Staphylococcus Aureus BacteremiaPhase 2CERTNCT04886284
Combination Cefazolin With Ertapenem for Methicillin-susceptible Staphylococcus Aureus Bacteremia
A Phase 2 study testing Ertapenem in people with Staphylococcus Aureus Bacteremia and Staphylococcus Aureus Septicemia, run by Todd C. Lee MD MPH FIDSA at 7 sites in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- Staphylococcus Aureus Bacteremia, Staphylococcus Aureus Septicemia, Staphylococcal Sepsis
- What is being tested?
- Ertapenem
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 60 participants
- Where
- 7 sitesCanada
- Study dates
- 20 May 2024to Jul 2027
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 15Show fewer
- 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.
Trial locations and contacts
7 sites in 1 country. Contact the study team or a site near you to ask about taking part.
7 sites in 1 country
Canada7 sites, 7 recruiting
- Recruiting
Foothills Medical Centre
Calgary, Alberta, T2N4Z6
Ranjani Somayaji, MD MPH
- Recruiting
Hamilton Health Sciences (Hamilton General Hospital and Juravinski Hospital)
Hamilton, Ontario, L8P1A2
Dominik Mertz, MD MSc
- Recruiting
Hospital de la Cité de la Sante
Laval, Quebec
Marco Bergevin, MD, Marco-Andres.Bergevin.med@ssss.gouv.qc.ca
Marco Bergevin, MD
- Recruiting
Jewish General Hospital
Montreal, Quebec, H3T 1E2
Leighanne Parkes, MD
- Recruiting
McGill University Health Centre (Royal Victoria Hospital and Montreal General Hospital)
Montreal, Quebec, H4A3J1
Lina Petrella, 514-934-1934 ext. 23730, lina.petrella@muhc.mcgill.ca
Emily G McDonald, MD MSc
- Recruiting
Niagara Health - St. Catharines site
Saint Catharines, Ontario, L2E6X2
Aidan Findlater, MD
- Recruiting
Surrey Memorial Hospital
Surrey, British Columbia
Christopher Condin, PhD, christopher.condin@fraserhealth.ca
Kevin Afra, MD, MHA, FRCPC
About this study
Official title: Combination Cefazolin With Ertapenem for Methicillin-susceptible Staphylococcus Aureus Bacteremia (CERT)
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.
This study is an approved sub-study of The Staphylococcus aureus Network Adaptive Platform (SNAP) trial (NCT05137119)
Read the 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.
- Conditions
- Staphylococcus Aureus Bacteremia, Staphylococcus Aureus Septicemia, Staphylococcal Sepsis, Staphylococcus Aureus Endocarditis
- Being tested
- Ertapenem, Placebo
- Keywords
- Staphylococcus aureus, Methicillin-susceptible, Bacteremia
- Medical subject headings
- Staphylococcal Infections, Bacteremia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ErtapenemDrug
Also called Invanz
Adjunctive ertapenem
PlaceboDrug
Saline placebo
| Study group | Role | What they receive |
|---|---|---|
| Ertapenem | Experimental | Ertapenem 1g IV daily infused over 2 hours x 5 days Receives: Drug: Ertapenem |
| Placebo | Placebo comparator | Saline placebo infused daily over 2 hours x 5 days Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Clinical success
Composite of: Patient alive, fever resolved, blood cultures negative for S. aureus, systolic blood pressure >=90mmHg not on vasopressors
Measured: Day 5
Secondary outcomes (11)
Blood culture clearance
Time between first positive and first negative blood culture
Measured: 30 days
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
Measured: 30 days
Length of stay
The time from initial emergency room visit until discharge from hospital in patients discharged alive
Measured: 90 days
All cause-mortality
Death from any cause
Measured: 90 days
C. diff infection
Any C. difficile infection within 56 days
Measured: 56 days
Gram-negative bacteremia
Any Gram-negative bacteremia within 56 days
Measured: 56 days
New colonization with carbapenemase producing organisms
Newly identified colonization with carbapenemase producing organisms to day 56
Measured: 56 days
Valve replacement surgery
Any valve replacement surgery occurring after the initial diagnosis
Measured: 56 days
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
Measured: Between Days 6 and 90 inclusive
Seizure
Any clinically identified seizure within 48 hours of discontinuation of combination therapy
Measured: 7 days
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
Measured: 7 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 May 2021
- Study start20 May 2024
- Primary completionApr 2027 (estimated)
- Study completionJul 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Staphylococcus Aureus BacteremiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Todd C. Lee MD MPH FIDSA
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Todd C. Lee MD MPH FIDSA, McGill University Health Centre/Research Institute of the McGill University Health Centre
- Investigators
- Todd C Lee, MD MPH FIDSA, Principal investigator, Research Institute of the McGill University Health CentreEmily G McDonald, MD MSc, Principal investigator, Research Institute of the McGill University Health CentreMatthew P Cheng, MD, Principal investigator, Research Institute of the McGill University Health Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04886284
- Sponsor's protocol ID
- 2021-7400
- Acronym
- CERT
- Status last verified
- Sep 2026
- First submitted
- 10 May 2021
- Last updated
- 11 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 31773134Sakoulas 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.
PubMed 27572414Cosgrove 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.
PubMed 19207079Bamberger 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.
PubMed 12183241Chambers 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.
PubMed 2345297Cheng 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.
PubMed 32667982Tong SYC, Mora J, Bowen AC, Cheng MP, Daneman N, Goodman AL, Heriot GS, Lee TC, Lewis RJ, Lye DC, Mahar RK, Marsh J, McGlothlin A, McQuilten Z, Morpeth SC, Paterson DL, Price DJ, Roberts JA, Robinson JO, van Hal SJ, Walls G, Webb SA, Whiteway L, Yahav D, Davis JS; Staphylococcus aureus Network Adaptive Platform (SNAP) Study Group. The Staphylococcus aureus Network Adaptive Platform Trial Protocol: New Tools for an Old Foe. Clin Infect Dis. 2022 Nov 30;75(11):2027-2034. doi: 10.1093/cid/ciac476.
PubMed 35717634Shah S, Clarke LG, Falcione BA, Shields RK, Smith BJ. Incidence and factors associated with rapid blood culture sterilization among patients receiving ertapenem combination therapy for MSSA bacteremia. Antimicrob Agents Chemother. 2026 Feb 4;70(2):e0130325. doi: 10.1128/aac.01303-25. Epub 2025 Dec 23.
PubMed 41433510