Azithromycin and cefixime combination versus azithromycin alone for the out-patient treatment of typhoid in South Asia; a randomised controlled trial

伤寒的特征是发烧和腹部症状。全球每年有1400多万儿童和成人受到影响。这些患者中有100万至200万人可能进展为严重和危及生命的并发症，包括肠出血、肠穿孔（穿孔）伴周围炎症（腹膜炎）以及嗜睡和昏迷综合征（脑病）。多达1%的伤寒患者可能死于这种疾病。伤寒病可在2-3周后复发，导致长期健康不佳，给家庭造成灾难性的经济损失，给卫生系统和社会造成负担。南亚是世界上最大的伤寒中心，每年的疾病负担估计为700万。有效的抗菌治疗可在4至6天内解决患者的疾病，并降低进展为危及生命的并发症的风险。如果在疾病早期开始，可以在门诊环境中给予7至10天的单次口服抗生素治疗，而不需要昂贵的住院治疗。在过去的20年中，氟喹诺酮类药物，如环丙沙星，已被成功使用。然而，在亚洲和撒哈拉以南非洲，引起伤寒的细菌中的抗菌素耐药性现已变得普遍。在南亚，伤寒对环丙沙星的耐药性很普遍。耐药性限制了有效抗菌药物的选择，并增加了患者患严重疾病的风险。由于这些问题，沙门氏菌最近被列入世卫组织优先病原体清单的“优先2：高”。一些专家呼吁在伤寒中使用抗菌药物组合，以提高治疗效果并减轻耐药性问题。这一建议没有得到高质量证据的支持。目前世界卫生组织推荐的标准治疗方案是口服阿奇霉素7天疗程。来自小型研究的新证据表明，阿奇霉素和头孢克肟联合使用可能比单独使用阿奇霉素获得更好的治愈效果。ACT-南亚研究旨在回答阿奇霉素和头孢克肟联合用药在门诊治疗无并发症伤寒中是否比阿奇霉素单药更有效的问题。在这项试验中，我们将在孟加拉国、印度、尼泊尔和巴基斯坦的伤寒流行地区的四个地点招募1500名患者。我们将在单药组中使用安慰剂（糖丸）代替头孢克肟，这样患者和研究团队都不知道哪个患者接受了哪种治疗。我们的目的是评估在完成一周的治疗时，以及在治疗开始后1个月和3个月的随访时，联合方案的治疗结果是否更好。这两种抗菌药物都被广泛使用，具有良好的安全性，但我们将仔细监测副作用。我们还将调查对家庭和卫生系统的财务影响。最近在巴基斯坦出现和传播的一种特别具有抗药性的伤寒菌株使这一问题更加紧迫。如果联合治疗优于单一抗生素治疗，则四个国家参与研究将使南亚和其他伤寒流行地区的结果普遍化。考虑到该地区伤寒的高负担，即使是治疗成功的微小改善也将转化为许多个人和家庭以及整个卫生系统的利益。例如，在南亚，700万伤寒患者的治疗失败率从15%（单独使用阿奇霉素）减少到10%，这意味着至少350，000名患者将经历更快的治愈，更少的住院，更少的经济影响。

Typhoid fever is characterized by fever and abdominal symptoms. It affects more than 14 million children and adults globally each year. Between one and two million of these patients may progress to severe and life-threatening complications including intestinal bleeding, intestinal puncture (perforation) with surrounding inflammation (peritonitis) and a syndrome of somnolence and coma (encephalopathy). Up to 1% of patients who get typhoid may die of the disease. A typhoid illness can be followed by a relapse 2-3 weeks later and lead to a prolonged period of ill health and catastrophic financial cost to the family with a resulting burden on the health system and society. In South Asia, which is the largest typhoid hub in the world, the annual burden of disease is estimated at seven million. Effective antimicrobial treatment leads to a resolution of the patient illness in 4 to 6 days and reduces risk of progression to life-threatening complications. If started early in the disease a 7 to 10-day course of treatment with a single oral antimicrobial treatment can be given in an out-patient setting without the need for expensive hospitalization. In the last 20 years fluoroquinolones, such as ciprofloxacin, have been successfully used. However antimicrobial resistance in the bacteria that cause typhoid fever has now become common in Asia and sub-Saharan Africa. In South Asia resistance to ciprofloxacin in typhoid is widespread. Resistance limits the choice of effective antimicrobials and increases the risk of patients developing severe disease. Because of these concerns Salmonella has been recently listed in the 'Priority 2: HIGH on the WHO Priority Pathogens List. A number of experts have called for the use of antimicrobial combinations in typhoid fever to improve the efficacy of treatment and mitigate the problems of resistance. This suggestion is not backed up by good quality evidence. A current standard regimen, recommended by the World Health Organization, is a 7-day course of the oral antimicrobial azithromycin. Emerging evidence from small studies suggests that a combination of azithromycin and cefixime may achieve a better cure than azithromycin alone. The ACT-South Asia study aims to answer the question whether a combination of azithromycin and cefixime is more effective than azithromycin alone in the outpatient treatment of uncomplicated typhoid fever. In this trial we will recruit 1500 patients across four sites in typhoid-endemic areas of Bangladesh, India, Nepal and Pakistan. We will use a placebo (sugar pill) instead of cefixime in the single drug arm so that neither the patient nor the study team know which patient is receiving which treatment. Our aim is to assess whether treatment outcomes are better with the combination regime at completion of the one week of treatment and again at follow-up one and three months after treatment was started. Both of these antimicrobials are widely used and have an excellent safety profiles, but we will carefully monitor for side effects. We will additionally investigate the financial implications for families and the health system. The recent emergence and spread of a particularly resistant typhoid strain in Pakistan adds urgency to this question. If the combination treatment is better than the single antibiotic treatment, the involvement of four countries in the study will allow generalization of the results across South Asia and other typhoid endemic areas. Considering the high burden of typhoid fever in this region even small improvements in the treatment success will translate into a benefit for many individuals and families and the health system as a whole. For example, a reduction in treatment failures in the 7 million patients with typhoid fever in South Asia from 15 % (with azithromycin alone) to 10 % using the antimicrobial combination, will mean at least 350,000 patients will experience a faster cure, fewer hospital admissions with less financial impact.