A Multicentre, Parallel Group Open-label Randomised Controlled Non-Inferiority Phase 3 Trial, of Ceftolozane-tazobactam Versus Meropenem for Definitive Treatment of Bloodstream Infection Due to Extended-Spectrum Beta-Lactamase (ESBL) and AmpC-producing Enterobacterales
试验速览
- 阶段
- 3 期
- 状态
- 撤回
- 试验地点
- 29
- 主要终点
- Mortality rate at 30 days
研究概览
简要总结
The purpose of this study is to determine whether ceftolozane-tazobactam is as effective as meropenem with respect to 30 day mortality in the treatment of bloodstream infection due to third-generation cephalosporin non-susceptible Enterobacterales or a known chromosomal AmpC-producing Enterobacterales (Enterobacter spp., Citrobacter freundii, Morganella morganii, Providencia spp. or Serratia marcescens).
详细描述
Enterobacterales are common causes of bacteraemia, and may produce extended-spectrum beta-lactamases (ESBLs) or AmpC beta-lactamases. ESBL or AmpC producers are typically resistant to third generation cephalosporins such as ceftriaxone, but susceptible to carbapenems. In no study has the outcome of treatment for serious infections for ESBL producers been significantly surpassed by carbapenems. Despite the potential advantages of carbapenems for treatment of ceftriaxone non-susceptible organisms, widespread use of carbapenems may cause selection pressure leading to carbapenem-resistant organisms. This is a significant issue since carbapenem-resistant organisms are treated with last-line antibiotics such as colistin.
Ceftolozane-tazobactam is a combination of a new beta-lactam antibiotic with an existing beta-lactamase inhibitor, tazobactam, and is active against ESBL and most AmpC producing organisms. In a large sample of ESBL- and AmpC-producing Enterobacterales isolates from urinary tract and intra-abdominal specimens, ceftolozane-tazobactam was susceptible in over 80%. It has been FDA approved for complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI), and more recently for hospital-acquired and ventilator-associated pneumonia (HAP/VAP). In addition, a pooled analysis of phase 3 clinical trials has shown favourable clinical cure rates with ceftolozane-tazobactam for cUTI and cIAI caused by ESBL-producing Enterobacterales. Given the issues of carbapenem resistant organisms, there is a need for establishing the efficacy of an alternative to carbapenems for serious infections.
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
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
- •Bloodstream infection defined as presence in at least one peripheral blood culture draw demonstrating Enterobacterales with proven non-susceptibility to third generation cephalosporins or cephalosporin susceptible species known to harbour chromosomal AmpC-beta-lactamases (Enterobacter spp., Klebsiella aerogenes, Citrobacter freundii, Morganella morganii, Providencia spp. or Serratia marcescens) during hospitalisation
- •Patient is aged 18 years and over (21 and over in Singapore)
- •The patient or approved proxy is able to provide informed consent
- •≤72 hours has elapsed since the first positive qualifying (index) blood culture collection
- •Expected to receive IV therapy for ≥5 days
排除标准
- •Known hypersensitivity to a cephalosporin or a carbapenem, or anaphylaxis to beta-lactam antibiotics
- •Participant with significant polymicrobial bloodstream infection (i.e. not a contaminant)
- •Treatment is not with the intent to cure the infection (i.e. palliative intent) or the expected survival is ≤4 days
- •Participant is pregnant or breast-feeding (tested for in women of child-bearing age only)
- •Use of concomitant antimicrobials with known activity against Gram-negative bacilli (except trimethoprim/sulfamethoxazole for Pneumocystis prophylaxis and when adding metronidazole for suspected IAI) in the first 5 days post-randomisation
- •Participant with CrCl <15 mL/minute or on renal replacement therapy (in addition, participants will be withdrawn from the study if CrCl reaches this level)
- •Previously randomised in the MERINO-3 trial or concurrently enrolled in another therapeutic antibiotic clinical trial
- •Blood culture isolate with in-vitro resistance to either meropenem or ceftolozane-tazobactam (known either at time of enrolment or during the course of study treatment, in which case the participant will be withdrawn)
研究组 & 干预措施
Ceftolozane-tazobactam
Participants will receive ceftolozane-tazobactam 3 grams (comprising ceftolozane 2 grams and tazobactam 1 gram) administered, every 8 hours, three times a day, intravenously over 60 mins
干预措施: Ceftolozane-Tazobactam (Drug)
Meropenem
Participants will receive meropenem 1 gram, every 8 hours, three times a day, intravenously over 30 mins.
干预措施: Meropenem (Drug)
结局指标
主要结局
Mortality rate at 30 days
时间窗: 30 days post randomisation
To compare the 30-day mortality from day of randomisation of each regimen
次要结局
- Clinical and microbiological success(5 days post randomisation)
- Serious adverse events(Day 1 to last dose plus 24 hours of treatment:)
- Clostridioides difficile infection(30 days post randomisation)
- Colonisation and/or infection with multi-resistant bacterial organisms(30 days post randomisation)
- Desirability of Outcome Ranking (DOOR) with partial credit(30 days post randomisation)
- Length of in-patient hospital and ICU stay(30 days post randomisation)
- Mortality rate at 14 days(14 days post randomisation)
- Functional bacteraemia score (FBS)(0 and 30 days post randomisation)
- Microbiological relapse(30 days post randomisation)
- Rates of new bloodstream infection(30 days post randomisation)