Association of Cefepime Trough Levels With Clinical Efficacy and Neurotoxicity in Patients With Febrile Neutropenia

April 26, 2021 updated by: Matthias Gijsen, Universitaire Ziekenhuizen KU Leuven
In this prospective monocenter observational study, the objective was to determine a safe and effective therapeutic window for cefepime in patients with neutropenic fever.

Study Overview

Status

Active, not recruiting

Conditions

Detailed Description

Cefepime, a fourth-generation cephalosporin, is widely prescribed for the treatment of serious bacterial infections. Cefepime has a more narrow spectrum and has relatively lower minimal inhibitory concentration (MIC) values compared to meropenem. Therefore cefepime is widely endorsed, and preferred over a carbapenem antibiotic, as a first line agent for the management of febrile neutropenia (FN) in hematologic patients.

Several studies have shown adequate exposure using the recommended 3x2 g dosing strategy for cefepime in most FN patients. The pharmacokinetic/pharmacodynamic (PKPD) target of fT100%>MIC, which is frequently used for BL AB in critically ill patients, is achieved in most patients. Subsets of patients have been shown to be at risk for underdosing, especially those with a higher than normal creatinine clearance, obese or cachectic patients and those infected with bacteria with a MIC >4 mg/L. Despite adequate cefepime exposure, the association with clinical outcome still needs to be confirmed on a large scale. An association between suboptimal PKPD target attainment and clinical outcome was shown on a large scale for β-lactam antibiotics. These data need to be validated for the specific antimicrobials agents and in subsets of patients. Another study suggested a cefepime PKPD target for clinical outcome of at least fT>MIC of 68% to 74% based on simulations using 2 existing population PK models. In a mixed population of critically and non-critically ill patients with Gram negative blood stream infections this threshold was a significant predictor of in-hospital mortality. A recent study, undertaken in patients with nosocomial pneumonia treated with cefepime, even reported clinical failure despite achievement of fT100%>MIC, they suggest a fCmin/MIC ratio of at least 2.1 as a better predictor for clinical failure in Gram negative bacterial pneumonia patients. Up until today, there are no explicit data linking PKPD target attainment with clinical outcome in FN patients.

With respect to cefepime toxicity, there is a lot of controversy on the upper limit that should not be exceeded in clinical practice. Cefepime toxicity is mainly neurological, going from mild confusion to seizures or encephalopathy. In the first study that assessed the relationship between cefepime PK and associated neurotoxicity, trough levels >22 mg/L were found to be associated with a 50% probability of neurological toxicity. However, a more recent study showed, using a non-parametric approach, that estimated rates of neurotoxicity using this threshold are very high and discordant with rates seen in clinical practice. Hence this threshold seems not representative for the clinical practice. Other PK parameters (Cmax, AUC, ...) and covariates (CrCl, Age, dose, duration of therapy, co-medication, …) probably also influence cefepime related neurotoxicity. Recently, an attempt to redefine cefepime's threshold for neurotoxicity was published in a retrospective cohort study. No neurotoxicity was observed below 35 mg/L for all samples (steady-state levels during continuous infusion, trough and non-trough levels during intermittent infusion). However, when looking only at trough levels, they also advise avoiding levels >20 mg/L until more information from prospective studies is available.

Moreover, until now there has only been one study investigating the carryover of cefepime in samples taken via a central venous catheter. This study suggested possible carryover for triple lumen catheters and peripherally-inserted central catheters. Due to the small sample size and the in vitro nature of this research, these results need to be confirmed.

The aim of this research is two-fold. Firstly, the aim is to investigate whether there is significant carryover of cefepime in samples taken via a central venous catheter. Next, the aim is to assess prospectively the relation between cefepime exposure and efficacy or safety in a FN patient population. As literature on these topics is scarce this research will further explore the exposure-response relationship in order to define a therapeutic window for maximal clinical cure and minimal neurotoxicity that can be used in future research and clinical practice.

Study Type

Observational

Enrollment (Actual)

98

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
    • Vlaams-Brabant
      • Leuven, Vlaams-Brabant, Belgium, 3000
        • University Hospitals Leuven

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Hemato-oncology patients treated with cefepime for neutropenic fever

Description

Inclusion Criteria:

  • admitted to the hemato-oncology ward
  • treated with cefepime for neutropenic fever
  • written informed consent

Exclusion Criteria:

- younger than 18 years old

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Therapeutic failure
Time Frame: From Day 2 before until Day 2 day after day of sampling
hemoculture positive for Gram negative bacteria during cefepime therapy
From Day 2 before until Day 2 day after day of sampling
Neurotoxicity: cognitive disturbance, confusion, depressed level of consciousness, encephalopathy, hallucinations, movements involuntary, seizure
Time Frame: From Day 2 before until Day 2 day after day of sampling
Percent of patients and trough levels associated with one of following symptoms during cefepime therapy: cognitive disturbance, confusion, depressed level of consciousness, encephalopathy, hallucinations, movements involuntary, seizure
From Day 2 before until Day 2 day after day of sampling
Carryover cefepime in samples via central venous catheter
Time Frame: From Day 2 before until Day 2 day after day of sampling
Difference between cefepime concentration in samples obtained via central venous catheter vs. samples obtained via peripheral venipuncture
From Day 2 before until Day 2 day after day of sampling

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Fever
Time Frame: From Day 2 before until Day 2 day after day of sampling
Presence of fever per day of treatment, defined as T° above 38°C on two occasions (min. 1h apart) or above 38.3°C on one occasion
From Day 2 before until Day 2 day after day of sampling
Clinical condition
Time Frame: From Day 2 before until Day 2 day after day of sampling
Evolution in clinical condition compared to the previous day as evaluated by the treating physician, per day of treatment
From Day 2 before until Day 2 day after day of sampling

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Universitaire Ziekenhuizen KU Leuven

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

August 1, 2019

Primary Completion (ACTUAL)

October 1, 2020

Study Completion (ANTICIPATED)

May 1, 2021

Study Registration Dates

First Submitted

January 28, 2020

First Submitted That Met QC Criteria

January 30, 2020

First Posted (ACTUAL)

January 31, 2020

Study Record Updates

Last Update Posted (ACTUAL)

April 28, 2021

Last Update Submitted That Met QC Criteria

April 26, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • S62297

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

To be discussed upon reasonable request

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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