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

据估计，2013年，严重的疟疾导致47.5万名非洲儿童死亡。大多数医院现在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人中就有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的儿童。一些严重疟疾感染的儿童也有更高的机会同时感染细菌。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(到1/4的几率)。在非洲儿童中，大约三分之一的严重疟疾死亡被认为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，从而找出哪些儿童真的患有这些细菌感染。所以有两种选择：没有人服用抗生素，或者每个人都服用抗生素。给所有这些儿童使用抗生素的问题是，他们中的大多数人并不需要它们，而对所有儿童使用抗生素可能会增加社区中出现耐药性的风险(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，剂量是多少，使用多长时间，没有达成一致。造成这些感染的主要细菌来自肠道，因为在严重疟疾时肠道变得“渗漏”，所以这些细菌可以进入血液。这些细菌经常对目前推荐的和普遍可用的抗菌药产生抗药性，或者没有得到治疗。现在需要的是检查一种可以通过口服给予的抗生素，这种抗生素有可能治疗最常见的感染原因，并找出给予(治疗感染)的正确剂量，以便进入下一步，这将是一项更大规模的试验，比较不同类型的抗生素，以改善短期和长期结果。我们计划对一种名为阿奇霉素的口服抗生素进行为期5天的3次剂量(10、15和20 mg/kg)的检查，以找到治愈105名患有严重疟疾的乌干达儿童感染的最佳剂量，这些儿童有最大的细菌合并感染风险。我们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阻止它对这些其他疾病起作用。此前的研究也表明，阿奇霉素可以帮助身体对抗感染，或许还有助于自身对抗疟疾。为了找出哪种剂量是正确的，我们将测量样本中阿奇霉素的水平，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。我们还想知道，我们是否可以识别患有严重疟疾的儿童，他们有风险或受到细菌感染，而那些没有受到细菌感染的儿童，未来可能会成为抗生素的目标。我们还将招募一小部分患有非严重疟疾住院的儿童(n=50)，以检查可以在患者床边进行的特殊血液测试结合临床症状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，以便我们能够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。使用这样的廉价测试将有助于非洲许多地区资源有限的医院，那里培养细菌的微生物服务很不发达，甚至根本不存在。

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.