Combination Cefazolin With Ertapenem for Methicillin-susceptible Staphylococcus Aureus Bacteremia

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Staphylococcus Aureus Bacteremia, Staphylococcus Aureus Septicemia, Staphylococcal Sepsis, Staphylococcus Aureus Endocarditis

Intervention / Treatment
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* Drug: Ertapenem
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ertapenem<br>Ertapenem 1g IV daily infused over 2 hours x 5 days | Drug: Ertapenem<br>* Adjunctive ertapenem<br>* Other names: Invanz;|
| Placebo Comparator: Placebo<br>Saline placebo infused daily over 2 hours x 5 days | Drug: Placebo<br>* Saline placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical success | Composite of: Patient alive, fever resolved, blood cultures negative for S. aureus, systolic blood pressure >=90mmHg not on vasopressors | Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood culture clearance | Time between first positive and first negative blood culture | 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 | 30 days | 
| Length of stay | The time from initial emergency room visit until discharge from hospital in patients discharged alive | 90 days | 
| All cause-mortality | Death from any cause | 90 days | 
| C. diff infection | Any C. difficile infection within 56 days | 56 days | 
| Gram-negative bacteremia | Any Gram-negative bacteremia within 56 days | 56 days | 
| New colonization with carbapenemase producing organisms | Newly identified colonization with carbapenemase producing organisms to day 56 | 56 days | 
| Valve replacement surgery | Any valve replacement surgery occurring after the initial diagnosis | 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 | Between Days 6 and 90 inclusive | 
| Seizure | Any clinically identified seizure within 48 hours of discontinuation of combination therapy | 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 | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Staphylococcus aureus, Methicillin-susceptible, Bacteremia