A Multicenter Non-inferiority Randomized Trial Comparing Cloxacillin Versus Cefazolin Efficacy for the Treatment of Bacteremia Caused by Methicillin-susceptible Staphylococcus Aureus (MSSA)
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 315
- 试验地点
- 1
- 主要终点
- Therapeutic efficacy
研究概览
简要总结
"Methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia remains a major cause of community- or hospital-acquired bloodstream infections with an overall mortality estimated around 25%. Anti-staphylococcal penicillins (APs) such as oxacillin or cloxacillin are recommended as first-line agents. With the exception of first-generation cephalosporin (1GC) such as cefazolin, no alternative has yet proven a similar efficacy. Due to an unfavourable safety profile for high doses used in severe infection, an uneasy dosing schedule in patients with renal failure and possible recurrent stock-out events for APs, alternative to APs are needed. This led to propose an open-label, randomized, controlled parallel groups, phase IV, non-inferiority trial comparing the efficacy, the safety, and the ecological impact of cefazolin versus cloxacillin for the treatment of MSSA bacteremia in adults.
The primary objective is to compare the therapeutic efficacy of cefazolin vs cloxacillin at day 90 after the inclusion. "
详细描述
"Methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia remains a major cause of community- or hospital-acquired bloodstream infections with an overall mortality estimated around 25%. Anti-staphylococcal penicillins (APs) such as oxacillin or cloxacillin are recommended as first-line agents. With the exception of first-generation cephalosporin (1GC) such as cefazolin, no alternative has yet proven a similar efficacy: studies evaluating other β-lactams exhibited 2 fold-increased rates of mortality, while a 3 fold-increased mortality rate was observed with vancomycin.
Recently, the safety of APs has been questioned, as both hypersensitivity reactions and renal impairment have been reported to be higher than 10%. Premature discontinuation of APs attributed to adverse events occurred in >20% of patients treated with high dosing of oxacillin (12g/day) for complicated MSSA bacteremia. This might be linked to the growing number of cumulative comorbid conditions and to ageing. In particular, administration and dosing schedule for APs are not well defined in patients with chronic kidney disease with decreased rate of glomerular filtration. Today, data are missing for renal adjustment.
In addition, stock-outs of essential antimicrobials are more and more frequent. In 2011, the production of the main generic for injectable oxacillin, distributed in France, was stopped. More recently, cloxacillin was also stock-out because of manufacturing problems. A limited production is currently available.
Due to an unfavourable safety profile for high doses used in severe infection, an uneasy dosing schedule in patients with renal failure and possible recurrent stock-out events for APs, alternative to APs are needed.
Cefazolin, intravenous 1GC, is more and more commonly used. Based on several large observational studies, its efficacy is believed to be similar to that of APs both in terms of relapse and mortality, even in complicated cases such as osteo-arthritis or infective endocarditis. The potential hydrolysis of cefazolin by Staphylococcus aureus type A ßlactamases had no clinical impact. These data led the American and European infectious disease Societies to consider cefazolin as the first alternative line agent for treatment of MSSA-associated infective endocarditis. Nevertheless, except for chronic dialysis question, all existing studies assessing the efficacy profiles of cefazolin compared to the APs contain a retrospective design and no randomized clinical trial (RCT) has been performed.
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
- •Age above 18 years
- •Blood culture positive to MSSA identified by standard bacteriologic techniques or by GeneXpert PCR
排除标准
- •Previous type 1 or grade 3 - 4 according to CTCAE hypersensitivity reaction to beta-lactams
- •Known pregnancy or breastfeeding women
- •Parenteral antimicrobial therapy active against MSSA for more than 72 hours after the positive SA blood culture ponction
- •Chronic renal failure defined by a glomerular filtration rate estimated < 30 mL/min/1,73m².
- •Presence of an intra-vascular implant (vascular or valvular prosthesis or cardiovascular implantable electronic device)
- •Patient with implanted material considered to be infected by SAMS and whose antibiotic treatment is longer than 70 days
- •New cerebro-spinal signs in the preceding month
- •Clinical examination compatible with recent stroke (<1 month), brain abscess or meningitis
- •Current other antibiotic therapy which cannot be ceased or substituted by study treatment
- •Mixed blood culture with more than one pathogen (excluding contaminants: Corynebacterium sp., Propionibacterium sp., Coagulase-Negative Staphylococci)
- •coagulapthy with TP< 50% (excepted for patients under avk anticoagulant treatment)
- •Absence of written informed consent from the patient
- •Limitation of care with expected life duration below 90 days
- •Patient under guardianship or trusteeship
- •No affiliation to social security (beneficiary or assignee)
- •Subject already involved in another interventional clinical research evaluating a medicinal product
- •Secondary exclusion criteria:
- •Diagnosis of meningitis made after randomisation
- •Diagnosis of brain abscess made after randomisation
- •Diagnosis of multiple infection made after randomisation
研究组 & 干预措施
Cloxacillin
Intravenous treatment by cloxacillin, 25 to 50 mg/kg every 4 or 6 hours, without doing less than the minimum daily dose of 8 g/day and without exceeding the maximum daily dose of 12 g/day, administered as a 60-minutes infusion.
干预措施: Cloxacillin (Drug)
Cefazolin
Intravenous treatment by cefazolin, 25 to 50 mg/kg every 8 hours (without exceeding the maximum daily dose of 6 g/day), administered as a 30-minutes infusion.
干预措施: Cefazolin (Drug)
结局指标
主要结局
Therapeutic efficacy
时间窗: 90 days after beginning of antibiotic treatment
"Composite efficacy criterion of the following: 1. Survival at day 90 2. Bacteriologic success at day 5 3. Absence of relapse at day 90 4. Clinical success at day 90"
次要结局
- Bacteriological efficacy(day 3, day 5 and day 90)
- Clinical efficacy(day 7 and day 90)
- Occurrence C. difficile infection(day 90)
- Mortality(day 90)
- Bacteriologic relapse(day 5)
- Proportions of patients for whom consensual treatment duration is respected(day 90)
- Occurrence of any adverse event(at day 7 and up to 6 weeks)
- Occurrence of grade 3 or grade 4 adverse event(at day 7 and up to 6 weeks)
- Prevalence of BlaZ genes in S. aureus strains isolated from patients with MSSA bacteremia(at inclusion)
- Link between BlaZ typing and bacteriologic efficacy(day 5)
- MICs distribution of cefazolin and cloxacillin in S. aureus strains isolated from patients with MSSA bacteremia(at inclusion)
- Premature discontinuation of studied antibiotic therapy due to the occurrence of an adverse event(day 90)
- Emergence of antimicrobial resistance in the faecal microbiota(at day 7, up to 6 weeks and at day 90)
- Changes in relative abundance of each bacterial phylum(at day 7, up to 6 weeks and at day 90)
- Changes in bacterial diversity within the intestinal microbiota(at day 7, up to 6 weeks and at day 90)
- Total body clearance of cloxacillin and cefazolin in patients with MSSA bacteremia(at day 3)
- Total body volume of distribution of cloxacillin and cefazolin in patients with MSSA bacteremia(at day 3)
- Area under the plasma concentration versus time curve (AUC) of cloxacillin and cefazolin(at day 5)
- Peak Plasma Concentration (Cmax) of cloxacillin and cefazolin(at day 5)
- Minimal inhibitory concentration (MIC) of cloxacillin and cefazolin(at day 5)
- Residual concentration (Cres) of cloxacillin and cefazolin(at day 5)
- The proportion of time between 2 administration during which the plasma concentration of the antimicrobial is above the MIC (%T>MIC).(at day 5)