Penicillin and Syphilis Treatment: Sole Option or One of a Few?

Scientist Alexander Fleming, FRS FRSE FRCS, discovered the world’s first broadly effective antibiotic, which he named penicillin.

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Though not the first antibiotic developed—that distinction would go to arsphenamine (Salvarsan)—the discovery of penicillin significantly altered the trajectory of modern medicine.¹ Despite the accidental finding of its mold precursor, penicillium, in 1928, widespread use of penicillin would not ultimately take off for nearly another 2 decades.¹ Although a host of other antibiotics have now supplanted penicillin for treatment of various infections, penicillin remains a mainstay of therapy for management of syphilis.² Additionally, Treponema pallidum, the causative organism implicated in syphilis infections, continues to demonstrate remarkable susceptibility to penicillin. However, in the era of drug shortages coupled with the impact of antibiotic allergy on treatment selection, the need for alternative therapeutic options in this setting has risen to a level of paramount importance.²

In a recent systematic review and meta-analysis by Callado and colleagues, authors sought to investigate the efficacy of nonpenicillin treatment strategies for management of nonneurological syphilis.² This study utilized the PICO framework, a specialized tool used to facilitate evidence-based literature searches.³ Articles that were included for analysis compared monotherapy with either penicillin or amoxicillin to other treatment strategies.² Studies reporting a small proportion of patients with neurosyphilis (< 1%) were notably not excluded.² Quality assessment of included studies was performed by independent reviewers.² The primary outcome of interest was serological response, based on specific definitions detailed in analyzed studies.²

A total of 27 studies met inclusion criteria, constituting 6710 syphilis events.² Included studies consisted of 10 randomized trials, 16 retrospective cohort studies and 1 prospective study.² Most studies were deemed to be of high quality (n = 22), while the remainder were thought to be fair.² More than 80% of analyzed studies (n = 22) compared penicillin to monotherapy with different agents, including doxycycline (n = 8), ceftriaxone (n=5), azithromycin (n = 5) and minocycline (n = 2); 1 study looked at doxycycline and ceftriaxone, evaluated separately.² The type of serological testing employed (treponemal and nontreponemal) varied among studies.² Most studies (n=24) defined the primary outcome as greater or equal to a 4-fold decline in titers of a nontreponemal test.²

Reported time to cure ranged from 6 to 24 months.² Twenty-one studies identified no difference between monotherapy with penicillin vs other treatment strategies with respect to the primary outcome of serological cure.
Study authors also performed stratified analyses comparing monotherapy with benzathine penicillin with doxycycline, ceftriaxone, and azithromycin monotherapies, respectively. No statistically significant differences in serological response were observed.² Notably, when analysis of penicillin with ceftriaxone was expanded to include an article that evaluated cefixime (a different third-generation cephalosporin), conclusions shifted in favor of cephalosporins.

Additionally, an analysis of penicillin compared to various combination therapies was conducted. Drug combinations characterized within these studies included penicillin plus doxycycline, penicillin plus ceftriaxone, penicillin plus ceftriaxone and doxycycline, penicillin plus azithromycin, penicillin plus amoxicillin and probenecid, and amoxicillin plus probenecid.² Overall, a small yet significant difference was observed in favor of combination therapy vs treatment with penicillin alone.² Moreover, associated heterogeneity within these stratified analyses was deemed to be low.²

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Reinfection was discussed in 16 articles and was most commonly defined as greater or equal to a 4-fold increase of titers during follow-up period (n = 8), with a few studies adding the development of new symptoms to this definition (n =3).² Reported rates of reinfection varied from none to greater than 50% of cases.² Only a third of included studies (n = 9) reported adverse effects.² Notably, gastrointestinal effects and Jarisch-Herxheimer reactions were reported in 6 and 4 of those studies, respectively.² In general, no significant difference in therapy-associated adverse effects were identified.²

The results of this systematic review and meta-analysis offers helpful insight into the prospect of alternative treatment strategies against nonneurological syphilis. More than 200,000 cases of syphilis were reported in the United States in 2022.⁴ This figure represents both an increase of more than 17% since 2001 and the largest number of reported syphilis cases since 1950.⁴ These trends have largely coincided with increases in demand and subsequent product shortages for intramuscular penicillin, underscoring the need for additional therapeutic options.⁵

For management of primary, secondary, or latent syphilis, the Centers for Disease Control and Prevention (CDC) only recommend use of alternative therapies in the setting of penicillin allergy.⁵ Alternate therapy with doxycycline is preferentially recommended in light of its optimal compliance rates, tolerability, and promising clinical data supporting its use.⁵ Ceftriaxone is also recommended as an alternate therapy, although full endorsement by the CDC for its use is limited by lack of clinical experience with this agent in addition to uncertainly regarding optimal dosing in latent syphilis.⁵ While efficacy of single-dose azithromycin in select cases of primary and secondary syphilis has been observed in literature, the CDC advises against use of this agent due to concerns regarding macrolide resistance in this setting.

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In the present study, comparable efficacy and safety outcomes were observed with doxycycline, ceftriaxone, and azithromycin monotherapies relative to standard-of-care therapy with penicillin. Moreover, slightly favorable outcomes were observed with cephalosporins and select combination therapies compared to penicillin monotherapy. The number of articles analyzed in this study, along with its robust review of alternate single-agent and combination-agent treatment strategies, were key strengths of this review. That said, this study was not without limitations.

Most studies included for analysis were retrospective cohort studies and not randomized trials. Furthermore, a handful of studies had missing or incomplete data for pertinent clinical outcomes including rate of reinfection and medication-associated adverse events. Lastly, this study focused on clinical outcomes for earlier stages of syphilis, thus rendering it challenging to extrapolate findings to patients with neurosyphilis, otosyphilis, or ocular syphilis. Although these findings add to the growing compendium of literature evaluating the utility of alternate treatment options for management of syphilis, further research is still warranted.

References

1. Hutchings MI, Truman AW, Wilkinson B. Antibiotics: past, present and future. Curr Opin Microbiol. 2019;51:72-80. doi:10.1016/j.mib.2019.10.008
2.Callado GY, Gutfreund MC, Pardo I, et al. Syphilis treatment: systematic review and meta-analysis investigating non-penicillin therapeutic strategies. Open Forum Infect Dis. 2024;11(4):ofae142. doi:10.1093/ofid/ofae142
3.Frandsen TF, Bruun Nielsen MF, Lindhardt CL, Eriksen MB. Using the full PICO model as a search tool for systematic reviews resulted in lower recall for some PICO elements. J Clin Epidemiol. 2020;127:69-75. doi:10.1016/j.jclinepi.2020.07.005
4.National overview of STIs, 2022. CDC. Updated January 30, 2024. Accessed April 1, 2024. https://www.cdc.gov/std/statistics/2022/ overview.htm.
5.Workowski KA, Bachmann LH, Chan PA, et al. Sexually transmitted infections treatment guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187. doi:10.15585/mmwr.rr7004a1