Bui N, Mert M, Mack WJ, She RC, Nieberg P, Spellberg B, Wong-Beringer A. Defining the Breakpoint Duration of Staphylococcus aureus Bacteremia Predictive of Poor Outcomes. Clin Infect Dis. 2020 Feb 3;70(4):566-573. doi: 10.1093/cid/ciz257.

  PMID: 30949675 BACKGROUND

• Gudiol F, Aguado JM, Almirante B, Bouza E, Cercenado E, Dominguez MA, Gasch O, Lora-Tamayo J, Miro JM, Palomar M, Pascual A, Pericas JM, Pujol M, Rodriguez-Bano J, Shaw E, Soriano A, Valles J. Diagnosis and treatment of bacteremia and endocarditis due to Staphylococcus aureus. A clinical guideline from the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC). Enferm Infecc Microbiol Clin. 2015 Nov;33(9):625.e1-625.e23. doi: 10.1016/j.eimc.2015.03.015. Epub 2015 May 1.

  PMID: 25937457 BACKGROUND

• Thwaites GE, Scarborough M, Szubert A, Nsutebu E, Tilley R, Greig J, Wyllie SA, Wilson P, Auckland C, Cairns J, Ward D, Lal P, Guleri A, Jenkins N, Sutton J, Wiselka M, Armando GR, Graham C, Chadwick PR, Barlow G, Gordon NC, Young B, Meisner S, McWhinney P, Price DA, Harvey D, Nayar D, Jeyaratnam D, Planche T, Minton J, Hudson F, Hopkins S, Williams J, Torok ME, Llewelyn MJ, Edgeworth JD, Walker AS; United Kingdom Clinical Infection Research Group (UKCIRG). Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2018 Feb 17;391(10121):668-678. doi: 10.1016/S0140-6736(17)32456-X. Epub 2017 Dec 14.

  PMID: 29249276 BACKGROUND

• Grillo S, Cuervo G, Carratala J, Grau I, Pallares N, Tebe C, Guillem Tio L, Murillo O, Ardanuy C, Dominguez MA, Shaw E, Gudiol C, Pujol M. Impact of beta-Lactam and Daptomycin Combination Therapy on Clinical Outcomes in Methicillin-susceptible Staphylococcus aureus Bacteremia: A Propensity Score-matched Analysis. Clin Infect Dis. 2019 Oct 15;69(9):1480-1488. doi: 10.1093/cid/ciz018.

  PMID: 30615122 BACKGROUND

• Grabein B, Graninger W, Rodriguez Bano J, Dinh A, Liesenfeld DB. Intravenous fosfomycin-back to the future. Systematic review and meta-analysis of the clinical literature. Clin Microbiol Infect. 2017 Jun;23(6):363-372. doi: 10.1016/j.cmi.2016.12.005. Epub 2016 Dec 9.

  PMID: 27956267 BACKGROUND

• Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gotzsche PC, Krleza-Jeric K, Hrobjartsson A, Mann H, Dickersin K, Berlin JA, Dore CJ, Parulekar WR, Summerskill WS, Groves T, Schulz KF, Sox HC, Rockhold FW, Rennie D, Moher D. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013 Feb 5;158(3):200-7. doi: 10.7326/0003-4819-158-3-201302050-00583.

  PMID: 23295957 BACKGROUND

• Grillo S, Pujol M, Miro JM, Lopez-Contreras J, Euba G, Gasch O, Boix-Palop L, Garcia-Pais MJ, Perez-Rodriguez MT, Gomez-Zorrilla S, Oriol I, Lopez-Cortes LE, Pedro-Botet ML, San-Juan R, Aguado JM, Gioia F, Iftimie S, Morata L, Jover-Saenz A, Garcia-Pardo G, Loeches B, Izquierdo-Cardenas A, Goikoetxea AJ, Gomila-Grange A, Dietl B, Berbel D, Videla S, Hereu P, Padulles A, Pallares N, Tebe C, Cuervo G, Carratala J; SAFO study group. Cloxacillin plus fosfomycin versus cloxacillin alone for methicillin-susceptible Staphylococcus aureus bacteremia: a randomized trial. Nat Med. 2023 Oct;29(10):2518-2525. doi: 10.1038/s41591-023-02569-0. Epub 2023 Oct 2.

  PMID: 37783969 DERIVED

• Grillo S, Cuervo G, Carratala J, San-Juan R, Aguado JM, Morata L, Gomez-Zorrilla S, Lopez-Contreras J, Gasch O, Gomila-Grange A, Iftimie S, Garcia-Pardo G, Calbo E, Boix-Palop L, Oriol I, Jover-Saenz A, Lopez-Cortes LE, Euba G, Aguirregabiria M, Garcia-Pais MJ, Gioia F, Pano JR, Pedro-Botet ML, Benitez RM, Perez-Rodriguez MT, Meije Y, Loeches-Yague MB, Horna G, Berbel D, Dominguez MA, Padulles A, Cobo S, Hereu P, Videla S, Tebe C, Pallares N, Miro JM, Pujol M; SAFO study group and the Spanish Network for Research in Infectious Diseases (REIPI). 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. BMJ Open. 2021 Aug 5;11(8):e051208. doi: 10.1136/bmjopen-2021-051208.

  PMID: 34353808 DERIVED

Study Officials

• Miquel Pujol Rojo, MD, PhD

  Hospital Universitari Bellvitge

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator, Medical Doctor

Study Record Dates

• First Submitted: May 20, 2019
• First Posted: May 22, 2019
• Study Start: May 31, 2019
• Primary Completion: February 24, 2022
• Study Completion: February 24, 2022
• Last Updated: April 21, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: immediately following publication and ending 5 years following article publication
• Access Criteria: Data will be shared with researchers who provide a methodologically sound proposal to achieve aims in the approved proposal.

Locations

ES (17)