Overview
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)
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.
Eligibility
The participant must fulfil all inclusion and exclusion criteria for the SNAP Platform
(NCT05137119) and also the following inclusion and exclusion criteria to be eligible for
this sub-study:
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.