Functional Consequence of Macrolide Resistance Mutations in T. pallidum

梅毒螺旋体大环内酯类抗性突变的功能后果

• 批准号: 8094182
• 负责人: Sheila A. Lukehart
• 金额: $ 7.8万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8094182
• 关键词: Address; Affect; Africa South of the Sahara; Aftercare; Alleles; Allergic Reaction; Antibiotics; Antibodies; Area; Azithromycin; Back; Bacteria; Baltimore; Behavioral; Benzathine Penicillin; Centers for Disease Control and Prevention (U.S.); China; Clinical; Clinical assessments; Czech Republic; DNA; Data; Development; Disadvantaged; Dose; Early treatment; Effectiveness; Epidemic; Equipoise; Failure; Frequencies; Geographic Locations; Goals; Guidelines; Healed; Health; Heterosexuals; Human; Individual; Infection; Injection of therapeutic agent; Length; Lesion; Macrolide Antibiotics; Macrolide-resistance; Macrolides; Madagascar; Microscopic; Modeling; Mutation; Neuraxis; Oral; Organism; Oryctolagus cuniculus; Pain; Patients; Penicillins; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Physicians; Point Mutation; Prevalence; Principal Investigator; Publications; Publishing; Recombinant DNA; Recommendation; Reporting; Resistance; Risk; Sampling; San Francisco; Site; Syphilis; Testing; Treatment Efficacy; Treatment Failure; Treponema pallidum; Voice; Western Europe; Work; clinical practice; clinical research site; clinically relevant; disorder prevention; effective therapy; evidence base; experience; falls; healing; men who have sex with men; rRNA Genes; research study; resistance mutation; response; sound; standard care; translational study

DESCRIPTION (provided by applicant): For many years, a single-dose oral treatment for syphilis has been sought. Benzathine penicillin G, used to treat syphilis for the past 50 years, has many disadvantages, including pain at injection sites, the possibility of an allergic reaction, and the inability of this form of penicillin to achieve treponemacidal levels in the central nervous system (a common site for Treponema pallidum dissemination). Published studies using the rabbit syphilis model demonstrated the effectiveness of azithromycin, an oral azalide antibiotic related to macrolides, for treating syphilis caused by the Nichols strain of T. pallidum. In several human studies, a single 1 or 2 gram dose of azithromycin was effective for treatment of early syphilis. However, recent publications document high frequencies of mutation A2058G in the 23S rRNA genes of circulating T. pallidum strains. In other bacteria, this mutation is associated with macrolide resistance. The Street 14 strain of T. pallidum contains the A2058G mutation, and, in the rabbit syphilis model, is resistant to macrolide and related drugs, including azithromycin. Similarly, azithromycin treatment failure has been documented in patients infected with T. pallidum bacteria that contain the same mutation. Nonetheless, a recent publication has questioned the clinical relevance of these 23S rDNA mutations; similar views have been voiced in discussions related to the development of the new syphilis treatment guidelines by the Centers for Disease Control and Prevention. Rather than continuing to speculate, it is essential to conduct the experiments that will directly determine whether these and other mutations impact the clinical response to azithromycin therapy. Although one could argue that sufficient equipoise exists (or does not exist) to justify a trial of azithromycin for treatment of patients with syphilis whose infecting organism harbors a 23S rDNA mutation, it is unlikely to be conducted in a timeframe that can inform our current clinical practice. The well-established rabbit model of syphilis is ideal for addressing the issue. The goals of the proposed project are 1) to determine the prevalence of A2058G and A2059G point mutations in the 23s rRNA genes of T. pallidum in samples collected from patients in widely disparate geographic regions; 2) to sequence the full 23s rRNA genes (both alleles) in a subset of these samples to identify other mutations that might be associated with macrolide resistance; and 3) to test the correlation of the identified mutations with clinical failure of azithromycin treatment in the well-established rabbit model of syphilis. To effectively treat our patients with syphilis, clinicians urgently need to know whether T. pallidum 23S rDNA mutations confer risk for azithromycin treatment failure. The results of our work will provide an evidence base on which sound treatment recommendations can be made. PUBLIC HEALTH RELEVANCE: The proposed studies will 1) determine whether mutations in the bacterium that causes syphilis affect response to treatment with azithromycin and 2) determine how frequently bacteria containing these mutations are present in syphilis patients from several geographical regions. If these mutations are found to be common and are shown to cause treatment failure, physicians will be advised not to use azithromycin for treating patients with syphilis.

描述(申请人提供)：多年来，人们一直在寻求单剂口服治疗梅毒。过去50年来一直用于治疗梅毒的苄星青霉素G有许多缺点，包括注射部位疼痛，有可能发生过敏反应，以及这种形式的青霉素无法在中枢神经系统达到梅毒螺旋体的杀灭水平(梅毒螺旋体传播的常见部位)。已发表的使用兔梅毒模型的研究表明，阿奇霉素是一种与大环内酯类相关的口服氮杂环类抗生素，用于治疗由梅毒螺旋体Nichols菌株引起的梅毒。在几项人体研究中，单剂1或2克阿奇霉素对治疗早期梅毒有效。然而，最近的文献记录了梅毒螺旋体循环菌株23S rRNA基因A2058G的高频率突变。在其他细菌中，这种突变与大环内酯类耐药性有关。梅毒螺旋体的Street 14菌株含有A2058G突变，在兔梅毒模型中，它对大环内酯类药物和包括阿奇霉素在内的相关药物具有抗药性。同样，阿奇霉素治疗在感染了含有相同突变的梅毒螺旋体细菌的患者中也被证明是失败的。尽管如此，最近的一份出版物质疑了这些23S rDNA突变的临床相关性；在与疾病控制和预防中心制定新的梅毒治疗指南有关的讨论中，也表达了类似的观点。与其继续推测，重要的是进行实验，直接确定这些突变和其他突变是否会影响阿奇霉素治疗的临床反应。尽管人们可能会争辩说，存在(或不存在)足够的平衡来证明阿奇霉素用于治疗感染机体带有23S rDNA突变的梅毒患者的试验是合理的，但它不太可能在一个可以为我们目前的临床实践提供信息的时间框架内进行。建立良好的梅毒兔模型是解决这一问题的理想方法。拟议项目的目标是：1)确定梅毒螺旋体23S rRNA基因A2058G和A2059G点突变的流行率；2)在这些样本的一个子集中对完整的23S rRNA基因(两个等位基因)进行测序，以确定可能与大环内酯类耐药性有关的其他突变；以及3)在已建立的梅毒兔模型中，测试已识别的突变与阿奇霉素治疗临床失败的相关性。为了有效地治疗梅毒患者，临床医生迫切需要了解梅毒螺旋体23S rDNA突变是否会增加阿奇霉素治疗失败的风险。我们的工作结果将为提出合理的治疗建议提供证据基础。 与公共卫生相关：拟议的研究将1)确定导致梅毒的细菌的突变是否会影响阿奇霉素治疗的反应，2)确定含有这些突变的细菌在几个地理区域的梅毒患者中出现的频率。如果这些突变被发现是常见的，并被证明导致治疗失败，医生将被建议不要使用阿奇霉素来治疗梅毒患者。