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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.
The objective of this meta-analysis was to compare the efficacy Disagreement regarding data extraction was resolved by discussion
of ceftriaxone and penicillin for the treatment of syphilis based on and consensus with another investigator (X.-X.J.).
data from published RCTs.
2.5. Quality assessment
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 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. 2. Summary diagram of risk of bias percentile chart. Fig. 4. Comparison of 12-month response rate and failure rate in patients treated
with ceftriaxone compared with those treated with penicillin.
compared with those treated with penicillin (failure rate, ceftria- penicillin and ceftriaxone may be overestimated as the first
xone 3/57 vs. penicillin 2/23; RR = 0.66, 95% CI 0.03–15.76; Z = 0.26; ceftriaxone was ‘contaminated’ by penicillin [27].
P = 0.79). There was evidence of significant heterogeneity between Thus, it is advisable to perform a skin test and to administer
trials (I2 = 66%; P = 0.09) (Fig. 4). ceftriaxone only to those patients allergic to penicillins but with a
negative skin test [28,29]. Rapid i.v. injection, unlabelled use and
4. Discussion previous patient history of allergic reactions to cephalosporins or
penicillins are risk factors that should be guarded against [30].
In this study, the efficacy of ceftriaxone and penicillin for the Penicillin is the mainstay of treatment for syphilis not because
treatment of syphilis was compared based on data obtained from of a RCT but because of habit and for historical reasons as it was the
published RCTs. There were no significant differences in 3-month first treatment available. Thus, penicillin has not proved to be a bet-
response rate, 6-month response rate, 12-month response rate, ter treatment than another from a statistical point of view, except
relapse rate, serofast rate or failure rate in patients treated with with regard to experience of practice. The current data suggest that
ceftriaxone compared with those treated with penicillin. There was ceftriaxone might justifiably be considered as a useful alternative to
no significant difference in the efficacy of syphilis treatment among penicillin, especially because a number of clinicians choose to use
various ceftriaxone doses used. In the included studies, there was it [22]. There are limitations to this meta-analysis. First, only seven
no evidence of side effects occurring in patients treated with cef- RCTs met the inclusion criteria and these included a limited num-
triaxone. Overall relapse rates for penicillin and ceftriaxone showed ber of patients. Second, the dosage of ceftriaxone differed between
no significant difference. Therefore, it appears that the efficacy of each trial.
ceftriaxone is equivalent to penicillin for the treatment of syphilis. In conclusion, currently available evidence has shown that the
The incidence of syphilis is rising sharply in many develop- efficacy of ceftriaxone for syphilis was not significantly different
ing countries as well as in North America and Western Europe, from penicillin. Larger, high-quality, double-blind trials are needed
predominantly in association with the increasing incidence of to confirm whether ceftriaxone can safely replace penicillin as a
HIV/AIDS infections. Although overall the syphilis morbidity rate treatment for syphilis.
has decreased since the advent of penicillin-based therapy [21], Funding: None.
syphilis continues to cause severe complications if not diagnosed Competing interests: None declared.
and treated at an early stage [22]. Penicillin is the standard Ethical approval: Not acquired.
therapeutic agent for the treatment of syphilis, especially in HIV-
1-infected patients, and is recommended by the US Centers for
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