Antibiotic Dosing in Geriatric Patients at the Emergency Department (AGED)

In this pilot study, we will investigate whether - with the current dosing regimens, used in the Ghent University Hospital - pharmacodynamic targets regarding beta-lactam antibiotics (more specific Amoxicilline-Clavulanate, Piperacillin-Tazobactam and Temocillin) are attained in frail patients admitted to the geriatric department.

Study Overview

• Status: Recruiting
• Conditions: Frail Elderly Syndrome; Frailty; Infection, Bacterial; Elderly Infection
• Intervention / Treatment: Diagnostic test: Blood sampling; Diagnostic test: Sputum sample; Diagnostic test: Hemoculture; Diagnostic test: Urine sample

Detailed Description

In drug research studies, older people - and especially patients with a geriatric profile or frailty risk - are very frequently excluded. Moreover, drug dosing is often extrapolated from studies in younger adults with failure to consider potential differences in pharmacokinetics (PK) and pharmacodynamics (PD).

Studies on dosing of beta-lactam antibiotics in geriatric or frail patients aged 75 years or older have, to the best of our knowledge, never been performed.

In this pilot study, we will investigate whether - with the current dosing regimens, used in the Ghent University Hospital - pharmacodynamic targets regarding beta-lactam antibiotics (more specific Amoxicilline-Clavulanate, Piperacillin-Tazobactam and Temocillin) are attained in frail patients admitted to the geriatric department.

This monocentric, prospective, observational trial is currently ongoing at the emergency department and geriatric department of the Ghent University Hospital.

Amoxicillin/clavulanic acid 1000/200mg of piperacillin-tazobactam 4000mg or temocillin 2000mg was infused intravenously over 30 minutes using a syringe pump. The standard dosing regimes were used.

An infusion catheter of minimum 18-gauge was placed in the contralateral arm to the arm in which the antibiotic dose was administered. Blood samples were collected from this catheter at first dose and assumed steady state conditions. Steady state was assumed to be reached after minimal 24h (> 4 doses at four - six hourly interval) of therapy. The goal was to obtain 5 first dose and 5 steady dose samples in every patient.

Material for bacteriological analysis, such as blood cultures, urine samples, sputum, were collected in every patient according to standard care. In case of bacterial growth, MIC's were measured on the reported strains when possible.

Amoxicillin, clavulanic acid, piperacillin, tazobactam and temocillin were measured using a validated ultra-performance liquid chromatographic method with tandem mass spectrometric detection.

Serum creatinine, cystatin C, procalcitonin, infection parameters (CRP, WBC count) and albumin were obtained from standard blood samples performed in these patients at day one and also later on during their therapy.

Three frailty score systems (KATZ, Geriatric 8 - G8, Cumulative Illness Rating Scale - CIRS) were calculated.

• Study Type: Observational
• Enrollment (Estimated): 180

Contacts and Locations

• Study Contact: Name: Peter De Paepe, Prof. Dr.; Phone Number: 003293325211; Email: peter.depaepe@uzgent.be
• Study Contact Backup: Name: Tania Desmet, Dr.; Phone Number: 003293321559; Email: tania.desmet@uzgent.be

Study Locations

• Belgium
  • Ghent, Belgium, 9000
    • Recruiting
    • University Hospital Ghent
    • Contact: Peter De Paepe, Prof. Dr.; Phone Number: 003293325211; Email: peter.depaepe@uzgent.be
    • Contact: Tania Desmet, Dr.; Phone Number: 003293321559; Email: tania.desmet@uzgent.be

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 75 years and older (Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Frail elderly patients with a minimum of 75 years old, presenting at the emergency department and in need for hospitalization at the geriatric ward, in which a betalactam antibiotic treatment was started.

Description

Inclusion Criteria:

• Patients presenting at the emergency department and later on admitted to the geriatric department
• Patient age 75 years or older
• Patients with geriatric profile according to KATZ scale, G8 screening test or CIRS score.
• Patient receiving antibiotic treatment (amoxicillin-clavulanate, piperacillin-tazobactam)
• Intravenous access available for blood sampling. For measurement of the peak concentration an intravenous access other than the drug infusion line is required.

Exclusion Criteria:

• Admission to other units than the geriatric department incl. the ICU.
• Absence of informed consent
• Known hypersensitivity to beta-lactam antibiotics
• Patients who received oral amoxicillin-clavulanate prior to admission will not be included in the iv. amoxicillin-clavulanate group.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Amoxicillin-clavulanate; Administration of amoxicillin-clavulanate as standard care therapy (4x or 6x 1g/d). Blood sampling in early and steady state dose (up to 5 samplings per dose). Collection of hemocultures, urine samples and sputum samples when possible.	Diagnostic test: Blood sampling; At predefined time points through a venous catheter already in place. Max. volume to be withdrawn: Maximum 4ml/sample. Maximum 10 samples/patient. A last blood sample will be taken, if necessary, after the end of antibiotic therapy, between day 7 and day 14. Though blood results preferably will be used from available data from tests already done during standard treatment. Samples are collected in lithium-heparin tubes (without gel) and centrifuged immediately (within a maximum of 30 minutes after sampling) at room temperature: 8 minutes at 1885g. Plasma is then collected and divided in two separated labelled Eppendorf tubes 1.5 ml and immediately frozen at - 80 °C. If this is not immediately possible, tubes are frozen at - 20 °C and at regular time points transferred to a freezer at - 80 °C (minimum twice a day).; Diagnostic test: Sputum sample; Bacteriological specimen, such as blood cultures, urine samples, sputum ea., which are usually collected in every patient according to standard care will be retained. If there is bacterial growth, MIC's will be calculated on these strains for study purpose.; Diagnostic test: Hemoculture; Bacteriological specimen, such as blood cultures, urine samples, sputum ea., which are usually collected in every patient according to standard care will be retained. If there is bacterial growth, MIC's will be calculated on these strains for study purpose.; Diagnostic test: Urine sample; Bacteriological specimen, such as blood cultures, urine samples, sputum ea., which are usually collected in every patient according to standard care will be retained. If there is bacterial growth, MIC's will be calculated on these strains for study purpose.
Piperacillin-tazobactam; Administration of piperacillin-tazobactam as standard care therapy (4x 4g/d). Blood sampling in early and steady state dose (up to 5 samplings per dose). Collection of hemocultures, urine samples and sputum samples when possible.	Diagnostic test: Blood sampling; At predefined time points through a venous catheter already in place. Max. volume to be withdrawn: Maximum 4ml/sample. Maximum 10 samples/patient. A last blood sample will be taken, if necessary, after the end of antibiotic therapy, between day 7 and day 14. Though blood results preferably will be used from available data from tests already done during standard treatment. Samples are collected in lithium-heparin tubes (without gel) and centrifuged immediately (within a maximum of 30 minutes after sampling) at room temperature: 8 minutes at 1885g. Plasma is then collected and divided in two separated labelled Eppendorf tubes 1.5 ml and immediately frozen at - 80 °C. If this is not immediately possible, tubes are frozen at - 20 °C and at regular time points transferred to a freezer at - 80 °C (minimum twice a day).; Diagnostic test: Sputum sample; Bacteriological specimen, such as blood cultures, urine samples, sputum ea., which are usually collected in every patient according to standard care will be retained. If there is bacterial growth, MIC's will be calculated on these strains for study purpose.; Diagnostic test: Hemoculture; Bacteriological specimen, such as blood cultures, urine samples, sputum ea., which are usually collected in every patient according to standard care will be retained. If there is bacterial growth, MIC's will be calculated on these strains for study purpose.; Diagnostic test: Urine sample; Bacteriological specimen, such as blood cultures, urine samples, sputum ea., which are usually collected in every patient according to standard care will be retained. If there is bacterial growth, MIC's will be calculated on these strains for study purpose.
Temocillin; Administration of temocillin as standard care therapy (2x or 3x 2g/d). Blood sampling in early and steady state dose (up to 5 samplings per dose). Collection of hemocultures, urine samples and sputum samples when possible.	Diagnostic test: Blood sampling; At predefined time points through a venous catheter already in place. Max. volume to be withdrawn: Maximum 4ml/sample. Maximum 10 samples/patient. A last blood sample will be taken, if necessary, after the end of antibiotic therapy, between day 7 and day 14. Though blood results preferably will be used from available data from tests already done during standard treatment. Samples are collected in lithium-heparin tubes (without gel) and centrifuged immediately (within a maximum of 30 minutes after sampling) at room temperature: 8 minutes at 1885g. Plasma is then collected and divided in two separated labelled Eppendorf tubes 1.5 ml and immediately frozen at - 80 °C. If this is not immediately possible, tubes are frozen at - 20 °C and at regular time points transferred to a freezer at - 80 °C (minimum twice a day).; Diagnostic test: Sputum sample; Bacteriological specimen, such as blood cultures, urine samples, sputum ea., which are usually collected in every patient according to standard care will be retained. If there is bacterial growth, MIC's will be calculated on these strains for study purpose.; Diagnostic test: Hemoculture; Bacteriological specimen, such as blood cultures, urine samples, sputum ea., which are usually collected in every patient according to standard care will be retained. If there is bacterial growth, MIC's will be calculated on these strains for study purpose.; Diagnostic test: Urine sample; Bacteriological specimen, such as blood cultures, urine samples, sputum ea., which are usually collected in every patient according to standard care will be retained. If there is bacterial growth, MIC's will be calculated on these strains for study purpose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood concentrations of amoxicillin-clavulanate.	To investigate whether blood concentrations with maximum antimicrobial activity are achieved with current dosing regimens in first-dose or early-dose conditions and in steady-state conditions.	Within the first 12 hours (early dose) of treatment and after 24 - 48 hours of treatment (steady state)
Blood concentrations of piperacillin-tazobactam.	To investigate whether blood concentrations with maximum antimicrobial activity are achieved with current dosing regimens in first-dose or early-dose conditions and in steady-state conditions.	Within the first 12 hours (early dose) of treatment and after 24 - 48 hours of treatment (steady state)
Blood concentrations of temocillin.	To investigate whether blood concentrations with maximum antimicrobial activity are achieved with current dosing regimens in first-dose or early-dose conditions and in steady-state conditions.	Within the first 12 hours (early dose) of treatment and after 24 - 48 hours of treatment (steady state)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measured total and unbound concentrations of beta-lactam antibiotics.	To compare measured total and unbound concentrations of beta-lactam antibiotics with predefined pharmacodynamic targets.	Within the first 12 hours (early dose) of treatment and after 24 - 48 hours of treatment (steady state)
Response to antimicrobial therapy.	To describe therapeutic response to antimicrobial therapy using procalcitonin.	The end of individual antibiotic therapy with an average of 1 week
Achievement of pharmacodynamic targets measured by questionnaire, vital signs, blood results and side effects.	To compare achievement of pharmacodynamic targets in early-dose and steady-state conditions.	The end of individual antibiotic therapy with an average of 1 week
Clearance of betalactam antibiotics.	To compare clearance of betalactam antibiotics and correlate with renal function using creatinin clearance en cystatin C.	Within the first 12 hours (early dose) of treatment and after 24 - 48 hours of treatment (steady state)

Collaborators and Investigators

• Sponsor: University Hospital, Ghent
• Investigators: Principal Investigator: Tania Desmet, Dr., University Hospital, Ghent

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2018
• Primary Completion (Actual): September 3, 2021
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: June 9, 2020
• First Submitted That Met QC Criteria: June 16, 2020
• First Posted (Actual): June 18, 2020

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 26, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: pharmacokinetics; pharmacodynamics; amoxicillin; piperacillin-tazobactam; temocillin
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections and Mycoses; Emergencies; Infections; Communicable Diseases; Frailty; Bacterial Infections
• Other Study ID Numbers: EC/2017/1369 (BC-01030)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Students participating at the study (registered ethical committee) can consult individual participant data.
• IPD Sharing Time Frame: During the whole study course.
• IPD Sharing Access Criteria: To be approved by ethical committee.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No