Non-inferiority Trial Comparing Cloxacillin vs Cefazolin in Methicillin-susceptible Staphylococcus Aureus Bacteremia

NCT03248063 | Completed

• 1 other identifier: P160943J
• Study Type: interventional
• Target: 315
• Locations: 1 country
• Sites: 1

Brief Summary

"Methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia remains a major cause of community- or hospital-acquired bloodstream infections with an overall mortality estimated around 25%. Anti-staphylococcal penicillins (APs) such as oxacillin or cloxacillin are recommended as first-line agents. With the exception of first-generation cephalosporin (1GC) such as cefazolin, no alternative has yet proven a similar efficacy. Due to an unfavourable safety profile for high doses used in severe infection, an uneasy dosing schedule in patients with renal failure and possible recurrent stock-out events for APs, alternative to APs are needed. This led to propose an open-label, randomized, controlled parallel groups, phase IV, non-inferiority trial comparing the efficacy, the safety, and the ecological impact of cefazolin versus cloxacillin for the treatment of MSSA bacteremia in adults. The primary objective is to compare the therapeutic efficacy of cefazolin vs cloxacillin at day 90 after the inclusion. "

Conditions

Bacteremia Due to Methicillin Susceptible Staphylococcus Aureus

Keywords

Staphylococcus aureus; bacteremia; cloxacillin; cefazolin

Outcome Measures

Primary Outcomes (1)

• Therapeutic efficacy

  "Composite efficacy criterion of the following: 1. Survival at day 90 2. Bacteriologic success at day 5 3. Absence of relapse at day 90 4. Clinical success at day 90"

  90 days after beginning of antibiotic treatment

Secondary Outcomes (22)

• Mortality

  day 90

• Bacteriological efficacy

  day 3, day 5 and day 90

• Bacteriologic relapse

  day 5

• Clinical efficacy

  day 7 and day 90

• Proportions of patients for whom consensual treatment duration is respected

  day 90

Study Arms (2)

Cloxacillin

ACTIVE COMPARATOR

Intravenous treatment by cloxacillin, 25 to 50 mg/kg every 4 or 6 hours, without doing less than the minimum daily dose of 8 g/day and without exceeding the maximum daily dose of 12 g/day, administered as a 60-minutes infusion.

Drug: Cloxacillin

Cefazolin

EXPERIMENTAL

Intravenous treatment by cefazolin, 25 to 50 mg/kg every 8 hours (without exceeding the maximum daily dose of 6 g/day), administered as a 30-minutes infusion.

Drug: Cefazolin

Interventions

Cloxacillin DRUG

Intravenous treatment by cloxacillin, 25 to 50 mg/kg every 4 or 6 hours, without doing less than the minimum daily dose of 8 g/day and without exceeding the maximum daily dose of 12 g/day, administered as a 60-minutes infusion. This treatment will be administered for at least 7 days by intravenous route. Dosing regimen will be adapted in patients with chronic renal failure (glomerular filtration rate below 30ml/min/1.73m²) and in patient with impaired hepatic function associated with renal impairment whatever the level of the estimation of the glomerular filtration rate, according to SPC.

Cloxacillin

Cefazolin DRUG

Intravenous treatment by cefazolin, 25 to 50 mg/kg every 8 hours (without exceeding the maximum daily dose of 6 g/day), administered as a 30-minutes infusion. This treatment will be administered for 14 days by intravenous route. Dosing regimen will be adapted in case of glomerular filtration rate between 30-50ml/min according to SPC. As currently recommended, investigators will be encouraged to use the intravenous route for the entire duration of treatment. However, in order to interfere as little as possible with usual practice in each center, the antimicrobial therapy will be let to the choice of the physician in charge of the patient after a minimum of 7 days of intravenous treatment.

Cefazolin

Eligibility Criteria

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

You may qualify if:

• Age above 18 years
• Blood culture positive to MSSA identified by standard bacteriologic techniques or by GeneXpert PCR

You may not qualify if:

• Previous type 1 or grade 3 - 4 according to CTCAE hypersensitivity reaction to beta-lactams
• Known pregnancy or breastfeeding women
• Parenteral antimicrobial therapy active against MSSA for more than 72 hours after the positive SA blood culture ponction
• Chronic renal failure defined by a glomerular filtration rate estimated \< 30 mL/min/1,73m².
• Presence of an intra-vascular implant (vascular or valvular prosthesis or cardiovascular implantable electronic device)
• Patient with implanted material considered to be infected by SAMS and whose antibiotic treatment is longer than 70 days
• New cerebro-spinal signs in the preceding month
• Clinical examination compatible with recent stroke (\<1 month), brain abscess or meningitis
• Current other antibiotic therapy which cannot be ceased or substituted by study treatment
• Mixed blood culture with more than one pathogen (excluding contaminants: Corynebacterium sp., Propionibacterium sp., Coagulase-Negative Staphylococci)
• coagulapthy with TP\< 50% (excepted for patients under avk anticoagulant treatment)
• Absence of written informed consent from the patient
• Limitation of care with expected life duration below 90 days
• Patient under guardianship or trusteeship
• No affiliation to social security (beneficiary or assignee)

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

François-Xavier Lescure

Paris, 75018, France

Location

Related Publications (2)

• Burdet C, Saidani N, Dupieux C, Lemaignen A, Canoui E, Surgers L, Vareil MO, Lefort A, Lepeule R, Peiffer-Smadja N, Charmillon A, Le Moing V, Boutoille D, Tolsma V, Abgrall S, Wolff M, Tattevin P, Esposito-Farese M, Vandenesch F, Duval X, Tubiana S, Lescure FX; CloCeBa Study Group. Cloxacillin versus cefazolin for meticillin-susceptible Staphylococcus aureus bacteraemia (CloCeBa): a prospective, open-label, multicentre, non-inferiority, randomised clinical trial. Lancet. 2025 Nov 15;406(10517):2349-2359. doi: 10.1016/S0140-6736(25)01624-1. Epub 2025 Oct 17.

  PMID: 41115439 RESULT

• Burdet C, Loubet P, Le Moing V, Vindrios W, Esposito-Farese M, Linard M, Ferry T, Massias L, Tattevin P, Wolff M, Vandenesch F, Grall N, Quintin C, Mentre F, Duval X, Lescure FX; CloCeBa study group. Efficacy of cloxacillin versus cefazolin for methicillin-susceptible Staphylococcus aureus bacteraemia (CloCeBa): study protocol for a randomised, controlled, non-inferiority trial. BMJ Open. 2018 Sep 1;8(8):e023151. doi: 10.1136/bmjopen-2018-023151.

  PMID: 30173161 DERIVED

MeSH Terms

Conditions

Staphylococcal Infections; Bacteremia

Interventions

Cloxacillin; Cefazolin

Condition Hierarchy (Ancestors)

Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Oxacillin; Penicillins; beta-Lactams; Lactams; Amides; Organic Chemicals; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Cephalosporins; Thiazines

Study Officials

• Xavier Lescure, MD, PhD

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 24, 2017
• First Posted: August 14, 2017
• Study Start: September 5, 2018
• Primary Completion: February 22, 2024
• Study Completion: March 10, 2025
• Last Updated: November 24, 2025

Record last verified: 2025-10

Locations

FR (1)