对患有无并发症骨关节感染的儿童和青少年口服与静脉注射经验性抗生素的比较:在丹麦进行的一项全国性随机对照非劣效性试验

IF 19.9 1区 医学 Q1 PEDIATRICS Lancet Child & Adolescent Health Pub Date : 2024-07-15 DOI:10.1016/S2352-4642(24)00133-0
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引用次数: 0

摘要

背景骨与关节感染(BJIs)通常采用静脉注射抗生素的方式进行治疗,这种治疗方式既麻烦又昂贵。目前还没有随机对照研究对初始口服抗生素是否与静脉注射治疗同样有效进行比较。我们的目的是研究在患有无并发症 BJI 的儿童和青少年中,初始口服抗生素与初始静脉注射抗生素后再口服抗生素的疗效和安全性。方法从 2020 年 9 月 15 日到 2023 年 6 月 30 日,这项全国范围的随机、非劣效试验纳入了在丹麦 18 家儿科医院之一就诊的 3 个月到 17 岁 BJI 患者。排除标准包括严重感染(即脓毒性休克、需要急性手术或软组织严重受累)、假体材料、合并症、既往 BJI 或纳入前接受抗生素治疗超过 24 小时。根据 C 反应蛋白浓度(35 毫克/升与≥35 毫克/升)对患者进行分层随机分配(1:1),最初接受大剂量口服抗生素或静脉注射头孢曲松(每天 100 毫克/千克,一次剂量)。对于 5 岁以下的患者,大剂量口服抗生素为复方阿莫西林(每天 100 毫克/千克)和克拉维酸(每天 12-5 毫克/千克),分 3 次服用;对于 5 岁或以上的患者,大剂量口服抗生素为双氯西林(每天 200 毫克/千克),分 4 次服用。至少 3 天后,当临床症状改善且 C 反应蛋白下降时,两组患者均接受标准剂量的口服抗生素治疗。主要结果是对所有未因其他诊断(即非北京和睦家医院)而提前终止治疗并参加主要结果评估的随机患者进行盲法评估,评估北京和睦家医院患者6个月后的后遗症,定义为受影响骨或关节的任何非典型活动度或功能。6个月后后遗症的风险差异小于5%意味着口服治疗的非劣效性。安全性结果为严重并发症、开始使用抗生素后的手术需求以及随机人群中与治疗相关的不良事件。该试验已在ClinicalTrials.gov上注册,编号为NCT04563325.研究结果248名疑似BJI的儿童和青少年被随机分配到初始口服抗生素(人数=123)或初始静脉注射抗生素(人数=125)。在排除了没有BJI(54人)或撤回同意书(2人)的患者后,101名患者被随机分配到口服治疗,91名患者被随机分配到静脉注射治疗。10名患者未参加主要结果评估。6个月后,口服组98名BJI患者中无一人出现后遗症,静脉注射组84名BJI患者中无一人出现后遗症(风险差异为0,单侧97-5% CI为0-0至3-8,非劣效性=0-012)。随机分组后,口服组 123 名患者中有 12 人(9-8%)接受了手术,而静脉注射组 125 名患者中有 7 人(5-6%)接受了手术(风险差异为 4-2%,95% CI 为 -2-7 至 11-5)。我们没有观察到严重的并发症。在无并发症的儿童和青少年 BJI 患者中,初始口服抗生素治疗效果并不优于初始静脉注射抗生素后再进行口服治疗的效果。这项研究结果为无并发症BJI的口服治疗带来了希望,避免了静脉导管的使用,符合抗菌药物管理的原则。
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Oral versus intravenous empirical antibiotics in children and adolescents with uncomplicated bone and joint infections: a nationwide, randomised, controlled, non-inferiority trial in Denmark

Background

Bone and joint infections (BJIs) are treated with intravenous antibiotics, which are burdensome and costly. No randomised controlled studies have compared if initial oral antibiotics are as effective as intravenous therapy. We aimed to investigate the efficacy and safety of initial oral antibiotics compared with initial intravenous antibiotics followed by oral antibiotics in children and adolescents with uncomplicated BJIs.

Methods

From Sept 15, 2020, to June 30, 2023, this nationwide, randomised, non-inferiority trial included patients aged 3 months to 17 years with BJIs who presented to one of the 18 paediatric hospital departments in Denmark. Exclusion criteria were severe infection (ie, septic shock, the need for acute surgery, or substantial soft tissue involvement), prosthetic material, comorbidity, previous BJIs, or antibiotic therapy for longer than 24 h before inclusion. Patients were randomly assigned (1:1), stratified by C-reactive protein concentration (<35 mg/L vs ≥35 mg/L), to initially receive either high-dose oral antibiotics or intravenous ceftriaxone (100 mg/kg per day in one dose). High-dose oral antibiotics were coformulated amoxicillin (100 mg/kg per day) and clavulanic acid (12·5 mg/kg per day) in three doses for patients younger than 5 years or dicloxacillin (200 mg/kg per day) in four doses for patients aged 5 years or older. After a minimum of 3 days, and upon clinical improvement and decrease in C-reactive protein, patients in both groups received oral antibiotics in standard doses. The primary outcome was sequelae after 6 months in patients with BJIs, defined as any atypical mobility or function of the affected bone or joint, assessed blindly, in all randomised patients who were not terminated early due to an alternative diagnosis (ie, not BJI) and who attended the primary outcome assessment. A risk difference in sequelae after 6 months of less than 5% implied non-inferiority of the oral treatment. Safety outcomes were serious complications, the need for surgery after initiation of antibiotics, and treatment-related adverse events in the as-randomised population. This trial was registered with ClinicalTrials.gov, NCT04563325.

Findings

248 children and adolescents with suspected BJIs were randomly assigned to initial oral antibiotics (n=123) or initial intravenous antibiotics (n=125). After exclusion of patients without BJIs (n=54) or consent withdrawal (n=2), 101 patients randomised to oral treatment and 91 patients randomised to intravenous treatment were included. Ten patients did not attend the primary outcome evaluation. Sequelae after 6 months occurred in none of 98 patients with BJIs in the oral group and none of 84 patients with BJIs in the intravenous group (risk difference 0, one-sided 97·5% CI 0·0 to 3·8, pnon-inferiority=0·012). Surgery after randomisation was done in 12 (9·8%) of 123 patients in the oral group compared with seven (5·6%) of 125 patients in the intravenous group (risk difference 4·2%, 95% CI –2·7 to 11·5). We observed no serious complications. Rates of adverse events were similar across both treatment groups.

Interpretation

In children and adolescents with uncomplicated BJIs, initial oral antibiotic treatment was non-inferior to initial intravenous antibiotics followed by oral therapy. The results are promising for oral treatment of uncomplicated BJIs, precluding the need for intravenous catheters and aligning with the principles of antimicrobial stewardship.

Funding

Innovation Fund Denmark and Rigshospitalets Forskningsfond.

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来源期刊
Lancet Child & Adolescent Health
Lancet Child & Adolescent Health Psychology-Developmental and Educational Psychology
CiteScore
40.90
自引率
0.80%
发文量
381
期刊介绍: The Lancet Child & Adolescent Health, an independent journal with a global perspective and strong clinical focus, presents influential original research, authoritative reviews, and insightful opinion pieces to promote the health of children from fetal development through young adulthood. This journal invite submissions that will directly impact clinical practice or child health across the disciplines of general paediatrics, adolescent medicine, or child development, and across all paediatric subspecialties including (but not limited to) allergy and immunology, cardiology, critical care, endocrinology, fetal and neonatal medicine, gastroenterology, haematology, hepatology and nutrition, infectious diseases, neurology, oncology, psychiatry, respiratory medicine, and surgery. Content includes articles, reviews, viewpoints, clinical pictures, comments, and correspondence, along with series and commissions aimed at driving positive change in clinical practice and health policy in child and adolescent health.
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