MICA: Developing a rectal formulation of ceftriaxone for community-based management of neonatal sepsis in low- and middle-income countries

新生儿败血症（28天以下婴儿的危及生命的感染）是热带国家儿童可预防死亡的最大单一原因，在每年估计发生的240万例死亡中，有50多万例是由新生儿败血症造成的。大多数死亡发生在家中或附近。通过注射及时给予有效的抗生素可以挽救生命，但在农村热带地区通常是不可能的，因为那里的保健中心离家往往要几个小时的路程。需要替代策略来在社区层面提供有效的治疗。自2012年以来，我们一直致力于头孢曲松栓剂制剂的药物开发。头孢曲松是一种用于治疗严重感染的抗生素，包括脑膜炎，其优点是每天只需服用一次，因为它是一种长效药物。我们的目标是以低成本使有效的社区新生儿脓毒症治疗可行，从而及早广泛使用，以防止高负担的低收入和中等收入国家中相当大比例的新生儿死于脓毒症。我们已经开发了几种原型栓剂，我们准备将测试转移到人类身上。我们有一个工业合作伙伴（Orofino Pharmaceuticals），他们已经评估了我们的候选制剂的工业生产可行性，并降低了生产吸收促进剂的成本，该吸收促进剂将与制剂中的抗生素结合。在这项研究项目中，我们计划生产两种不同的栓剂，并首先评估它们在泰国健康成年人中的吸收情况。根据这项研究的吸收和安全性结果，我们将选择在婴儿中进行测试的主要配方。我们计划给60名因感染住院治疗的婴儿一剂栓剂，除了他们的常规治疗外，并评估栓剂中抗生素的吸收。如果头孢曲松通过这种途径被充分吸收并且耐受性良好，我们将在大型试验中评估这种制剂，以测量对死亡率的影响，长期目标是将治疗纳入全球治疗指南。这将为高负担的低收入和中等收入国家的广泛采用铺平道路。

Neonatal sepsis (life-threatening infection in infants aged below 28 days of age) is the single greatest cause of preventable death in children living in tropical countries, being responsible for more than half a million of the estimated 2.4 million deaths that occur each year. Most deaths occur at or near home. Prompt administration of effective antibiotics by injection is life saving, but is usually not possible in the rural tropics where health centres are frequently several hours' journey away from home. Alternative strategies are needed to deliver effective treatment at the community level.Since 2012 we have worked on the pharmaceutical development of a suppository formulation of ceftriaxone. Ceftriaxone is an antibiotic used to treat severe infections, including meningitis, which has the advantage of being dosed just once day because it is a long-acting medicine. Our goal is to make effective community-based neonatal sepsis treatment feasible at low cost, and therefore used early and widely enough to prevent a substantial proportion of neonatal deaths from sepsis in high-burden low- and middle-income countries. We have developed several prototype suppositories already and we are ready to move testing into humans. We have an industrial partner (Orofino Pharmaceuticals) who has evaluated our candidate formulations for feasibility for industrial production and has lowered the cost of producing the absorption enhancer that will be combined with the antibiotic in the formulation. In this research project we plan to manufacture two different suppositories and assess how well they are absorbed in healthy adults in Thailand first. Based on absorption and safety results from this study we will then select the leading formulation to be tested in babies. We plan to give 60 babies who are in hospital under treatment for an infection one dose of the suppository in addition to their usual treatment and evaluate the absorption of antibiotic in the suppository. If ceftriaxone is absorbed adequately by this route and is well-tolerated, we will assess this formulation in large trials to measure impact on mortality, with the longer term goal of including the treatment in global treatment guidelines. This would pave the way for widespread uptake in high burden low- and middle-income countries.