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

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ClinicalTrials.gov Identifier: NCT03248063
Recruitment Status : Recruiting
First Posted : August 14, 2017
Last Update Posted : May 27, 2020
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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. "


Condition or disease Intervention/treatment Phase
Bacteremia Due to Methicillin Susceptible Staphylococcus Aureus Drug: Cloxacillin Drug: Cefazolin Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter Non-inferiority Randomized Trial Comparing Cloxacillin Versus Cefazolin Efficacy for the Treatment of Bacteremia Caused by Methicillin-susceptible Staphylococcus Aureus (MSSA)
Actual Study Start Date : September 5, 2018
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : September 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Cloxacillin
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

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.


Experimental: Cefazolin
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
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.




Primary Outcome Measures :
  1. Therapeutic efficacy [ Time Frame: 90 days after beginning of antibiotic treatment ]

    "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"


Secondary Outcome Measures :
  1. Mortality [ Time Frame: day 90 ]
    Mortality rate at day 90

  2. Bacteriological efficacy [ Time Frame: day 3, day 5 and day 90 ]
    Proportions of patients with a negative set of blood culture at day 3, at day 5 and at day 90

  3. Bacteriologic relapse [ Time Frame: day 5 ]
    Proportion of patients with bacteriologic success at day 5 in whom a strain of S. aureus with identical in vitro antibiotic susceptibility pattern than the one isolated at inclusion is isolated from at least 1 blood culture during the follow up

  4. Clinical efficacy [ Time Frame: day 7 and day 90 ]
    Proportions of patients improving all signs and symptoms related to the infection at day 7 and at day 90

  5. Proportions of patients for whom consensual treatment duration is respected [ Time Frame: day 90 ]
    Proportion of patients for whom the antibiotic duration from randomization is in accordance with consensual guidelines obtained by the Delphi method

  6. Occurrence of any adverse event [ Time Frame: at day 7 and up to 6 weeks ]
    Proportions of patients with any adverse event at day 7, at the end of studied antibiotic therapy (EoST) and at the end of all antibiotic therapy (EoAT)

  7. Occurrence of grade 3 or grade 4 adverse event [ Time Frame: at day 7 and up to 6 weeks ]
    7. Proportions of patients with any grade 3 or grade 4 adverse event at day 7, at EoST and at EoAT

  8. Premature discontinuation of studied antibiotic therapy due to the occurrence of an adverse event [ Time Frame: day 90 ]
    Proportion of patients with premature discontinuation of studied antibiotic therapy due to the occurrence of an adverse event

  9. Occurrence C. difficile infection [ Time Frame: day 90 ]
    Proportion of patients with C. difficile infection

  10. Prevalence of BlaZ genes in S. aureus strains isolated from patients with MSSA bacteremia [ Time Frame: at inclusion ]
    Proportion of type A, type B, type C and type D BlaZ genes

  11. Link between BlaZ typing and bacteriologic efficacy [ Time Frame: day 5 ]
    Type of BlaZ gene. Proportion of patients with a negative blood culture at day 5.

  12. MICs distribution of cefazolin and cloxacillin in S. aureus strains isolated from patients with MSSA bacteremia [ Time Frame: at inclusion ]
    MICs of cefazolin and cloxacillin

  13. Emergence of antimicrobial resistance in the faecal microbiota [ Time Frame: at day 7, up to 6 weeks and at day 90 ]
    Proportion of patients with emergence of 3rd generation cephalosporin-resistant Enterobacteriaceae in fecal swabs at day 7, at EoAT and at day 90

  14. Changes in relative abundance of each bacterial phylum [ Time Frame: at day 7, up to 6 weeks and at day 90 ]
    comparison of the variation from baseline of the logarithm of proportions of each bacterial phylum at inclusion, EoAT and day 90

  15. Changes in bacterial diversity within the intestinal microbiota [ Time Frame: at day 7, up to 6 weeks and at day 90 ]
    comparison of the change from baseline of shannon index within the intestinal microbiota between inclusion and day 90

  16. Total body clearance of cloxacillin and cefazolin in patients with MSSA bacteremia [ Time Frame: at day 3 ]
  17. Total body volume of distribution of cloxacillin and cefazolin in patients with MSSA bacteremia [ Time Frame: at day 3 ]
  18. Area under the plasma concentration versus time curve (AUC) of cloxacillin and cefazolin [ Time Frame: at day 5 ]
  19. Peak Plasma Concentration (Cmax) of cloxacillin and cefazolin [ Time Frame: at day 5 ]
  20. Minimal inhibitory concentration (MIC) of cloxacillin and cefazolin [ Time Frame: at day 5 ]
  21. Residual concentration (Cres) of cloxacillin and cefazolin [ Time Frame: at day 5 ]
  22. The proportion of time between 2 administration during which the plasma concentration of the antimicrobial is above the MIC (%T>MIC). [ Time Frame: at day 5 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

Exclusion Criteria:

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

Secondary exclusion criteria:

  1. Diagnosis of meningitis made after randomisation
  2. Diagnosis of brain abscess made after randomisation
  3. Diagnosis of multiple infection made after randomisation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03248063


Contacts
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Contact: Xavier Lescure, MD, PhD 01 40 25 69 94 ext 33 xavier.lescure@aphp.fr
Contact: Charles Burdet, MD, PhD charles.burdet@inserm.fr

Locations
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France
François-Xavier Lescure Recruiting
Paris, France, 75018
Contact: François-Xavier Lescure, MD-PhD       xavier.lescure@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Xavier Lescure, MD, PhD Assistance Publique - Hôpitaux de Paris
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03248063    
Other Study ID Numbers: P160943J
First Posted: August 14, 2017    Key Record Dates
Last Update Posted: May 27, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Staphylococcus aureus
bacteremia
cloxacillin
cefazolin
Additional relevant MeSH terms:
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Bacteremia
Bacterial Infections
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Cefazolin
Cloxacillin
Anti-Bacterial Agents
Anti-Infective Agents