Divala Titus H, Corbett Elizabeth L, Kandulu Chikondi, Moyo Brewster, MacPherson Peter, Nliwasa Marriott, French Neil, Sloan Derek J, Chiume Lingstone, Ndaferankhande Masiye John, Chilanga Sanderson, Majiga Sabina Tazirwa, Odland Jon Øyvind, Fielding Katherine L
Helse Nord TB Initiative, Kamuzu University of Health Sciences, Blantyre, Malawi; TB Centre, London School of Hygiene & Tropical Medicine, Bloomsbury, London, UK; Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi.
Helse Nord TB Initiative, Kamuzu University of Health Sciences, Blantyre, Malawi; TB Centre, London School of Hygiene & Tropical Medicine, Bloomsbury, London, UK; Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi.
Lancet Glob Health. 2023 Apr;11(4):e556-e565. doi: 10.1016/S2214-109X(23)00052-9.
Clinical practice and diagnostic algorithms often assume that tuberculosis can be ruled out in mycobacteriology-negative individuals whose symptoms improve with a trial-of-antibiotics. We aimed to investigate diagnostic performance, clinical benefit, and antimicrobial resistance using a randomised controlled trial.
In this three-arm, individually randomised, open-label, controlled trial, we enrolled Malawian adults (aged ≥18 years) attending primary care who reported being unwell for at least 14 days (including cough) with no immediate indication for hospitalisation at Limbe and Ndirande Health Centres in Blantyre. Participants were randomly allocated (1:1:1) to azithromycin (500 mg taken once per day for 3 days), amoxicillin (1 g taken three times per day for 5 days), or standard of care with no immediate antibiotics, stratified by study site. Sputum at enrolment and day 8 was tested for tuberculosis (microscopy, Xpert MTB/RIF, and culture). The primary efficacy outcome was day 8 specificity (percentage with symptom improvement among mycobacteriology-negative participants), and day 29 clinical outcome (death, hospitalisation, or missed tuberculosis diagnosis) among all randomised participants. This study is registered with ClinicalTrials.gov, NCT03545373.
Between Feb 25, 2019, and March 14, 2020, 5825 adults were screened and 1583 (mean age 36 years; 236 [14·9%] HIV positive) were randomly assigned to standard of care (530 participants), azithromycin (527 participants), or amoxicillin (526 participants) groups. Overall, 6·3% (100 of 1583 participants) had positive baseline sputum mycobacteriology. 310 (79·1%) of 392 patients receiving standard of care reported symptom improvement at day 8, compared with 340 (88·7%) of 383 patients receiving azithromycin (adjusted difference 8·6%, 95% CI 3·9-13·3%; p<0·0004) and 346 (89·4%) of 387 receiving amoxicillin (adjusted difference 8·8%, 4·0-13·6%; p=0·0003). The proportion of participants with day 29 composite clinical outcomes was similar between groups (standard of care 1% [7 of 530 participants], azithromycin 1% [6 of 527 participants], amoxicillin 2% [12 of 526 participants]).
Routine outpatient trial-of-antibiotics during tuberculosis investigations modestly improved diagnostic specificity for mycobacteriologically confirmed tuberculosis but had no appreciable effect on death, hospitalisation, and missed tuberculosis diagnosis. These results confirm the limited benefit of trial-of-antibiotics, presenting an opportunity for discontinuation of trial-of-antibiotics and improved antimicrobial stewardship during tuberculosis screening, without affecting clinical outcomes.
Northern Norway Regional Health Authority (Helse Nord RHF), Commonwealth Scholarship Commission in the UK, Wellcome Trust, UK Medical Research Council, and the UK Department for International Development.
临床实践和诊断算法通常认为，对于那些在进行抗生素试验性治疗后症状有所改善的分枝杆菌学检查呈阴性的个体，可以排除结核病。我们旨在通过一项随机对照试验来研究其诊断性能、临床获益及抗菌药物耐药性。
在这项三臂、个体随机、开放标签的对照试验中，我们纳入了马拉维年龄≥18岁的成年人，这些人在布兰太尔的林贝和恩迪兰德健康中心接受初级保健，自述不适至少14天（包括咳嗽），且无立即住院指征。参与者按研究地点分层，随机分配（1:1:1）至阿奇霉素组（500mg，每日服用1次，共3天）、阿莫西林组（1g，每日服用3次，共5天）或不立即使用抗生素的标准治疗组。在入组时和第8天采集痰液进行结核病检测（显微镜检查、Xpert MTB/RIF检测和培养）。主要疗效指标为第8天的特异性（分枝杆菌学检查阴性参与者中症状改善的百分比）以及所有随机分组参与者中第29天的临床结局（死亡、住院或漏诊结核病）。本研究已在ClinicalTrials.gov注册，注册号为NCT03545373。
2019年2月25日至2020年3月14日期间，共筛查了5825名成年人，1583人（平均年龄36岁；236人[14.9%]HIV阳性）被随机分配至标准治疗组（530名参与者）、阿奇霉素组（527名参与者）或阿莫西林组（526名参与者）。总体而言，6.3%（1583名参与者中的100人）基线痰液分枝杆菌学检查呈阳性。接受标准治疗的392名患者中，310人（79.1%）在第8天报告症状改善，接受阿奇霉素治疗的383名患者中有340人（88.7%）症状改善（校正差异8.6%，95%CI 3.9 - 13.3%；p<0.0004），接受阿莫西林治疗的387名患者中有346人（89.4%）症状改善（校正差异8.8%，4.0 - 13.6%；p = 0.0003）。各组第29天综合临床结局的参与者比例相似（标准治疗组1%[530名参与者中的7人]，阿奇霉素组1%[527名参与者中的6人]，阿莫西林组2%[526名参与者中的12人]）。
在结核病调查期间进行常规门诊抗生素试验性治疗可适度提高分枝杆菌学确诊结核病的诊断特异性，但对死亡、住院和漏诊结核病无明显影响。这些结果证实了抗生素试验性治疗的益处有限，为在结核病筛查期间停用抗生素试验性治疗及改善抗菌药物管理提供了机会，且不影响临床结局。
挪威北部地区卫生局（Helse Nord RHF）、英国英联邦奖学金委员会、惠康信托基金会、英国医学研究理事会以及英国国际发展部。
