Reexamining Syphilis: An Update on Epidemiology, Clinical Manifestations, and Management

Molly E Kent, PharmD; Frank Romanelli, PharmD MPH BCPS


The Annals of Pharmacotherapy. 2008;42(2):226-236. 

In This Article


The utility of penicillin in treating syphilis was established before the introduction of randomized, controlled clinical trials.[24] Due to a lack of randomized clinical trials, the exact dosage, duration, and preparation used are largely empiric and based on uncontrolled trials, case series, expert opinion, and clinical experience. Current treatment guidelines are based on disease staging, with later stages requiring longer treatment duration as the treponemes are dividing more slowly. Oral penicillin preparations are currently not recommended for the treatment of syphilis. To help avoid drug errors, clinicians should be aware that various preparations of parenteral penicillin exist. Recently, a clinic in Los Angeles inadvertently used Bicillin CR (benzathine penicillin 1.2 million units and procaine penicillin 1.2 million units) instead of recommended Bicillin LA (benzathine penicillin 2.4 million units) to treat syphilis, resulting in patients receiving half of the recommended dose of benzathine penicillin.[51]

Early Syphilis (Primary, Secondary, and Early Latent)

Early studies utilizing penicillin for the treatment of syphilis largely used procaine penicillin or aqueous penicillin. Due to the less frequent and more convenient administration schedule, benzathine penicillin is currently recommended for the treatment of early syphilis ( Table 2 ).[24] Approximately 15% of patients treated with benzathine penicillin for early syphilis will fail to respond to therapy when response is defined as a fourfold drop in nontreponemal titers after one year.

Treatment options for patients who are allergic to penicillin or who refuse parenteral therapy are based on even more limited data.[24] Ceftriaxone has been shown to be equally efficacious to penicillin in a few small studies, although the optimal dose has yet to be established.[24,52,53,54] Unlike benzathine penicillin, which does not penetrate the CSF, ceftriaxone adequately penetrates the CSF and therefore may theoretically provide additional benefit.[2] There is more literature supporting the use of tetracycline than of doxycycline; however, doxycycline is currently recommended as first-line therapy due to decreased gastrointestinal adverse effects, less frequent dosing, and presumed equal efficacy.[2,24]

Late Latent Syphilis

The goal of treatment in late latent syphilis is to prevent the progression to tertiary syphilis.[24] Previous data demonstrated unacceptable failure rates of 10-21% in patients receiving total doses of penicillin G 2.4-5.9 million units intramuscularly and led to the conclusion that these doses may be too low to be effective.[55] The current recommended dosage of 2.4 million units intramuscularly administered weekly for 3 doses (7.2 million units total) is therefore estimated, but clinical experience shows it is likely effective. Patients allergic to penicillin who are treated with alternative regimens consisting of oral doxycycline and/or tetracycline warrant close clinical and serologic follow-up.[24]

Tertiary Syphilis

Tertiary syphilis of the gumma or cardiovascular type should be treated the same as late latent syphilis in all patients, including those with a penicillin allergy.[24] The goal of treatment at this stage is to prevent further complications, as therapy is minimally effective in reversing damage that has already occurred.


Since benzathine penicillin G does not penetrate the CSF, aqueous penicillin G or procaine penicillin G plus probenecid for 10-14 days is the recommended regimen for the treatment of neurosyphilis at any stage ( Table 2 ).[1,24] Since patients with tertiary syphilis should be treated for 3 weeks, benzathine penicillin can be added for up to 3 weeks following the above-cited regimens for patients with neurosyphilis in the late stage of syphilis.

There are limited therapeutic options available for the treatment of neurosyphilis in patients who are allergic to penicillin. Ceftriaxone is the recommended alternative, although there is some risk of cross-sensitivity.[24] There are no recommendations concerning extended treatment duration with ceftriaxone in patients with tertiary syphilis. Chloramphenicol has been shown to achieve adequate CSF levels and a therapeutic response in patients with neurosyphilis.[56,57] Additionally, there are some pharmacokinetic data demonstrating that doxycycline 200 mg by mouth twice daily achieves sufficient concentrations in the CSF with 26% penetration.[58] Due to the small number of patients in these studies, limited or lack of clinical experience, and the incidence of aplastic anemia with chloramphenicol, these regimens cannot be recommended.[24] The only other alternative for patients is penicillin desensitization following available published protocols.[59,60,61,62]

Jarisch-Herxheimer Reaction. As T. pallidum undergoes antibiotic-induced death, it may release significant amounts of cytokines whose activities may lead to the frequently occurring Jarisch-Herxheimer reaction.[13] Symptoms include acute fever, myalgia, headache, and tachycardia.[1] Additional symptoms, described as "therapeutic shock," include exacerbation of current syphilis symptoms such as chancre or rash.[2,13] The reaction usually starts within hours of treatment initiation and is normally limited to approximately 24 hours.[1] Analgesics and antipyretics may be useful in symptom management but have not been shown to have any value in prevention. Additional complications in pregnant females include increased uterine activity, fetal cardiac distress, and, in severe cases, preterm delivery or fetal death.

Response to Treatment

Patients should be evaluated clinically and serologically following treatment as appropriate, based on their disease stage, CSF status, and HIV status ( Table 3 ).[24] Nontreponemal tests are used to evaluate serological response because treponemal tests will remain persistently positive despite effective treatment and disease eradication.


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