Clinical Management of Early Syphilis

Katherine M Holman; Edward W HookIII


Expert Rev Anti Infect Ther. 2013;11(8):839-843. 

In This Article

Abstract and Introduction


Early syphilis therapy was a focus of intense research in the early 20th century with many and varied approaches being used. The development of penicillin and its efficacy in the treatment of syphilis transformed syphilis management for many with and at risk for infection. However, problems such as beta-lactam allergies and the desire for easily administered, alternate therapies have led to evaluation of multiple other drugs, with doxycycline currently recommended as the main alternative. Ceftriaxone and azithromycin have been shown to be effective, however, each has its own difficulties. Follow-up relies on serological testing, leading to concerns when these tests do not decline appropriately. Given concerns about the potential for increased risk for treatment failure, patients with HIV and pregnant women are of particular concern.


Management of syphilis, often referred to as the 'great imitator,' is and has been a societal and public health challenge throughout the history of medicine. References to syphilis occur throughout historical records, often expressing societal aspersions toward persons with the infection, and therapy for syphilis was a major focus of scientific research until the middle of the 20th century. Prior to the discovery of penicillin, many and varied therapies were used, including mercury-containing compounds, bismuth and malaria-induced fever therapies.[1,2] Early in the 20th century, Paul Ehrlich's discovery of the efficacy of salvarsan (compound 606), an arsenical compound, paved the way for more effective treatments.[2] Even then, however, therapies were not standardized, but all had aspects in common: long, intensive treatment courses and toxic side effects, leading some to speculate the treatment was worse than the disease. Prior to 1940, therapy for syphilis was arduous and questionably effective.

Alexander Fleming's discovery of penicillin changed the face of syphilis treatment forever. Following Howard Florey's techniques for production of medically usable penicillin in 1940 and John Mahoney's first trial as syphilis treatment in 1943,[2] effective and remarkably safe therapy was available for the first time. Initial penicillin compounds, however, had very short serum half-lives and there was much uncertainty about adequate dosing. Initial studies used the sodium salt of penicillin, and determined a total dose of penicillin required for cure of infection, albeit the drug had to be administered at impractically short dosing intervals.[3] Subsequently, longer acting formulations, including penicillin with beeswax-oil and procaine penicillin, allowed for more practical daily dosing.[4] Creation of depot forms, including PAM (penicillin in oil with aluminum monostearate) and benzathine penicillin, allowed for still longer intervals between dosing.[4]

Studies in the 1940s and 50s involving thousands of patients clearly demonstrated the utility of penicillin for syphilis therapy, however, methodological limitations, which included mixed regimens of penicillin and arsenicals, make application of these data to present-day care difficult.[3,5–7] Nonetheless, supported by those trials as well as years of experience, benzathine penicillin G has become the mainstay of therapy in the USA for early syphilis treatment.

Despite its 'wonder drug' status, penicillin was, and remains, not an ideal therapy for all persons with syphilis. It requires parenteral administration, and, as the drug became more widely used, allergies arose (up to 10% of patients may report penicillin allergy).[8] Also, in resource poor settings, access to safe injection equipment may be limited. Alternative therapies began to be evaluated in the 1950s and 60s.

Erythromycin's treponemocidal properties were first demonstrated in the 1950s,[9] however, much about the drug – dose, duration, formulation – remained unclear. Initial reports favored the estolate formulation, however hepatotoxicity, particularly in pregnant patients, subsequently resulted in disfavor.[10] Erythromycin-base preparations had variable blood levels, while erythromycin–ethylsuccinate and erythromycin–stearate formulations did not have much data to support their efficacy. Ultimately, a total of 20 g of erythromycin orally in divided doses was recommended for early syphilis treatment[9] based on small studies and case series. In 1965, to address the lack of data comparing the recommended treatment regimens, the Venereal Disease Branch of the CDC commenced the most definitive comparative study to date. Schroeter et al. reported on the results, which recommended that the standard 20 g erythromycin regimen be increased to 30 g due to unacceptable levels of treatment failure with the lower dose.[11] Years later, continued uncertainty, concerns about patient adherence to multiple daily doses and reports of treatment failure, and resulting congenital syphilis, in pregnant women led to the removal of erythromycin from treatment recommendations.[10]

Evaluations of tetracycline for syphilotherapy followed in due course. Initial reports varied, with treatment failures attributed to variations in potency of early formulations, however, 30 g of tetracycline over 10 days was found to be effective.[12] Although reports of effective treatment were noted in pregnant women, due to concerns over maternal hepatotoxicity and fetal adverse events, tetracyclines remained undesirable. Doxycycline soon became the favored drug over tetracycline due to its favorable dosing: every 12 h versus every 6 h. Initially, courses were prolonged,[13] but ultimately, 14-day courses of therapy were recommended and remain the standard alternative therapy to benzathine penicillin in the USA today.