Adjustment of Antibiotic Dosage in Pediatric Oncology Patients With Febrile Neutropenia and Augmented Renal Clearance

NCT06293677 | Recruiting Phase 4 DMC

• 1 other identifier: 2023-01013
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This clinical trial focuses on children with cancer who face infections after receiving chemotherapy. Chemotherapy affects the bone marrow, leading to a decrease in the production of certain white blood cells, particularly those that defend against bacterial infections (neutrophils). One significant concern is febrile neutropenia, where children experience a fever during a period of low white blood cell count. This condition often results from bacterial infections, necessitating prompt wide-spectrum antibiotic treatment. However, some children eliminate antibiotics in the urine too quickly during febrile neutropenia. Their kidneys function more than they normally do (renal hyperfiltration). This can lead to insufficient exposure to antibiotics to control the infection. The current standard antibiotic regimens do not account for this variable elimination rate. In this study we focus on two antibiotics used in this context: piperacillin-tazobactam and meropenem. The main questions this study aims to answer are, in these children:

• Would higher doses of antibiotics result in better blood levels of antibiotics?
• Would they have more sides effects with higher antibiotics dosages?
• Would they recover more quickly with higher antibiotic doses? All patients will undergo a blood test upon hospital arrival, including an assessment of renal function. If renal function is normal or diminished, the patient will receive the standard antibiotic dose. Children with increased renal function will be randomly assigned to two groups during each episode of febrile neutropenia. One group will receive standard antibiotic dosages, while the other will receive higher doses to compensate for renal hyperfiltration. Throughout the study, antibiotic levels in the blood will be monitored for all patients. This monitoring will determine if target concentrations can be achieved more quickly with experimental dosages and will allow doctors to readjust the doses if needed.

Conditions

Febrile Neutropenia

Keywords

Febrile neutropenia; Augmented Renal Clearance; Pediatric cancer; Therapeutic Drug monitoring TDM; Children; Wilde-spectrum antibiotic dosage; Glomerular filtration rate GFR

Outcome Measures

Primary Outcomes (1)

• Achievement of antibiotic concentration targets in the intervention group (1i) vs control groupe (1c)

  Intervention-drug blood concentration both above the lower limit and below the upper limit of the therapeutic target ranges on the first trough dosage before the fourth dose after treatment initiation.

  During the first 24 hours of the intervention, before the fourth dose of antibiotic

Secondary Outcomes (5)

• Achievement of antibiotic concentration targets in control group 2

  During the first 24 hours of the intervention, before the fourth dose of antibiotic

• Fever duration

  During the intervention

• Side effects of antibiotic therapy

  During the intervention and up to 2 weeks after

• Number of dosage adjustments required to achieve the target concentration

  During the intervention

• Difference between eGFR measured by creatinine-based Schwartz formula and other eGFR calculation formulas

  Baseline, pre-intervention

Study Arms (3)

Control Group 1c

ACTIVE COMPARATOR

Group 1c includes patients with augmented renal clearance (ARC) who have been randomized to receive a standard dosage of antibiotic (méropenem or piperacilline-tazobactam)

Drug: Standard dosages of piperacillin-tazobactam or meropenem

Intervention DAR-ARC Group 1i

EXPERIMENTAL

Group 1i (DAR-ARC) includes patients with ARC who have been randomized to receive an experimental dosage of antibiotic (méropenem or piperacilline-tazobactam)

Drug: Dosage Adjustment Rules for Augmented Renal Clearance (DAR-ARC) for piperacillin-tazobactam and meropenem

Control Group 2

ACTIVE COMPARATOR

Control Group 2 includes patients with normal or decreased renal function who will receive standard dosage of antibiotic (méropenem or piperacilline-tazobactam)

Drug: Standard dosages of piperacillin-tazobactam or meropenem

Interventions

Dosage Adjustment Rules for Augmented Renal Clearance (DAR-ARC) for piperacillin-tazobactam and meropenem DRUG

Meropenem dosages according to eGFR \[mL/min/1.73 m²\] : eGFR 120-149 : 40 mg/kg q6 h eGFR 150-199 : 30 mg/kg q4h eGFR 200-299 : 40 mg/kg q4h eGFR \>/= 300 : 40 mg/kg q4h Piperacillin-tazobatam dosages according to eGFR \[mL/min/1.73 m²\] : eGFR 120-149 : 150 mg/kg q6 h eGFR 150-199 : 120 mg/kg q4h eGFR 200-299 : 150 mg/kg q4h eGFR \>/= 300 : 180 mg/kg q4h The maximum doses for the antibiotic prescription before the first drug monitoring will be 2gr of MER every 4 hours and 4gr of PIP every 4 hours. The duration of infusion will be set to 2 h.

Intervention DAR-ARC Group 1i

Standard dosages of piperacillin-tazobactam or meropenem DRUG

Meropenem dosages according to eGFR \[mL/min/1.73 m²\] : eGFR\> 50 : 40mg/kg q8h eGFR 25-49 : 40mg/kg q12h eGFR 15-24 : 20mg/kg q12h Piperacillin-tazobactam : eGFR \>50 : 100mg/kg q6h eGFR 20-49 : 50mg/kg q6h eGFR 15-29 : 50 mg/kg q8h

Control Group 1c; Control Group 2

Eligibility Criteria

• Age: 61 Days - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Oncologic patients aged 2 months to 17 years (older than 60 days and younger than 18 years),
• High probability of febrile neutropenia during the study period
• Written informed consent from parents and adolescents older than 14 years

You may not qualify if:

• Neutropenia not related to cancer and/or chemotherapy
• Refusal to participate
• Non-French speaking parents/patients older than 11 years old
• Febrile neutropenia or agranulocytosis defined as:
• Neutropenia: absolute neutrophils \<500 cells/µL or agranulocytosis: absolute neutrophils \<100 cells/µL or patients expected to be neutropenic in the next 24 hours due to ongoing chemotherapy
• body temperature (tympanic or axillary) ≥38°C during at least one hour or a single T ≥38.5°C
• At least 2 weeks after the end of the previous antibiotic treatment for another included episode of febrile neutropenia.
• Severe renal failure (GFR\<15 mL/min/1.73 m²)
• Pregnancy
• Inability to obtain the first therapeutic drug monitoring (TDM) result within 72 hours of sampling (e.g. admission before or during public holidays laboratory closure)

Sponsors & Collaborators

• Centre Hospitalier Universitaire Vaudois: lead
• Unisanté Centre universitaire de médecine générale et santé publique: collaborator
• FORCE Fondation Recherche sur le Cancer de l'Enfant: collaborator

Study Sites (1)

Centre Hospitelier Universitaire Vaudois (CHUV)

Lausanne, Canton of Vaud, 1011, Switzerland

RECRUITING

Related Publications (8)

• Petersson J, Giske CG, Eliasson E. Standard dosing of piperacillin and meropenem fail to achieve adequate plasma concentrations in ICU patients. Acta Anaesthesiol Scand. 2016 Nov;60(10):1425-1436. doi: 10.1111/aas.12808. Epub 2016 Sep 21.

  PMID: 27655029 BACKGROUND

• Scharf C, Paal M, Schroeder I, Vogeser M, Draenert R, Irlbeck M, Zoller M, Liebchen U. Therapeutic Drug Monitoring of Meropenem and Piperacillin in Critical Illness-Experience and Recommendations from One Year in Routine Clinical Practice. Antibiotics (Basel). 2020 Mar 21;9(3):131. doi: 10.3390/antibiotics9030131.

  PMID: 32245195 BACKGROUND

• Udy AA, Roberts JA, Lipman J. Implications of augmented renal clearance in critically ill patients. Nat Rev Nephrol. 2011 Jul 19;7(9):539-43. doi: 10.1038/nrneph.2011.92.

  PMID: 21769107 BACKGROUND

• Hirai K, Ihara S, Kinae A, Ikegaya K, Suzuki M, Hirano K, Itoh K. Augmented Renal Clearance in Pediatric Patients With Febrile Neutropenia Associated With Vancomycin Clearance. Ther Drug Monit. 2016 Jun;38(3):393-7. doi: 10.1097/FTD.0000000000000270.

  PMID: 27172381 BACKGROUND

• Imani S, Buscher H, Marriott D, Gentili S, Sandaradura I. Too much of a good thing: a retrospective study of beta-lactam concentration-toxicity relationships. J Antimicrob Chemother. 2017 Oct 1;72(10):2891-2897. doi: 10.1093/jac/dkx209.

  PMID: 29091190 BACKGROUND

• McDonald C, Cotta MO, Little PJ, McWhinney B, Ungerer JP, Lipman J, Roberts JA. Is high-dose beta-lactam therapy associated with excessive drug toxicity in critically ill patients? Minerva Anestesiol. 2016 Sep;82(9):957-65. Epub 2016 Apr 7.

  PMID: 27054905 BACKGROUND

• de With K, Allerberger F, Amann S, Apfalter P, Brodt HR, Eckmanns T, Fellhauer M, Geiss HK, Janata O, Krause R, Lemmen S, Meyer E, Mittermayer H, Porsche U, Presterl E, Reuter S, Sinha B, Strauss R, Wechsler-Fordos A, Wenisch C, Kern WV. Strategies to enhance rational use of antibiotics in hospital: a guideline by the German Society for Infectious Diseases. Infection. 2016 Jun;44(3):395-439. doi: 10.1007/s15010-016-0885-z.

  PMID: 27066980 BACKGROUND

• Andre P, Diezi L, Dao K, Crisinel PA, Rothuizen LE, Chtioui H, Decosterd LA, Diezi M, Asner S, Buclin T. Ensuring Sufficient Trough Plasma Concentrations for Broad-Spectrum Beta-Lactam Antibiotics in Children With Malignancies: Beware of Augmented Renal Clearance! Front Pediatr. 2022 Jan 5;9:768438. doi: 10.3389/fped.2021.768438. eCollection 2021.

  PMID: 35083184 BACKGROUND

MeSH Terms

Conditions

Febrile Neutropenia; Neoplasms

Interventions

Meropenem

Condition Hierarchy (Ancestors)

Neutropenia; Agranulocytosis; Leukopenia; Cytopenia; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukocyte Disorders

Intervention Hierarchy (Ancestors)

Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Pierre-Alex Crisinel

  Centre Hospitalier Universitaire Vaudois

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Margherita Plebani

CONTACT

+41(0)795563598; Margherita.Plebani@chuv.ch

Pierre-Alex Crisinel

CONTACT

+41(0)795568627; pierre-alex.crisinel@chuv.ch

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of the Unit of Pediatric Infectious Diseases and Vaccinology

Model Details: Our study is an open-label, re-randomized controlled trial in multi-episodes settings. So the care team, researchers and patients will be informed of the allocation group. Patients will be able to participate in each episode of febrile neutropenia. At each inclusion the patient may be in a different group.

Study Record Dates

• First Submitted: February 20, 2024
• First Posted: March 5, 2024
• Study Start: March 1, 2024
• Primary Completion: March 1, 2026
• Study Completion: March 1, 2026
• Last Updated: July 11, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)