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.
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Proportion of patients that attain the (FLU or CZO) target concentration (100% fT 2 to 12 mg/L) in blood.
研究概览
简要总结
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".
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
There will be no blinding in this study. The antibiotic concentrations in the control group will be measured but not communicated to the study team or the treating physician.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
intervention group
Subjects randomized into the intervention group will receive FLU or CZO respectively as continuous infusion as soon as targeted S. aureus treatment is initiated (+24h). The choice of antibiotic is determined by the treating physician in accordance to the recommendations of the infectious diseases (ID) specialists. The loading dose and dose adjustments of FLU and CZO will be determined by the use of a pharmacokinetic modelling application. The maximum daily dose will not exceed the daily licensed dose according to the Summary of Product Characteristics (SmPC).
干预措施: FLU or CZO as continuous infusion (Drug)
control group
Subjects randomized to the control group will receive standard of care intermittent bolus infusion FLU or CZO dosed according to the recommendations of the ID specialist and treating physician. Drug concentration will be 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.
干预措施: standard FLU or CZO intermittent bolus administration (Drug)
结局指标
主要结局
Proportion of patients that attain the (FLU or CZO) target concentration (100% fT 2 to 12 mg/L) in blood.
时间窗: On day 3 after inclusion
For the assessment of the primary endpoint (100% fT 2 to 12 mg/L), the plasma concentration of FLU or CZO will be measured at day 3 after inclusion of the patient.
次要结局
- Proportion of patients attaining the target (FLU or CZO) concentration at second TDM(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)
- Incidence of high (e.g. 100% fT>12 mg/L) (FLU or CZO) concentrations(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)
- Intra-individual variability in FLU und CZO total and unbound plasma concentrations(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)
- Incidence of low concentrations (e.g. 100% fT<2mg/L) (FLU or CZO) concentrations(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)
- Incidence of potential drug-related toxicity during the course of treatment (e.g. nephrotoxicity, hepatotoxicity, neurotoxicity)(From Day 0 (enrolment) until discharge (up to 6 weeks))
- Percentage of days with optimal target attainment in relation to total study treatment duration(From Day 0 (enrolment) until discharge (up to 6 weeks))