Azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a phase II randomised controlled trial.

IF 7 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL BMC Medicine Pub Date : 2024-11-06 DOI:10.1186/s12916-024-03712-5
Roisin Connon, Peter Olupot-Olupot, Arthur M A Pistorius, William Okiror, Tonny Ssenyondo, Rita Muhindo, Sophie Uyoga, Ayub Mpoya, Thomas N Williams, Diana M Gibb, A Sarah Walker, Rob Ter Heine, Elizabeth C George, Kathryn Maitland
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Abstract

Background: African children with severe malaria are at increased risk of non-typhoidal salmonellae co-infection. Broad-spectrum antibiotics are recommended by guidelines but the optimal class and dose have not been established. We investigated the optimal dose of oral dispersible azithromycin and whether simple clinical criteria and point-of-care biomarkers could target antibiotics to those at greatest risk of bacterial co-infection.

Methods: We conducted a phase I/II trial in Ugandan children with severe malaria comparing a 5-day course of azithromycin: 10, 15 and 20 mg/kg of azithromycin (prescribed by weight bands) spanning the dose-range effective for other salmonellae infection. We generated relevant pharmacokinetic (PK) data by sparse sampling during dosing intervals and investigated associations between azithromycin exposure and potential mechanisms (PK-pharmacodynamics) using change in C-reactive protein (CRP), a putative marker of sepsis, at 72 h (continuous) and microbiological cure (7-day) (binary), alone and as a composite with 7-day and 90-day survival. To assess whether clinical or biomarkers could identify those at risk of sepsis, a non-severe malaria control was concurrently enrolled.

Results: Between January 2020 and January 2022, 105 cases were randomised azithromycin doses: 35 to 10 mg/kg, 35 to 15 mg/kg and 35 to 20 mg/kg. Fifty non-severe malaria controls were concurrently enrolled. CRP reduced in all arms by 72 h with a mean reduction of 65.8 mg/L (95% CI 57.1, 74.5) in the 10 mg/kg arm, 64.8 mg/L (95% CI 56.5, 73.1; p = 0.87) in the 20 mg/kg arm and a smaller reduction 51.2 mg/L (95% CI 42.9, 59.5; p = 0.02) in the 15 mg/kg arm. Microbiological cure alone outcome was not analysed as only one pathogen was found among cases. Three events contributed to the composite outcome of 7-day survival and microbiological cure, with no events in the 15 mg/kg arm. The odds ratio comparing 20 vs 10 mg/kg was 0.50 (95% CI 0.04, 5.79); p = 0.58. Due to the low number of pathogens identified, it was not possible to identify better methods for targeting antibiotics including both the cases and controls.

Conclusions: We found no evidence for an association between systemic azithromycin exposure and reduction in CRP. Further work is needed to better identify children at highest risk from bacterial co-infection.

Trial registration: ISRCTN49726849 (registered on 27th October 2017).

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阿奇霉素治疗非洲儿童严重疟疾细菌合并感染(TABS-PKPD):II 期随机对照试验。
背景:患有严重疟疾的非洲儿童合并感染非伤寒沙门氏菌的风险增加。指南推荐使用广谱抗生素,但最佳类别和剂量尚未确定。我们研究了口服分散型阿奇霉素的最佳剂量,以及简单的临床标准和护理点生物标志物是否能针对细菌合并感染风险最大的人群使用抗生素:我们在患有严重疟疾的乌干达儿童中开展了一项I/II期试验,比较了阿奇霉素的5天疗程:10、15和20毫克/千克阿奇霉素(按体重带处方),其剂量范围跨越了对其他沙门氏菌感染有效的剂量范围。我们在给药间隔期间通过稀疏取样生成了相关的药代动力学(PK)数据,并利用脓毒症的假定标志物 C 反应蛋白(CRP)在 72 小时内的变化(连续)和微生物治愈(7 天)(二元),研究了阿奇霉素暴露与潜在机制(PK-药效学)之间的关联,并将其与 7 天和 90 天存活率进行了综合。为了评估临床或生物标志物能否识别脓毒症高危人群,还同时招募了非重症疟疾对照组:结果:2020 年 1 月至 2022 年 1 月期间,105 例患者随机接受了阿奇霉素剂量治疗:结果:2020 年 1 月至 2022 年 1 月期间,105 例病例随机接受阿奇霉素剂量治疗:35 至 10 毫克/公斤、35 至 15 毫克/公斤和 35 至 20 毫克/公斤。同时还招募了50名非重症疟疾对照组患者。所有剂量组的 CRP 在 72 小时内均有所降低,10 毫克/公斤剂量组平均降低 65.8 毫克/升(95% CI 57.1,74.5),20 毫克/公斤剂量组平均降低 64.8 毫克/升(95% CI 56.5,73.1;p = 0.87),15 毫克/公斤剂量组平均降低 51.2 毫克/升(95% CI 42.9,59.5;p = 0.02)。由于病例中仅发现一种病原体,因此未对微生物治愈结果进行分析。在 7 天存活率和微生物治愈率的综合结果中,15 毫克/千克治疗组中没有发生三起事件。20 mg/kg 与 10 mg/kg 的几率比为 0.50(95% CI 0.04,5.79);P = 0.58。由于确定的病原体数量较少,因此无法确定更好的抗生素靶向方法,包括病例和对照组:我们没有发现证据表明系统性阿奇霉素暴露与 CRP 下降之间存在关联。需要进一步开展工作,以更好地识别细菌合并感染风险最高的儿童:ISRCTN49726849(2017年10月27日注册)。
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来源期刊
BMC Medicine
BMC Medicine 医学-医学:内科
CiteScore
13.10
自引率
1.10%
发文量
435
审稿时长
4-8 weeks
期刊介绍: BMC Medicine is an open access, transparent peer-reviewed general medical journal. It is the flagship journal of the BMC series and publishes outstanding and influential research in various areas including clinical practice, translational medicine, medical and health advances, public health, global health, policy, and general topics of interest to the biomedical and sociomedical professional communities. In addition to research articles, the journal also publishes stimulating debates, reviews, unique forum articles, and concise tutorials. All articles published in BMC Medicine are included in various databases such as Biological Abstracts, BIOSIS, CAS, Citebase, Current contents, DOAJ, Embase, MEDLINE, PubMed, Science Citation Index Expanded, OAIster, SCImago, Scopus, SOCOLAR, and Zetoc.
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