Clinical trial NCT05655091: Target Attainment of Continuous Infusion Flucloxacillin and Cefazolin Coupled With TDM vs. Standard of Care Treatment in Patients With Complicated S. Aureus Infection
Official title: Can Continuous Infusion Coupled With Therapeutic Drug Monitoring Optimize Flucloxacillin and Cefazolin Target Attainment Compared to Standard Intermittent Bolus Dosing in Patients With Complicated Staphylococcus Aureus Infections? A Randomized, Controlled Interventional Pilot Trial.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Complicated Staphylococcus Aureus (S. Aureus) Infections (CSAI)
Keywords: Therapeutic drug monitoring (TDM)
Flucloxacillin (FLU)
Cefazolin (CZO)
β-lactam antibiotics
antibiotic plasma concentration
standard intermittent bolus administration
continuous infusion
Staphylococcus aureus
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
First posted: 2022-12-16
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Single-centre, randomised, controlled, interventional pilot trial
Primary purpose: TREATMENT

Brief summary: This prospective randomized, controlled interventional pilot trial, aims to compare the achievement of the optimal target concentration with continuously administered flucloxacillin (FLU) or cefazolin (CZO) coupled with TDM and subsequent dose adjustment versus standard of care (intermittent bolus application without TDM-guidance) in patients with complicated Staphylococcus aureus (S. aureus) infections (CSAI). The overall goal is to individualize and optimize antibiotic treatment in a very vulnerable group of patients overcoming the standard strategy of "one-dose-fits-all".

Detailed description: Therapeutic drug monitoring (TDM) has recently been established as one of the cornerstones to individualize treatment of β-lactam antibiotics. It is particularly useful in patients hospitalized in the intensive care unit (ICU) being at risk to not achieve optimal antibiotic plasma concentrations due to a strongly altered metabolism. Along the same lines, continuous administration of β-lactam antibiotics instead of standard intermittent bolus administration may maintain drug concentrations in the target range throughout the dosing interval, and even contribute to a decrease in mortality. This prospective randomized, controlled interventional pilot trial, aims to compare the achievement of the optimal target concentration with continuously administered flucloxacillin (FLU) or cefazolin (CZO) coupled with TDM and subsequent dose adjustment versus standard of care (intermittent bolus application without TDM-guidance) in patients with complicated Staphylococcus aureus (S. aureus) infections (CSAI). The overall goal is to individualize and optimize antibiotic treatment in a very vulnerable group of patients overcoming the standard strategy of "one-dose-fits-all". The primary objective of this trial is to evaluate the achievement of the optimal pharmacological target concentration (100% fT 2 to 12 mg/L) in blood on day 3 after inclusion with continuous infusion FLU and CZO in combination with real-time TDM and subsequent dose adjustment, versus the current standard of care in patients with CSAI, and to estimate the effect size for future trials. To evaluate the PKPD of unbound FLU or CZO in the intervention versus the control group as measured by the following:

* Drug concentration at second or later TDM including the incidence of high (e.g. 100% fT\>12 mg/L) and low concentrations (e.g. 100% fT\<2mg/L)
* Incidence of potential drug-related toxicity during the course of treatment (e.g. nephrotoxicity, hepatotoxicity, neurotoxicity)
* Time to optimal target attainment and percentage of days with optimal target attainment in relation to total study drug treatment duration
* Intra-individual variability in FLU und CZO total and unbound plasma concentrations
* Factors associated with pharmacological target attainment (e.g. kidney function, protein, albumin, age, sex, weight, concomitant medication)

Sub-study I:

- Evaluation of the pharmacological profile of penicillin in patients in whom treatment was changed from FLU or CZO to penicillin due to a penicillin susceptible S. aureus strain.

Sub-study II:

- Assessment of patient satisfaction, rest-activity rhythms and sleep quality by actigraphy, sleep diaries and questionnaire in patients admitted to a general ward.

Patients will be randomized in two parallel groups stratified to the use of FLU or CZO in a 1:1 ratio to be treated either by continuous infusion plus TDM and dose adjustment or by standard intermittent bolus application.

Drug concentrations will be measured at day 1, 3, 5, 7, 10 and thereafter two times weekly until treatment period is completed (i.e. up to 6 weeks) or until discharge. After discharge, TDM will be performed 1x/week if the patient is treated in the outpatient parenteral antibiotic treatment (OPAT) program but without any dose adjustments. Dose adjustments of FLU and CZO in the intervention group will be performed according to a pharmacokinetic modelling application that is based on the data of our previous studies TARGET \[2\] and TARGET II (unpublished data). In the control group, blood samples will be drawn and analysed directly, but the results will not be communicated to the study team or a physician involved in the treatment of the patient. No TDM-guided dose adjustment will be performed in the control group

Eligibility criteria: Inclusion Criteria:

* Informed Consent as documented by signature. For patients, who are not able to sign consent, a physician not involved in the current study has to confirm that patient's interest and rights are guaranteed during participation in the current study. Subsequently, informed consent will be obtained as soon as possible from the patient or his/her legally authorised representative.
* Age ≥ 18 years
* CSAI which is defined as (i) blood stream infection (BSI) with S. aureus or (ii) deep-seated infections caused by S. aureus (e.g. osteoarticular infections, deep-seated abscesses) without BSI.
* Intended or active (less than 24 hours) treatment with FLU or CZO

Exclusion Criteria:

* Patients on hemodialysis or eGFR\<10 ml/min as these patients have a special pharmacokinetic
* Patients on Cytosorb® therapy
* Patients with liver cirrhosis CHILD B and C
* Patients who are very likely to stop treatment with FLU or CZO in the next 48 hours as per treating physician (because of treatment failure, switch to oral medication, palliative care, allergy etc.) or who are very likely to be discharged or transferred to another hospital in the next 48 hours as per treating physician.
* Polymicrobial infection except concomitant isolation of a likely contaminant (e.g. Staphylococcus epidermidis or Cutibacterium acnes). If an additional pathogen is identified after inclusion of the patient into the study, the patient will remain in the study.
* CSAI caused by methicillin-resistant S. aureus (MRSA)
* Participation in another study with investigational drug within the 30 days preceding and during the present study
* Previous enrolment into the current study
* Any uncontrolled or significant concurrent illness that would put the patient at a greater risk or limit compliance with the study requirements at the discretion of the investigator

Primary outcomes:
measure: Proportion of patients that attain the (FLU or CZO) target concentration (100% fT 2 to 12 mg/L) in blood.
timeFrame: On day 3 after inclusion
Secondary outcomes:
measure: Proportion of patients attaining the target (FLU or CZO) concentration at second TDM
timeFrame: At day 1, 3, 5, 7, 10 and thereafter two times weekly until treatment period is completed (i.e. up to 6 weeks) or until discharge
measure: Incidence of high (e.g. 100% fT>12 mg/L) (FLU or CZO) concentrations
timeFrame: At day 1, 3, 5, 7, 10 and thereafter two times weekly until treatment period is completed (i.e. up to 6 weeks) or until discharge
measure: Incidence of low concentrations (e.g. 100% fT<2mg/L) (FLU or CZO) concentrations
timeFrame: At day 1, 3, 5, 7, 10 and thereafter two times weekly until treatment period is completed (i.e. up to 6 weeks) or until discharge
measure: Incidence of potential drug-related toxicity during the course of treatment (e.g. nephrotoxicity, hepatotoxicity, neurotoxicity)
timeFrame: From Day 0 (enrolment) until discharge (up to 6 weeks)
measure: Percentage of days with optimal target attainment in relation to total study treatment duration
timeFrame: From Day 0 (enrolment) until discharge (up to 6 weeks)
measure: Intra-individual variability in FLU und CZO total and unbound plasma concentrations
timeFrame: At day 1, 3, 5, 7, 10 and thereafter two times weekly until treatment period is completed (i.e. up to 6 weeks) or until discharge
Other outcomes:
measure: Change in drug concentration of penicillin (in patients in whom treatment was changed from FLU or CZO to penicillin (Outcome of sub-study I))
timeFrame: From Day 1 after enrolment until treatment period is completed (i.e. up to 6 weeks)
measure: Rest-activity rhythms in patients admitted to a general ward (Outcome of sub-study II)
timeFrame: From Day 0 (enrolment) until until end of treatment (up to 6 weeks)
measure: Change in Sequential Organ Failure Assessment (SOFA) score
timeFrame: From Day 0 (enrolment) until day 10
measure: Time to first negative blood culture
timeFrame: From Day 0 (enrolment) until discharge (approx. 2 weeks)
measure: Change in inflammation parameters (C-reactive protein)
timeFrame: From Day 0 (enrolment) until end of treatment (up to 6 weeks)
measure: Change in All-cause mortality rate at day 30 and day 90
timeFrame: At day 30 and day 90 after enrolment
measure: Quality of life using the EuroQol™ 5D-5L Questionnaire
timeFrame: At day 90 after enrolment
measure: Serious adverse events
timeFrame: From Day 1 after enrolment until three month follow-up
Locations:
city: Basel
country: Switzerland
facility: University Hospital Basel, Division of Internal Medicine
Study officials:
affiliation: University Hospital Basel, Division of Internal Medicine
name: Michael Osthoff, PD Dr. med.
role: PRINCIPAL_INVESTIGATOR
References: