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（由申请人提供）：多年来，人们一直在寻找治疗梅毒的单剂量口服疗法。过去 50 年用于治疗梅毒的苯扎辛青霉素 G 有许多缺点，包括注射部位疼痛、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（梅毒螺旋体传播的常见部位）达到密螺旋体水平。已发表的使用兔梅毒模型的研究证明了阿奇霉素（一种与大环内酯类相关的口服氮杂内酯类抗生素）对于治疗由梅毒螺旋体尼科尔斯菌株引起的梅毒的有效性。在多项人体研究中，单次 1 或 2 克剂量的阿奇霉素可有效治疗早期梅毒。然而，最近的出版物记录了流行的梅毒螺旋体菌株的 23S rRNA 基因中存在高频率突变 A2058G。在其他细菌中，这种突变与大环内酯类耐药性相关。 Street 14 梅毒株含有 A2058G 突变，在兔梅毒模型中，对大环内酯类药物和相关药物（包括阿奇霉素）具有耐药性。同样，在感染含有相同突变的梅毒螺旋体细菌的患者中也有阿奇霉素治疗失败的记录。尽管如此，最近的一篇出版物质疑这些 23S rDNA 突变的临床相关性；在疾病控制和预防中心有关制定新梅毒治疗指南的讨论中也表达了类似的观点。 与其继续推测，有必要进行实验来直接确定这些突变和其他突变是否影响对阿奇霉素治疗的临床反应。尽管有人可能会争辩说，存在（或不存在）足够的平衡来证明阿奇霉素用于治疗感染生物体带有 23S rDNA 突变的梅毒患者的试验是合理的，但它不太可能在可以为我们当前的临床实践提供信息的时间范围内进行。完善的梅毒兔子模型是解决这个问题的理想选择。拟议项目的目标是 1) 确定从不同地理区域的患者收集的样本中梅毒螺旋体 23s rRNA 基因中 A2058G 和 A2059G 点突变的患病率； 2) 对这些样本的子集中的完整 23s rRNA 基因（均为等位基因）进行测序，以确定可能与大环内酯类耐药相关的其他突变； 3) 在成熟的兔梅毒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 突变是否会带来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。 公共健康相关性：拟议的研究将 1) 确定引起梅毒的细菌突变是否影响对阿奇霉素治疗的反应，2) 确定包含这些突变的细菌在多个地理区域的梅毒患者中出现的频率。如果发现这些突变很常见并且导致治疗失败，将建议医生不要使用阿奇霉素治疗梅毒患者。