Received: 29 May 2020 Revised: 10 July 2020 Accepted: 13 July 2020

DOI: 10.1111/dth.14025

ORIGINAL ARTICLE

Azithromycin vs penicillin G benzathine for early syphilis:

A meta-analysis of randomized controlled trials

Yizhi Li1,2 | Guan Jiang1,2

1
Department of Dermatology, Affiliated
Hospital of Xuzhou Medical University,
Xuzhou, China
2
Department of Dermatology, Xuzhou Medical
University, Xuzhou, China
Correspondence
Guan Jiang, Department of Dermatology,
Affiliated Hospital of Xuzhou Medical
University, Xuzhou 221002, China.
Email: dr.guanjiang@xzhmu.edu.cn
Funding information
the Jiangsu Provincial Medical Talent
Foundation
Abstract
Syphilis is a very serious infection that causes acute cutaneous manifestations. Peni-
cillin is the gold standard for treating syphilis. This meta-analysis was conducted
based on self-published randomized controlled trials (RCTs) data to compare the effi-
cacy of azithromycin with penicillin for treating syphilis. RCTs on azithromycin vs
penicillin for the treatment of syphilis were retrieved from the Cochrane Library,
MEDLINE, EBSCO, Embase, Ovid, and other databases, and the estimated risk ratio
(RR) and 95% confidence interval (CI) were used to study the following outcome indi-
cators: 3-month response rate, 6-month response rate, 12-month response rate,
recurrence rate, serum fixation rate, and failure rate. This meta-analysis included
seven RCTs involving 639 subjects (of whom 335 were treated with azithromycin
and 304 were treated with penicillin). There was no significant difference in the
3-month response rate (RR = 0.97, 95% CI: 0.79-1.19), 6-month response rate
(RR = 1.01, 95% CI: 0.85-1.20), 12-month response rate (RR = 1.02, 95% CI:
0.97-1.09), serum fixation rate (RR = 0.71, 95% CI: 0.24-2.12), and failure rate
(RR = 0.62, 95% CI: 0.33-1.16). In summary, there is no evidence in the literature that
azithromycin is less effective than penicillin for treating syphilis.

KEYWORDS

azithromycin, meta-analysis, penicillin G benzathine, RCTs, syphilis

1 | I N T RO DU CT I O N Due to the lack of an effective vaccine against syphilis, treatment

Syphilis, a multistage infectious disease, is caused by Treponema palli-
dum subsp. and is usually transmitted sexually. Once a successful infec-
tion occurs, T. pallidum is capable of disseminating to almost all tissues
of the host, where it may remain latent for a long period or induce pro-
tean clinical presentations. It can even penetrate human placenta,
resulting in miscarriage, premature birth, stillbirth, or congenital syphilis.
The World Health Organization has estimated that there are 12 million
new cases of syphilis globally every year, with 90% occurring in devel-
oping countries,1 but its incidence has also increased in North America
and Western Europe, where most of the cases involved men who have
sex with men. Significantly, syphilis has been shown to contribute to
1-4
increased risk of acquisition and transmission of HIV infection.
Hence, this disease is a crucial concern to public health globally.
relies completely on antibiotics. Parenteral penicillin has been the
first-line regimen for treating syphilis; however, it is not accessible to
patients in resource-limited settings, where safe injection devices are
not readily available. Furthermore, with its extensive use, the inci-
dence of penicillin allergy is almost up to 10%.5 Although rec-
ommended by some specialists,6-8 most desensitization seems
impractical for primary care providers, as it presents the risk of ana-
phylaxis, thereby requiring special emergency medical devices and
drugs for rescue therapy. Therefore, patients with penicillin allergy
have to appeal for alternative antibiotics. In this regard, azithromycin,
ceftriaxone, and doxycycline/tetracycline have been employed as
penicillin alternatives for many years.9 However, the efficacy of peni-
cillin alternatives in treating syphilis has been assessed in very limited
studies, some of which have shown contradictory results.10

Dermatologic Therapy. 2020;e14025. wileyonlinelibrary.com/journal/dth © 2020 Wiley Periodicals LLC. 1 of 7

https://doi.org/10.1111/dth.14025
2 of 7
Therefore, it remains unclear whether the alternative drugs differ
in terms of efficacy. To date, no documented study has simulta-
neously assessed the efficacy of penicillin and azithromycin for
treating syphilis.
This meta-analysis aims to compare the efficacy of azithromycin
and benzathine penicillin for syphilis based on published randomized
controlled trial (RCT) data.
2 | MATERIALS AND METHODS
2.1 | Retrieval strategy
We searched databases such as that of the Cochrane Library,
MEDLINE, EBSCO, Embase, Ovid, and clinical trial websites (January
1, 1988 to December 31, 2019). The search terms were based on
MeSH words or keywords, and the following search terms were used:
“azithromycin” or “penicillin” or “syphilis” and “randomized controlled
trials.”. We retrieved additional information by manually searching the
reference lists of related articles. Language restrictions were not
imposed.
LI AND JIANG
2.2 | Inclusion and exclusion criteria
According to the inclusion criteria, RCTs should (a) report the treat-
ment of early syphilis, including the primary, secondary, and early
latent syphilis; (b) compare penicillin with azithromycin; (c) include
patients with no history of allergies to azithromycin; (d) have no
restrictions on the nationality and ethnicity of the study participants;
(e) report adequate data on outcomes.
The exclusion criteria were (a) nonrandomized, nonclinical con-
trolled trials; (b) trials with missing data (eg, total number of patients,
3-/6-/12-month response, serum fixation nontreponemal antibody
test results in remaining within a narrow range for 1 year after com-
pletion of recommended therapy,11 failure rate); (c) duplicate reports,
trials with low methodological quality, trials with significant bias.
2.3 | Research selection
Two researchers checked titles and abstracts to select eligible studies. We
retrieved the full text of potentially relevant studies. Two review authors
checked the full text records to identify the studies that met the inclusion
F I G U R E 1 Flow chart of the article
and selection process. RCT, randomized
controlled trial
LI AND JIANG 3 of 7

criteria. Disagreements about research options were resolved by dis- included RCTs. The aspects of assessments included (a) the generation
cussing and reaching consensus with me and another researcher. of a random allocation scheme (random sequence generation);
(b) allocation concealment; (c) blinding method for subjects and
researchers; (d) blinding method for outcome assessment; (e) incomplete
2.4 | Data extraction outcome data; (f) selective reporting; and (g) other sources of bias.

Two researchers extracted information from eligible studies. The data

included first author name, year of publication, study quality, syphilis
stage, intervention, median patient age, the number of patients in the
study, the dose and duration of azithromycin or penicillin, and outcomes.
The outcome of interest was the effect of treatment at 3, 6, and
12 months of follow-up, including (a) response rate, (b) serum fixation
rate (use of nontreponemal antibodies to test changes in serum titers),
and (c) failure rate. Response was defined as a 4-fold reduction in sexu-
ally transmitted disease (STD) laboratory test/rapid plasma reagin vene-
real disease research laboratory test/rapid plasma reagin (VDRL/RPR)
titer and no increase in the titer during the observation period. Relapse
was defined as a 4-fold reduction in VDRL/RPR titer, and then recovery
to the original level or higher. Serum fixation was defined as the contin-
uous VDRL/RPR titer after syphilis treatment, no titer changes occur-
ring during follow-up, and no signs of clinical progress. Failure was
defined as an increase in VDRL/RPR of >4 times, no initial response,
sustained titer ≥1:64, or clinical progression of the disease. Disagree-
ments about data extraction were resolved by discussing and reaching
consensus with the author and another researcher.
2.6 | Statistical methods
Statistical analysis was performed using Review Manager v.5.0 software
(Cochrane Collaboration, Oxford, UK). For dichotomous variables, out-
comes were reported as relative hazard ratio (RR) and 95% confidence
interval (CI) . P values <.05 were considered statistically significant.
Heterogeneity between studies was determined by a Q test
based on 32 and an I2 test12 Fixed-effects models were used for out-
come data with low evidence of heterogeneity (P > .1; I2 = 50%). For
outcome data with significant evidence of heterogeneity (P < .1;
I2 > 50%), random-effects models were used. To analyze the trial to
determine the influencing factors, the effects models were used. If
heterogeneity was not clinically significant, a random-effects model
was applied.13 Sensitivity analysis was performed to determine
whether the results were robust and reliable.14
3 | RE SU LT S

Two researchers selected literature based on the inclusion and exclusion

2.5 | Quality assessment criteria. The literature selection process is based on the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses guidelines
Two researchers used the Cochrane Intervention Systematic Review flow chart (Figure 1). The search identified 969 potential articles, 80 of
Manual Version 5.3.3 to assess the methodological quality of the which were considered likely to meet the inclusion criteria. After analyzing

TABLE 1 Summary of the characteristics of the seven randomized control trials included in the meta-analysis

No. of
Author Stage of syphilis Intervention (C/T) Median age, y (C/T) patients Dosage and duration

Luo Primary and secondary Azithromycin 34.7 (20-48) 26 Azithromycin 1.0 g orally, once daily (14 d)

Penicillin 35.3 (22-46) 26 Benzathine penicillin 2.4 MU im once a week (2-3 times)

Shan Primary and secondary Azithromycin 35.03 (25-45) 45 Azithromycin 500 mg orally, once daily (14 d)

Penicillin 35.58 (25-46) 45 Benzathine penicillin 2.4 MU im once a week (3-5 times)

Qian Primary and secondary Azithromycin 39.69 (18-55) 35 1.0 g the first day, reduce to 0.5 g the next day (14 d)
Penicillin 40.37 (20-57) 36 Benzathine penicillin 2.4 MU im once a week (3 times)

Lv Primary and secondary Azithromycin 35.4 (21-47) 58 1.0 g the first day, reduce to 0.5 g the next day (14 d)

Penicillin 35.1 (22-45) 58 Benzathine penicillin 2.4 MU im once a week (3 times)

He Primary, secondary, Azithromycin 44.34 80 Azithromycin 0.5 g orally, once daily (14 d)
or early latent

Penicillin 46.22 80 Benzathine penicillin 2.4 MU im once a week (3-5 times)

Zhang Primary and secondary Azithromycin 37.35 (29-68) 38 1.0 g the first day, reduce to 0.5 g the next day (21 d)

Penicillin 38.67 (38-70) 38 Benzathine penicillin 2.4 MU im once a week (3 times)

Hook Primary, secondary, Azithromycin 29.98 (18-56) 21 Azithromycin 2.0 g orally, once daily (14 d)
or early latent

Penicillin 29 (18-46) 32 Benzathine penicillin 2.4 MU im once or twice a week (14 d)

Abbreviations: C/T, control group/test group; im, intramuscularly; MU, million units.
4 of 7 LI AND JIANG

FIGURE 2 Risk of bias graph

the full text of the articles, 73 studies were excluded, and 7 RCTs15-21 met
the inclusion criteria based on the criteria of the present review.

3.1 | Included studies

A total of 639 patients participated in the included RCTs. The patients

were 18 to 70 years old, and they had primary, secondary, or early
latent syphilis. No pregnant women or patient with coexisting HIV
infection were included in the 639 patients. Of the 639 patients,
335 were treated with azithromycin and 304 were treated with peni-
cillin via intramuscular or oral administration (Table 1).
Of the 73 excluded studies, 12 reported only the efficacy of peni-
cillin or azithromycin, nine studies compared penicillin with drugs
other than azithromycin, and 52 studies were not RCTs.

3.2 | Methodological quality of included studies

Of the seven RCTs included in this study, all seven reported random-
ized methods and performed allocation hiding, and the outcome data
for three of them were incomplete (Figures 2 and 3).

3.3 | Three-month response rate

Five RCTs reported data on the 3-month response rate to treatment.

A meta-analysis showed no significant difference in the 3-month
response rates for patients treated with azithromycin compared with
patients treated with penicillin (3-month response rate, azithromycin FIGURE 3 Risk of bias summary
77/228 vs penicillin 77/226; RR = 0.97, 95% CI 0.79-1.19; Z = 0.31,
P = .76). There was no evidence of significant heterogeneity between
the trials (I2 = 0%; P = .89) (Figure 4).
azithromycin-treated patients was not significantly different from
that of penicillin-treated patients (6-month response rate,
3.4 | Six-month response rate azithromycin 110/228 vs penicillin 105/224; RR = 1.01, 95% CI
0.85-1.20; Z = 0.08, P = .93). There was no evidence of signifi-
Five RCTs described data on the 6-month response rate to treat- cant heterogeneity between the trials (I2 = 0%; P = .94)
ment. A meta-analysis showed that the 6-month response rate of (Figure 5).
LI AND JIANG 5 of 7

3.5 | Twelve-month response rate azithromycin-treated patients was not significantly different from that
of penicillin-treated patients (serum fixation rate, azithromycin 3/64
Five RCTs described data on the 12-month response rate to treat- vs penicillin 3/64; RR = 0.71; 95% CI 0.24-2.12; Z = 0.61, P = .54).
ment. A meta-analysis showed that the 12-month response rate of There was no evidence of significant heterogeneity between the trials
azithromycin-treated patients was not significantly different from that (I2 = 0%, P = .73) (Figure 7).
of penicillin-treated patients (12-month response rate, azithromycin
132/225 vs penicillin 127/222; RR = 1.02, 95% CI 0.97-1.09;
Z = 0.79, P = .43). There was no evidence of significant heterogeneity 3.7 | Failure rate
between the trials (I2 = 0%; P = .99) (Figure 6).
Six RCTs described data on the treatment failure rate. A meta-analysis
showed that the 6-month response rate of azithromycin-treated patients
3.6 | Serum fixation rate was not significantly different from that of penicillin-treated patients
(failure rate, azithromycin 13/238 vs penicillin 24/235; RR = 0.62, 95%
Two RCTs described data on the serum fixation rate to treatment. A CI 0.33-1.16; Z = 1.50, P = .13). There was no evidence of significant het-
meta-analysis showed that the 6-month response rate of erogeneity between the trials (I2 = 53%; P = .08) (Figure 8).

FIGURE 4 Comparison of 3-month response rate between azithromycin-treated patients and penicillin-treated patients

FIGURE 5 Comparison of 6-month response rate between azithromycin-treated patients and penicillin-treated patients

FIGURE 6 Comparison of 12-month response rate between azithromycin-treated patients and penicillin-treated patients
6 of 7
FIGURE 7 Comparison of serum fixation rate between azithromycin-treated patients and penicillin-treated patients
FIGURE 8 Comparison of failure rate between azithromycin-treated patients and penicillin-treated patients
4 | DISCUSSION
In this study, the efficacy of azithromycin and penicillin in the treat-
ment of syphilis was compared based on data from published RCTs.
Compared with patients treated penicillin, patients treated with
azithromycin had a better 3-, 6-, and 12-month response rate. There
were no significant differences in relapse rates, serum fixation rates,
or failure rates. There was no significant difference in the syphilis
treatment effect of among the various azithromycin doses used. In
the included studies, there was no evidence to suggest the presence
of adverse effects in the azithromycin-treated patients. There is no
significant difference in the overall recurrence rate of penicillin- and
azithromycin-treated patients.22 Therefore, azithromycin appears to
be as effective as penicillin in the treatment of syphilis.
It is worth mentioning that azithromycin can also effectively treat
other sexually transmitted diseases, such as nongonococcal urethritis
and chlamydia trachomatis infection.23 In one study, azithromycin 1 g
appears to be an effective and safe alternative to doxycycline for the
treatment of chlamydial and nonchlamydial urethritis, and its single-
24
dose administration is an advantage in terms of patient compliance.
Collectively, azithromycin may be an effective approach to treat a
potential coinfection with early syphilis and chlamydia.
The incidence of syphilis has risen sharply in many developing
countries and in North America and Western Europe, and is mainly
related to the increasing HIV/AIDS infection rates, although the over-
all incidence of syphilis has declined since the advent of penicillin-
based treatments.25 Nevertheless, if not diagnosed and treated early,
26
syphilis can still cause serious complications. Penicillin is the stan-
dard treatment for syphilis, especially for patients infected with
HIV-1, and it is recommended by the Centers for Disease Control and
LI AND JIANG
Prevention. However, adverse events associated with penicillin
administration against syphilis include allergies or intolerance to intra-
muscular injection.
For syphilis, doxycycline and tetracycline appear to be as effec-
tive as penicillin and are recommended as second-line options. How-
ever, these drugs must be taken orally, which means poor compliance.
Azithromycin is also considered a potential alternative to penicillin in
the treatment of syphilis. However, the clinical effect of azithromycin
for treating syphilis is still controversial.27 The present meta-analysis
shows that the efficacy of azithromycin for treating syphilis is compa-
rable to that of penicillin.
As the data are limited and cannot provide guidance for clinical
practice, there are no clear clinical guidelines on this aspect; the
U.S. Food and Drug Administration (FDA) lacks recognition of studies
related to this. In the China National Emerging Infectious Diseases
Research Network, nearly 80% of the reports submitted by infectious
disease consultants in 1998 involved the use of azithromycin for
treating early syphilis.
As the physicians consulted are all infectious disease specialists,
this response may overestimate nationwide practices. Nevertheless, it
should not be ignored, especially when specialists often initiate prac-
tices that are eventually adopted by general practitioners. Clinicians
choose azithromycin because a patient has been or has been
suspected of being allergic to penicillin. It allows to expand the thera-
peutic panel in the management of syphilis, especially in the case of
allergy to penicillin, without restricting its effectiveness.
Penicillin is the mainstay of syphilis treatment, not because of
RCTs confirmation, but because of habit and history, and it is the first
available treatment. Therefore, from a statistical point of view, in addi-
tion to practical experience, penicillin has not been proven to be a
LI AND JIANG
better treatment. The current data suggest that azithromycin may be
considered an effective alternative to penicillin, especially when many
clinicians choose to use it. The present meta-analysis has the follow-
ing limitations. First, only seven RCTs met the inclusion criteria, and
the number of patients included is limited. Second, the dose of
azithromycin varied from trial to trial.
5 | C O N CL U S I O N S
In summary, currently available evidence has shown that the efficacy
of azithromycin for syphilis was not significantly different from peni-
cillin. In the future, large-scale, high-quality, placebo-controlled
double-blind trials are needed to determine whether azithromycin can
safely replace penicillin and treat syphilis.
ACKNOWLEDGMENT
This work was supported by Affiliated Hospital of Xuzhou Medical
University.
CONF LICT OF IN TE RE ST
The authors declare no potential conflict of interest.
AUTHOR CONTRIBUTIONS
Guan Jiang conceived and designed the experiments. Guan Jiang and
Yizhi Li performed the experiments and analyzed the data. Yizhi Li
wrote the paper.
ORCID
Guan Jiang https://orcid.org/0000-0001-9641-1207
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How to cite this article: Li Y, Jiang G. Azithromycin vs
penicillin G benzathine for early syphilis: A meta-analysis of
randomized controlled trials. Dermatologic Therapy. 2020;
e14025. https://doi.org/10.1111/dth.14025