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Combination Cefazolin With Ertapenem for Methicillin-susceptible Staphylococcus Aureus Bacteremia (CERT)

Primary Purpose

Staphylococcus Aureus Bacteremia, Staphylococcus Aureus Septicemia, Staphylococcal Sepsis

Status
Not yet recruiting
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Ertapenem
Placebo
Sponsored by
Todd C. Lee MD MPH FIDSA
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Staphylococcus Aureus Bacteremia focused on measuring Staphylococcus aureus, Methicillin-susceptible, Bacteremia

Eligibility Criteria

18 Years - 100 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Adult >=18 years old
  2. S. aureus bacteremia within the past 48 hours:

    • with any unknown MRSA status (in centers with <15% prevalence of MRSA in their annual blood cultures) or known negative MRSA screening swab within 90 days OR
    • which has already been shown to be MSSA
  3. Current receipt of cefazolin or where it would be clinically appropriate (according to treating ID specialist) to switch to cefazolin as the backbone therapy (open label, non-study drug).

NOTE: Up to an additional 12-24 hours of open label non-study VANCOMYCIN, LINEZOLID or DAPTOMYCIN may be allowed if there is sepsis and clinical concern for MRSA has not been excluded.

Exclusion Criteria:

Clinical:

  1. At time of recruitment, the patient has already clinically improved with at least one subsequent negative culture at >24 hours incubation
  2. Anaphylaxis to any beta-lactam antibiotic (and any allergy to ertapenem) Polymicrobial bacteremia (not including skin commensals)
  3. Known seizure disorder
  4. Any receipt of valproic acid
  5. Expected mortality within 48 hours
  6. Need for critical care resources but "do not resuscitate" status precludes the receipt of critical care
  7. Unable to provide informed consent and no available healthcare proxy (with ethics approval for deferred consent in cases of severe illness)

Administrative:

  1. Refusal to provide informed consent
  2. Refusal of healthcare team to participate
  3. No reliable means of outpatient contact (telephone/email/text)
  4. Previously enrolled
  5. Patients whose isolate is identified as MRSA post-enrollment will be subsequently excluded (see below).

Note that because MSSA is much more common than MRSA in Canada (90% of all S. aureus bacteremia at MUHC, for example, are MSSA and in the presence of a negative MRSA screening swab or unknown MRSA status, this means that the risk of MRSA is less than 5%). We believe time to combination therapy is likely linked to benefit, therefore we will recruit the patients as soon as S. aureus is identified but potentially prior to confirmation the organism is MSSA. Where possible, rapid MRSA detection techniques will be deployed; however with conventional screening this will mean approximately a 12-24 hours delay. Organisms subsequently identified as MRSA will be excluded from the intention to treat analysis and the sample size will be adjusted accordingly to ensure the total enrollment meets study goals.

Sites / Locations

  • McGill University Health Centre (Royal Victoria Hospital and Montreal General Hospital)

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Ertapenem

Placebo

Arm Description

Ertapenem 1g IV daily infused over 2 hours x 5 days

Saline placebo infused daily over 2 hours x 5 days

Outcomes

Primary Outcome Measures

Clinical success
Composite of: Patient alive, fever resolved, blood cultures negative for S. aureus, systolic blood pressure >=90mmHg not on vasopressors

Secondary Outcome Measures

Blood culture clearance
Time between first positive and first negative blood culture
Clinical improvement
Time to clinical improvement defined as the time until fever resolved, blood cultures sterile, and systolic blood pressure >=90mmHg not on vasopressors in patients who survive to clinical improvement
Length of stay
The time from initial emergency room visit until discharge from hospital in patients discharged alive
All cause-mortality
Death from any cause
C. diff infection
Any C. difficile infection within 56 days
Gram-negative bacteremia
Any Gram-negative bacteremia within 56 days
New colonization with carbapenemase producing organisms
Newly identified colonization with carbapenemase producing organisms to day 56
Valve replacement surgery
Any valve replacement surgery occurring after the initial diagnosis
Recurrent isolation of MSSA from a sterile site
Any positive culture of MSSA from a sterile site (blood, cerebral spinal fluid, joint aspirate, bone, etc.) occurring after the end of combination therapy
Seizure
Any clinically identified seizure within 48 hours of discontinuation of combination therapy
Acute Kidney Injury
An increase in serum creatinine to ≥1.5 times baseline OR new requirement for hemodialysis at any time in the first 7 days from randomization

Full Information

First Posted
May 10, 2021
Last Updated
February 21, 2022
Sponsor
Todd C. Lee MD MPH FIDSA
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1. Study Identification

Unique Protocol Identification Number
NCT04886284
Brief Title
Combination Cefazolin With Ertapenem for Methicillin-susceptible Staphylococcus Aureus Bacteremia
Acronym
CERT
Official Title
Combination Cefazolin With Ertapenem for Methicillin-susceptible Staphylococcus Aureus Bacteremia (CERT)
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Not yet recruiting
Study Start Date
July 2022 (Anticipated)
Primary Completion Date
March 2023 (Anticipated)
Study Completion Date
July 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Todd C. Lee MD MPH FIDSA

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
There is a variety of in vitro, in vivo (animal model), and human case series data which suggests that the addition of ertapenem to cefazolin could improve outcomes in methicillin-susceptible S. aureus bacteremia. No randomized controlled trial has been performed.
Detailed Description
Cefazolin is licensed in Canada for the management of infections due to susceptible Staphylococcus aureus, including bacteremia. It has been commonly used for decades in this disease and, when compared in observational studies to anti-staphylococcal penicillins, has demonstrated reduced mortality. Nevertheless, in the treatment of methicillin-susceptible S. aureus (MSSA) bacteremia, there remains significant opportunities to improve clinical outcomes. Indeed, S. aureus bacteremia kills more Canadians annually than myeloma, melanoma, renal, ovarian or stomach cancers. Overall mortality approached 18% in a recent Canadian clinical trial performed by our group (Cheng et al, 2020). The duration of bacteremia, particularly after antibiotherapy is recognized as a major risk factor for mortality. Interventions which reduce the duration of bacteremia, without increasing the frequency of renal failure like gentamicin (Cosgrove et al, 2009) or the combination of vancomycin and flucloxacillin in MRSA (Tong et al, 2020), are among the most promising candidates for larger phase 3 studies designed to impact patient mortality. Ertapenem is a commonly used antibiotic which has been on the Canadian market for more than 15 years. It is most commonly used in patients with infections caused by extended-spectrum beta-lactamase producing Enterobacteraciae; however, it has a broad spectrum of activity including Gram-positive bacteria such as S. aureus. Indeed, the drug is licensed in Canada for the treatment of complicated skin and soft tissue infections commonly caused by S. aureus. In S. aureus the carbapenem antibiotics like ertapenem have exceptional affinity to the essential penicillin-binding protein (PBP), PBP1, exceeding even that of the antistaphylococcal β-lactams (Chambers et al, 1990). This complements the relative PBP2 proclivity of cefazolin (Bamberger et al, 2002). The combination of cefazolin with ertapenem has also been shown to be synergistic in vitro (Sakoulas et al, 2016), in vivo in the mouse and rat models (Sakoulas et al, 2016; Ulloa et al, 2020), and in a small human case series (Ulloa et al, 2020). Based on this data, there is compelling theory (attack on 2 PBPs), in vitro, in vivo, and human case evidence to support an exploratory phase 2 RCT of cefazolin-ertapenem for the treatment of MSSA bacteremia.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Staphylococcus Aureus Bacteremia, Staphylococcus Aureus Septicemia, Staphylococcal Sepsis, Staphylococcus Aureus Endocarditis
Keywords
Staphylococcus aureus, Methicillin-susceptible, Bacteremia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Ertapenem
Arm Type
Experimental
Arm Description
Ertapenem 1g IV daily infused over 2 hours x 5 days
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Saline placebo infused daily over 2 hours x 5 days
Intervention Type
Drug
Intervention Name(s)
Ertapenem
Other Intervention Name(s)
Invanz
Intervention Description
Adjunctive ertapenem
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Saline placebo
Primary Outcome Measure Information:
Title
Clinical success
Description
Composite of: Patient alive, fever resolved, blood cultures negative for S. aureus, systolic blood pressure >=90mmHg not on vasopressors
Time Frame
Day 5
Secondary Outcome Measure Information:
Title
Blood culture clearance
Description
Time between first positive and first negative blood culture
Time Frame
30 days
Title
Clinical improvement
Description
Time to clinical improvement defined as the time until fever resolved, blood cultures sterile, and systolic blood pressure >=90mmHg not on vasopressors in patients who survive to clinical improvement
Time Frame
30 days
Title
Length of stay
Description
The time from initial emergency room visit until discharge from hospital in patients discharged alive
Time Frame
90 days
Title
All cause-mortality
Description
Death from any cause
Time Frame
90 days
Title
C. diff infection
Description
Any C. difficile infection within 56 days
Time Frame
56 days
Title
Gram-negative bacteremia
Description
Any Gram-negative bacteremia within 56 days
Time Frame
56 days
Title
New colonization with carbapenemase producing organisms
Description
Newly identified colonization with carbapenemase producing organisms to day 56
Time Frame
56 days
Title
Valve replacement surgery
Description
Any valve replacement surgery occurring after the initial diagnosis
Time Frame
56 days
Title
Recurrent isolation of MSSA from a sterile site
Description
Any positive culture of MSSA from a sterile site (blood, cerebral spinal fluid, joint aspirate, bone, etc.) occurring after the end of combination therapy
Time Frame
Between Days 6 and 90 inclusive
Title
Seizure
Description
Any clinically identified seizure within 48 hours of discontinuation of combination therapy
Time Frame
7 days
Title
Acute Kidney Injury
Description
An increase in serum creatinine to ≥1.5 times baseline OR new requirement for hemodialysis at any time in the first 7 days from randomization
Time Frame
7 days
Other Pre-specified Outcome Measures:
Title
Health-related quality of life
Description
This will be assessed using the EQ-5D-5L questionnaire
Time Frame
90 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
100 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult >=18 years old S. aureus bacteremia within the past 48 hours: with any unknown MRSA status (in centers with <15% prevalence of MRSA in their annual blood cultures) or known negative MRSA screening swab within 90 days OR which has already been shown to be MSSA Current receipt of cefazolin or where it would be clinically appropriate (according to treating ID specialist) to switch to cefazolin as the backbone therapy (open label, non-study drug). NOTE: Up to an additional 12-24 hours of open label non-study VANCOMYCIN, LINEZOLID or DAPTOMYCIN may be allowed if there is sepsis and clinical concern for MRSA has not been excluded. Exclusion Criteria: Clinical: At time of recruitment, the patient has already clinically improved with at least one subsequent negative culture at >24 hours incubation Anaphylaxis to any beta-lactam antibiotic (and any allergy to ertapenem) Polymicrobial bacteremia (not including skin commensals) Known seizure disorder Any receipt of valproic acid Expected mortality within 48 hours Need for critical care resources but "do not resuscitate" status precludes the receipt of critical care Unable to provide informed consent and no available healthcare proxy (with ethics approval for deferred consent in cases of severe illness) Administrative: Refusal to provide informed consent Refusal of healthcare team to participate No reliable means of outpatient contact (telephone/email/text) Previously enrolled Patients whose isolate is identified as MRSA post-enrollment will be subsequently excluded (see below). Note that because MSSA is much more common than MRSA in Canada (90% of all S. aureus bacteremia at MUHC, for example, are MSSA and in the presence of a negative MRSA screening swab or unknown MRSA status, this means that the risk of MRSA is less than 5%). We believe time to combination therapy is likely linked to benefit, therefore we will recruit the patients as soon as S. aureus is identified but potentially prior to confirmation the organism is MSSA. Where possible, rapid MRSA detection techniques will be deployed; however with conventional screening this will mean approximately a 12-24 hours delay. Organisms subsequently identified as MRSA will be excluded from the intention to treat analysis and the sample size will be adjusted accordingly to ensure the total enrollment meets study goals.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sarah Elsayed
Phone
514-934-1934
Ext
23730
Email
sarah.elsayed@idtrials.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Todd C Lee, MD MPH FIDSA
Organizational Affiliation
Research Institute of the McGill University Health Centre
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Emily G McDonald, MD MSc
Organizational Affiliation
Research Institute of the McGill University Health Centre
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Matthew P Cheng, MD
Organizational Affiliation
Research Institute of the McGill University Health Centre
Official's Role
Principal Investigator
Facility Information:
Facility Name
McGill University Health Centre (Royal Victoria Hospital and Montreal General Hospital)
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H4A3J1
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
31773134
Citation
Ulloa ER, Singh KV, Geriak M, Haddad F, Murray BE, Nizet V, Sakoulas G. Cefazolin and Ertapenem Salvage Therapy Rapidly Clears Persistent Methicillin-Susceptible Staphylococcus aureus Bacteremia. Clin Infect Dis. 2020 Sep 12;71(6):1413-1418. doi: 10.1093/cid/ciz995.
Results Reference
background
PubMed Identifier
27572414
Citation
Sakoulas G, Olson J, Yim J, Singh NB, Kumaraswamy M, Quach DT, Rybak MJ, Pogliano J, Nizet V. Cefazolin and Ertapenem, a Synergistic Combination Used To Clear Persistent Staphylococcus aureus Bacteremia. Antimicrob Agents Chemother. 2016 Oct 21;60(11):6609-6618. doi: 10.1128/AAC.01192-16. Print 2016 Nov.
Results Reference
background
PubMed Identifier
19207079
Citation
Cosgrove SE, Vigliani GA, Fowler VG Jr, Abrutyn E, Corey GR, Levine DP, Rupp ME, Chambers HF, Karchmer AW, Boucher HW. Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic. Clin Infect Dis. 2009 Mar 15;48(6):713-21. doi: 10.1086/597031.
Results Reference
background
PubMed Identifier
12183241
Citation
Bamberger DM, Herndon BL, Fitch J, Florkowski A, Parkhurst V. Effects of neutrophils on cefazolin activity and penicillin-binding proteins in Staphylococcus aureus abscesses. Antimicrob Agents Chemother. 2002 Sep;46(9):2878-84. doi: 10.1128/AAC.46.9.2878-2884.2002.
Results Reference
background
PubMed Identifier
2345297
Citation
Chambers HF, Sachdeva M. Binding of beta-lactam antibiotics to penicillin-binding proteins in methicillin-resistant Staphylococcus aureus. J Infect Dis. 1990 Jun;161(6):1170-6. doi: 10.1093/infdis/161.6.1170.
Results Reference
background
PubMed Identifier
32667982
Citation
Cheng MP, Lawandi A, Butler-Laporte G, De l'Etoile-Morel S, Paquette K, Lee TC. Adjunctive Daptomycin in the Treatment of Methicillin-susceptible Staphylococcus aureus Bacteremia: A Randomized, Controlled Trial. Clin Infect Dis. 2021 May 4;72(9):e196-e203. doi: 10.1093/cid/ciaa1000.
Results Reference
background

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Combination Cefazolin With Ertapenem for Methicillin-susceptible Staphylococcus Aureus Bacteremia

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