Population Pharmacokinetics and Pharmacodynamics of Beta-lactams of Interest in Adult Patients From Intensive Care Units
试验速览
- 阶段
- 不适用
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Impact of renal function on total plasma concentrations
研究概览
简要总结
Antibiotics are still most often administered on an empiric fashion, as defined for the general population with dosages only adapted based on weight and renal and/or hepatic functions. As a result, serum concentrations show important interpatient variations with the risk of being subtherapeutic or toxic. Recent studies with temocillin, ceftriaxone, or meropenem confirm this for patients in intensive care units.
The aim of the study will be to measure the total and free concentrations of temocillin, ceftriaxone, and meropenem in patients hospitalized in Intensive Care Units for pulmonary infections or another infection for which one of the above mentioned antibiotics is indicated. Patients will be stratified according to the level of their renal function. The antibiotics will be assayed in plasma as well as other accessible fluids in order to assess their pharmacokinetic properties.
详细描述
- Background, Literature Survey and Justification of The Study
1.1. Introduction
β-lactams efficacy depends primarily from the time interval during which the plasma concentration remains above the minimal inhibitory concentration (MIC) of the antibiotic against the target organism(s) (Craig, 1998). It is generally accepted that the free concentration of the antibiotic must remain above the MIC for at least 40 to 70% of the interval between two successive administrations, and should even reach 100% for severe infections in patients hospitalized in Intensive Care Units (MacGowan, 2011). The free concentration must reach a value of 4 x the MIC for 40 to 70% (Mohd Hafiz et al., 2012) or even 100 % (Tam et al., 2005) of the dosing interval in order to prevent the emergence of resistance.
Due to the large inter- and intraindividual variations between patients, it is difficult to reach the desired concentrations if relying only on usual dosage recommendations and/or using standard dosing regimens. Moreover, Intensive Care patients are difficult patients in this context (Roberts et al., 2014) due to gross perturbations related to underlying diseases and abnormalities (arterial hypertension, cardiac rhythm alterations, renal and/or hepatic insufficiency) and the necessary interventions (artificial ventilation, surgery, artificial feeding, and so on...). They also show important variations in the level of plasma proteins and rapid and unpredictable fluctuations of their renal function (Beumier et al., 2015; Goncalves-Pereira and Povoa, 2011; Roberts and Lipman, 2009), all of which are known to modulate the pharmacokinetics of β-lactams (Goncalves-Pereira and Povoa, 2011; Hayashi et al., 2013; Sime et al., 2012; Udy et al., 2012; Wong et al., 2013). The concentration of the free fraction will be especially modified for those β-lactams with large protein binding such as temocillin or ceftriaxone (Schleibinger et al., 2015; Ulldemolins et al., 2011; Van Dalen et al., 1987; Wong et al., 2013), but may also be altered for β-lactams that are mainly excreted via the renal route (temocillin, ceftriaxone, meropenem) (Carlier et al., 2013; Simon et al., 2006; Vandecasteele et al., 2015).
1.2. Clinical Interest of temocillin, ceftriaxone and meropenem and State of the Art Concerning their dosing
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
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
- •Patients with suspicion or documentation of of an infection requiring intravenous antibiotic therapy (this includes any patient admitted to the Intensive Care Unit for an infection (or developing an infection) that calls for administration of temocillin, ceftriaxone or meropenem).
排除标准
- •Patients allergic to β-lactams
- •IgE-mediated hypersensibility to penicillins
- •any biological abnormality that the attending physician considers as susceptible to delay or perturb in a significant manner the interpretation of the trial
- •lack of accepted informed consent
- •patient with therapeutic limitations
研究组 & 干预措施
Sampling if GFR = or > 30 mL/min
Note: GFR = Glomerular Filtration Rate
Patients with a normal of moderately decreased renal function
- Temocillin: 6 g in continuous infusion over 24 h;
- Ceftriaxone: bolus 2 g (in 30 min) every 12h
- Meropenem: prolonged infusion (3 h) of 2 g every 8h
Blood sampling for antibiotic (temocillin, ceftriaxone or meropenem) pharmacokinetic analysis / Tissue sampling (lung) for determination of antibiotic content when possible / Collection of fluid samples (bronchoalveolar lavage, drainage fluid) for determination of antibiotic concentration when possible
干预措施: blood sampling (Drug)
Sampling if GFR = or > 30 mL/min
Note: GFR = Glomerular Filtration Rate
Patients with a normal of moderately decreased renal function
- Temocillin: 6 g in continuous infusion over 24 h;
- Ceftriaxone: bolus 2 g (in 30 min) every 12h
- Meropenem: prolonged infusion (3 h) of 2 g every 8h
Blood sampling for antibiotic (temocillin, ceftriaxone or meropenem) pharmacokinetic analysis / Tissue sampling (lung) for determination of antibiotic content when possible / Collection of fluid samples (bronchoalveolar lavage, drainage fluid) for determination of antibiotic concentration when possible
干预措施: Tissue sampling (lung) (Drug)
Sampling if GFR = or > 30 mL/min
Note: GFR = Glomerular Filtration Rate
Patients with a normal of moderately decreased renal function
- Temocillin: 6 g in continuous infusion over 24 h;
- Ceftriaxone: bolus 2 g (in 30 min) every 12h
- Meropenem: prolonged infusion (3 h) of 2 g every 8h
Blood sampling for antibiotic (temocillin, ceftriaxone or meropenem) pharmacokinetic analysis / Tissue sampling (lung) for determination of antibiotic content when possible / Collection of fluid samples (bronchoalveolar lavage, drainage fluid) for determination of antibiotic concentration when possible
干预措施: Collection of fluid samples (Drug)
Sampling if GFR < 30 mL/min
Patients with severe renal insufficiency or hemodialysis:
- Temocillin: 6 g in continuous infusion over 24 h;
- Ceftriaxone: bolus 2 g (in 30 min) every 12h
- Meropenem: prolonged infusion (3 h) of 2 g every 8h
Blood sampling for antibiotic (temocillin, ceftriaxone or meropenem) pharmacokinetic analysis / Tissue sampling (lung) for determination of antibiotic content if possible / Collection of fluid samples (bronchoalveolar lavage, drainage fluid) for determination of antibiotic concentration if possible
干预措施: blood sampling (Drug)
Sampling if GFR < 30 mL/min
Patients with severe renal insufficiency or hemodialysis:
- Temocillin: 6 g in continuous infusion over 24 h;
- Ceftriaxone: bolus 2 g (in 30 min) every 12h
- Meropenem: prolonged infusion (3 h) of 2 g every 8h
Blood sampling for antibiotic (temocillin, ceftriaxone or meropenem) pharmacokinetic analysis / Tissue sampling (lung) for determination of antibiotic content if possible / Collection of fluid samples (bronchoalveolar lavage, drainage fluid) for determination of antibiotic concentration if possible
干预措施: Tissue sampling (lung) (Drug)
Sampling if GFR < 30 mL/min
Patients with severe renal insufficiency or hemodialysis:
- Temocillin: 6 g in continuous infusion over 24 h;
- Ceftriaxone: bolus 2 g (in 30 min) every 12h
- Meropenem: prolonged infusion (3 h) of 2 g every 8h
Blood sampling for antibiotic (temocillin, ceftriaxone or meropenem) pharmacokinetic analysis / Tissue sampling (lung) for determination of antibiotic content if possible / Collection of fluid samples (bronchoalveolar lavage, drainage fluid) for determination of antibiotic concentration if possible
干预措施: Collection of fluid samples (Drug)
结局指标
主要结局
Impact of renal function on total plasma concentrations
时间窗: 36 months
Measurement of total plasma antibiotic concentrations (measurement by a validated HPLC-MS-MS after suitable extraction; no predefined value set \[exploratory\])
次要结局
- Impact of the plasma protein concentration and of their nature on the free concentration of antibiotics(36 months)
- Tissular and fluid penetration of antibiotics (total)(36 months)
- Tissular and fluid penetration of antibiotics (free)(36 months)
- Pharmacokinetic analysis and population pharmacokinetics: time above a critical concentration value for total and free concentrations(36 months)
- Covariables analysis: biometric values: weight(36 months)
- Covariables analysis: biometric values: height(36 months)
- Covariables analysis: biometric values: age(36 months)
- Covariables analysis: biochemical data: serum total protein and albumin(36 months)
- Covariables analysis: biochemical data: elevation hepatic transaminases(36 months)
- Covariables analysis: biochemical data: blood urea and creatinine(36 months)
- Covariable analysis: clinical status with respect to infection(36 months)
- Covariable analysis: renal function(36 months)
- Pharmacokinetic analysis and population pharmacokinetics: Cmax (total and free)(36 months)
- Pharmacokinetic analysis and population pharmacokinetics: Cmin (total and free)(36 months)
研究者
Paul M. Tulkens
Professor
Université Catholique de Louvain