Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA.
Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA.
EBioMedicine. 2021 Mar;65:103281. doi: 10.1016/j.ebiom.2021.103281. Epub 2021 Mar 12.
Penicillin G, the current standard treatment for syphilis, has important drawbacks, but virtually no preclinical or clinical studies have been performed to identify viable alternatives. We tested, both in vitro and in vivo, three marketed antibiotics with adequate pharmacological properties to treat syphilis.
We used an in vitro culturing system of T. pallidum to perform drug susceptibility testing and applied quantitative PCR targeting the tp0574 gene to measure bacterial growth. To confirm in vivo efficacy, fifteen rabbits were infected intradermally with T. pallidum at eight sites each and randomly allocated to an experimental treatment (linezolid, moxifloxacin, clofazimine) or a control arm (benzathine penicillin G [BPG], untreated). The primary outcome was treatment efficacy defined as the time to lesion healing measured from the date of treatment start. Secondary outcomes were absence of treponemes or treponemal mRNA in injection sites, absence of seroconversion, and cerebrospinal fluid (CSF) abnormalities and negative rabbit infectivity tests (RIT).
Linezolid showed in vitro bactericidal activity at concentrations of 0.5 µg/mL or higher. When administered orally to experimentally infected rabbits, it induced healing of early lesions at a time similar to BPG (hazard ratio 3.84; 95% CI 2.05-7.17; p < 0.0001 compared to untreated controls). In linezolid-treated animals, dark-field microscopy and qPCR assessment showed no presence of treponemes after day 3 post-treatment start, serologic test did not convert to positive, CSF had no abnormalities, and RIT was negative. Moxifloxacin and clofazimine failed to inhibit bacterial growth in vitro and could not cure the infection in the rabbit model.
Linezolid, a low-cost oxazolidinone, has in vitro and in vivo activity against T. pallidum, with efficacy similar to BPG in treating treponemal lesions in the animal model. Our findings warrant further research to assess the efficacy of linezolid as an alternative to penicillin G to treat syphilis in human clinical trials.
European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant agreement No. 850450).
青霉素 G 是目前治疗梅毒的标准治疗方法，但存在重要缺陷，但几乎没有进行过临床前或临床研究来确定可行的替代方法。我们在体外和体内测试了三种具有足够治疗梅毒药理学特性的市售抗生素。
我们使用梅毒螺旋体体外培养系统进行药物敏感性测试，并应用针对 tp0574 基因的定量 PCR 测量细菌生长。为了确认体内疗效，将 15 只兔在 8 个部位皮内感染梅毒螺旋体，随机分配到实验组（利奈唑胺、莫西沙星、氯法齐明）或对照组（苄星青霉素 G [BPG]、未治疗）。主要疗效终点定义为从治疗开始之日起测量皮损愈合所需的时间。次要终点是注射部位无密螺旋体或密螺旋体 mRNA，无血清学转换，脑脊液（CSF）异常和兔感染性试验（RIT）阴性。
利奈唑胺在浓度为 0.5 µg/mL 或更高时显示出体外杀菌活性。当口服给予实验感染的兔时，它诱导早期病变愈合的时间与 BPG 相似（危险比 3.84；95%CI 2.05-7.17；与未治疗的对照组相比，p <0.0001）。在利奈唑胺治疗的动物中，暗场显微镜和 qPCR 评估显示在治疗开始后第 3 天没有密螺旋体，血清学检测未转为阳性，CSF 无异常，RIT 为阴性。莫西沙星和氯法齐明不能抑制体外细菌生长，不能治愈兔模型中的感染。
利奈唑胺是一种低成本的恶唑烷酮，具有体外和体内抗梅毒螺旋体活性，在治疗动物模型中的密螺旋体病变方面与 BPG 疗效相当。我们的发现值得进一步研究，以评估利奈唑胺作为青霉素 G 替代治疗人类梅毒的临床试验的疗效。
欧洲研究理事会（ERC）根据欧盟地平线 2020 研究和创新计划（赠款协议号：850450）。
