CONTinuous Infusion Versus Intermittent Dosing of ceftaZidime/AVIbactam in Critically Ill Patients With Klebsiella Pneumoniae OXA-48 or Pseudomonas Aeruginosa Infections: A Single-centre Randomized Open-label Trial (ZAVICONT)
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 140
- 主要终点
- microbiological success rate
研究概览
简要总结
Ceftazidime/avibactam (CZA) is an essential treatment option for managing infections caused by multidrug-resistant (MDR) gram-negative (G-) bacteria, including Klebsiella pneumoniae OXA-48 and carbapenem-resistant Pseudomonas aeruginosa. Critically ill intensive care unit (ICU) patients frequently exhibit altered pharmacokinetics (PK) of CZA, potentially compromising optimal PK/pharmacodynamic (PD) target attainment with standard dosing regimens. This study compares the efficacy of continuous infusion (CI) versus conventional intermittent dosing (ID) of CZA in critically ill ICU patients with severe infections caused by K. pneumoniae OXA-48 or P. aeruginosa.
This single-centre, randomized, open-label trial will be conducted at a tertiary care hospital within the University Hospital Centre in Zagreb, Croatia, with a 1:1 allocation ratio. One hundred forty critically ill ICU patients requiring CZA treatment will be randomized to receive either ID (2 g/0.5 g every 8 hours over 2 hours) or an equivalent dose in CI (6 g/1.5 g continuously over 24 hours).
The primary outcome is the microbiological success rate. Secondary outcomes include clinical success rate, time to symptom improvement, length of ICU and hospital stay, 28-day all-cause mortality, pathogen recurrence rate, time to weaning from mechanical ventilation, cumulative vasoactive-inotropic score, adverse events, and the ratio of ceftazidime plasma concentration to the pathogen's minimum inhibitory concentration (C/MIC).
This trial seeks to provide evidence on the optimal administration strategy for CZA in critically ill ICU patients with severe infections due to MDR G- pathogens.
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
- Double (Participant, Outcomes Assessor)
盲法说明
Patients will not be informed of their group assignment to maintain study integrity. We opted for this study design, which is not fully blinded, for several practical and clinical reasons. First, the dosing regimen of the drug is complex. According to the SmPC, ceftazidime/avibactam is administered as a prolonged infusion over 2 hours every 8 hours. In a placebo-controlled design, all patients would require an additional infusion, either placebo or the active drug, following the initial 2-hour infusion. By not including a placebo, the control group will follow the SmPC dosing regimen (2-hour infusions every 8 hours), while the intervention group will receive the drug as a continuous infusion over 24 hours. Second, the study involves administration in cardiac and cardiac surgery intensive care units, where patients are at a more significant risk of volume overload. The study was designed without a placebo-controlled arm to minimise unnecessary fluid administration.
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age above or equal to 18 years of age.
- •Able to provide informed consent personally or by his/her next of kin, as requested by the Ethics Committee.
- •Disease-specific
- •Critically ill patients requiring admission to the intensive care unit (medical or surgical).
- •Diagnosed with severe infections.
- •At least one microbiological sample positive for Klebsiella pneumoniae OXA-48 or Pseudomonas aeruginosa.
- •Requiring a prescription for ceftazidime/avibactam, by clinical judgement
排除标准
- •Known or suspected hypersensitivity to ceftazidime/avibactam, excipients, or any other cephalosporin antibacterial agent. Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other β-lactam antibacterial agent (e.g. penicillins, monobactams or carbapenems).
- •Withdrawal of informed consent.
- •Age above 85 years of age.
- •Female who is pregnant or breast-feeding.
- •Participation (i.e. signed informed consent) in any other interventional clinical trial of an approved or non-approved antibacterial agent within 30 days before screening.
- •Any disorder which, in the investigator's opinion, might jeopardize the participant's safety or compliance with the protocol.
- •Laboratory values
- •Severe neutropenia before or during ceftazidime/avibactam administration.
- •Medical conditions
- •Death within 48 hours following randomization.
- •Concomitant acquired immunodeficiency syndrome.
- •Presence or history of malignant neoplasms or in situ carcinomas.
- •Duration of ceftazidime/avibactam administration is shorter than 72 hours.
研究组 & 干预措施
Continuos ceftazidime/avibactam infusion
Continuous infusion will include a loading dose of 2 g/0.5 g administered over 2 hours, followed by continuous infusion of 6 g/1.5 g over 24 hours, equivalent to 0.25 g of ceftazidime per hour. The drug reconstitution and dilution process are shown in Figure 2. The final volume of a solution of CZA will be 50 mL, which gives the concentration of ceftazidime 40 mg/mL, with a 4:1 concentration ratio for avibactam (10 mg/mL). The solution will be administered via an infusion syringe with an infusion rate of 6.25 mL/h. Dose adjustments will be applied according to renal function, calculated using the Cockroft-Gault formula
干预措施: Continuos ceftazidime/avibactam infusion (Drug)
Intermitent dosing as per SMPC
Intermittent dosing, as outlined in the SmPC, consists of 2 g/0.5 g administered by prolonged infusion over 2 hours every 8 hours. Dose adjustments will be applied according to renal function, calculated using the Cockroft-Gault formula.
干预措施: Intermitent dosing as per SMPC (Drug)
结局指标
主要结局
microbiological success rate
时间窗: 28 days
The aim of this study is to investigate efficacy of continuous infusion of ceftazidime/avibactam compared to conventional intermittent dosing, in treating critically ill ICU patients with severe infections caused by Klebsiella pneumoniae OXA-48 or Pseudomonas aeruginosa. The primary outcome of the study is microbiological success rate, defined by proportion of patients in whom the causative pathogen is absent from specimen at the site of infection.
次要结局
- clinical success rate(28 day)
- length of ICU stay(28 day)
- length of hospital stay(28 day)
- time to weaning from mechanical ventilation(28 days)
- time to symptoms improvement(28 day)
- all-cause 28-day mortality after ceftazidime/avibactam initiation(28 day)
- pathogen recurrence rate on day 28(28 day)
- cumulative vasoactive-inotropic score (VIS)(28 day)
研究者
Ivan Šitum, MD
subinvestigator
Clinical Hospital Centre Zagreb