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

Abstract

Background Penicillin's long-standing role as the gold 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 non-neurological syphilis. Methods We searched MEDLINE, CINAHL, Embase, Cochrane, Scopus, and Web of Science from database inception to August 28th, 2023, and included studies that compared penicillin or amoxicillin monotherapy to other treatments for the management of non-neurological 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 6,478 screened studies, 27 met the inclusion criteria, summing 6,710 patients. The studies were considerably homogeneous, and stratified analyses considering each alternative treatment separately revealed that penicillin monotherapy did not outperform ceftriaxone (pooled OR, 1.66; 95% CI, 0.97–2.84; I2 = 0%), azithromycin (pooled OR, 0.92; 95% CI, 0.73–1.18; I2 = 0%), or doxycycline (pooled OR, 0.82; 95% CI, 0.61–1.10; I2 = 1%) monotherapies regarding serological conversion. Conclusions Alternative treatment strategies have equivalent serological cure rates to penicillin, potentially reducing global dependence on this antibiotic.

Prevalence and Treatment Outcomes of Syphilis among People with Human Immunodeficiency Virus (HIV) Engaging in High-Risk Sexual Behavior: Real World Data from Northern Greece, 2019–2022

“…The prevalence of syphilis stages varies among different studies [32]. We noted that the majority of syphilis cases involved latent stages, with only one case presenting as neurosyphilis.…”

“…The treatment of choice for all stages of syphilis (excluding neurosyphilis) in PWH remains intramuscular BPG, with reported rates of serological response ranging from 70% to 95% in the international literature [22,32]. Alternative treatment options include doxycycline and ceftriaxone [22].…”

“…The need for new antimicrobial agents is an ongoing domain of discussion and research [15,16]. While penicillin remains highly effective for syphilis, the exploration of new treatments is motivated by factors such as penicillin shortages, patient inconvenience with multiple injections, and allergies [32]. There have been reports of penicillin-resistant strains of syphilis, although they are still relatively rare [39].…”

“…There have been reports of penicillin-resistant strains of syphilis, although they are still relatively rare [39]. A recent systematic review and metaanalysis of 27 studies showed that monotherapy with penicillin did not outperform other monotherapies, such as doxycycline, ceftriaxone, and azithromycin, in terms of serological conversion [32]. This suggests a potential to reduce global reliance on penicillin, including for PWH, when it is unavailable.…”

Comment on Callado et al: “Syphilis Treatment: Systematic Review and Meta-analysis Investigating Nonpenicillin Therapeutic Strategies”

“…To the Editor —In an era of steadily increasing rates of syphilis, dramatic rises in congenital syphilis, and intermittent scarcity of first-line benzathine penicillin G (BPG), providers and health jurisdictions are more frequently turning to alternative treatment options. Callado et al conducted a systematic review and meta-analysis to summarize evidence from clinical trials and cohort studies through August 2023 comparing 3 nonpenicillin antibiotics with BPG for the treatment of syphilis [ 1 ]. The meta-analysis includes 5 studies that evaluated azithromycin as monotherapy for syphilis, all of which took place between 1995 and 2014.…”