Faculty of Medicine, Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland.
Faculty of Medicine, Clinical Research Center, Geneva University Hospitals, Geneva, Switzerland.
JAMA. 2020 Jun 2;323(21):2160-2169. doi: 10.1001/jama.2020.6348.
Antibiotic overuse drives antibiotic resistance. Gram-negative bacteremia is a common infection that results in substantial antibiotic use.
To compare the clinical effectiveness of C-reactive protein (CRP)-guided, 7-day, and 14-day antibiotic durations 30, 60, and 90 days after treatment initiation.
DESIGN, SETTING, AND PARTICIPANTS: Multicenter, noninferiority, point-of-care randomized clinical trial including adults hospitalized with gram-negative bacteremia conducted in 3 Swiss tertiary care hospitals between April 2017 and May 2019, with follow-up until August 2019. Patients and physicians were blinded between randomization and antibiotic discontinuation. Adults (aged ≥18 years) were eligible for randomization on day 5 (±1 d) of microbiologically efficacious therapy for fermenting, gram-negative bacteria in blood culture(s) if they were afebrile for 24 hours without evidence for complicated infection (eg, abscess) or severe immunosuppression.
Randomization in a 1:1:1 ratio to an individualized CRP-guided antibiotic treatment duration (discontinuation once CRP declined by 75% from peak; n = 170), fixed 7-day treatment duration (n = 169), or fixed 14-day treatment duration (n = 165).
The primary outcome was the clinical failure rate at day 30, defined as the presence of at least 1 of the following, with a non-inferiority margin of 10%: recurrent bacteremia, local suppurative complication, distant complication (growth of the same organism causing the initial bacteremia), restarting gram-negative-directed antibiotic therapy due to clinical worsening suspected to be due to the initial organism, or death due to any cause. Secondary outcomes included the clinical failure rate on day 90 of follow-up.
Among 504 patients randomized (median [interquartile range] age, 79 [68-86] years; 306 of 503 [61%] were women), 493 (98%) completed 30-day follow-up and 448 (89%) completed 90-day follow-up. Median antibiotic duration in the CRP group was 7 (interquartile range, 6-10; range, 5-28) days; 34 of the 164 patients (21%) who completed the 30-day follow-up had protocol violations related to treatment assignment. The primary outcome occurred in 4 of 164 (2.4%) patients in the CRP group, 11 of 166 (6.6%) in the 7-day group, and 9 of 163 (5.5%) in the 14-day group (difference in CRP vs 14-day group, -3.1% [1-sided 97.5% CI, -∞ to 1.1]; P < .001; difference in 7-day vs 14-day group, 1.1% [1-sided 97.5% CI, -∞ to 6.3]; P < .001). By day 90, clinical failure occurred in 10 of 143 patients (7.0%) in the CRP group, 16 of 151 (10.6%) in the 7-day group, and 16 of 153 (10.5%) in the 14-day group.
Among adults with uncomplicated gram-negative bacteremia, 30-day rates of clinical failure for CRP-guided antibiotic treatment duration and fixed 7-day treatment were noninferior to fixed 14-day treatment. However, interpretation is limited by the large noninferiority margin compared with the low observed event rate, as well as low adherence and wide range of treatment durations in the CRP-guided group.
ClinicalTrials.gov Identifier: NCT03101072.
重要性：抗生素滥用导致抗生素耐药性。革兰氏阴性菌血症是一种常见的感染，会导致大量使用抗生素。
目的：比较 C 反应蛋白 (CRP) 指导的 7 天和 14 天抗生素疗程，在治疗开始后 30、60 和 90 天的临床疗效。
设计、地点和参与者：这是一项多中心、非劣效性、即时护理随机临床试验，纳入了 2017 年 4 月至 2019 年 5 月期间在瑞士 3 家三级护理医院住院的革兰氏阴性菌血症成人患者，随访至 2019 年 8 月。患者和医生在随机分组和抗生素停药之间处于盲态。如果发热消退 24 小时且无复杂感染（如脓肿）或严重免疫抑制的证据，在血液培养中发现发酵革兰氏阴性菌的微生物治疗第 5 天（±1 天）符合入组条件的成年患者（年龄≥18 岁）可随机分组至 CRP 指导的个体化抗生素治疗持续时间（一旦 CRP 从峰值下降 75%即停止；n=170）、固定 7 天治疗持续时间（n=169）或固定 14 天治疗持续时间（n=165）。
干预措施：随机分为 1:1:1 比例至 CRP 指导的个体化抗生素治疗持续时间（一旦 CRP 从峰值下降 75%即停止；n=170）、固定 7 天治疗持续时间（n=169）或固定 14 天治疗持续时间（n=165）。
主要结果和测量：主要结局为第 30 天的临床失败率，定义为以下至少 1 种情况：复发性菌血症、局部化脓性并发症、远处并发症（引起初始菌血症的同一病原体生长）、因怀疑为初始病原体引起的临床恶化而重新开始针对革兰氏阴性菌的抗生素治疗、或任何原因导致的死亡。次要结局包括第 90 天的临床失败率。
结果：在 504 例随机患者中（中位[四分位距]年龄，79[68-86]岁；306 例[61%]为女性），493 例（98%）完成了 30 天随访，448 例（89%）完成了 90 天随访。CRP 组的中位抗生素持续时间为 7 天（四分位距，6-10；范围，5-28）天；164 例完成 30 天随访的患者中，有 34 例（21%）存在与治疗分配相关的方案违反。CRP 组有 4 例（2.4%）、7 天组有 11 例（6.6%）、14 天组有 9 例（5.5%）患者发生主要结局（CRP 组与 14 天组差异，-3.1%[1 侧 97.5%CI，-∞ 至 1.1]；P<0.001；7 天组与 14 天组差异，1.1%[1 侧 97.5%CI，-∞ 至 6.3]；P<0.001）。第 90 天，CRP 组有 10 例（7.0%）、7 天组有 16 例（10.6%）、14 天组有 16 例（10.5%）患者发生临床失败。
结论：在无并发症的革兰氏阴性菌血症成人患者中，CRP 指导的抗生素治疗持续时间和固定 7 天治疗的 30 天临床失败率与固定 14 天治疗无差异。然而，与低观察到的事件率相比，较大的非劣效性边界以及 CRP 指导组中较低的依从性和广泛的治疗持续时间限制了其解释。
试验注册：ClinicalTrials.gov 标识符：NCT03101072。
