Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
Myanmar-Oxford Clinical Research Unit, Yangon, Myanmar; Medical Action Myanmar, Yangon, Myanmar.
Lancet Glob Health. 2019 Jan;7(1):e119-e131. doi: 10.1016/S2214-109X(18)30444-3.
In southeast Asia, antibiotic prescription in febrile patients attending primary care is common, and a probable contributor to the high burden of antimicrobial resistance. The objective of this trial was to explore whether C-reactive protein (CRP) testing at point of care could rationalise antibiotic prescription in primary care, comparing two proposed thresholds to classify CRP concentrations as low or high to guide antibiotic treatment.
We did a multicentre, open-label, randomised, controlled trial in participants aged at least 1 year with a documented fever or a chief complaint of fever (regardless of previous antibiotic intake and comorbidities other than malignancies) recruited from six public primary care units in Thailand and three primary care clinics and one outpatient department in Myanmar. Individuals were randomly assigned using a computer-based randomisation system at a ratio of 1:1:1 to either the control group or one of two CRP testing groups, which used thresholds of 20 mg/L (group A) or 40 mg/L CRP (group B) to guide antibiotic prescription. Health-care providers were masked to allocation between the two intervention groups but not to the control group. The primary outcome was the prescription of any antibiotic from day 0 to day 5 and the proportion of patients who were prescribed an antibiotic when CRP concentrations were above and below the 20 mg/L or 40 mg/L thresholds. The primary outcome was analysed in the intention-to-treat and per-protocol populations. The trial is registered with ClinicalTrials.gov, number NCT02758821, and is now completed.
Between June 8, 2016, and Aug 25, 2017, we recruited 2410 patients, of whom 803 patients were randomly assigned to CRP group A, 800 to CRP group B, and 807 to the control group. 598 patients in CRP group A, 593 in CRP group B, and 767 in the control group had follow-up data for both day 5 and day 14 and had been prescribed antibiotics (or not) in accordance with test results (per-protocol population). During the trial, 318 (39%) of 807 patients in the control group were prescribed an antibiotic by day 5, compared with 290 (36%) of 803 patients in CRP group A and 275 (34%) of 800 in CRP group B. The adjusted odds ratio (aOR) of 0·80 (95% CI 0·65-0·98) and risk difference of -5·0 percentage points (95% CI -9·7 to -0·3) between group B and the control group were significant, although lower than anticipated, whereas the reduction in prescribing in group A compared with the control group was not significant (aOR 0·86 [0·70-1·06]; risk difference -3·3 percentage points [-8·0 to 1·4]). Patients with high CRP concentrations in both intervention groups were more likely to be prescribed an antibiotic than in the control group (CRP ≥20 mg/L: group A vs control group, p<0·0001; CRP ≥40 mg/L: group B vs control group, p<0·0001), and those with low CRP concentrations were more likely to have an antibiotic withheld (CRP <20 mg/L: group A vs control group, p<0·0001; CRP <40 mg/L: group B vs control group, p<0·0001). 24 serious adverse events were recorded, consisting of 23 hospital admissions and one death, which occurred in CRP group A. Only one serious adverse event was thought to be possibly related to the study (a hospital admission in CRP group A).
In febrile patients attending primary care, testing for CRP at point of care with a threshold of 40 mg/L resulted in a modest but significant reduction in antibiotic prescribing, with patients with high CRP being more likely to be prescribed an antibiotic, and no evidence of a difference in clinical outcomes. This study extends the evidence base from lower-income settings supporting the use of CRP tests to rationalise antibiotic use in primary care patients with an acute febrile illness. A key limitation of this study is the individual rather than cluster randomised study design which might have resulted in contamination between the study groups, reducing the effect size of the intervention.
Wellcome Trust Institutional Strategic Support Fund grant (105605/Z/14/Z) and Foundation for Innovative New Diagnostics (FIND) funding from the Australian Government.
在东南亚，初级保健机构发热患者中抗生素处方很常见，这是导致抗菌药物耐药负担沉重的一个可能因素。本试验的目的是探讨在初级保健中使用即时检测的 C 反应蛋白（CRP）检测是否可以合理使用抗生素，比较两种分类 CRP 浓度的建议阈值，即低值或高值，以指导抗生素治疗。
我们在泰国的六个基层医疗单位和缅甸的三个基层医疗诊所和一个门诊部门进行了一项多中心、开放标签、随机、对照试验，纳入了至少 1 岁、有记录发热或主诉发热（无论之前是否使用过抗生素以及除恶性肿瘤以外的合并症）的参与者。使用基于计算机的随机系统，以 1:1:1 的比例将参与者随机分配到对照组或 CRP 检测组 1（CRP 检测组 A）或 CRP 检测组 2（CRP 检测组 B），组 A 和组 B 分别采用 20 mg/L 和 40 mg/L 的 CRP 阈值指导抗生素处方。卫生保健提供者对两组干预措施之间的分配情况不知情，但对对照组知情。主要结局是从第 0 天到第 5 天开具任何抗生素的处方情况，以及 CRP 浓度高于或低于 20 mg/L 或 40 mg/L 阈值时开具抗生素的患者比例。主要结局在意向治疗和符合方案人群中进行分析。该试验在 ClinicalTrials.gov 注册，编号为 NCT02758821，现已完成。
2016 年 6 月 8 日至 2017 年 8 月 25 日，我们招募了 2410 名患者，其中 803 名随机分配到 CRP 检测组 A，800 名随机分配到 CRP 检测组 B，807 名随机分配到对照组。CRP 检测组 A 中有 598 名、CRP 检测组 B 中有 593 名和对照组中有 767 名在第 5 天和第 14 天有随访数据，并根据检测结果（符合方案人群）开具了抗生素（或未开具）。在试验期间，对照组 807 名患者中有 318 名（39%）在第 5 天开具了抗生素，而 CRP 检测组 A 中有 803 名患者中的 290 名（36%）和 CRP 检测组 B 中有 800 名患者中的 275 名（34%）在第 5 天开具了抗生素。CRP 检测组 B 与对照组相比，调整后的优势比（aOR）为 0.80（95%CI 0.65-0.98），风险差异为-5.0%（95%CI-9.7 至-0.3），尽管低于预期，但 CRP 检测组 A 与对照组相比，开具抗生素的比例无显著差异（aOR 0.86[0.70-1.06]；风险差异-3.3%[-8.0 至 1.4]）。在两组干预组中，CRP 浓度较高的患者更有可能开具抗生素（CRP≥20 mg/L：组 A 与对照组相比，p<0.0001；CRP≥40 mg/L：组 B 与对照组相比，p<0.0001），而 CRP 浓度较低的患者更有可能不使用抗生素（CRP<20 mg/L：组 A 与对照组相比，p<0.0001；CRP<40 mg/L：组 B 与对照组相比，p<0.0001）。共记录了 24 例严重不良事件，包括 23 例住院和 1 例死亡，均发生在 CRP 检测组 A 中。只有 1 例严重不良事件被认为可能与研究有关（CRP 检测组 A 中 1 例住院）。
在初级保健机构发热的患者中，即时检测 CRP 并采用 40 mg/L 的阈值可以适度但显著减少抗生素的处方，CRP 较高的患者更有可能开具抗生素，且无证据表明临床结局存在差异。本研究扩展了来自低收入环境的证据，支持使用 CRP 检测来合理使用初级保健患者急性发热性疾病的抗生素。本研究的一个主要局限性是个体而非整群随机设计，这可能导致研究组之间存在交叉污染，从而降低干预措施的效果大小。
惠康信托机构战略支持基金（105605/Z/14/Z）和创新新诊断基金会（FIND）资助澳大利亚政府。
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