Hla Thel K, Osowicki Joshua, Marsh Julie A, Salman Sam, Page-Sharp Madhu, Yoo Okhee, Azzopardi Kristy, Morici Michael, Batty Kevin T, Barr Renae K, Enkel Stephanie L, Kado Joseph, Hatchuel Lara, Fulurija Alma, McCarthy James S, Snelling Thomas L, Steer Andrew C, Carapetis Jonathan, Manning Laurens
Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, Nedlands, WA, Australia; Medical School, University of Western Australia, Crawley, WA, Australia; Department of Infectious Diseases, Fiona Stanley Hospital, WA, Australia.
Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Infectious Diseases Unit, Department of General Medicine, The Royal Children's Hospital Melbourne, VIC, Australia.
Lancet Microbe. 2025 May;6(5):101038. doi: 10.1016/j.lanmic.2024.101038. Epub 2025 Mar 26.
The in-vivo plasma concentration of penicillin needed to prevent Streptococcus pyogenes pharyngitis, recurrent acute rheumatic fever, and progressive rheumatic heart disease is not known. We used a human challenge model to assess the minimum penicillin concentration required to prevent streptococcal pharyngitis.
In CHIPS, a randomised, double-blind, placebo-controlled, human challenge trial, healthy adult volunteers were randomly assigned by a computer-generated random sequence to target steady-state penicillin plasma concentrations (placebo, 3, 6, 9, 12, or 20 ng/mL). The study was a single-centre trial held in Perth, WA, Australia. Participants had to be healthy adults, aged 18-40 years, at low risk of complicated S pyogenes disease, and without high type-specific IgG antibodies against the emm75 S pyogenes challenge strain. Participants and staff involved in clinical care remained masked to treatment allocation for the duration of the study. Individualised 5-day continuous intravenous infusions of penicillin were commenced 12 h before direct pharyngeal application of the emm75 challenge strain. The primary endpoint was clinical pharyngitis. This trial is registered on the Australian New Zealand Clinical Trials Registry, ACTRN12621000751875, and is completed.
Between Aug 23, 2022, and July 31, 2023, 60 participants were randomly assigned (35 [58%] were female and 25 [42%] were male), with 57 included in the analysis. The clinical pharyngitis endpoint was met in eight (57%) of 14 in the placebo group, four (44%) of nine in the 3 ng/mL target steady-state penicillin plasma concentration group, four (44%) of nine in the 6 ng/mL group, none of eight in the 9 ng/mL group, none of eight in the 12 ng/mL group, and none of nine in the 20 ng/mL group. No severe or serious adverse events occurred. Using Bayesian concentration-response modelling, the minimum steady-state plasma concentration of penicillin for which 90% of participants would avoid clinical pharyngitis was 8·1 ng/mL (95% credible interval 6·1-10·9).
When steady-state penicillin concentrations are greater than 9 ng/mL, few people will develop experimental emm75 S pyogenes pharyngitis. These data will inform efforts to improve long-acting penicillin preparations and dosage regimens to prevent recurrent rheumatic fever and rheumatic heart disease.
The National Health and Medical Research Council of Australia.
预防化脓性链球菌性咽炎、复发性急性风湿热和进行性风湿性心脏病所需的青霉素体内血浆浓度尚不清楚。我们使用人体激发模型来评估预防链球菌性咽炎所需的最低青霉素浓度。
在CHIPS（一项随机、双盲、安慰剂对照的人体激发试验）中，健康成年志愿者通过计算机生成的随机序列被随机分配至目标稳态青霉素血浆浓度组（安慰剂组、3、6、9、12或20 ng/mL）。该研究是在澳大利亚西澳大利亚州珀斯进行的单中心试验。参与者必须是18至40岁的健康成年人，患复杂化脓性链球菌疾病风险较低，且不存在针对化脓性链球菌emm75激发菌株的高型特异性IgG抗体。参与临床护理的参与者和工作人员在研究期间对治疗分配情况保持盲态。在直接咽部应用emm75激发菌株前12小时开始进行为期5天的个体化青霉素持续静脉输注。主要终点是临床咽炎。该试验已在澳大利亚新西兰临床试验注册中心注册，注册号为ACTRN12621000751875，且已完成。
在2022年8月23日至2023年7月31日期间，60名参与者被随机分配（35名[58%]为女性，25名[42%]为男性），57名纳入分析。安慰剂组14名中有8名（57%）达到临床咽炎终点，3 ng/mL目标稳态青霉素血浆浓度组9名中有4名（44%），6 ng/mL组9名中有4名（44%），9 ng/mL组8名中无1名，12 ng/mL组8名中无1名，20 ng/mL组9名中无1名。未发生严重或重大不良事件。使用贝叶斯浓度-反应模型，90%的参与者可避免临床咽炎的最低稳态血浆青霉素浓度为8.1 ng/mL（95%可信区间6.1 - 10.9）。
当稳态青霉素浓度大于9 ng/mL时，很少有人会发生实验性emm75化脓性链球菌性咽炎。这些数据将为改进长效青霉素制剂和给药方案以预防复发性风湿热和风湿性心脏病的努力提供参考。
澳大利亚国家卫生与医学研究委员会。
