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

Trial Summary

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.

Is optimized beta-lactam dosing safe for humans?

Studies on beta-lactam antibiotics, including cefotaxime, piperacillin/tazobactam, and meropenem, in critically ill children showed that while some adverse events were reported, none were directly linked to the beta-lactam treatment, suggesting a general safety in humans. ^{1 2 3 4 5}

How does the drug Iohexol differ from other treatments for bacterial infections?

Iohexol is not typically used for treating bacterial infections; it is a contrast agent used in imaging studies. The clinical trial may be exploring its use in optimizing beta-lactam dosing, which is unique as it involves a non-antibiotic agent to potentially enhance the effectiveness of traditional antibiotics. ^{1 4 6 7 8}

What is the purpose of this trial?

The purpose of this study is to evaluate the abilities of Cystatin C (CysC) and CysC-based estimated Glomerular Filtration Rate (eGFR) equations to characterize the pharmacokinetics (PK) profiles of meropenem and cefepime relative to Serum Creatinine (SCR), Serum Creatinine based Equation (SCRE)and iohexol at the population and individual levels in critically ill adult patients with suspected or documented AMR Gram-negative infections. We hypothesize that CysC and CysC-based eGFR equations will characterize the PK profiles of meropenem and cefepime at the population and individual levels with greater accuracy and precision than SCR and SCREs. Iohexol will be administered to patients enrolled in the study and serve as the reference indicator of measured Glomerular Filtration Rate (mGFR), which is the gold standard assessment of kidney function. We hypothesize that the predictive performances of CysC and CysC-based eGFR equations in estimating the PK profiles of meropenem and cefepime at the population and individual levels will be comparable to iohexol. The information obtained in this study will be used to develop PK/pharmacodynamics (PD) optimized meropenem and cefepime dosing schemes based on the renal function biomarker population PK (PopPK) model with the best predictive performance for clinical use in the treatment of critically ill adult patients with suspected or documented AMR Gram-negative infections and varying degrees of renal function. The primary objective of this study is to compare the abilities of renal function biomarkers (CysC, CysC-based eGFR equations, SCR, SCREs) relative to iohexol to characterize the PK profiles of meropenem and cefepime in critically ill adult patients with suspected or documented AMR Gram-negative infections.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Findings from Research

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]

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]

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]

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 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]

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]

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]

References

1. Switzerland 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. [2018]

2. United States 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? [2022]

3. England pubmed.ncbi.nlm.nih.gov

Pharmacodynamics of cefepime in patients with Gram-negative infections. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Beta-Lactams Therapeutic Monitoring in Septic Children-What Target Are We Aiming for? A Scoping Review. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

Beta-lactam exposure and safety in intermittent or continuous infusion in critically ill children: an observational monocenter study. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetic evaluation of beta-lactam antibiotics. [2019]

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

Predictive Performance of Physiologically Based Pharmacokinetic Modelling of Beta-Lactam Antibiotic Concentrations in Adipose, Bone, and Muscle Tissues. [2023]

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

A Multicenter Randomized Trial of Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. [2022]