Early Intravenous to Oral Antibiotic Switch in Uncomplicated Staphylococcus Aureus Bacteraemia: The EVOS Randomized Controlled Trial
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 290
- 试验地点
- 12
- 主要终点
- Rate of SAB-relapse
研究概览
简要总结
The Early Intravenous to Oral Antibiotic Switch in Uncomplicated Staphylococcus aureus Bacteraemia (EVOS) study is a multicentre, randomized, open-label, parallel group, phase 3, non-inferiority trial of early intravenous to oral antibiotic switch in comparison with standard intravenous antibiotic regime among patients with uncomplicated Staphylococcus aureus bacteraemia (SAB). The study is based on the hypothesis that an early switch from IV to oral antimicrobial therapy is non-inferior and safe compared to conventional minimum 14-day course of IV therapy in patients with low-risk uncomplicated SAB.
详细描述
The study is conducted at 12 government tertiary hospitals with infectious diseases physicians in Malaysia. The study population comprises of 290 patients with uncomplicated SAB who have received 3 to 7 days of definitive IV antimicrobial therapy. Eligible participants are randomized 1:1 into 2 groups, early oral antibiotic switch versus standard IV antibiotic therapy, following the inclusion and exclusion criteria.
The study consists of 3 stages for each patient with a duration of approximately 12 weeks: screening and enrolment, open-label treatment with 7 to 11 days of study antibiotics, and follow-up until day 90 post-randomization. Phone call or inpatient follow up will be conducted at Day 7-11, Day 30, and Day 90 post- randomization to review patient's condition.
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
- •Blood culture positive for Staphylococcus aureus (S. aureus).
- •Received 3 to 7 days of definitive IV antimicrobial therapy, defined as:
- •Cloxacillin or cefazolin for methicillin-sensitive staphylococcus aureus (MSSA); Vancomycin or ceftaroline for methicillin-resistant staphylococcus aureus (MRSA).
- •Proven in-vitro susceptibility and adequate dosing given (as determined by the principal investigator).
- •Achieved clearance of bacteraemia, defined as at least one documented latest negative follow-up blood culture obtained within 72 hours after the initiation of definitive IV antimicrobial therapy.
- •Achieved defervescence, defined as sustained body temperature ≤37.5°C within 48 hours before randomization.
- •Able to provide written informed consent to participate trial.
排除标准
- •Evidence of metastatic infection of S. aureus: for example, infective endocarditis, intraabdominal abscess, lung empyema, and osteomyelitis. Radiological investigations such as chest X-ray, ultrasound, echocardiogram, and CT scan are not mandatory prior to enrolment, but should be done at the discretion of the treating physician if clinically indicated.
- •Septic shock, defined as hypotension requiring vasopressors to maintain MAP ≥65 mmHg despite adequate volume resuscitation.
- •Received more than 5 days of non-study antibiotics as empirical therapy prior to enrolment.
- •Polymicrobial bloodstream infection, defined as isolation of pathogens other than S. aureus from a blood culture obtained prior to randomization. Common skin contaminants such as coagulase-negative staphylococci, Bacillus spp., and diphtheroid will not be considered to represent polymicrobial infection.
- •Known history of S. aureus infection within the past 3 months.
- •Inability to tolerate oral therapy or poor absorption of oral medications, or not suitable for ongoing IV therapy (for example, difficult intravenous access)
- •No options of oral antibiotic available for patient due to:
- •In vitro resistance of S. aureus to all oral study drugs.
- •Known contraindications to receive the active oral study drugs. For example, hypersensitivity reaction to trimethoprim-sulfamethoxazole, thrombocytopenia secondary to linezolid etc.
- •Non-availability of oral study drugs at the study sites.
- •Patient is concomitantly receiving oral antibiotics which are active against S. aureus. For example, trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis.
- •Presence of a non-removable foreign body such as prosthetic heart valve, vascular graft, pacemaker, automated implantable cardioverter-defibrillator, ventriculoperitoneal shunt, prosthetic joint, and fracture fixation implant
- •Failure or inability to remove intravascular catheter that is present when first positive blood culture was drawn.
- •Known comorbidity that increased the risk of complicated infections:
- •End-stage renal disease
- •Severe liver disease (Child-Pugh class C)
- •Severe immunodeficiency:
- •HIV-positive patients with CD4<200 cells/uL or AIDS
- •primary immunodeficiency disorders
- •high-dose steroid therapy (>1 mg/kg prednisone or equivalent doses given for > 4 weeks or planned during intervention)
- •immunosuppressive therapy
- •neutropenia (<500 neutrophils/μl) at randomization or neutropenia expected during intervention phase due to immunosuppressive treatment
- •solid organ or hematopoietic stem cell transplantation within the past 6 months or planned during treatment period
- •13.Short life expectancy < 3 months
- •14.Pregnancy (for women of childbearing potential)
研究组 & 干预措施
Early Oral Switch Therapy (EOS)
Patients will switch from IV therapy to oral antibiotics for 7 to 11 days to achieve a total 14 days of definitive antimicrobial therapy for SAB.
First choice oral antibiotics for MSSA and MRSA: Tab. Trimethoprim-sulfamethoxazole (TMP 10mg/kg/day)
Alternative oral antibiotics for MSSA: Tab. Clindamycin 600mg TDS, Tab. Cephalexin 1gm QID, Tab Linezolid 600mg BD
Alternative oral antibiotics for MRSA: Tab. Linezolid 600mg BD
干预措施: Tab. Trimethoprim-sulfamethoxazole, Tab. Clindamycin, Tab. Cephalexin, or Tab. Linezolid (Drug)
Standard IV therapy (SIV)
Patients will continue with IV therapy for 7 to 11 days to achieve a total 14 days of definitive antimicrobial therapy for SAB.
First choice IV antibiotics for MSSA: IV Cloxacillin 2g every 4 or 6 hours
Alternative IV antibiotics for MSSA: IV Cefazolin 2g TDS
First choice IV antibiotics for MRSA: IV Vancomycin 15-20mg/kg BD
Alternative IV antibiotics for MRSA: IV Ceftaroline 600mg TDS
干预措施: IV Cloxacillin, IV Cefazolin, IV Vancomycin, or IV Ceftaroline (Drug)
结局指标
主要结局
Rate of SAB-relapse
时间窗: 90 days
defined as any new positive blood culture with S. aureus, and/or newly diagnosed metastatic S. aureus infection resulting from hematogenous dissemination
次要结局
- Number of days of hospitalization(90 days)
- Rate of complications related to IV therapy(90 days)
- Rate of Clostridium difficile diarrhoea(90 days)
- Rate of all-cause mortality(90 days)
- Rate of adverse events(30 days)
研究者
Steven Lim Chee Loon
Infectious Diseases Physician
Ministry of Health, Malaysia