Cefazolin + Ertapenem for Staph Bacteremia

(CERT Trial)

Recruiting at 4 trial locations

Overseen By Lina Petrella

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Todd C. Lee MD MPH FIDSA

Must be taking: Cefazolin

Must not be taking: Valproic acid

Disqualifiers: Seizure disorder, Anaphylaxis, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 5

Duration: 1 week

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding the antibiotic ertapenem to cefazolin can improve treatment outcomes for people with a blood infection caused by methicillin-susceptible Staphylococcus aureus (MSSA). Participants will receive either ertapenem or a placebo, alongside their current cefazolin treatment. The study seeks adults who have had a Staphylococcus aureus infection in their blood within the last 48 hours and are currently receiving cefazolin. The goal is to determine if this combination can better fight the infection and improve recovery. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must not be taking valproic acid, and you should be able to switch to cefazolin if you are not already on it.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using two antibiotics, ertapenem and cefazolin, together might help treat a serious blood infection called methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. This combination quickly clears the bacteria from the blood.

Ertapenem, approved for treating various infections, is generally considered safe. One study found that only a small number of patients experienced severe side effects, with most side effects being mild, such as nausea or mild diarrhea.

Overall, the combination of ertapenem and cefazolin appears well-tolerated. However, everyone reacts differently to treatments. Prospective trial participants should discuss any concerns with a doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about Ertapenem for treating Staph bacteremia because it offers a potentially faster and more targeted approach. Unlike the standard antibiotics typically used, Ertapenem is a carbapenem antibiotic that could be more effective against resistant strains of bacteria due to its broad-spectrum activity. It is administered intravenously over just five days, which might lead to quicker symptom relief compared to more prolonged treatments. This novel use of Ertapenem could change how quickly and effectively we treat serious bacterial infections.

What evidence suggests that this trial's treatments could be effective for Staph bacteremia?

This trial will compare ertapenem with a placebo to evaluate its effectiveness in treating methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. Research has shown that combining ertapenem with cefazolin may effectively treat this blood infection. In past cases, this combination successfully treated infections that did not respond well to other treatments. Specifically, studies found that adding ertapenem to cefazolin cleared the infection from the blood quickly, often within just 24 hours. This suggests that the combination might be more effective than using cefazolin alone. While more research is needed, early results are promising for those dealing with this serious infection. ^{1 3 5 6 7}

Who Is on the Research Team?

Todd C Lee, MD MPH

Principal Investigator

Research Institute of the McGill University Health Centre

Emily G McDonald, MD MSc

Principal Investigator

Research Institute of the McGill University Health Centre

Matthew P Cheng, MD

Principal Investigator

Research Institute of the McGill University Health Centre

Are You a Good Fit for This Trial?

Adults over 18 with a recent S. aureus blood infection, who are either on cefazolin or can switch to it. Excluded if they have improved with negative cultures, severe beta-lactam allergy, seizure disorders, expected mortality within 48 hours, or critical care needs but 'do not resuscitate' status.

Inclusion Criteria

I am currently taking cefazolin or can switch to it for my treatment.

I have a recent S. aureus infection and either don't know if it's MRSA, tested negative for MRSA, or it's confirmed MSSA.

Exclusion Criteria

Expected mortality within 48 hours

Patients whose isolate is identified as MRSA post-enrollment will be subsequently excluded.

I have taken valproic acid.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Ertapenem 1g IV daily or a saline placebo infused over 2 hours for 5 days

1 week

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of health-related quality of life and clinical improvement

90 days

Multiple visits (in-person and virtual)

Extended Monitoring

Participants are monitored for secondary outcomes such as C. diff infection, Gram-negative bacteremia, and new colonization with carbapenemase producing organisms

56 days

What Are the Treatments Tested in This Trial?

Interventions

• Ertapenem
• Placebo

Trial Overview This trial tests whether adding Ertapenem to Cefazolin treatment improves outcomes in patients with methicillin-susceptible Staphylococcus aureus bacteremia compared to a placebo group.

How Is the Trial Designed?

Group I: Ertapenem Experimental Treatment 1 Intervention

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

Group II: Placebo Placebo Group 1 Intervention

Saline placebo infused daily over 2 hours x 5 days

Ertapenem is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Invanz for:

• Complicated intra-abdominal infections
• Complicated skin and soft tissue infections
• Diabetic foot infections
• Community-acquired pneumonia

Approved in United States as Invanz for:

• Complicated intra-abdominal infections
• Complicated skin and skin structure infections
• Community-acquired pneumonia
• Complicated urinary tract infections

Approved in Canada as Invanz for:

• Complicated intra-abdominal infections
• Complicated skin and soft tissue infections
• Community-acquired pneumonia

Approved in Japan as Invanz for:

• Complicated intra-abdominal infections
• Complicated skin and soft tissue infections
• Septicemia

Who Is Running the Clinical Trial?

Todd C. Lee MD MPH FIDSA

Lead Sponsor

Trials

3

Recruited

660+

Published Research Related to This Trial

The combination of cefazolin and ertapenem was effective in treating 11 cases of persistent methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, achieving immediate clearance in 8 cases within 24 hours.

Despite modest in vitro synergy, the combination showed enhanced effectiveness in a rat model of MSSA endocarditis, suggesting that this treatment could be a promising option for patients with refractory MSSA infections and should be explored further in clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cefazolin and Ertapenem Salvage Therapy Rapidly Clears Persistent Methicillin-Susceptible Staphylococcus aureus Bacteremia. Ulloa, ER., Singh, KV., Geriak, M., et al.[2022]

Cefazolin combined with ertapenem is an effective treatment for difficult cases of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, showing promise in clinical settings.

The combination of these antibiotics enhances the release of interleukin-1β from immune cells, primarily due to ertapenem, which may help explain their strong effectiveness in the body despite only modest synergy observed in laboratory tests.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is the Success of Cefazolin plus Ertapenem in Methicillin-Susceptible Staphylococcus aureus Bacteremia Based on Release of Interleukin-1 Beta? Smelter, D., Hayney, M., Sakoulas, G., et al.[2022]

The combination of ertapenem and cefazolin effectively cleared refractory methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia in a patient, showing strong synergy in both in vitro and in vivo models.

In a murine skin infection model, this combination demonstrated enhanced bactericidal activity compared to using either drug alone, suggesting it could be a promising treatment option for MSSA infections and warrants further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cefazolin and Ertapenem, a Synergistic Combination Used To Clear Persistent Staphylococcus aureus Bacteremia. Sakoulas, G., Olson, J., Yim, J., et al.[2018]

Linezolid combined with ertapenem demonstrated strong in vitro synergy against methicillin-resistant Staphylococcus aureus (MRSA) strains, suggesting a potential effective treatment strategy.

In an in vivo rabbit endocarditis model, this combination showed highly synergistic activity after 4 days of treatment, indicating its efficacy in a real-world infection scenario.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro and in vivo assessment of linezolid combined with ertapenem: a highly synergistic combination against methicillin-resistant Staphylococcus aureus. Jacqueline, C., Caillon, J., Grossi, O., et al.[2018]

Ertapenem, a carbapenem antibiotic, was well tolerated in clinical trials involving 240 healthy volunteers and 2046 patients, with most adverse events being mild to moderate in intensity.

The safety profile of ertapenem was comparable to that of piperacillin-tazobactam and ceftriaxone, with no significant differences in adverse events or safety concerns between elderly and younger patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of ertapenem. Teppler, H., Gesser, RM., Friedland, IR., et al.[2018]

A patient with COVID-19 pneumonia and persistent methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infection (BSI) achieved blood culture sterilization within 24 hours after starting a combination therapy of cefazolin and ertapenem, following 11 days of positive blood cultures.

This case suggests that cefazolin and ertapenem combination therapy may be an effective treatment strategy for rapidly clearing MSSA from the bloodstream, potentially reducing the risk of severe complications associated with prolonged bacteremia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Persistent Methicillin-Susceptible Bacteremia Rapidly Cleared with Cefazolin and Ertapenem Combination Therapy in a Patient with COVID-19. Ilges, D., Krishnan, G., Geng, E.[2022]

Ertapenem is an effective antibiotic approved for treating various complicated infections, including complicated intra-abdominal infections and community-acquired pneumonia, in both adults and children over 3 months old.

It has a broad spectrum of activity against resistant Gram-negative bacteria and is comparable in efficacy to other antibiotics, while also offering the convenience of once-daily dosing and good tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ertapenem: a review of its use in the treatment of bacterial infections. Keating, GM., Perry, CM.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5075066/

Cefazolin and Ertapenem, a Synergistic Combination Used ... Ertapenem and cefazolin were used in combination to successfully clear refractory methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12533716/

Ertapenem Combined With Anti-Staphylococcal Beta-Lactam ... Similar success has been reported using this combination to treat adults with persistent MSSA bacteremia and preterm low-birth-weight infants ...

3. journals.asm.org journals.asm.org/doi/10.1128/aac.02166-21

Is the Success of Cefazolin plus Ertapenem in Methicillin ... A comparison of safety and outcomes with cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus bloodstream infections.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04886284

Combination Cefazolin With Ertapenem for Methicillin ... Nevertheless, in the treatment of methicillin-susceptible S. aureus (MSSA) bacteremia, there remains significant opportunities to improve clinical outcomes.

5. journals.sagepub.com journals.sagepub.com/doi/10.1177/20499361251343969

Adjunctive β-lactams for Staphylococcus aureus bacteremia The addition of ertapenem to cefazolin resulted in rapid blood culture sterilization within 24 h. Subsequent case series corroborated the ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3879226/

Evaluation of Ertapenem use with Impact Assessment on ... Mortality rate in these 172 cases was 13.4% (23 cases), where 6 died of other causes, and 5 others died because of concurrent infections, for example ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2008/021337s028lbl.pdf

INVANZ® - accessdata.fda.gov Ertapenem has been shown to be active against most isolates of the following microorganisms in vitro and in clinical infections. (See INDICATIONS AND USAGE):.