Treatment Strategies for Bacterial Blood Infections

Recruiting at 36 trial locations

Overseen By Mithun Mohan George

Age: Any Age

Sex: Any

Trial Phase: Academic

Sponsor: Sunnybrook Health Sciences Centre

Disqualifiers: Palliative care, Moribund, Polymicrobial infection, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 90 days

2500 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests different treatment strategies for bacterial infections in the blood, specifically those caused by Gram-negative bacteria. It compares various antibiotics and procedures to determine the best way to manage these infections and limit antibiotic resistance. Patients admitted to a participating hospital with a positive blood culture showing a Gram-negative bacterium might be suitable for this trial. Each part of the trial focuses on a different treatment choice, such as which antibiotics to use or whether to replace a central line (a tube used to administer medication). As an unphased trial, this study allows patients to contribute to important research that could enhance future treatment options for bacterial infections.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, there are exclusions related to drug interactions and medical contraindications, so it's best to discuss your specific medications with the trial team.

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

Studies have shown that cephalosporins, a type of antibiotic, are generally well-tolerated, though some concerns exist. For instance, cefiderocol, a specific cephalosporin, was linked to higher death rates in some patients with severe infections. However, in other situations, it proved as effective as standard treatments.

The safety of switching from stronger to milder antibiotics like cephalosporins remains less clear. Researchers continue to study the safety and effectiveness of this approach.

Conversely, oral beta-lactams, another type of antibiotic, appear safe for treating certain bloodstream infections. Studies suggest that patients who switched to oral beta-lactams experienced similar outcomes to those on other treatments and had shorter hospital stays, indicating good tolerance.

These findings inform the safety profile of treatments studied in the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it's exploring different strategies to tackle bacterial blood infections more effectively. One approach compares using cephalosporins against carbapenems for low-risk AmpC organisms, potentially reducing reliance on broad-spectrum antibiotics and minimizing resistance. Another strategy investigates the benefits of de-escalation, which could help tailor antibiotic use to the patient's needs and curb unnecessary exposure. The trial also looks into using oral beta-lactams versus non-beta-lactams, offering the possibility of more convenient oral treatments. Lastly, it examines the necessity of routine follow-up blood cultures and the decision between retaining or replacing central vascular catheters, aiming to refine patient management and reduce complications. Through these comparisons, researchers hope to optimize treatment plans and improve patient outcomes.

What evidence suggests that this trial's treatments could be effective for bacterial blood infections?

Research has shown that cephalosporins, a type of antibiotic, may effectively treat certain serious blood infections caused by Gram-negative bacteria. In some studies, about 64% of patients were cured using cefiderocol, a specific cephalosporin. This trial may administer cephalosporins or carbapenems to compare their effectiveness for low-risk AmpC organisms.

Switching from broad-range antibiotics to more specific ones, known as de-escalation, has demonstrated potential benefits. In some cases, the success rate for treating these infections reached 74.1%. This trial will compare de-escalation strategies with no de-escalation to evaluate their effectiveness.

For some blood infections caused by Enterobacterales bacteria, using oral beta-lactams as a follow-up treatment after IV antibiotics has proven effective. Studies suggest this is a reasonable option for transitioning from intravenous treatments. This trial will assess the effectiveness of oral beta-lactams versus oral non-beta-lactams in such cases. ^{1 2 6 7 8}

Who Is on the Research Team?

Rob A Fowler, MD

Principal Investigator

Sunnybrook Health Sciences Centre

Nick Daneman, MD

Principal Investigator

Sunnybrook Health Sciences Centre

Are You a Good Fit for This Trial?

This trial is for patients with Gram-negative bloodstream infections, which can lead to conditions like sepsis. Participants must meet certain health standards not specified here. People who don't fit the study's specific medical criteria cannot join.

Inclusion Criteria

Positive blood culture with Gram negative (GN) bacterium

Included in BALANCE+ platform

Positive blood culture with GN bacterium, of the following species: i. Serratia spp. ii Morganella spp. iii Providencia spp. iv Proteus spp. other than P.mirabilis

Exclusion Criteria

> 24 hours since index blood culture susceptibility results finalization

I cannot switch to a milder treatment due to allergies, resistance, or other health risks.

Pregnancy

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive various treatment strategies for Gram-negative bloodstream infections, including antibiotic de-escalation, oral antibiotic choices, and central line management

90 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, with a focus on outcomes such as reinfection, readmission, and antimicrobial resistance

90 days

Open-label extension (optional)

Participants may continue to receive treatment as part of the adaptive platform trial, with adjustments based on interim analyses

What Are the Treatments Tested in This Trial?

Interventions

• Cephalosporin
• De-escalation
• Oral beta-lactams

Trial Overview

The BALANCE+ trial tests different treatments for bacterial blood infections: routine vs no follow-up blood culture, de-escalation of treatment or not, oral beta-lactams vs other drugs, and strategies for managing central vascular catheters.

How Is the Trial Designed?

Group I: Routine follow-up blood culture VS No routine follow-up blood culture Active Control 1 Intervention

Group II: Cephalosporin VS Carbapenem for low risk AmpC organisms Active Control 1 Intervention

Group III: De-escalation VS No De-escalation Active Control 1 Intervention

Group IV: Oral beta-lactams VS Oral Non-beta-lactams Active Control 1 Intervention

Group V: Central vascular catheter retention VS Central vascular catheter replacement Active Control 1 Intervention

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

Approved in United States as Fetroja for:

• Urinary Tract Infection
• Bacterial Pneumonia

Approved in European Union as Cefiderocol for:

• Complicated urinary tract infections
• Hospital-acquired pneumonia
• Ventilator-associated pneumonia

Approved in Canada as Cefiderocol for:

• Complicated urinary tract infections
• Hospital-acquired pneumonia
• Ventilator-associated pneumonia

Who Is Running the Clinical Trial?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Published Research Related to This Trial

Cefiderocol is effective against complicated urinary tract infections (cUTIs) caused by Gram-negative bacteria, showing a higher clinical and microbiological eradication rate compared to imipenem-cilastatin (73% vs. 55%).

Despite its efficacy, cefiderocol is associated with higher all-cause mortality in certain patients, and its use should be restricted to cases where alternative treatments are limited, particularly in patients with renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cefiderocol, a New Siderophore Cephalosporin for the Treatment of Complicated Urinary Tract Infections Caused by Multidrug-Resistant Pathogens: Preclinical and Clinical Pharmacokinetics, Pharmacodynamics, Efficacy and Safety. Lee, YR., Yeo, S.[2023]

Cefiderocol is a new antibiotic that effectively targets Gram-negative bacteria by utilizing their iron transport systems, making it a promising option for treating complicated urinary tract infections and certain types of pneumonia in adults with limited treatment options.

However, the CREDIBLE-CR trial indicated a higher all-cause mortality in patients treated with cefiderocol, particularly those with severe infections from Acinetobacter spp., highlighting the need for further phase III studies to assess its safety and efficacy in serious infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cefiderocol, a new antibiotic against multidrug-resistant Gram-negative bacteria. Silva, JT., López-Medrano, F.[2023]

Cefiderocol is the first siderophore cephalosporin approved for treating serious Gram-negative bacterial infections, showing strong effectiveness against multidrug-resistant strains and stability against various β-lactamases.

In clinical trials, cefiderocol was found to be noninferior to standard treatments for complicated urinary tract infections and nosocomial pneumonia, although it had a higher all-cause mortality rate in patients with carbapenem-resistant infections, indicating the need for careful patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cefiderocol: A Review in Serious Gram-Negative Bacterial Infections. Syed, YY.[2023]

Cefiderocol is a new antibiotic effective against difficult-to-treat gram-negative bacteria, including those resistant to carbapenems, as shown in clinical trials for hospital-acquired pneumonia.

Despite its efficacy, a clinical trial indicated an increase in mortality in patients treated with cefiderocol, highlighting the need for further evaluation of its safety and effectiveness in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cefiderocol. Soriano, MC., Montufar, J., Blandino-Ortiz, A.[2023]

The development of new β-lactam/β-lactamase inhibitor (BL/BLIs) combinations has shown promising results in combating the rapidly evolving resistance of Gram-negative bacteria, with several compounds undergoing phase 3 and real-world studies.

Cefiderocol is highlighted for its unique mechanism of action, which distinguishes it from other BL/BLIs, and the overview includes detailed insights into various compounds' clinical outcomes and pharmacokinetic properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microbiological, Clinical, and PK/PD Features of the New Anti-Gram-Negative Antibiotics: β-Lactam/β-Lactamase Inhibitors in Combination and Cefiderocol-An All-Inclusive Guide for Clinicians. Principe, L., Lupia, T., Andriani, L., et al.[2022]

Cefiderocol is an innovative antibiotic that effectively targets Gram-negative bacteria by utilizing a unique mechanism of active transport, allowing it to bypass common resistance mechanisms, making it a promising option for treating severe infections.

Clinical data suggest that cefiderocol provides significant therapeutic benefits for adult patients with serious bacterial infections, particularly when other treatment options are limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Burden of the Serious and Difficult-to-Treat Infections and a New Antibiotic Available: Cefiderocol. Taheri, Y., Joković, N., Vitorović, J., et al.[2021]

Cefiderocol is a newly approved antibiotic that effectively targets multidrug-resistant Gram-negative bacteria, including carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa, making it a crucial option for critically ill patients with limited treatment choices.

In clinical studies, cefiderocol demonstrated non-inferiority to meropenem in terms of all-cause mortality for patients with nosocomial pneumonia, although a warning was added due to a higher observed mortality rate compared to best available therapy in some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of critically ill patients with cefiderocol for infections caused by multidrug-resistant pathogens: review of the evidence. Viale, P., Sandrock, CE., Ramirez, P., et al.[2023]

Cefiderocol, a new antibiotic effective against multidrug-resistant Gram-negative bacteria, was found to have transferable resistance determinants that can significantly elevate its minimum inhibitory concentration (MIC), indicating potential treatment challenges.

The study identified that the acquisition of an accessory fec operon can confer cefiderocol resistance, suggesting that both the blaVIM gene and the fec operon work together to increase resistance, which poses a risk for broader bacterial resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The acquisition of transferable extrachromosomal fec operon is associated with a cefiderocol MIC increase in Enterobacterales. Kocer, K., Boutin, S., Heeg, K., et al.[2023]

Cefiderocol is a promising new antibiotic effective against resistant Gram-negative bacteria, particularly those resistant to carbapenems, making it a strong candidate for empirical treatment in high-risk patients with severe infections.

It shows excellent in vitro activity against various beta-lactamase-producing Gram-negatives and non-fermenting bacteria, suggesting it could be crucial in managing infections where traditional antibiotics fail.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of cefiderocol in clinical practice. Maseda, E., Suárez de la Rica, A.[2023]

A military soldier with severe injuries from a blast in Afghanistan developed a serious infection caused by New Delhi metallo-beta-lactamase-producing E. coli, which is increasingly common worldwide.

He was effectively treated with tigecycline and cefiderocol, the latter being a new antibiotic designed to combat serious infections from drug-resistant bacteria, highlighting its potential in treating challenging infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carbapenem-Resistant Enterobacterales Infection After Massive Blast Injury: Use of Cefiderocol Based Combination Therapy. Carney, BW., Rizzo, JA., Alderete, JF., et al.[2023]

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