Cefazolin + Ertapenem for Staph Bacteremia

(CERT Trial)

Recruiting at3 trial locations

Overseen by Todd C Lee, MD MPH

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

Trial Summary

What is the purpose of this trial?

This trial tests if adding the antibiotic ertapenem to cefazolin can better treat severe bloodstream infections caused by MSSA. It aims to help patients who still face high death rates with current treatments by using two antibiotics that attack the bacteria in different ways. Ertapenem and cefazolin have been used together to successfully treat persistent MSSA bacteremia, showing potential synergy in studies.

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.

What data supports the effectiveness of the drug combination of cefazolin and ertapenem for treating Staph bacteremia?

Research shows that the combination of cefazolin and ertapenem successfully cleared persistent Staphylococcus aureus bloodstream infections, even in cases where other treatments failed. This combination was effective in both laboratory and animal studies, and it rapidly cleared infections in patients, including those with COVID-19. ^{1 2 3 4 5}

Is the combination of cefazolin and ertapenem safe for humans?

Ertapenem, one of the drugs in the combination, has been tested in many studies and is generally well tolerated, with common mild side effects like diarrhea and nausea. No major safety concerns were found, and it has a similar safety profile to other antibiotics like piperacillin-tazobactam and ceftriaxone. ^{1 2 4 6 7}

How is the drug combination of cefazolin and ertapenem unique for treating Staph bacteremia?

The combination of cefazolin and ertapenem is unique because it rapidly clears persistent methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, often within 24 hours, and shows enhanced effectiveness compared to using either drug alone. This combination works synergistically, meaning the drugs work better together than separately, and it may stimulate the immune system to help fight the infection. ^{1 2 3 4 5}

Research Team

Todd C Lee, MD MPH

Principal Investigator

Research Institute of the McGill University Health Centre

Matthew P Cheng, MD

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

Eligibility Criteria

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 18 years old or older.

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

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

I have taken valproic acid.

Expected mortality within 48 hours

Trial Timeline

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

Treatment Details

Interventions

• Ertapenem (Carbapenem)
• Placebo (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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Findings from Research

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Cefazolin and Ertapenem Salvage Therapy Rapidly Clears Persistent Methicillin-Susceptible Staphylococcus aureus Bacteremia. [2022]

2. United States 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? [2022]

3. United States 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. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Cefazolin and Ertapenem, a Synergistic Combination Used To Clear Persistent Staphylococcus aureus Bacteremia. [2018]

5. Egypt pubmed.ncbi.nlm.nih.gov

Persistent Methicillin-Susceptible Bacteremia Rapidly Cleared with Cefazolin and Ertapenem Combination Therapy in a Patient with COVID-19. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Ertapenem: a review of its use in the treatment of bacterial infections. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Safety and tolerability of ertapenem. [2018]