Clinical Infectious Diseases

MAJOR ARTICLE

A Multicenter Study Evaluating Ceftriaxone and

Benzathine Penicillin G as Treatment Agents for Early
Syphilis in Jiangsu, China
Yuping Cao,1 Xiaohong Su,1 Qianqiu Wang,1 Huazhong Xue,1 Xiaofeng Zhu,1 Chuanfu Zhang,1 Juan Jiang,1 Shuzhen Qi,1 Xiangdong Gong,1 Xiaofang Zhu,2
Min Pan,2 Hong Ren,3 Wenlong Hu,3 Zhiping Wei,4 Meihua Tian,4 and Weida Liu1
1
Institute of Dermatology and Skin Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, 2Department of Dermatology, Northern Jiangsu People’s Hospital,
Yangzhou, 3Department of Dermatology, The First People’s Hospital of Lianyungang, and 4Department of Dermatology, Affiliated Hospital of Xuzhou Medical University, China

Background.  The aim of this study was to assess the efficacy of ceftriaxone and benzathine penicillin G (BPG) in nonpregnant,
immunocompetent adults with early syphilis because there is a lack of clinical evidence supporting ceftriaxone as an alternative
treatment for early syphilis without an human immunodeficiency virus coinfection.
Methods.  A randomized, open-label controlled study evaluating the efficacy of ceftriaxone and BPG was conducted in 4 hos-
pitals in Jiangsu Province. Treatment comprised either ceftriaxone (1.0 g, given intravenously, once daily for 10 days) or BPG (2.4
million units, given intramuscularly, once weekly for 2 weeks). A serological response was defined as a ≥4-fold decline in the rapid
plasma reagin (RPR) titer.
Results.  In all, 301 patients with early syphilis were enrolled in this study; 230 subjects completed the follow-ups. The serologi-
cal response at 6 months of follow up was observed in 90.2% in ceftriaxone group and 78.0% in BPG group (P = .01). There was no
significant difference between treatment groups in patients with primary or early latent syphilis, but among patients with secondary
syphilis the difference was highly significant (95.8% vs 76.2%; P < .01). Moreover, patients exhibiting a Jarisch-Herxheimer reaction
after treatment might have a shorter period before a serological response (P = .03).
Conclusions.  In this study, ceftriaxone regimen was noninferior to the BPG regimen in nonpregnant, immunocompetent
patients with early syphilis.
Keywords.  early syphilis; immunocompetent; ceftriaxone; penicillin.

Syphilis is a sexually transmitted disease caused by Treponema
pallidum [1]. In recent decades, syphilis-related morbid con-
ditions have dramatically increased in China and are becom-
ing both a burden and a threat to public health. The total
reported syphilis rate in China was 11.7/100 000 in 2009 [2] and
32.9/100 000 in 2013 [3]. This disease has challenged scientists
and clinicians since its first appearance in the late 1400s, and the
best practices for its management remain controversial.
Guidelines for defining and treating syphilis vary throughout
the world. In North American and European guidelines, a single
intramuscular administration of 2.4 million units (MU) of ben-
zathine penicillin G (BPG) is recommended for treating early
syphilis [4, 5]. In contrast, the recommended therapy for early
Received 11 February 2017; editorial decision 21 June 2017; accepted 14 July 2017.
Correspondence: X.  Su, Department of STD, Institute of Dermatology and Skin Hospital,
Chinese Academy of Medical Sciences and Peking Union Medical College, 12 Jiangwangmiao
Rd, Xuanwu District, Nanjing, Jiangsu, China 210042 (suxh@ncstdlc.org).
Clinical Infectious Diseases®  2017;XX(00):1–7
© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society
of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
DOI: 10.1093/cid/cix611
syphilis in China is 2.4 MU of BPG administered intramuscu-
larly once per week for 2 weeks [6]. BPG has been considered
the standard treatment for early syphilis since it was first used
for this indication in 1943 [7]. However, both shortage of BPG
worldwide and patients who are allergic to penicillin present a
major challenge [8]. Moreover, BPG is considered ineffective for
neurosyphilis treatment because it does not lead to detectable
levels of penicillin in the cerebrospinal fluid (CSF) [9].
There are many reasons that patients cannot use penicillin
to treat syphilis, so several alternative therapies were suggested,
including doxycycline and ceftriaxone. There were no standard-
ized criteria to choose alternative therapies. Several studies had
showed the effectiveness of doxycycline in treating early syph-
ilis, where retreatment rates are slightly higher in early syph-
ilis than with penicillin regimens [10]. The response rate was
63.4%–92.4% in early syphilis in several studies [11–13]. There
are circumstances under which doxycycline cannot be used,
notably in pregnancy.
As another alternative therapy for syphilis, ceftriaxone has
shown antitreponemal activity in animal models, is well tol-
erated, penetrates the central nervous system (CNS), and has
a long half-life that is suitable for once-daily dosing [14, 15].

Efficacy of Ceftriaxone for Syphilis  • CID 2017:XX (XX XXXX) • 1

Several studies have shown its effectiveness in treating neu-
rosyphilis and primary and secondary syphilis in special
populations, such as patients with human immunodefi-
ciency virus (HIV)–infected, pregnant patients and alco-
holic patients [14, 16, 17]. There is no report elucidating the
sensitivity of T. pallidum to ceftriaxone in China, but several
studies have evaluated the clinical efficacy of ceftriaxone for
treating syphilis at the small scale [18, 19]. However, there is a
lack of clinical evidence supporting ceftriaxone as an alterna-
tive treatment for early syphilis without an HIV coinfection.
Thus, more studies on its efficacy under these circumstances
are needed.
A randomized, open-label controlled study was designed to
compare 1.0 g of ceftriaxone administered intravenously daily
for 10 days and 2 doses of 2.4 MU of BPG administered intra-
muscularly at weekly intervals to treat nonpregnant, immuno-
competent patients with early syphilis.
MATERIALS AND METHODS
Study Population
HIV-negative, nonpregnant, adult patients with untreated
early syphilis were enrolled in the study. The disease stage
classification was considered early when the patient pres-
entation included the following features: (1) primary syph-
ilis: dark-field T.  pallidum–positive or rapid plasma reagin
(RPR)–positive test results confirmed by the T.  pallidum
particle agglutination (TPPA) test, positive genital ulcers or
chancres, and adenopathy near the primary infection site; (2)
secondary syphilis: RPR- and TPPA-positive test results and
classic palmar/plantar rash, condylomata lata, and mucocu-
taneous patches; and (3) early latent syphilis: seroreactivity
without other evidence of primary or secondary syphilis and
either negative syphilis serological results within the past
2  years or a recent sex partner with documented primary,
secondary, or early latent syphilis. Subjects were excluded
from the study if they had a positive skin-test reaction to the
penicillin or ceftriaxone antigen or a history of penicillin or
ceftriaxone allergy. The selection of BPG or ceftriaxone ther-
apy was randomized.
Study Protocol
Subjects were enrolled in 4 hospitals in Jiangsu Province,
including the Institute of Dermatology and Skin Hospital
of Chinese Academy of Medical Science, Northern Jiangsu
People’s Hospital, the First People’s Hospital of Lianyungang,
and the Affiliated Hospital of Xuzhou Medical University, from
November 2013 through November 2015. The study proto-
col and consent form have been approved by the institutional
review boards from all 4 hospitals. All patients provided written
consent to receive treatment and provide serum samples during
the follow-ups. All clinical data were collected by the physicians
managing the patients. The patients were randomly assigned
2 • CID 2017:XX (XX XXXX) •  Cao et al
to be treated with either ceftriaxone (1.0 g, given intravenously
once daily for 10 days) or BPG (2.4 MU, given intramuscularly
once weekly for 2 weeks). Serum RPR and TPPA results were
determined at baseline, at 14 days, and at 3, 6, 9, and 12 months
for all patients.
Study Design and Statistical Analysis
All follow-up biological results were collected for analysis.
A  serological response was defined as a ≥4-fold decline in
the initial serum RPR titer within 6  months of treatment [5].
Because 4-fold drop at 12 months was considered an adequate
serological response for early latent syphilis, mentioned in the
Canadian guidelines on sexually transmitted infections [20], a
≥4-fold decline in RPR titers at the 6- and 12-month follow-up
visits were set as primary and secondary end points, respec-
tively. Treatment failure was defined as a ≥4-fold increase in
the titer, and serofast was defined as a ≤2-fold titer decrease or
increase within 12 months after therapy [5].
We hypothesized that the ceftriaxone regimen was nonin-
ferior to BPG in nonpregnant, immunocompetent patients
with early syphilis. The noninferiority in terms of the serolog-
ical response rate after ceftriaxone therapy relative to that of
BPG therapy would be supported if the lower boundary of the
2-sided 95% confidence interval (1-sided α = –0.025; β = .10)
for the difference in the serological response rates between the
2 groups was at least –0.05 (that is, the noninferiority margin
was set to 5%).
Differences in categorical variables were compared using the
2
χ test. As continuous variables, changes in serum RPR titers,
which were used to define the serological responses, were com-
pared using the Mann-Whitney test. The median time to attain
a serological response in responsive patients was estimated
using the Kaplan-Meier method and compared using the log-
rank test. Cox regression analyses were used to assess the influ-
ence of age, sex, initial RPR titers, stage of early syphilis and
Jarisch-Herxheimer (J-H) reaction on serological response. The
J-H reaction is defined as an acute febrile reaction frequently
accompanied by headache, myalgia, fever, and other symptoms
that can occur within the first 24 hours after the initiation of any
therapy for syphilis [15]. Differences were considered statisti-
cally significant at P < .05 (2-sided). Data were analyzed using
SPSS, version 18.0 (SPSS).
RESULTS
Selection of Eligible Patients
A total of 340 patients with early syphilis were identified
between 2013 and 2015. Of these, 39 patients were excluded,
and the remaining 301 were enrolled in the study. The 39
excluded patients were treated with doxycycline. Of the
enrolled patients, 150 were treated with ceftriaxone, and 151
with BPG (Figure 1). Syphilis had been diagnosed for the first
time in all patients.
Figure 1.  Patient selection flow diagram. Abbreviations: BPG, benzathine penicillin G; RPR, rapid plasma reagin.

Deviations From the Protocol
Eleven patients (primary syphilis with chancres) in the 2 treat-
ment groups (7 in the ceftriaxone and 4 in the BPG group) had
negative baseline serum RPR titers, and 60 patients (31 in the
ceftriaxone and 29 in the BPG group) had no follow-up data.
The rates of patients without follow-up were 21.7% (31 of
143) and 19.7% (29 of 147) in the ceftriaxone and BPG groups,
respectively. There was no significant difference in the number
of patients lost to follow-up between the 2 treatment groups
(P = .68).
treatment arms rose as the time passed by. The serological
response was observed in 90.2% in the ceftriaxone and 78.0%
in the BPG group (P = .01) after 6 months of follow up, and
92.0% and 81.4%, respectively (P  =  .02), after 12  months.
There was no significant difference between treatment groups
in patients with primary or early latent syphilis (P  >  .05),
but among patients with secondary syphilis the difference
Table  1.  Baseline Characteristics of 230 Follow-up Patients With Early
Syphilis

Clinical and Serological Follow-Up Patients by Treatment Group, No. (%)

The main characteristics of the 230 subjects who completed fol- Characteristic Ceftriaxone (n = 112) BPG (n = 118) P Value
low-up visits are shown in Table  1. There were no significant Sex
differences between the 2 treatment groups in age, sex, initial  Male 48 (42.9) 59 (50.0) .30
RPR titers, or heterogeneity of early syphilis stages (P  >  .05).  Female 64 (57.1) 59 (50.0)
The median follow-up period was 9  months. There were no Age, y
 18–35 58 (51.8) 71 (60.2) .69
differences in the numbers of patients with each type of syphi-
 36–54 44 (39.3) 42 (35.6)
lis between the 2 treatment groups (P = .22). The probable J-H
 55–65 10 (8.9) 5 (4.2)
reaction rate was 41.1% in the ceftriaxone and 31.4% in BPG Sexual partners in past 3 mo, No.
group (P  =  .13). Skin lesions disappeared within a month of  ≤1 60 (53.6) 62 (52.5) .88
the treatments for all follow-up patients. No patients reported  ≥2 52 (46.4) 56 (47.5)
serious adverse events, and adverse effects related to study Current syphilis stage
 Primary 20 (17.9) 25 (21.2) .22
drugs, other than J-H reaction, were not observed. The use of
 Secondary 72 (64.2) 63 (53.4)
other antibiotics during the study follow-up period was not   Early latent 20 (17.9) 30 (25.4)
monitored. RPR titer
We assessed improvements in serum RPR titers by compar-  ≤1:8 30 (26.8) 28 (23.7) .59
ing the baseline values with those at the different follow-up  ≥1:16 82 (73.2) 90 (76.3)

times (Table  2). The rates of serological responses in both Abbreviations: BPG, benzathine penicillin G; RPR, rapid plasma reagin.

Efficacy of Ceftriaxone for Syphilis  • CID 2017:XX (XX XXXX) • 3

Table 2.  Serological Outcomes at Different Intervals After Treatment

Serological Responsea by Interval After Treatment, No. (%)

Treatment 14 d (n = 221) 3 mo (n = 225) 6 mo (n = 230) 9 mo (n = 230) 12 mo (n = 230)

Ceftriaxone 22/108 (20.3) 86/110 (78.2) 101/112 (90.2) 101/112 (90.2) 103/112 (92.0)
BPG 18/113 (15.9) 86/115 (74.8) 92/118 (78.0) 94/118 (79.7) 96/118 (81.4)

Abbreviations: BPG, benzathine penicillin G; n, number of patients with available serological results at each time point.
a
Serological response defined as ≥4-fold decline in rapid plasma reagin.

was highly significant (95.8% vs 76.2% at 6 months, P < .01)
(Table 3).
Because a decline in the serum RPR titer may depend on the
initial titer and the stage of early syphilis [21], the initial RPR
titers and the improvements in serum RPR titers for different
stages were analyzed. At 12  months after therapy, a serologi-
cal response was observed in 82.8% of participants with base-
line RPR titers ≤1:8, and in 87.8% participants with titers >1:8
(P  =  .33). However, serological responses of primary syphilis,
secondary syphilis, and early latent syphilis after 12  months
of treatment were 100%, 87.4%, and 72%, respectively, which
meant significant differences in serological responses between
different stages (P < .01).
Because high serum RPR titers probably decrease more
rapidly than low titers [21, 22], the time to achieve serological
response was analyzed. No significant difference was found in
the delay before a serological response between the 2 groups
(log-rank test, P  =  .29) (Figure  2). Meanwhile, whether other
factors (age, sex, initial RPR titer, syphilis stage, and J-H reac-
tion) had an influence on the serological response of syphilis was
also evaluated (Table 4). The stage of syphilis was associated with
the serological response, especially when comparing early latent
syphilis with primary syphilis (P = .02). Moreover, the J-H reac-
tion was positively related to the serological response of syphilis
(P = .03).
In all, 15 patients were determined to have a serofast status
after the 12-month follow-up; 6 were in the ceftriaxone group,
and 9 were in the BPG group. The serofast rate was not corre-
lated with the type of treatment (P = .49). One case of serolog-
ical failure was observed in the BPG arm. Fifteen patients (12
in the BPG and 3 in the ceftriaxone arm) had a documented
≥4-fold decline in RPR with a subsequent ≥4-fold increase. In 2
of these 15 patients, the increase was due to reinfection, because
their RPR had turned to negative at 6-month visit. Among the
left 13 patients, 1 patient rejected retreatment, and 12 received
repeated treatment with BPG (2.4 MU, given intramuscularly
once weekly for 3 weeks) or ceftriaxone (1.0–2.0 g, given intra-
venously once daily for 10–15 days).
DISCUSSION
The incidence of syphilis is increasing dramatically in many
developing countries, predominantly in China. Although
the definitions of and treatment guidelines for syphilis vary
throughout the world, the treatment of early syphilis has
changed little over the past few decades [5, 15]. BPG remains
the recommended global therapy for early syphilis. However, up
to 10% of individuals cannot be treated with penicillin because
of allergic reactions [23] or a worldwide penicillin shortage, and
treatment failures or relapse can occur [24]. Therefore, there is
an unmet need for novel treatment options.
Most patients allergic to penicillin can tolerate cephalo-
sporin. Studies of in vitro sensitivity have shown that the min-
imal inhibitory concentration of ceftriaxone for T. pallidum is
very low, approximately 0.0006 µg/mL [25]. Moreover, a daily
1.0-g ceftriaxone dose achieves levels well above the minimal
inhibitory concentration. Zhou et al [26] reported that ceftriax-
one was effective in pregnant patients with syphilis who showed
an allergic reaction to penicillin. Psomas et  al [27] evaluated
the efficacy of ceftriaxone as an alternative regimen for early

Table 3.  Serological Responses of Follow-up Patients by Syphilis Stage and Follow-up Interval

Participants at 6-mo, No. (%) Participants at 12-mo, No. (%)

Syphilis Stage Ceftriaxone BPG Ceftriaxone BPG

Primary 19/20 (95.0) 24/25 (96.0) 20/20 (100) 25/25 (100)

Secondary 69/72 (95.8)a 48/63 (76.2) 70/72 (97.2)a 48/63 (76.2)
Early latent 13/20 (65.0) 20/30 (66.7) 13/20 (65.0) 23/30 (76.7)
Total 101/112 (90.2)b 92/118 (78.0) 103/112 (92.0)b 96/118 (81.4)

Abbreviation: BPG, benzathine penicillin G. 

a
P < .01.
b
P < .05.

4 • CID 2017:XX (XX XXXX) •  Cao et al

 2 weeks were compared in terms of decreases in nontreponemal
antibody titers in nonpregnant, immunocompetent patients
with early syphilis. At both 6- and 12-month follow-up visits,
the rate of serological response was significantly higher in the
ceftriaxone group than in the BPG group among patients with
secondary syphilis, but not among those with primary or early
latent syphilis (P < .01) (Table 3).
The results of the present study may be contrary to most con-
clusions of recent studies, in which the effect of ceftriaxone was
equal to that of BPG in the treatment of several types of syphilis
[17, 27, 28]. As mentioned above, the patients enrolled in those
studies were coinfected with HIV with or without neurosyph-
ilis, the clinical patient data were collected in single centers,
and the sample sizes were very small. Moreover, the treatment
administration was not randomized, and there was no stand-
ardized ceftriaxone dose. These factors may lead to biased con-
clusions. To avoid these issues, the present study was designed
Figure 2.  Kaplan–Meier curves showing delay before serological response after
the 2 treatments. Abbreviation: BPG, benzathine penicillin G. to be a multicenter, randomized, open-label investigation with a
fixed dose and course of ceftriaxone in nonpregnant, immuno-
competent patients with early syphilis. Thus, the current study
syphilis in HIV-infected patients. However, to date, compared has greater power (93%) for determining the efficacy of treat-
with the penicillin therapy, clinical studies on the efficacy of cef- ment with ceftriaxone compared with that of BPG in patients
triaxone for treating early syphilis are rare. with early syphilis.
A meta-analysis of the effect of ceftriaxone compared with In the present study, most subjects showed a serological
that of penicillin for the treatment of early syphilis showed that response <6 months after the completion of therapy. A higher
the 12-month response rates were 83% (73 of 88) and 71% (63 probability of serological responses for patients at an earlier
of 89), respectively, in the ceftriaxone and BPG groups [24]. stage of infection was also observed. Participants with primary
Furthermore, most reports evaluating the efficacy of ceftriax- syphilis would show serological responses earlier than those
one for the treatment of syphilis do so in HIV-infected patients with early latent syphilis (P = .02) (Table 4). Notably, the better
with or without neurosyphilis [24, 28]. Ceftriaxone was found treatment response of subjects with secondary syphilis in the
to effectively improve CSF markers for neurosyphilis and was ceftriaxone group may be due to the infection of the CNS by
probably a superior treatment, given the decrease in serum RPR T. pallidum, which is common in early syphilis [29]. In present
titers [28]. However, there are few prospective studies on the study, whether asymptomatic CNS infection was more common
efficacy of ceftriaxone-treated, nonpregnant, immunocompe- in secondary syphilis was unknown, because lumbar punctures
tent patients with early syphilis. were not performed in those patients.
In the present trial, the effectiveness of daily ceftriaxone Reportedly, up to 30%–40% of patients with early syphilis
administration for 10 days and weekly BPG administration for exhibit evidence of CNS invasion by T. pallidum [9, 30]. Marra
et  al [25] reported that ceftriaxone achieved higher CSF con-
centrations than penicillin did. Therefore, ceftriaxone might
Table  4.  Adjusted Hazard Ratios and 95% CIs for Characteristics be a good option for treating CNS T.  pallidum infections.
Associated With Serological Responses From Cox Regression Analysis
Ceftriaxone is reportedly effective for all presentations of neu-
Adjusted Hazard Ratio
rosyphilis, including asymptomatic cases [17, 27, 31]. Maybe
Parameter P Value (95% CI) this was why ceftriaxone resulted in better serological responses
Age .70 … than BPG in the current study. It is worth mentioning that for
  36–54 vs 18–35 y .57 1.09 (.81–1.47) primary syphilis, serological responses rates were 100% in both
  55–65 vs 18–35 y .47 1.22 (.71–2.11) groups, meaning that BPG should be first-line treatment of pri-
Male vs female .41 1.13 (.84–1.53)
mary syphilis when considering efficacy and cost.
Syphilis stage .07 …
The J-H reaction is more likely to occur in patients with
  Early latent vs primary .02 0.57 (.35–.92)
  Secondary vs primary .17 0.75 (.50–1.12) early syphilis. The serological response was associated with the
Baseline RPR titer ≤1:8 vs＞1:8 .43 0.86 (.59–1.25) occurrence of a J-H reaction (P = .03), indicating that patients
J-H reaction, yes vs no .03 1.40 (1.03–1.90) exhibiting J-H reactions after treatment might respond serolog-
Abbreviations: CI, confidence interval; J-H, Jarisch-Herxheimer; RPR, rapid plasma reagin. ically earlier than those without J-H reactions.

Efficacy of Ceftriaxone for Syphilis  • CID 2017:XX (XX XXXX) • 5

 Although several positive results were found in the present
study, the limitations of the investigation should be mentioned.
First, this study is limited by the 12-month follow-up period
and by the missing data for some of the follow-up visits. If the
follow-up period were longer, further research could be per-
formed on the serofast population. Second, lumbar punctures
were not performed in subjects with a serofast status. Finally, in
contrast with BPG treatment, ceftriaxone is better for secondary
syphilis with asymptomatic CNS infection, syphilis in special
populations, such as HIV-infected or pregnant patients, and
syphilis after failed BPG treatment. However, the exact dose,
frequency, and treatment course of ceftriaxone recommended
for early syphilis differ across many countries’ guidelines [9].
The present study observed only 1 fixed dose and treatment
course for ceftriaxone. Daily ceftriaxone administration via
intravenous injections increased both the total treatment cost
and the level of inconvenience.
Based on our findings, the ceftriaxone regimen was nonin-
ferior to the BPG regimen in nonpregnant, immunocompetent
patients with early syphilis. Because of its cost, ease of admin-
istration, and narrow spectrum, BPG should still be preferred
for treating patients with primary or early latent syphilis.
Moreover, patients who experience a J-H reaction after treat-
ment may respond serologically earlier than those who do
not. Furthermore, whether ceftriaxone at a daily dose of 1.0 g
administrated intravenously for 10  days could be a preferred
alternative treatment of secondary syphilis needs to be deter-
mined based on data from future prospective studies.
Notes
Acknowledgments.  The authors thank Dr Hao Yu for assistance in
determining the random assignment of patients to either treatment group.
Financial support.  This work was supported by Jiangsu Provincial
Special Fund for Clinical Science and Technology from the Scientific and
Technological Office of Jiangsu Province (grant BL2012003).
Potential conflicts of interest.  All authors: No reported conflicts of
interest. All authors have submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Conflicts that the editors consider relevant to
the content of the manuscript have been disclosed.
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