Pharmocokinetics of azithromycin in severe malaria bacterial co-infection in African children

2013年，估计有47.5万非洲儿童死于严重疟疾。现在大多数医院都在使用快速有效的抗疟疾药物，但仍有大量儿童死亡（每10人中约有1人死亡）。为了减少这一数字，我们需要找到更好的方法来管理这些患病儿童。一些患有严重疟疾感染的儿童也有更高的机会同时感染由细菌引起的感染。这些细菌感染增加了患有严重疟疾的儿童在医院死亡的风险（至1 / 4的机会）。据认为，非洲儿童中大约三分之一的严重疟疾死亡是由这些细菌感染造成的。问题是，大多数非洲医院无法从血液中培养细菌，以确定哪些儿童确实患有这些细菌感染。所以有两种选择：没有人使用抗生素，或者每个人都使用抗生素。给所有这些儿童服用抗生素的问题是，他们中的大多数人并不需要抗生素，对所有儿童使用抗生素会增加社区耐药的风险（这意味着抗生素对真正需要它们的人不起作用）。对于患有严重疟疾的儿童应该使用哪种抗生素、使用多少剂量或使用多长时间，目前还没有达成一致意见。导致这些感染的主要细菌来自肠道，因为在严重的疟疾中，肠道变得“渗漏”，所以这些细菌可以进入血液。这些细菌通常对目前推荐的和普遍可用的抗菌素具有耐药性，或者无法治疗。现在需要的是研究一种可以口服的抗生素，这种抗生素有可能治疗最常见的感染原因，并找出（治疗感染）的正确剂量，以便进行下一步，这将是一个更大的试验，比较不同类型的抗生素，以改善短期和长期结果。我们计划研究连续5天口服阿奇霉素的3种剂量（10、15和20毫克/公斤），以找到治疗105名重症疟疾住院儿童感染的最佳剂量，这些儿童的细菌合并感染风险最大。我们之所以选择阿奇霉素，是因为它不常用于治疗其他感染，所以在许多患有严重疟疾的儿童中使用它，不应该阻止它对这些其他疾病的作用。先前的研究也表明，阿奇霉素可以帮助身体对抗感染，也许还有助于对抗疟疾。为了找出正确的剂量，我们将测量送到奈梅亨专业实验室的样品中的阿奇霉素水平，并将药理学数据与研究中儿童的临床和感染（微生物）结果进行比较，以便我们为未来的临床试验选择最佳和最安全的剂量。我们还想弄清楚我们是否可以识别出患有严重疟疾的儿童，他们有细菌感染的风险，而那些没有，这样抗生素就可以在未来成为目标。我们还将招募一小部分患有非严重疟疾的住院儿童（n=50），以检查可以在患者床边进行的结合临床症状的特殊血液检查是否可以预测哪些患有严重疟疾的儿童确实患有细菌感染和疟疾，因此需要抗生素。我们希望这样做，这样我们就可以在未来更好地针对真正需要的儿童使用抗生素，并减少我们使用的抗生素总量。这是为了阻止抗生素耐药性的传播。使用这种廉价的检测方法将有助于非洲许多地区资源有限的医院，在这些地区，培养细菌的微生物服务不发达或根本不存在。

Severe malaria killed an estimated 475,000 African children in 2013. Fast-acting effective antimalarial drugs are now used in most hospitals, but a large number of children still die (~1 in every 10). To reduce this number, we need to find better ways to manage these sick children. Some children with severe malaria infection also have a higher chance of also having infections caused by bacteria at the same time. These bacterial infections increase the risk of children with severe malaria dying in hospital even more (to ~1 in 4 chance). Around one-third of all severe malaria deaths in African children are thought to be due to these bacterial infections. The problem is that most African hospitals are not able to grow the bacteria from blood to work out which children really have these bacterial infections. So there are two options: no one gets antibiotics, or everyone gets antibiotics. The problem with giving all these children antibiotics is that most of them don't need them, and using antibiotics for all children can increase the risk of resistance in the community (meaning antibiotics stop working for people who really need them). There is no agreement on which antibiotics, at what dose or for how long, they should be used in children with severe malaria. The main bacteria responsible for these infections come from the gut, because the gut becomes 'leaky' in severe malaria so these bugs can cross over into the blood. These bacteria are frequently resistant to, or are not treated by, currently recommended and commonly available antimicrobials. What is needed now is to examine one of the antibiotics that can be given by mouth which has the potential to treat most common causes of infections and to find out what is the correct dose to give (to treat infections) in order to progress to the next step which will be a larger trial comparing different types of antibiotics to improve both short term and longer term outcomes. We plan to examine 3 doses (10, 15 and 20mg/kg) of an oral antibiotic called azithromycin given for 5 days to find the optimal dose for curing infection in 105 Uganda children hospitalized with severe malaria that have the greatest risk of bacterial co-infection. We have chosen azithromycin because it is not used commonly to treat other infections, so using it in many children with severe malaria should not stop it working for these other conditions. Previous studies have also suggested that azithromycin could help the body fight infections and maybe helpful itself against malaria. To find out which is the right dose we will measure the levels of azithromycin in samples sent to a specialist laboratory in Nijmegen and pharmacological data will be compared to the clinical and infection (microbiological) outcomes of the children in the study in order for us to select the optimal and safest dose for future clinical trials. We also want to find out whether we can identify children with severe malaria who are at risk or bacterial infection and those who are not so antibiotics could be targeted in future. We will also recruit a small number of children (n=50) hospitalised with non-severe malaria to examine whether special blood tests that could be done at the patient's bedside in combination with clinical signs could predict which children with severe malaria really have bacterial infections as well as malaria and so need antibiotics. We want to do this so that we can target antibiotics better in future to children who really need them, and reduce the total amount of antibiotics we use. This is to stop the spread of antibiotic resistance. Using cheap tests like this would help resource-limited hospitals across many parts of Africa where microbiological services to grow bacteria are poorly developed or non-existent.