A Multi-centre Study to Define Novel Individualised Dosing Regimens to Maximise Antibiotic Effectiveness for Treatment of Pneumonia in Intensive Care Units
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 179
- 试验地点
- 6
- 主要终点
- Volume of distribution (Vd) of benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam in ICU patients with pneumonia
研究概览
简要总结
Pneumonia is the most common infection in intensive care unit (ICU) patients and occurs in 10% of all ICU admissions. Unfortunately, ICU patient outcomes remain poor with a high mortality rate associated with pneumonia despite recent therapeutic advances.
Previous studies of antibiotics used in ICU patients, which includes ceftriaxone, meropenem and piperacillin/tazobactam, have quantified major differences in pharmacokinetics (PK) between ICU and non-ICU patients, with ICU patients displaying a unique spectrum of plasma concentration-time profiles. These PK differences can lead to suboptimal antibiotic concentrations in blood, which have been associated with a reduced likelihood of clinical cure for pneumonia. Furthermore, highlighting the importance of optimised dosing for pneumonia is that multi-drug resistant (MDR) pathogens emerge during antibiotic therapy in approximately half of the ICU patients, frequently emerging from the lung.
Previous work has highlighted how infection site concentrations determine patient outcome. For pneumonia, the infection site is best described as the epithelial lining fluid (ELF) in the lung.
Although optimal antibiotic therapy should be considered a priority for ICU patients with pneumonia to improve the persisting poor outcomes, the dosing regimens that can achieve therapeutic concentrations at the infection site (i.e., ELF) in ICU patients with pneumonia remain unknown.
The PNEUDOS study aims to address this significant knowledge gap by defining novel individualised dosing regimens that can maximise antibiotic efficacy by achieving therapeutic concentrations in the blood and ELF of ICU patients with pneumonia. These dosing regimens can then be validated in future clinical trials.
详细描述
Hypotheses
- The pharmacokinetics of benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam are significantly different in ICU patients with pneumonia when compared to those of non-ICU and non-infected patients.
- Altered beta-lactam antibiotic dosing approaches, as opposed to "contemporary" or "standard" dosing, are required for maximally effective blood (i.e., plasma) and epithelial lining fluid beta-lactam exposures in ICU patients with pneumonia.
- Beta-lactam antibiotic exposures in epithelial lining fluid influence levels of lung inflammation in ICU patients with pneumonia.
Objective: The overall objective of this study is to characterise the plasma and epithelial lining fluid pharmacokinetics of important antibiotics in ICU patients with pneumonia to define optimal dosing regimens that maximise therapeutic outcomes.
Specific objectives
- To describe the population pharmacokinetics of benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam (in plasma, epithelial lining fluid and urine) in ICU patients with pneumonia.
- To design optimised dosing regimens for benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam that maximise the achievement of effective epithelial lining fluid exposures in ICU patients with pneumonia.
- To characterise the effects of beta-lactam antibiotic (benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam) exposures in epithelial lining fluid on lung inflammation in ICU patients with pneumonia.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
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
- •Adult (≥18 years old) ICU patients
- •Confirmed or suspected either community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically diagnosed lung infection
- •Patient has been prescribed or is receiving one of the study drugs (benzylpenicillin, ceftriaxone, meropenem, or piperacillin/tazobactam) for the treatment of pneumonia in the ICU
- •Patient is sedated and receiving mechanical ventilation
- •Patient has arterial line and urinary catheter in situ for blood and urine samplings
- •Informed consent to participate in the study
排除标准
- •Suspected or known hypersensitivity towards beta-lactam antibiotics (pre- or post-enrolment)
- •Receiving renal replacement therapy (RRT)
- •Pregnant patients or lactating mothers
- •Has received study antibiotic for more than 72 hours (at time of Occasion 1) during current infective episode.
研究组 & 干预措施
Benzylpenicillin
ICU patients receiving benzylpenicillin for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Blood sampling (Other)
Benzylpenicillin
ICU patients receiving benzylpenicillin for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Epithelial lining fluid sampling (Other)
Benzylpenicillin
ICU patients receiving benzylpenicillin for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Urine sampling (Other)
Benzylpenicillin
ICU patients receiving benzylpenicillin for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Study antibiotics include benzylpenicillin, ceftriaxone, meropenem, and piperacillin/tazobactam (Drug)
Ceftriaxone
ICU patients receiving ceftriaxone for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Blood sampling (Other)
Ceftriaxone
ICU patients receiving ceftriaxone for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Epithelial lining fluid sampling (Other)
Ceftriaxone
ICU patients receiving ceftriaxone for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Urine sampling (Other)
Ceftriaxone
ICU patients receiving ceftriaxone for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Study antibiotics include benzylpenicillin, ceftriaxone, meropenem, and piperacillin/tazobactam (Drug)
Meropenem
ICU patients receiving meropenem for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Blood sampling (Other)
Meropenem
ICU patients receiving meropenem for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Epithelial lining fluid sampling (Other)
Meropenem
ICU patients receiving meropenem for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Urine sampling (Other)
Meropenem
ICU patients receiving meropenem for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Study antibiotics include benzylpenicillin, ceftriaxone, meropenem, and piperacillin/tazobactam (Drug)
Piperacillin/tazobactam
ICU patients receiving piperacillin/tazobactam for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Blood sampling (Other)
Piperacillin/tazobactam
ICU patients receiving piperacillin/tazobactam for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Epithelial lining fluid sampling (Other)
Piperacillin/tazobactam
ICU patients receiving piperacillin/tazobactam for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Urine sampling (Other)
Piperacillin/tazobactam
ICU patients receiving piperacillin/tazobactam for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)
干预措施: Study antibiotics include benzylpenicillin, ceftriaxone, meropenem, and piperacillin/tazobactam (Drug)
结局指标
主要结局
Volume of distribution (Vd) of benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam in ICU patients with pneumonia
时间窗: Days 1 - 6 of antibiotic therapy
Population mean value of volume of distribution (Vd) in L/kg
Drug clearance (CL) of benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam in ICU patients with pneumonia
时间窗: Days 1 - 6 of antibiotic therapy
Population mean value of clearance (CL) in L/hr
Optimised dosing regimens for benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam that maximise the achievement of effective plasma exposure in ICU patients with pneumonia
时间窗: Days 1 - 6 of antibiotic therapy
Dosing regimens required to attain therapeutic concentrations in plasma will be evaluated using Monte Carlo dosing simulations. Therapeutic concentration is defined as concentrations above the minimum inhibitory concentration (MIC) of a pathogen for 100% of the dosing interval (100% T\>MIC) in plasma
Optimised dosing regimens for benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam that maximise the achievement of effective epithelial lining fluid exposure in ICU patients with pneumonia
时间窗: Days 1 - 6 of antibiotic therapy
Dosing regimens required to attain therapeutic concentrations at the site of infection will be evaluated using Monte Carlo dosing simulations. Therapeutic concentration is defined as concentrations above the minimum inhibitory concentration (MIC) of a pathogen for 100% of the dosing interval (100% T\>MIC) in the epithelial lining fluid
The effect of lung inflammation on beta-lactam antibiotic exposures
时间窗: Days 1 - 6 of antibiotic therapy
To characterise the effects of beta-lactam (benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam) exposures in epithelial lining fluid on lung inflammation (using inflammatory cytokines/mediators) in ICU patients with pneumonia
次要结局
未报告次要终点