Efficacy of Doxycycline in the Treatment of Syphilis.

CLINICAL THERAPEUTICS crossm Efficacy of Doxycycline in the Treatment of Syphilis Ting Dai,a Rui Qu,a Jinfen Liu,a Pingyu Zhou,b Qianqiu Wangc Department of Dermatology, Shanghai Xuhui Central Hospital, Shanghai, People's Republic of Chinaa; Department of STD Institute, Shanghai Skin Disease Hospital, Shanghai, People's Republic of Chinab; Department of Clinical Management, National Center for STD Control, Institute of Dermatology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, People's Republic of Chinac ABSTRACT Doxycycline is an alternative antibiotic drug for the treatment of syphilis, but data on its efficacy, especially data on its efficacy against late latent syphilis, are limited. A retrospective study was conducted to evaluate the effectiveness of doxycycline for the treatment of patients with different stages of syphilis. Patients who received doxycycline treatment between June 2011 and June 2014 were involved. The serological response to doxycycline was defined as either a negative toluidine red unheated serum test (TRUST) result or a ⱖ4-fold decrease in titer at 12 months following the treatment. Univariate and multivariate logistic regression analyses were performed to identify factors associated with the serological response. During the study period, a total of 163 syphilis patients were treated with doxycycline, and 118 patients completed doxycycline treatment and the 12-month follow-up. Among the 118 patients, the serological response rate at 12 months was 100.0% (7/7) in patients with primary syphilis, 96.9% (62/64) in patients with secondary syphilis, 91.3% (21/23) in patients with early latent syphilis, and 79.2% (19/24) in patients with late latent syphilis. The total serological response rates were 92.4% (109/118) for preprotocol (PP) patients and 66.9% (109/163) for all intention-to-treat (ITT) patients. In multivariate analysis, patients who serologically responded at 12 months following treatment were positively associated with a higher baseline TRUST titer and an earlier syphilis stage than nonresponders. Our study showed excellent treatment outcomes in patients with different stages of syphilis. Our data, along with those from other reports, support the usage of doxycycline as a good alternative therapeutic option in the treatment of syphilis. Received 27 May 2016 Returned for modification 17 July 2016 Accepted 5 October 2016 Accepted manuscript posted online 24 October 2016 Citation Dai T, Qu R, Liu J, Zhou P, Wang Q. 2017. Efficacy of doxycycline in the treatment of syphilis. Antimicrob Agents Chemother 61:e01092-16. https://doi.org/ 10.1128/AAC.01092-16. Copyright © 2016 American Society for Microbiology. All Rights Reserved. Address correspondence to Pingyu Zhou, , or Qianqiu Wang, . P.Z. and Q.W. contributed equally to this study. KEYWORDS syphilis, doxycycline, efficacy S yphilis is a serious infection that can cause acute cutaneous manifestations, chronic compromise of the cardiovascular and nervous systems, and serious effects on reproductive and neonatal health. Syphilis also increases the risk of human immunodeficiency virus (HIV) acquisition and transmission (1). The World Health Organization has estimated that 10 million new infections still occur each year (2). Syphilis therefore remains a worldwide public health problem. Without a vaccine, the efficient diagnosis and the efficient treatment of syphilis are essential for effective syphilis control. Both U.S. and European guidelines recommend parenterally administered penicillin G for the treatment of all stages of syphilis (3, 4). Although benzathine penicillin is the recommended first-line treatment for syphilis in China, it is not available in many hospitals in China. Doxycycline, tetracycline, and azithromycin were preferred alternative agents in patients allergic to penicillin, especially those who cannot tolerate intramuscular injections. The early success of azithromycin led to considerable enthusiasm (5–7). However, an increased number of azithromycin treatment failures associated with a 23S rRNA mutation for macrolide resistance has been reported from several areas in recent years (8–11). The rate of macrolide resistance is extremely high in China, January 2017 Volume 61 Issue 1 e01092-16 Antimicrobial Agents and Chemotherapy aac.asm.org 1 Dai et al. Antimicrobial Agents and Chemotherapy with the 23S rRNA A2058G mutation being present in 91.9% of the patients from a national survey (12). Azithromycin treatment failure was reported in Shanghai, China (13), and our previous study showed that the 23S rRNA A2058G mutation reported in Shanghai ranked as the most frequent mutation in China (14). Tetracycline can cause more gastrointestinal side effects and requires more frequent dosing than doxycycline (15). Therefore, doxycycline is endorsed as an alternative preferred therapy. Regimens of doxycycline of 100 mg orally twice daily for 14 days for early syphilis and 28 days for late syphilis have been used for many years. However, studies of doxycycline for the treatment of syphilis are rare, and their results are partly contradictory (16–21). Early case series reported a very high rate of response to doxycycline treatment, but in most studies the dose was different from the currently recommended dose (16, 17). Recent reports of studies that used the recommended doxycycline dose showed a much lower response rate (18, 21). Most of these reports about doxycycline were from small case series, and none of them included patients with the late stage of syphilis. The decreased use of macrolides could result in the increased use of tetracyclines or doxycycline. The potential for the development of additional tetracycline or doxycycline resistance due to selective pressure should be a cause for increased concern. To provide more convincing data about doxycycline treatment, we conducted a retrospective study to evaluate the response rates of patients with different stages of syphilis treated with the recommended dose of doxycycline; factors associated with the serological response were also assessed. RESULTS Study population. From June 2011 to June 2014, a total of 163 syphilis patients were treated with doxycycline. Of the 163 intention-to-treat (ITT) patients, 129 completed 6 months of follow-up and 118 completed 12 months of follow-up. The 118 patients who completed 12 months of follow-up were included in the study. Of the 45 patients lost to 12 months of follow-up, 19 did not attend any follow-up visits and were excluded from the study (Fig. 1). Of the 19 patients, 3 did not complete doxycycline treatment because of impaired liver function. Among the 118 preprotocol (PP) participants, the median age was 48.0 years (age range, 20 to 69 years), 67 (56.8%) were male, 7 (5.9%) were men who have sex with men (MSM), and 2 (1.7%) were HIV positive. More than half of the patients (n ⫽ 64, 54.2%) had secondary syphilis, 7 (5.9%) had primary syphilis, 23 (19.5%) had early latent syphi (...truncated)