Staphylococcal Sepsis, Staphylococcus Aureus Bacteremia, Staphylococcus Aureus Endocarditis, Staphylococcus Aureus Septicemia
Conditions
Keywords
Staphylococcus aureus, Methicillin-susceptible, Bacteremia
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. This study is an approved sub-study of The Staphylococcus aureus Network Adaptive Platform (SNAP) trial (NCT05137119)
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.
Interventions
DRUGErtapenem
Adjunctive ertapenem
DRUGPlacebo
Saline placebo
Sponsors
Todd C. Lee MD MPH FIDSA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
The participant must fulfil all inclusion and
Exclusion criteria
for the SNAP Platform (NCT05137119) and also the following inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical success | Day 5 | Composite of: Patient alive, fever resolved, blood cultures negative for S. aureus, systolic blood pressure \>=90mmHg not on vasopressors |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Blood culture clearance | 30 days | Time between first positive and first negative blood culture |
| Clinical improvement | 30 days | 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 | 90 days | The time from initial emergency room visit until discharge from hospital in patients discharged alive |
| All cause-mortality | 90 days | Death from any cause |
| C. diff infection | 56 days | Any C. difficile infection within 56 days |
| Gram-negative bacteremia | 56 days | Any Gram-negative bacteremia within 56 days |
| New colonization with carbapenemase producing organisms | 56 days | Newly identified colonization with carbapenemase producing organisms to day 56 |
| Valve replacement surgery | 56 days | Any valve replacement surgery occurring after the initial diagnosis |
| Recurrent isolation of MSSA from a sterile site | Between Days 6 and 90 inclusive | 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 | 7 days | Any clinically identified seizure within 48 hours of discontinuation of combination therapy |
| Acute Kidney Injury | 7 days | 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 |
Countries
Canada
Contacts
CONTACTLina Petrella
PRINCIPAL_INVESTIGATORTodd C Lee, MD MPH FIDSA
Research Institute of the McGill University Health Centre
PRINCIPAL_INVESTIGATOREmily G McDonald, MD MSc
Research Institute of the McGill University Health Centre
PRINCIPAL_INVESTIGATORMatthew P Cheng, MD
Research Institute of the McGill University Health Centre
Outcome results
None listed