Syphilis Treatment: Systematic Review and Meta-Analysis Investigating Nonpenicillin Therapeutic Strategies

Abstract Background Penicillin's long-standing role as the reference standard in syphilis treatment has led to global reliance. However, this dependence presents challenges, prompting the need for alternative strategies. We performed a systematic literature review and meta-analysis to evaluate the efficacy of these alternative treatments against nonneurological syphilis. Methods We searched MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, Embase, Cochrane, Scopus, and Web of Science from database inception to 28 August 2023, and we included studies that compared penicillin or amoxicillin monotherapy to other treatments for the management of nonneurological syphilis. Our primary outcome was serological cure rates. Random-effect models were used to obtain pooled mean differences, and heterogeneity was assessed using the I2 test. Results Of 6478 screened studies, 27 met the inclusion criteria, summing 6710 patients. The studies were considerably homogeneous, and stratified analyses considering each alternative treatment separately revealed that penicillin monotherapy did not outperform ceftriaxone (pooled odds ratio, 1.66 [95% confidence interval, .97–2.84]; I2 = 0%), azithromycin (0.92; [.73–1.18]; I2 = 0%), or doxycycline (0.82 [.61–1.10]; I2 = 1%) monotherapies with respect to serological conversion. Conclusions Alternative treatment strategies have serological cure rates equivalent to penicillin, potentially reducing global dependence on this antibiotic.

Penicillin is universally recognized as the reference standard therapy for treating syphilis in all stages [1].Its targeted action on bacterial cell wall synthesis has rendered Treponema pallidum highly susceptible, and remarkably there are no documented cases of penicillin resistance in the medical literature [2].Despite penicillin's widespread use worldwide, its therapeutic merits and established efficacy over many years have made it synonymous with syphilis treatment in practical clinical settings.Many countries have heavily relied on this single-drug approach for managing patients with syphilis.However, this comes with significant challenges.Penicillin shortages in certain centers has led to adverse impacts on syphilis control efforts [3,4].Moreover, penicillin allergies also pose challenges to the management of syphilis [5].
The pursuit of penicillin alternatives for syphilis treatment is essential.It ensures that fluctuations in the availability of a single drug do not have a detrimental impact on managing a disease responsible for significant morbidity.In this systematic literature review and meta-analysis, we investigate the efficacy of alternative drug strategies for nonneurological syphilis treatment.By analyzing comparative studies, we explore these alternatives' effectiveness in managing nonneurological syphilis.

Systematic Review and Search Strategies
This systematic literature review adhered to both the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [6] and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines [7].It was registered on Prospero on 8 September 2023 (registration no.CRD42023458547).

Search Strategy
Our search strategy was developed with the guidance of a health sciences librarian.We conducted comprehensive searches across multiple databases, including MEDLINE (PubMed), the Cumulative Index to Nursing and Allied Health Literature, Cochrane CENTRAL, Web of Science, Scopus, and Embase.Our search encompassed publications from the inception of each database up to 28 August 2023 (Supplementary Table 1).
This study uses the PICO framework [8].Focusing on patients diagnosed with nonneurological syphilis (P), the study compares treatment strategies not solely based on penicillin (I) against conventional penicillin or amoxicillin monotherapies (C).Our primary outcome of interest (O) was serological cure rates.
We excluded comments or reviews, noncomparative studies, pilot studies, studies performed solely in children, and those including strictly neurosyphilis, otosyphilis, and/or ocular syphilis.However, studies that presented a reported small proportion of patients (<1%) identified as neurosyphilis were not excluded.
All titles and/or abstracts were examined (G.Y. C. and A. R. M.), and those deemed unsuitable were excluded.Disparities were resolved through discussion.After this first evaluation, all the remaining articles were fully read, and the studies that met the inclusion criteria were included in the systematic review (Figure 1).

Data Abstraction and Quality Assessment
Of 10 independent reviewers (G.Y. C., M. C. G., I. P., M. K. H., V. L., M. M. S., G. R. N., T. A. M., R. O. D., and A. R. M.), 2 abstracted data from each article using a standardized abstraction form (Supplementary Form 1).We recorded the publication year, study period, design, population, setting, analyzed drugs, dosage, duration of the compared strategies, serological response definition, cure rates, and adverse effects associated with treatment.
We used the Downs and Black scale [9] to assess the quality of the studies included in our review.Each article underwent a thorough evaluation, with all the original scale's questions being addressed, and we calculated a total score.We made a modification to question 27, substituting the multiple-choice options with a simple yes/no response format.The maximum achievable score on this scale was 28.Our reviewers independently assessed the individual components' quality, and any disparities were resolved through discussion.

Patient Consent Statement
The present investigation is a systematic literature review and meta-analysis of published data, so no patient-informed consent was required.

Statistical Analysis
Our outcome of interest was a serological response according to the definition presented by the analyzed article.For all the studies, we considered information referring to the longest reported follow-up.We evaluated responses to the compared therapy strategies by using a random-effects model.This model estimated pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs).We determined weights for the analysis in accordance with the approach outlined by DerSimonian and Laird [10].We performed stratified analyses considering each studied drug, study design, publication period, location, nontreponemal/treponemal tests applied, human immunodeficiency virus (HIV) serological status, and other variables (Supplementary Table 2).
Heterogeneity between studies was evaluated using the I 2 statistic and the Cochran Q statistic test.We used Cochrane Review Manager (RevMan), Web edition 4.12.0.Publication bias was evaluated by visual inspection of funnel plots with RevMan (Supplementary Figure 2) and was also evaluated by applying the Egger test with Comprehensive Meta-Analysis software, version 4 (Biostat).
We included a total of 6710 syphilis events from all 27 studies in our analysis.All studies in this systematic review included patients with nonneurological stages of syphilis.In addition, 4 included a total of 34 patients with neurosyphilis [15,24,29,30].Since the proportion of these patients was low (0.5% of all included patients), we opted to maintain these studies in our main analysis.However, we performed a stratified analysis of studies that did not include any participants with neurological syphilis (Supplementary Figures 1H-1J).
We intended to compare penicillin monotherapy with other strategies.As 4 studies considered 3 comparison groups each [18,20,24,28], we had to choose a pair of groups to include in the meta-analysis.For Hook et al (2002) [18] and Shao et al [28], we chose the intervention group to be patients who received azithromycin (4 g) and minocycline (4 weeks), respectively, because the difference in outcomes was greater between these groups and the penicillin group.For Kiddugavu et al [20], and Psomas et al [24], the selected criteria were based on the similarity in the number of participants included in the penicillin and the intervention groups (azithromycin and ceftriaxone groups, respectively).For Hook et al (2010) [19], we included data reported in the intention-to-treat analysis because it maximized the number of included patients.On this first global analysis, the degree of heterogeneity was acceptable (P = .04;I 2 = 36%).However, to mitigate this heterogeneity level and compare each treatment strategy more precisely, we performed a stratified analysis based on the comparator antibiotic regimen used.
We also analyzed the 5 studies that compared BPG with ceftriaxone [13,15,22,24,30] (Figure 3).We observed no significant difference between the rates of cure (pooled OR, 1.66 [95% CI, .97-2.84]).This analysis was performed with low heterogeneity (P = .47;I 2 = 0%).However, when we added the study that evaluated cefixime [23], another third-generation cephalosporin similar to ceftriaxone, the conclusion favored the use of cephalosporins (pooled OR, 1.67 [95% CI, 1.04-2.69]),with *The first value refers to the control group (BPG), the second value refers to the first intervention group, and the third value refers to the second intervention group.
The funnel plot (Supplementary Figure 2) revealed that the 27 studies included in the meta-analysis were reasonably balanced around the pooled ORs.Thus, there was little evidence of publication bias.The Egger test also did not indicate publication bias among those studies included in the meta-analysis (P = .81).

DISCUSSION
In this systematic review and meta-analysis, various drug strategies have been shown as viable alternatives to penicillin in treating nonneurological syphilis.For example, monotherapy with drugs such as doxycycline, ceftriaxone, and azithromycin had outcomes similar to those of traditional penicillin monotherapy in terms of safety and efficacy.Combination therapies also appear to be viable alternatives.
To the best of our knowledge, the present study represents the most comprehensive systematic review and meta-analysis comparing multiple interventions for syphilis therapy, and it is the  [12,17,21,24,27,31,32,34,37].Odds ratios (ORs) were determined using the Mantel-Haenszel random-effects method and are shown with 95% confidence intervals (CIs).Figure 3. Forest plot of syphilis serological conversion after BPG monotherapy or ceftriaxone monotherapy [13,15,22,24,30].Odds ratios (ORs) were determined with the Mantel-Haenszel random-effects method and are shown with 95% confidence intervals (CIs).
only review that includes studies evaluating drug combination strategies.Our results have shown that penicillin is not more effective than other strategies in terms of serological response.On the contrary, we have found similarities when comparing penicillin with tetracycline and azithromycin and a slight advantage favoring cephalosporins and combination treatment.These results are similar to those obtained by other reviews [38][39][40].
The acceptability of treatment to patients is a fundamental consideration in therapeutic recommendations.Understandably, patients may prefer oral or intramuscular administration over intravenous, and they may prefer taking medication as infrequently as possible, whether daily or weekly.Convenience is a crucial aspect of a treatment plan, as it significantly influences a patient's adherence to treatment until its completion.Given this, it might be more appropriate for some patients to take oral antibiotics (eg, doxycycline and azithromycin) instead of intravenous drugs (eg, ceftriaxone) or intramuscular drugs (eg, BPG).For instance, the potential benefits of shorter treatment durations, improved accessibility, and reduced costs [41] associated with alternative antibiotics could significantly enhance the feasibility and success of syphilis treatment, especially in settings with limited resources.Furthermore, coinfection with other bacteria, such as Chlamydia trachomatis and Neisseria gonorrhoeae, may not be uncommon, and patients could benefit from the use of doxycycline [42].
Globally, people with syphilis are commonly coinfected with HIV [43].Our stratified analysis focusing exclusively on people living with HIV indicated that this population can derive equal benefits from alternative drug strategies with respect to efficacy and security.This knowledge holds significant relevance in the healthcare of these individuals, as they are at increased risk of becoming immunodeficient, necessitating careful consideration when selecting medications.
In their latest guidelines on treatment for sexually transmitted infections [5], the Centers for Disease Control and Prevention (CDC) recommends penicillin G as the first-line   [11,14,16,20,26,36].Odds ratios (ORs) were determined with the Mantel-Haenszel random-effects method and are shown with 95% confidence intervals (CIs).
treatment for syphilis across all stages, but they do acknowledge alternative options for individuals with penicillin allergies.In this regard, the CDC exercises caution but endorses doxycycline and tetracycline as viable alternatives, with a preference for doxycycline, given its better compliance rates and reduced incidence of gastrointestinal adverse effects.Furthermore, the CDC notes the effectiveness of ceftriaxone and azithromycin but discourages the latter due to rising concerns about antibiotic resistance [44].Our results do not invalidate penicillin as the reference standard for treating nonneurological syphilis.Instead, they indicate that there are consistent data affirming that other alternatives can be considered in scenarios where penicillin is not available.
Our study has several limitations.First, most studies (17 of 27) were nonrandomized.Second, there were missing data on important analyzed aspects, including adverse events related to drugs and information about reinfected patents.Therefore, we could not perform a statistical analysis focused on reinfection.In addition, variety concerning treponemal and nontreponemal tests may have affected the homogeneity of the analysis.Moreover, the absence of a standardized definition for serological cure and the varying criteria for the ideal serological cure time may have affected the homogeneity of our analysis.Heterogeneity was also observed in certain analyses, which could stem from variations in study designs, geographic locations, and patient populations.
Fourth, it was beyond the scope of this review to assess the financial impact or other unintended consequences of adopting any of the analyzed drugs for syphilis treatment, especially in the context of population-wide strategies.Fifth, our inclusion criteria were limited to comparative studies, which required the presence of a control group (penicillin and derivatives) and ≥1 intervention group (involving other drugs or strategies).This approach excluded studies that focused solely on a single drug, potentially limiting our understanding of adverse effects and associated costs for that specific drug.Sixth, our review specifically excluded studies focused on children, neurosyphilis, ocular syphilis, and otosyphilis.Therefore, it remains uncertain whether the conclusions drawn from our metaanalysis can be extrapolated to patients with these conditions.It is vital to note that while our study focused on early syphilis stages, it is particularly important for healthcare providers to conduct a thorough workup to ensure the proper staging of syphilis, as inadequate treatment in more advanced cases can lead to poor outcomes.Seventh, none of the drug combination strategies were evaluated by more than one study, which has limited our stratified analysis.We were only able to evaluate a "drug combination" group, without stratifying it into specific strategies.
In conclusion, considering our findings and limitations, it is evident that further research is essential in syphilis therapy.More randomized controlled trials are needed to establish a robust foundation for treatment recommendations.In addition, the absence of standardized definitions for serological cure and ideal time frames for seroconversion necessitates the development of uniform criteria to enhance the consistency of future analyses.Moreover, extending investigations to include patients with neurosyphilis, ocular syphilis, and otosyphilis is crucial, given our study's focus on nonneurological syphilis.Finally, studying the financial impacts of various treatment options is crucial as population-wide syphilis management strategies advance.Our study indicates that alternative drug strategies, such as ceftriaxone, azithromycin, and doxycycline monotherapies, can reduce the dependency on penicillin for nonneurological syphilis, including among HIV-positive patients, in scenarios where penicillin use is not feasible.

Figure 1 .
Figure 1.Literature search for articles that evaluated the syphilis treatment alternatives against nonneurological syphilis.Abbreviation: CINAHL, Cumulative Index to Nursing and Allied Health Literature.