International Journal of Antimicrobial Agents 47 (2016) 6–11

Contents lists available at ScienceDirect

International Journal of Antimicrobial Agents

journal homepage: http://www.elsevier.com/locate/ijantimicag

Review

Meta-analysis of ceftriaxone compared with penicillin for the

treatment of syphilis
Zhen Liang a,1 , Ya-Ping Chen b,1 , Chun-Sheng Yang c,1 , Wen Guo d , Xiao-Xiao Jiang e ,
Xi-Feng Xu f , Shou-Xin Feng f , Yan-Qun Liu g,∗ , Guan Jiang g,h,∗
a
Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, China
b
Department of Oncology, Yancheng City No. 1 People’s Hospital, Yancheng 224000, China
c
Department of Dermatology, Affiliated Huai’an Hospital of Xuzhou Medical College, Huai’an 223002, China
d
Department of Radiotherapy, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu 221002, China
e
Department of Urologic Surgery, Yancheng City No. 1 People’s Hospital, Yancheng 224000, China
f
Department of Stereotactic Radiosurgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002, China
g
Department of Dermatology, Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002, China
h
Center for Disease Control and Prevention of Xuzhou City, Xuzhou 221006, Jiangsu Province, China

a r t i c l e i n f o a b s t r a c t

Article history: Penicillin is the gold standard for treating syphilis. However, allergic reactions, poor drug tolerance and
Received 26 June 2015 limited efficacy in patients remain a challenging problem. The objective of this meta-analysis was to
Accepted 27 October 2015 compare the efficacy of ceftriaxone and penicillin based on data obtained from published randomised con-
trolled trials (RCTs). The Cochrane Library, Medline, EBSCO, EMBASE and Ovid databases were searched
Keywords: for RCTs of ceftriaxone vs. penicillin for the treatment of syphilis. Estimated risk ratios (RRs) and 95% con-
Meta-analysis
fidence intervals (CIs) were used to investigate the following outcome measures: 3-month response rate;
Syphilis
6-month response rate; 12-month response rate; relapse rate; serofast rate; and failure rate. Seven RCTs
Ceftriaxone
Penicillin involving 281 participants (159 patients who received ceftriaxone and 122 patients who received peni-
Randomised controlled trial cillin) were included in the meta-analysis. There were no significant differences in 3-month response rate
(RR = 1.12, 95% CI 0.89–1.42), 6-month response rate (RR = 1.02, 95% CI 0.75–1.38), 12-month response
rate (RR = 1.04, 95% CI 0.82–1.32), relapse rate (RR = 0.91, 95% CI 0.45–1.84), serofast rate (RR = 0.69, 95%
CI 0.22–2.12) or failure rate (RR = 0.66, 95% CI 0.03–15.76) in patients treated with ceftriaxone compared
with those treated with penicillin. In conclusion, there is no evidence in the literature that ceftriaxone is
less efficient than penicillin.
© 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction developing countries as well as among poor and marginalised

Syphilis is a sexually transmitted disease caused by infection
with the spirochete Treponema pallidum [1]. Clinical manifesta-
tions of syphilis include meningeal and central nervous system
(CNS) symptoms, which can occur early in the course of untreated
disease [2]. Syphilis infections arise in various subpopulations
owing to changing sexual and social norms, outbreaks in individ-
uals infected with human immunodeficiency virus (HIV), substance
abuse, global travel and migration, and underinvestment in pub-
lic health services. Globally, there are great variations in the
incidence of syphilis, and the disease is most prevalent in
∗ Corresponding authors. Tel.: +86 18936372033.
E-mail address: dr.guanjiang@gmail.com (G. Jiang).
1
These three authors contributed equally to this manuscript.
http://dx.doi.org/10.1016/j.ijantimicag.2015.10.020
0924-8579/© 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
people [3].
Penicillin has been recommended as the mainstay of treatment
for all types of syphilis since it was first used for this indication
in 1943 [4]. However, penicillin cannot be used in up to 10% of
individuals owing to allergic reactions [5], and treatment failures
can occur, particularly in individuals with HIV co-infection and in
cases of neurosyphilis. There is an unmet need for novel treat-
ment options in syphilis-infected individuals who are allergic or
intolerant to penicillin.
Ceftriaxone, a third-generation cephalosporin antibiotic, is a
promising alternative to penicillin for the treatment of syphilis. It is
well tolerated, has good CNS penetration and effectiveness for neu-
rosyphilis, including asymptomatic forms, and has a long half-life
that enables once-daily dosing [6,7]. Randomised controlled tri-
als (RCTs) have compared the efficacy of ceftriaxone and penicillin
for the treatment of syphilis; however, the efficacy of ceftriaxone
remains controversial.
 Z. Liang et al. / International Journal of Antimicrobial Agents 47 (2016) 6–11
The objective of this meta-analysis was to compare the efficacy
of ceftriaxone and penicillin for the treatment of syphilis based on
data from published RCTs.
2. Materials and methods
2.1. Search strategy
The Cochrane Library, Medline, EBSCO, EMBASE and Ovid
databases as well as clinical trial websites (1 January 1988 to 5
January 2014) were searched. Search terms were based on MeSH
words or keywords using the following search terms: ‘ceftriaxone’
OR ‘penicillin’ OR ‘syphilis’ AND ‘randomised controlled trials’.
Additional information was retrieved through a hand search of the
reference lists from relevant articles. No language restrictions were
applied.
2.2. Inclusion and exclusion criteria
Inclusion criteria were RCTs that: (i) reported on treatments of
early syphilis including primary, secondary and latent stages; (ii)
compared penicillin vs. ceftriaxone; (iii) included patients with no
history of allergy to ceftriaxone or penicillin; (iv) had no restriction
on nationality and ethnicity of research subjects; and (v) reported
sufficient data on outcomes of interest.
Exclusion criteria were: (i) non-randomised and non-clinical
controlled trials; (ii) trials with missing data [e.g. total number of
patients, 3-, 6- or 12-month response rates, and relapse, serofast
(the nontreponemal antibody test results remain in a tight range 1
year after the recommended therapy) [8] and failure rates]; and (iii)
duplicate reports, trials of poor methodological quality and trials
with obvious bias.
2.3. Study selection
Two investigators (G.J. and Y.-P.C.) independently examined the
titles and abstracts to select eligible studies. The full text of poten-
tially relevant studies was retrieved. Two review authors (Z.L. and
W.G.) independently examined the full-text records to determine
which studies met the inclusion criteria. Disagreement regarding
study selection was resolved by discussion and consensus with
another investigator (X.-X.J.).
2.4. Data extraction
Two investigators (G.J. and Y.-P.C.) independently extracted
information from eligible studies. Data included the name of the
first author, year of publication, quality of the study, stage of
syphilis, intervention, median patient age, number of patients in
the study, dosage and duration of ceftriaxone or penicillin, and
outcomes.
The outcomes of interest were treatment efficacy at 3-, 6-
and 12 months of follow-up and included (i) response rates and
(ii) relapse rates, serofast rates using nontreponemal antigen test
changes in serum titres, and failure rates. Response was defined
as a ≥4-fold decrease in Venereal Disease Research Laboratory
Test/rapid plasma reagin (VDRL/RPR) titre with no increase during
the observation period. Relapse was defined as a ≥4-fold decrease
in VDRL/RPR titre followed by a return to the original level or
higher. Serofast was defined as a persistent titre of VDRL/RPR after
syphilis treatment, whereby no change in titre occurred during the
follow-up period, and no signs of clinical progression. Failure was
defined as a ≥4-fold rise in VDRL/RPR without an initial response,
a persistent titre of ≥1:64, or clinical progression of the disease.
7
Disagreement regarding data extraction was resolved by discussion
and consensus with another investigator (X.-X.J.).
2.5. Quality assessment
Two investigators (G.J. and Y.-P.C.) used the ‘Cochrane handbook
for systematic reviews of interventions version 5.0.0 to assess the
methodological quality of the included RCTs, which assessed: (i)
generation of the random allocation scheme (random sequence
generation); (ii) allocation concealment; (iii) blinding of partic-
ipants and personnel; (iv) blinding of outcome assessment; (v)
incomplete outcome data; (vi) selective reporting; and (vii) other
sources of bias.
2.6. Statistical methods
Statistical analyses were conducted using Review Manager v.5.0
software (Cochrane Collaboration, Oxford, UK). For dichotomous
variables, outcomes were reported as relative risk ratio (RR) and
95% confidence interval (CI). A P-value of <0.05 was considered
statistically significant.
Heterogeneity among studies was determined by 2 -based Q-
test and I2 test [9,10]. A fixed-effects model was used for outcome
data with evidence of low heterogeneity (P > 0.1; I2 ≤ 50%). For
outcome data with evidence of significant heterogeneity (P < 0.1;
I2 > 50%), trials were analysed to identify the contributing factors.
If heterogeneity was not clinically significant, a random-effects
model was applied. Sensitivity analysis was conducted to confirm
whether the results were robust and reliable [11].
3. Results
Two investigators independently selected literature on the basis
of the inclusion and exclusion criteria [12,13]. The literature selec-
tion process is presented in the PRISMA flow chart (Fig. 1) according
to the PRISMA guidelines. The searches identified 969 potential
articles, and 80 studies were identified as potentially eligible for
inclusion. After analysing the full-text articles, 73 studies were
excluded and seven RCTs were found eligible for inclusion accord-
ing to the criteria for this review [14–20].
3.1. Included studies
In total, 281 patients were enrolled in the included RCTs.
Patients were aged 18–61 years and were experiencing primary,
secondary or latent stage syphilis. Of the 281 patients, 159 received
ceftriaxone and 122 received penicillin. Drugs were administered
intramuscularly or intravenously. The characteristics of the seven
included RCTs are shown in Table 1.
Of the 73 excluded studies, 12 studies only reported efficacy
results for penicillin or ceftriaxone, 9 studies compared penicillin
with a drug other than ceftriaxone, and 52 studies were not RCTs.
3.2. Methodological quality of included studies
Of the seven RCTs that were included in this study, all seven
studies mentioned the randomisation method and that allocation
concealment was conducted, and three of the studies had incom-
plete outcome data (Fig. 2).
3.3. Three-month response rate
Data reporting on 3-month response rate to treatment were
described in three RCTs. The meta-analysis demonstrated no sig-
nificant difference in the 3-month response rate in patients treated
with ceftriaxone compared with those treated with penicillin
8 Z. Liang et al. / International Journal of Antimicrobial Agents 47 (2016) 6–11

Fig. 1. Flow chart of article screening and selection process. RCT, randomised controlled trial.

Table 1
Summary of the characteristics of the seven trials included in the meta-analysis.

Reference Stage of syphilis Intervention Median (IQR) No. of patients Dosage and duration
patient age (years)

Marra et al. (2000) Secondary Ceftriaxone 34 (22–59) 14 Ceftriaxone 2.0 g i.v. once daily for 10 days
[14] Penicillin 16 Penicillin 4 MU i.v. q4h for 10 days
Schöfer et al. Primary and Ceftriaxone N/R 14 Ceftriaxone 4 × 1 g i.m. every 2 days
(1989) [19] secondary Penicillin 14 Clemizole penicillin G 1 MIU i.m. daily for 15
days
Moorthy et al. Primary Ceftriaxone 28 (18–44) 13 Ceftriaxone 3 g i.m., or 2 g i.m. daily for 2 days,
(1987) [15] or 2 g i.m. daily for 5 days
Penicillin 5 Benzathine penicillin 2.4 × 106 U i.m.
Smith et al. (2004) Latent Ceftriaxone 34.5 (23–56) 14 Ceftriaxone 1 g i.m. for 15 days
[17] Penicillin 35.4 (25–61) 10 Procaine penicillin 2.4 MU i.m. for 15 days
Spornraft-Ragaller Primary, secondary Ceftriaxone 40.5 (29–47) 12 Eight patients received 2 g once daily for 10–14
et al. (2011) [18] or latent days; two patients received 2 g for 21 days;
and two patients received 1 g for 14 days
Penicillin 42 (33–57) 12 Eight patients received benzathine penicillin
2.4 MU i.m. in weekly intervals for 3 weeks
(n = 7) or 2 weeks (n = 1); two patients received
clemizole penicillin G 1 MU i.m. daily for 14
days or 21 days; and two patients received
penicillin G 3 × 10 MU i.v. daily for 21 days
Psomas et al. Primary, secondary Ceftriaxone 42 (23–49) 49 Ceftriaxone 1 g or 2 g daily for 14–21 days
(2012) [16] or early latent Penicillin 52 Benzathine benzylpenicillin 1, 2 or 3 i.m.
injections in a single daily dose of 2.4 MIU at
1-week intervals
Dowell et al. (1992) Secondary Ceftriaxone 34.9 43 Ceftriaxone 1 g (or rarely 2 g) i.v. for 10–14
[20] consecutive days or 1 g i.m. on weekdays until
10–14 doses administered
Penicillin 13 Benzathine penicillin three doses of 2.4 MU at
weekly intervals

IQR, interquartile range; i.v., intravenous; MU, million units; q4h, every 4 h; N/R, not reported; i.m., intramuscular; MIU, million International Units.
Because syphilis has primary, secondary and latent stages, and penicillin has been recommended as the mainstay of treatment for all types of syphilis, we summarise the
characteristics of the seven trials with three different stages included in the meta-analysis.
 Z. Liang et al. / International Journal of Antimicrobial Agents 47 (2016) 6–11
Fig. 2. Summary diagram of risk of bias percentile chart.
(3-month response rate, ceftriaxone 33/38 vs. penicillin 21/27;
RR = 1.12, 95% CI 0.89–1.42; Z = 0.96; P = 0.34). There was no evi-
dence of significant heterogeneity between trials (I2 = 0%; P = 0.83)
(Fig. 3).
3.4. Six-month response rate
Data reporting on 6-month response rate to treatment were
described in three RCTs. The meta-analysis demonstrated no sig-
nificant difference in the 6-month response rate in patients treated
with ceftriaxone compared with those treated with penicillin
(6-month response rate, ceftriaxone 44/61 vs. penicillin 14/19;
RR = 1.02, 95% CI 0.75–1.38; Z = 0.12; P = 0.91). There was no evi-
dence of significant heterogeneity between trials (I2 = 0%; P = 0.94)
(Fig. 3).
3.5. Twelve-month response rate
Data reporting on 12-month response rate to treatment were
described in five RCTs. The meta-analysis demonstrated no signif-
icant difference in the 12-month response rate in patients treated
with ceftriaxone compared with those treated with penicillin
(12-month response rate, ceftriaxone 73/88 vs. penicillin 63/89;
RR = 1.04, 95% CI 0.82–1.32; Z = 0.31; P = 0.76). There was evidence of
significant heterogeneity between trials (I2 = 63%; P = 0.03) (Fig. 4).
9
Fig. 3. Comparison of 3-month response rate, 6-month response rate, relapse rate
and serofast rate in patients treated with ceftriaxone compared with those treated
with penicillin.
Fig. 4. Comparison of 12-month response rate and failure rate in patients treated
with ceftriaxone compared with those treated with penicillin.
3.6. Relapse rate
Data reporting on relapse rate after treatment were described in
three RCTs. The meta-analysis demonstrated no significant differ-
ence in relapse rate in patients treated with ceftriaxone compared
with those treated with penicillin (relapse rate, ceftriaxone 17/91
vs. penicillin 12/59; RR = 0.91, 95% CI 0.45–1.84; Z = 0.27; P = 0.79).
There was no evidence of significant heterogeneity between trials
(I2 = 0%; P = 0.59) (Fig. 3).
3.7. Serofast rate
Data reporting on serofast rate after treatment were described in
three RCTs. The meta-analysis demonstrated no significant differ-
ence in serofast rate in patients treated with ceftriaxone compared
with those treated with penicillin (serofast rate, ceftriaxone 7/69
vs. penicillin 5/35; RR = 0.69, 95% CI 0.22–2.12; Z = 0.65; P = 0.51).
There was no evidence of significant heterogeneity between trials
(I2 = 0%, P = 0.61) (Fig. 3).
3.8. Failure rate
Data reporting on the incidence of treatment failure were
described in two RCTs. The meta-analysis demonstrated no signif-
icant difference in failure rate in patients treated with ceftriaxone
10 Z. Liang et al. / International Journal of Antimicrobial Agents 47 (2016) 6–11
compared with those treated with penicillin (failure rate, ceftria-
xone 3/57 vs. penicillin 2/23; RR = 0.66, 95% CI 0.03–15.76; Z = 0.26;
P = 0.79). There was evidence of significant heterogeneity between
trials (I2 = 66%; P = 0.09) (Fig. 4).
4. Discussion
In this study, the efficacy of ceftriaxone and penicillin for the
treatment of syphilis was compared based on data obtained from
published RCTs. There were no significant differences in 3-month
response rate, 6-month response rate, 12-month response rate,
relapse rate, serofast rate or failure rate in patients treated with
ceftriaxone compared with those treated with penicillin. There was
no significant difference in the efficacy of syphilis treatment among
various ceftriaxone doses used. In the included studies, there was
no evidence of side effects occurring in patients treated with cef-
triaxone. Overall relapse rates for penicillin and ceftriaxone showed
no significant difference. Therefore, it appears that the efficacy of
ceftriaxone is equivalent to penicillin for the treatment of syphilis.
The incidence of syphilis is rising sharply in many develop-
ing countries as well as in North America and Western Europe,
predominantly in association with the increasing incidence of
HIV/AIDS infections. Although overall the syphilis morbidity rate
has decreased since the advent of penicillin-based therapy [21],
syphilis continues to cause severe complications if not diagnosed
and treated at an early stage [22]. Penicillin is the standard
therapeutic agent for the treatment of syphilis, especially in HIV-
1-infected patients, and is recommended by the US Centers for
Disease Control and Prevention (CDC) [23]. However, adverse
events associated with the administration of penicillin for syphilis
include allergy or intolerance to intramuscular injections.
Doxycycline and tetracycline appear to be as effective as peni-
cillin for syphilis and are recommended as second-line options.
However, these drugs have to be taken orally, which means that
adherence is poor [23,24]. Ceftriaxone has also been suggested as a
potential alternative to penicillin for treating syphilis. Marra et al.
[25] reported that ceftriaxone achieved higher concentrations in
cerebrospinal fluid (CSF) than penicillin. This observation suggests
that ceftriaxone has a better ability to penetrate the CNS, therefore
this drug may be a good option for treating neurosyphilis. Fur-
thermore, ceftriaxone differs from other cephalosporins as it has
a long half-life of ca. 7 h. However, the clinical efficacy of ceftria-
xone for treating syphilis remains controversial. This meta-analysis
indicates that the efficacy of ceftriaxone for syphilis is equiva-
lent to penicillin. In accordance with these data, Zhou et al. [26]
reported that some patients with isolates resistant to penicillin or
who showed an allergic reaction to this drug may respond to cef-
triaxone. The study of Marra et al. revealed that intravenous (i.v.)
ceftriaxone may be a reasonable alternative to penicillin for treating
HIV-1-infected patients with neurosyphilis [25].
Despite having limited data for guidance in clinical practice, no
well-stated clinical guidelines and lack of approval for the practice
from the US Food and Drug Administration (FDA), nearly one in five
infectious disease consultants from the Infectious Diseases Society
of America Emerging Infections Network submitted reports of using
ceftriaxone for treating early-stage syphilis in 1998.
As physicians who were queried were specialists in infectious
diseases, this response may overestimate national practice. None
the less, it should not be ignored, particularly since specialists
often initiate practices that are eventually adopted by general-
ists. These clinicians chose to use ceftriaxone because patients
who required therapy were, or were suspected to be, allergic
to penicillin and thus these patients may also have reactions to
other ␤-lactam antibiotics. In fact, it is estimated that 3–7% of
patients with a history of penicillin allergy may have reactions
to cephalosporins. However, crossed allergic reactions between
penicillin and ceftriaxone may be overestimated as the first
ceftriaxone was ‘contaminated’ by penicillin [27].
Thus, it is advisable to perform a skin test and to administer
ceftriaxone only to those patients allergic to penicillins but with a
negative skin test [28,29]. Rapid i.v. injection, unlabelled use and
previous patient history of allergic reactions to cephalosporins or
penicillins are risk factors that should be guarded against [30].
Penicillin is the mainstay of treatment for syphilis not because
of a RCT but because of habit and for historical reasons as it was the
first treatment available. Thus, penicillin has not proved to be a bet-
ter treatment than another from a statistical point of view, except
with regard to experience of practice. The current data suggest that
ceftriaxone might justifiably be considered as a useful alternative to
penicillin, especially because a number of clinicians choose to use
it [22]. There are limitations to this meta-analysis. First, only seven
RCTs met the inclusion criteria and these included a limited num-
ber of patients. Second, the dosage of ceftriaxone differed between
each trial.
In conclusion, currently available evidence has shown that the
efficacy of ceftriaxone for syphilis was not significantly different
from penicillin. Larger, high-quality, double-blind trials are needed
to confirm whether ceftriaxone can safely replace penicillin as a
treatment for syphilis.
Funding: None.
Competing interests: None declared.
Ethical approval: Not acquired.
References
[1] Little JW. Syphilis: an update. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2005;100:3–9.
[2] Pao D, Goh BT, Bingham JS. Management issues in syphilis. Drugs
2002;62:1447–61.
[3] Fenton KA, Breban R, Vardavas R, Okano JT, Martin T, Aral S, et al. Infec-
tious syphilis in high-income settings in the 21st century. Lancet Infect Dis
2008;8:244–53.
[4] Yang CJ, Lee NY, Chen TC, Lin YH, Liang SH, Lu PL, et al. One dose versus
three weekly doses of benzathine penicillin G for patients co-infected with
HIV and early syphilis: a multicenter, prospective observational study. PLOS
ONE 2014;9:e109667.
[5] Yates AB. Management of patients with a history of allergy to ␤-lactam antibi-
otics. Am J Med 2008;121:572–6.
[6] Shann S, Wilson J. Treatment of neurosyphilis with ceftriaxone. Sex Transm
Infect 2003;79:415–6.
[7] US Centers for Disease Control and Prevention. Sexually transmitted diseases
treatment guidelines, 2015. Atlanta, GA: CDC; 2015.
[8] Causer LM, Kaldor JM, Conway DP, Leslie DE, Denham I, Karapanagiotidis T,
et al. An evaluation of a novel dual treponemal/nontreponemal point-of-care
test for syphilis as a tool to distinguish active from past treated infection. Clin
Infect Dis 2015;61:184–91.
[9] Higgins J, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat
Med 2002;21:1539–58.
[10] Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in
meta-analyses. BMJ 2003;327:557–60.
[11] Jiang G, Li RH, Sun C, Jia HY, Lei TC, Liu YQ. Efficacy and safety between temozolo-
mide alone and temozolomide-based double therapy for malignant melanoma:
a meta-analysis. Tumour Biol 2014;35:315–22.
[12] Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting
items for systematic reviews and meta-analyses: the PRISMA statement. Int J
Surg 2010;8:336–41. Erratum in: Int J Surg 2010;8:658.
[13] Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al.
The PRISMA statement for reporting systematic reviews and meta-analyses of
studies that evaluate health care interventions: explanation and elaboration. J
Clin Epidemiol 2009;62:e1–34.
[14] Marra CM, Boutin P, McArthur JC, Hurwitz S, Simpson PA, Haslett JA, et al. A
pilot study evaluating ceftriaxone and penicillin G as treatment agents for neu-
rosyphilis in human immunodeficiency virus-infected individuals. Clin Infect
Dis 2000;30:540–4.
[15] Moorthy TT, Lee CT, Lim KB, Tan T. Ceftriaxone for treatment of primary syphilis
in men: a preliminary study. Sex Transm Dis 1987;14:116–8.
[16] Psomas KC, Brun M, Causse A, Atoui N, Reynes J, Le Moing V. Efficacy of cef-
triaxone and doxycycline in the treatment of early syphilis. Med Mal Infect
2012;42:15–9.
[17] Smith NH, Musher DM, Huang DB, Rodriguez PS, Dowell ME, Ace W, et al.
Response of HIV-infected patients with asymptomatic syphilis to intensive
intramuscular therapy with ceftriaxone or procaine penicillin. Int J STD AIDS
2004;15:328–32.
 Z. Liang et al. / International Journal of Antimicrobial Agents 47 (2016) 6–11
[18] Spornraft-Ragaller P, Abraham S, Lueck C, Meurer M. Response of HIV-infected
patients with syphilis to therapy with penicillin or intravenous ceftriaxone. Eur
J Med Res 2011;16:47–51.
[19] Schöfer H, Vogt HJ, Milbradt R. Ceftriaxone for the treatment of primary and
secondary syphilis. Chemotherapy 1989;35:140–5.
[20] Dowell ME, Ross PG, Musher DM, Cate TR, Baughn RE. Response of latent
syphilis or neurosyphilis to ceftriaxone therapy in persons infected with human
immunodeficiency virus. Am J Med 1992;93:481–8.
[21] Brown DL, Frank JE. Diagnosis and management of syphilis. Am Fam Physician
2003;68:283–90.
[22] Enders M, Hunjet A, Gleich M, Imdahl R, Mühlbacher A, Schennach H, et al.
Performance evaluation of the Elecsys syphilis assay for the detection of total
antibodies to Treponema pallidum. Clin Vaccine Immunol 2015;22:17–26.
[23] Ghanem KG, Erbelding EJ, Cheng WW, Rompalo AM. Doxycycline compared
with benzathine penicillin for the treatment of early syphilis. Clin Infect Dis
2006;42:e45–9.
[24] Wong T, Singh AE, De P. Primary syphilis: serological treatment response to
doxycycline/tetracycline versus benzathine penicillin. Am J Med 2008;121:
903–8.
11
[25] Marra CM, Slatter V, Tartaglione TA, Baker-Zander SA, Lukehart SA. Evaluation
of aqueous penicillin G and ceftriaxone for experimental neurosyphilis. J Infect
Dis 1992;165:396–7.
[26] Zhou P, Gu Z, Xu J, Wang X, Liao K. A study evaluating ceftriaxone as a treat-
ment agent for primary and secondary syphilis in pregnancy. Sex Transm Dis
2005;32:495–8.
[27] Pichichero ME, Casey JR. Safe use of selected cephalosporins in penicillin-
allergic patients: a meta-analysis. Otolaryngol Head Neck Surg 2007;136:
340–7.
[28] Antunez C, Blanca-Lopez N, Torres MJ, Mayorga C, Perez-Inestrosa E, Montañez
MI, et al. Immediate allergic reactions to cephalosporins: evaluation of cross-
reactivity with a panel of penicillins and cephalosporins. J Allergy Clin Immunol
2006;117:404–10.
[29] Shalviri G, Yousefian S, Gholami K. Adverse events induced by ceftriaxone: a
10-year review of reported cases to Iranian Pharmacovigilance Centre. J Clin
Pharm Ther 2012;37:448–51.
[30] Augenbraun M, Workowski K. Ceftriaxone therapy for syphilis: report from the
emerging infections network. Clin Infect Dis 1999;29:1337–8.