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PharmacokineticsNCT04250038

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

An observational study of Pharmacokinetics and Pharmacodynamics, run by Universitaire Ziekenhuizen KU Leuven at 1 site in Belgium.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

In this prospective monocenter observational study, the objective was to determine a safe and effective therapeutic window for cefepime in patients with neutropenic fever. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Pharmacokinetics, Pharmacodynamics, Cefepime
How many people
98 participants
Where
1 siteBelgium
Study dates
1 Aug 2019to 1 May 2021
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Study population: Hemato-oncology patients treated with cefepime for neutropenic fever

Who may be able to join

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

Who cannot join

  • younger than 18 years old

Trial locations and contacts

1 site in 1 country.

Belgium1 site

  • University Hospitals Leuven

    Leuven, Vlaams-Brabant, 3000

Other trials in Belgium

About this study

In this prospective monocenter observational study, the objective was to determine a safe and effective therapeutic window for cefepime in patients with neutropenic fever.

Read the 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.

Keywords
Cefepime, Pharmacokinetic, Neurotoxicity, Febrile neutropenia, Exposure
Medical subject headings
Neurotoxicity Syndromes, Febrile Neutropenia

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Therapeutic failure

    hemoculture positive for Gram negative bacteria during cefepime therapy

    Measured: From Day 2 before until Day 2 day after day of sampling

  2. Neurotoxicity: cognitive disturbance, confusion, depressed level of consciousness, encephalopathy, hallucinations, movements involuntary, seizure

    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

    Measured: From Day 2 before until Day 2 day after day of sampling

  3. Carryover cefepime in samples via central venous catheter

    Difference between cefepime concentration in samples obtained via central venous catheter vs. samples obtained via peripheral venipuncture

    Measured: From Day 2 before until Day 2 day after day of sampling

Secondary outcomes (2)

  1. Fever

    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

    Measured: From Day 2 before until Day 2 day after day of sampling

  2. Clinical condition

    Evolution in clinical condition compared to the previous day as evaluated by the treating physician, per day of treatment

    Measured: From Day 2 before until Day 2 day after day of sampling

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Jan 2020
  2. Study start1 Aug 2019
  3. Primary completion1 Oct 2020
  4. Study completion1 May 2021 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Prospective
Enrolment
98 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04250038
Sponsor's protocol ID
S62297
Status last verified
Apr 2021
First submitted
28 Jan 2020
Last updated
28 Apr 2021
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided: To be discussed upon reasonable request

Publications

  • Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, Kaukonen KM, Koulenti D, Martin C, Montravers P, Rello J, Rhodes A, Starr T, Wallis SC, Lipman J; DALI Study. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014 Apr;58(8):1072-83. doi: 10.1093/cid/ciu027. Epub 2014 Jan 14.

    PubMed 24429437

  • Rhodes NJ, Kuti JL, Nicolau DP, Van Wart S, Nicasio AM, Liu J, Lee BJ, Neely MN, Scheetz MH. Defining Clinical Exposures of Cefepime for Gram-Negative Bloodstream Infections That Are Associated with Improved Survival. Antimicrob Agents Chemother. 2015 Dec 14;60(3):1401-10. doi: 10.1128/AAC.01956-15.

    PubMed 26666929

  • Aitken SL, Altshuler J, Guervil DJ, Hirsch EB, Ostrosky-Zeichner LL, Ericsson CD, Tam VH. Cefepime free minimum concentration to minimum inhibitory concentration (fCmin/MIC) ratio predicts clinical failure in patients with Gram-negative bacterial pneumonia. Int J Antimicrob Agents. 2015 May;45(5):541-4. doi: 10.1016/j.ijantimicag.2014.12.018. Epub 2015 Jan 19.

    PubMed 25665726

  • Lamoth F, Buclin T, Pascual A, Vora S, Bolay S, Decosterd LA, Calandra T, Marchetti O. High cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients with mild impairment of renal function. Antimicrob Agents Chemother. 2010 Oct;54(10):4360-7. doi: 10.1128/AAC.01595-08. Epub 2010 Jul 12.

    PubMed 20625153

  • Rhodes NJ, Kuti JL, Nicolau DP, Neely MN, Nicasio AM, Scheetz MH. An exploratory analysis of the ability of a cefepime trough concentration greater than 22 mg/L to predict neurotoxicity. J Infect Chemother. 2016 Feb;22(2):78-83. doi: 10.1016/j.jiac.2015.10.009. Epub 2015 Dec 17.

    PubMed 26712584

  • Huwyler T, Lenggenhager L, Abbas M, Ing Lorenzini K, Hughes S, Huttner B, Karmime A, Uckay I, von Dach E, Lescuyer P, Harbarth S, Huttner A. Cefepime plasma concentrations and clinical toxicity: a retrospective cohort study. Clin Microbiol Infect. 2017 Jul;23(7):454-459. doi: 10.1016/j.cmi.2017.01.005. Epub 2017 Jan 19.

    PubMed 28111294

  • Marsh E, Verhoven SM, Groszek JJ, Fissell WH, An G, Patel P, Creech B, Shotwell M. Beta-lactam carryover in arterial and central venous catheters is negligible. Clin Chim Acta. 2018 Nov;486:265-268. doi: 10.1016/j.cca.2018.08.008. Epub 2018 Aug 15.

    PubMed 30118674

Questions about this trial

What is this clinical trial studying?

An observational study of Pharmacokinetics and Pharmacodynamics, run by Universitaire Ziekenhuizen KU Leuven at 1 site in Belgium.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 28 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Therapeutic failure (time frame: From Day 2 before until Day 2 day after day of sampling). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04250038, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Apr 2021.

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