Melbourne Sexual Health Centre, Alfred Health, Melbourne, VIC, Australia; Central Clinical School, Monash University, Melbourne, VIC, Australia.
Sydney Sexual Health Centre, Sydney Hospital, Sydney, NSW, Australia; School of Public Health and Community Medicine, University of New South Wales, Sydney, NSW, Australia.
Lancet Infect Dis. 2019 Aug;19(8):833-842. doi: 10.1016/S1473-3099(19)30116-1. Epub 2019 Jun 10.
Antibiotic-resistant gonorrhoea represents a global public health threat, and new therapies are needed. We aimed to compare the efficacy and safety of solithromycin, a fourth generation macrolide, with ceftriaxone plus azithromycin for the treatment of gonorrhoea.
We did an open-label, multicentre, non-inferiority trial of patients aged 15 years or older with uncomplicated untreated genital gonorrhoea at two sites in Australia and one site in the USA. Patients were randomly assigned (1:1) to receive single dose oral solithromycin 1000 mg or intramuscular ceftriaxone 500 mg plus oral azithromycin 1000 mg. Neisseria gonorrhoeae cultures were obtained at baseline and test of cure (day 7 ± 2). The primary outcome was the proportion of patients with eradication of genital N gonorrhoeae based on culture at test of cure, assessed in the microbiological intention-to-treat (mITT) population, which included all randomly assigned patients who received any dose of study drug and had a positive genital culture for N gonorrhoeae at baseline. Non-inferiority of solithromycin was to be concluded if the lower limit of the 95% CI for the between-group differences was greater than -10%. Safety was analysed in all patients who received any dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02210325.
Between Sept 3, 2014, and Aug 27, 2015, 262 patients were randomly assigned and 261 received treatment (130 in the solithromycin group and 131 in the ceftriaxone plus azithromycin group). In the mITT population, 99 (80%) of 123 patients in the solithromycin group and 109 (84%) of 129 patients in the ceftriaxone plus azithromycin group had N gonorrhoeae eradication at test of cure (difference -4·0%, 95% CI -13·6 to 5·5), thus solithromycin did not meet the criterion for non-inferiority at the prespecified -10% margin. The frequency of adverse events was higher in the solithromycin group than the ceftriaxone plus azithromycin group (69 [53%] of 130 patients vs 45 [34%] of 131 patients), the most common of which were diarrhoea (31 [24%] of 130 patients vs 20 [15%] of 131 patients), and nausea (27 [21%] of 130 patients vs 15 [11%] of 131 patients).
Solithromycin as a single 1000 mg dose is not a suitable alternative to ceftriaxone plus azithromycin as first-line treatment for gonorrhoea. If insufficient duration of solithromycin exposure at the infection site in a subset of individuals was the reason for treatment failures, this might be adequately addressed with dose adjustment. However, any further trials with longer dosing need to consider the potential risk of gastrointestinal effects and liver enzyme elevations.
Cempra Pharmaceuticals.
耐抗生素淋病球菌代表了一个全球性的公共卫生威胁，因此需要新的治疗方法。我们旨在比较第四代大环内酯类药物索利霉素与头孢曲松加阿奇霉素治疗淋病的疗效和安全性。
我们在澳大利亚的两个地点和美国的一个地点进行了一项开放标签、多中心、非劣效性试验，纳入了年龄在 15 岁及以上、未经治疗的单纯性生殖器淋病球菌感染的患者。患者被随机分配（1:1）接受单次口服索利霉素 1000mg 或肌肉注射头孢曲松 500mg 加口服阿奇霉素 1000mg。在基线和治疗后第 7 天（±2 天）时获得淋病奈瑟菌培养物。主要结局是根据治疗后第 7 天的培养结果，在微生物学意向治疗（mITT）人群中评估患者生殖器淋病奈瑟菌清除的比例，mITT 人群包括所有接受任何剂量研究药物且基线时生殖器淋病奈瑟菌培养阳性的随机分配患者。如果组间差异的 95%CI 下限大于-10%，则可得出索利霉素非劣效性的结论。所有接受任何剂量研究药物的患者均进行安全性分析。本试验在 ClinicalTrials.gov 注册，编号为 NCT02210325。
2014 年 9 月 3 日至 2015 年 8 月 27 日，共有 262 名患者被随机分配，261 名患者接受了治疗（索利霉素组 130 名，头孢曲松加阿奇霉素组 131 名）。在 mITT 人群中，索利霉素组 123 名患者中有 99 名（80%）和头孢曲松加阿奇霉素组 129 名患者中有 109 名（84%）在治疗后第 7 天清除了淋病奈瑟菌（差异为-4.0%，95%CI-13.6 至 5.5%），因此索利霉素未达到预设的-10%差异的非劣效性标准。索利霉素组不良事件的发生率高于头孢曲松加阿奇霉素组（索利霉素组 130 名患者中有 69 名[53%]，头孢曲松加阿奇霉素组 131 名患者中有 45 名[34%]），最常见的是腹泻（索利霉素组 130 名患者中有 31 名[24%]，头孢曲松加阿奇霉素组 131 名患者中有 20 名[15%]）和恶心（索利霉素组 130 名患者中有 27 名[21%]，头孢曲松加阿奇霉素组 131 名患者中有 15 名[11%]）。
索利霉素作为单一 1000mg 剂量，不适合作为淋病的一线治疗药物替代头孢曲松加阿奇霉素。如果个体感染部位的索利霉素暴露时间不足是治疗失败的原因，那么通过调整剂量可能会得到充分解决。然而，任何进一步的、需要更长时间给药的试验都需要考虑胃肠道副作用和肝酶升高的潜在风险。
Cempra 制药公司。
