Optimized Beta-lactam Dosing for Bacterial Infections

Recruiting at 9 trial locations

Overseen By Thomas Lodise

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: Meropenem, Cefepime

Disqualifiers: Diabetes, Pregnancy, Sickle cell, others

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

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

Compensation: Varies

Number of Visits: 2

Duration: 2 days

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how well certain kidney function tests can predict the behavior of two antibiotics, meropenem and cefepime, in the body. These tests may help fine-tune dosing for individuals battling tough Gram-negative bacterial infections that resist usual treatments. The study seeks critically ill adults in the ICU already receiving either meropenem or cefepime for these infections. Participants must remain in the ICU for the study duration and have no allergies to contrast agents like iohexol, a type of contrast dye used in imaging tests. As a Phase 4 trial, this research aims to understand how these FDA-approved antibiotics can benefit more patients.

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 be receiving meropenem or cefepime as part of your treatment to participate.

What is the safety track record for iohexol?

Research has shown that iohexol, the treatment used in this study, is generally safe when used correctly. This contrast dye is often used in medical imaging to help doctors see certain areas of the body more clearly. In the past, some side effects, such as brain inflammation, have been reported with iohexol after certain types of injections. However, these are rare and usually linked to specific methods, like spinal injections, which are not used in this study. When administered as an IV (intravenous) infusion, iohexol is usually well-tolerated.

Since this study is in Phase 4, the treatment has already been approved for use, and its safety is well-established. This phase often focuses on improving how the treatment is used or understanding its effects better in different situations, rather than just basic safety. Generally, the risk of serious side effects is low, but monitoring participants remains important, especially in a study setting. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about optimizing beta-lactam dosing for bacterial infections using iohexol because it introduces a novel approach to enhance the effectiveness of existing antibiotics like meropenem and cefepime. Unlike traditional treatments that rely solely on the antibiotics themselves, iohexol is used to map kidney function, which helps in tailoring the dosing more precisely to individual patient needs. This personalized approach aims to maximize the antibiotics' effectiveness while minimizing potential side effects, offering a promising step forward in treating tough bacterial infections in critically ill patients.

What evidence suggests that this trial's treatments could be effective for AMR Gram-negative infections?

This trial will involve adult ICU patients receiving either meropenem or cefepime as part of their clinical management. Studies have shown that both antibiotics effectively treat serious bacterial infections, especially those resistant to other drugs. They work by breaking down the bacteria's protective walls, allowing the immune system to fight the infection more easily. Research indicates that adjusting doses based on kidney function can improve treatment outcomes. Participants in this trial will receive Iohexol, a dye used in medical scans, to accurately measure kidney function and ensure the correct antibiotic dose for each patient. Overall, these antibiotics have proven effective against tough infections, and precise dosing can enhance their efficacy. ^{3 4 6 7 8}

Are You a Good Fit for This Trial?

This trial is for critically ill adults with suspected or confirmed antibiotic-resistant Gram-negative bacterial infections. Participants must have kidney function that can be measured and agree to take the study drug, Iohexol.

Inclusion Criteria

2. Residing in an ICU.

3. Documented or suspected AMR Gram-negative infection for which the prospective participant is receiving meropenem or cefepime as part of their clinical management.

4. Expectation that the prospective participant will reside in the ICU and receive meropenem or cefepime for the duration of the study, and that all study procedures will be completed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive meropenem or cefepime with iohexol administration for PK profiling

2 days

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Iohexol

Trial Overview

The study tests if Cystatin C (CysC) and equations based on it are better than traditional methods at predicting how drugs like meropenem and cefepime work in patients' bodies. Iohexol is used as a reference to measure kidney function accurately.

How Is the Trial Designed?

Group I: Arm 1 Experimental Treatment 1 Intervention

Adult patients in the ICU receiving either meropenem or cefepime as part of their clinical management will receive one dose of IV iohexol 1500 mgI (5 mL) via slow push administration on Study Days 1 and 2 prior to the start of first or second daily meropenem or cefepime dose. N=150

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

In a study involving 432 critically ill patients with severe sepsis, continuous infusion of β-lactam antibiotics did not result in better outcomes compared to intermittent infusion, with no significant difference in ICU-free days or 90-day survival rates.

Both treatment methods showed similar rates of clinical cure and organ failure-free days, indicating that the method of antibiotic delivery may not impact the effectiveness of treatment in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multicenter Randomized Trial of Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. Dulhunty, JM., Roberts, JA., Davis, JS., et al.[2022]

In a study of 384 critically ill patients, 16% did not achieve the necessary antibiotic concentrations for effective treatment, leading to a 32% lower chance of positive clinical outcomes.

Higher levels of antibiotic exposure, measured as 50% and 100% f T>MIC, were linked to better patient outcomes, suggesting that personalized dosing strategies could improve recovery in severely ill patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients? Roberts, JA., Paul, SK., Akova, M., et al.[2022]

In a study of 36 patients treated with cefepime, a significant correlation was found between successful treatment outcomes and the duration that cefepime levels exceeded 4.3 times the minimum inhibitory concentration (MIC) during the dosing interval.

The findings support existing laboratory data indicating that beta-lactam antibiotics like cefepime are most effective when their concentrations are maintained above approximately 4 times the MIC, suggesting a need for further validation in larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamics of cefepime in patients with Gram-negative infections. Tam, VH., McKinnon, PS., Akins, RL., et al.[2022]

Continuous infusion (CI) of beta-lactam antibiotics in critically ill children resulted in a higher likelihood of achieving optimal pharmacokinetic exposure compared to intermittent infusion (II), with 69% of CI patients meeting the target versus 47% of II patients.

While CI improved the chances of optimal exposure, it also increased the risk of overexposure, highlighting the need for regular therapeutic drug monitoring in these patients to ensure safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta-lactam exposure and safety in intermittent or continuous infusion in critically ill children: an observational monocenter study. Debray, A., Callot, D., Hirt, D., et al.[2023]

A new mathematical model successfully replicated human pharmacokinetics of the beta-lactam antibiotic FK037 in mice, allowing for effective comparison of drug behavior across species.

The study found that the therapeutic efficacy of FK037 against pneumonia was closely linked to the time the drug concentration remained above the minimum inhibitory concentration (MIC), highlighting the importance of this parameter in determining dosing strategies for beta-lactam antibiotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simulation of human plasma levels of beta-lactams in mice by multiple dosing and the relationship between the therapeutic efficacy and pharmacodynamic parameters. Hatano, K., Wakai, Y., Watanabe, Y., et al.[2018]

A new method has been developed to predict the concentration of beta-lactam antibiotics in tissues based on their plasma levels after intravenous injection, which can enhance understanding of how these drugs work in the body.

This method uses specific factors related to the drug's distribution and protein binding, allowing for better comparisons of antibiotic effectiveness across different patient groups and improving the interpretation of pharmacokinetic data.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic evaluation of beta-lactam antibiotics. Derendorf, H.[2019]

A review of 21 studies on beta-lactam antibiotics in septic pediatric patients highlights the importance of individualized antimicrobial therapy based on pharmacokinetic/pharmacodynamic (PK/PD) parameters to effectively treat life-threatening infections.

Strategies such as prolonging infusion times and increasing frequency of administration were commonly used to enhance the effectiveness of beta-lactams, suggesting that therapeutic monitoring could improve treatment outcomes in septic children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta-Lactams Therapeutic Monitoring in Septic Children-What Target Are We Aiming for? A Scoping Review. Morales Junior, R., Pereira, GO., Tiguman, GMB., et al.[2022]

This study evaluated the accuracy of physiologically based pharmacokinetic (PBPK) models in predicting tissue concentrations of five beta-lactam antibiotics in healthy adults, finding that while plasma concentration predictions were fairly accurate, tissue concentration predictions were less reliable.

The research highlighted that using unbound interstitial fluid (uISF) concentrations for evaluating target attainment had limited impact compared to unbound plasma concentrations, indicating a need for improved PBPK models to better predict tissue drug levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictive Performance of Physiologically Based Pharmacokinetic Modelling of Beta-Lactam Antibiotic Concentrations in Adipose, Bone, and Muscle Tissues. De Sutter, PJ., De Cock, P., Johnson, TN., et al.[2023]

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