EARLY ORAL SWITCH THERAPY IN LOW-RISK STAPHYLOCOCCUS AUREUS BLOODSTREAM INFECTION - SABATO
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 215
研究概览
简要总结
Abstract Background: Staphylococcus aureus bloodstream infection is treated with at least 14 days of intravenous antimicrobials. We assessed the efficacy and safety of an early switch to oral therapy in patients at low risk for complications related to S aureus bloodstream infection. Methods: In this international, open-label, randomised, controlled, non-inferiority trial done in 31 tertiary care hospitals in Germany, France, the Netherlands, and Spain, adult patients with low-risk S aureus bloodstream infection were randomly assigned after 5-7 days of intravenous antimicrobial therapy to oral antimicrobial therapy or to continue intravenous standard therapy. Randomisation was done via a central web-based system, using permuted blocks of varying length, and stratified by study centre. The main exclusion criteria were signs and symptoms of complicated S aureus bloodstream infection, non-removable foreign devices, and severe comorbidity. The composite primary endpoint was the occurrence of any complication related to S aureus bloodstream infection (relapsing S aureus bloodstream infection, deep-seated infection, and mortality attributable to infection) within 90 days, assessed in the intention-to-treat population by clinical assessors who were masked to treatment assignment. Adverse events were assessed in all participants who received at least one dose of study medication (safety population). Due to slow recruitment, the scientific advisory committee decided on Jan 15, 2018, to stop the trial after 215 participants were randomly assigned (planned sample size was 430 participants) and to convert the planned interim analysis into the final analysis. The decision was taken without knowledge of outcome data, at a time when 126 participants were enrolled. The new sample size accommodated a non-inferiority margin of 10%; to claim non-inferiority, the upper bound of the 95% CI for the treatment difference (stratified by centre) had to be below 10 percentage points. The trial is closed to recruitment and is registered with ClinicalTrials.gov (NCT01792804), the German Clinical trials register (DRKS00004741), and EudraCT (2013-000577-77). Findings: Of 5063 patients with S aureus bloodstream infection assessed for eligibility, 213 were randomly assigned to switch to oral therapy (n=108) or to continue intravenous therapy (n=105). Mean age was 63·5 (SD 17·2) years and 148 (69%) participants were male and 65 (31%) were female. In the oral switch group, 14 (13%) participants met the primary endpoint versus 13 (12%) in the intravenous group, with a treatment difference of 0·7 percentage points (95% CI -7·8 to 9·1; p=0·013). In the oral switch group, 36 (34%) of 107 participants in the safety population had at least one serious adverse event compared with 27 (26%) of 103 participants in the intravenous group (p=0·29). Interpretation: Oral switch antimicrobial therapy was non-inferior to intravenous standard therapy in participants with low-risk S aureus bloodstream infection. However, it is necessary to carefully assess patients for signs and symptoms of complicated S aureus bloodstream infection at the time of presentation and thereafter before considering early oral switch therapy. Funding: Deutsche Forschungsgemeinschaft. Translations: For the German, Spanish, French and Dutch translations of the abstract see Supplementary Materials section.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized controlled study
- 盲法
- Open (masking not used)
入排标准
- 年龄范围
- 18 Years 至 one（—）
- 性别
- All
入选标准
- •Age at least 18 years
- •Not legally incapacitated
- •Written informed consent from the trial subject has been obtained
- •Blood culture positive for S. aureus not considered to represent contamination
- •At least one negative follow-up blood culture obtained within 24-96 hours after the start of adequate antimicrobial therapy to rule out persistent bacteremia and absence of a blood culture positive for S. aureus at the same time or thereafter.
- •Five to seven full days of appropriate i.v. antimicrobial therapy administered prior to randomization documented in the patient chart. Appropriate therapy has all of the following characteristics:
- •oAntimicrobial therapy has to be initiated within 72h after the first positive blood culture was drawn.
- •oProvided in-vitro susceptibility and adequate dosing (as judged by the principle investigator) preferred agents for pre-randomization antimicrobial therapy are: flucloxacillin, cloxacillin, vancomycin, and daptomycin. However, the following parenteral antimicrobials are allowed:
- •oMSSA: penicillinase-resistant penicillins (e.g. flucloxacillin, cloxacillin), ß-lactam plus ß-lactamase-inhibitors (e.g. ampicillin+sulbactam, piperacillin+tazobactam), cephalosporins (except ceftazidime), carbapenems, clindamycin, fluoroquinolones, trimethoprim-sulfamethoxazole, doxycycline, tigecycline, vancomycin, teicoplanin, telavancin, linezolid, daptomycin, ceftaroline, ceftobiprole, and macrolides.
- •oMRSA: vancomycin, teicoplanin, telavancin, fluoroquinolones, clindamycin, trimethoprim-sulfamethoxazole, doxycycline, tigecycline, linezolid, daptomycin, macrolides, ceftaroline, and ceftobiprole.
排除标准
- •Polymicrobial bloodstream infection, defined as isolation of pathogens other than S. aureus from a blood culture obtained in the time from two days prior to the first positive blood culture with S. aureus until randomization. Common skin contaminants (coagulase-negative staphylococci, diphteroids, Bacillus spp., and Propionibacterium spp.) detected in one of several blood cultures will not be considered to represent polymicrobial infection
- •Recent history (within 3 months) of prior S. aureus bloodstream infection
- •In vitro resistance of S. aureus to all oral or all i.v. study drugs
- •Contraindications in reference document for all oral or all i.v. study drugs
- •Previously planned treatment with active drug against S. aureus during intervention phase (e.g. cotrimoxazol prohylaxis)
- •Signs and symptoms of complicated SAB as judged by an ID physician. Complicated infection is defined as at least one of the following:
- •odeep-seated focus: e.g. endocarditis, pneumonia, undrained abscess, empyema, and osteomyelitis
- •oseptic shock, as defined by the AACP criteria (23), within 4 days before randomization
- •oprolonged bacteremia: positive follow-up blood culture more than 72h after the start of adequate antimicrobial therapy
- •obody temperature >38 °C on two separate days within 48h before randomization
- •Presence of the following non-removable foreign bodies (if not removed 2 days or more before randomization):
- •oprosthetic heart valve
- •odeep-seated vascular graft with foreign material (e.g. PTFE or dacron graft). Hemodialysis shunts are not considered deep-seated vascular grafts (s. below).
- •oventriculo-atrial shunt
- •Presence of a prosthetic joint (if not removed 2 days or more before randomization). This is not an exclusion criterion, if all of the following conditions are fulfilled:
- •oprosthetic joint was implanted at least 6 months prior, and
- •ocatheter-related infection, skin and soft tissue infection, or surgical wound infection is present (as defined below), and
- •ojoint infection unlikely (no clinical or imaging signs)
- •Presence of a pacemaker or an automated implantable cardioverter defibrillator (AICD) device (if not removed 2 days or more before randomization). This is not an exclusion criterion, if all of the following conditions are fulfilled: o pacemaker or AICD was implanted at least 6 months prior, and
- •ocatheter-related infection, skin and soft tissue infection, or surgical wound infection is present (as defined below), and
- •ono clinical signs of infective endocarditis, and
- •oinfective endocarditis unlikely by echocardiography (preferably TEE), and
- •opocket infection unlikely (no clinical or imaging signs)
- •Failure to remove any intravascular catheter which was present when first positive blood culture was drawn within 4 days of the first positive blood culture
- •Severe liver disease. This is not an exclusion criterion, if the following condition is fulfilled: o catheter-related infection, skin and soft tissue infection, or surgical wound infection is present (as defined below)
- •End-stage renal disease. This is not an exclusion criterion, if all of the following conditions are fulfilled:
- •ocatheter-related infection, skin and soft tissue infection, or surgical wound infection is present (as defined below), and
- •ono clinical signs of infective endocarditis, and
- •oinfective endocarditis unlikely by echocardiography (preferably TEE), and
- •oin patients with a hemodialysis shunt with a non-removable foreign