Syphilis Treatment & Management

Penicillin is the treatment of choice for treating syphilis. According to the Centers for Disease Control and Prevention (CDC) (see current CDC recommendations), patients with known penicillin allergies should undergo penicillin allergy skin testing and penicillin desensitization, if necessary.^[25] The 2010 CDC STD treatment guidelines recommend desensitization in penicillin-allergic pregnant women, followed by treatment with penicillin.^[18]

Clinical and serologic conversions are the endpoints of medical treatment for syphilis. Follow-up Venereal Disease Research Laboratory (VDRL) test levels should be obtained to document treatment efficacy.

Penicillin

Penicillin was established as an effective treatment for syphilis before the widespread use of randomized clinical trials.^[18] The treatment guidelines published by the CDC (see current CDC recommendations) are based largely on uncontrolled trials and expert opinion. Guidelines are based on staging, with later stages requiring longer courses of treatment due to the slower rate of bacterial replication.

Penicillin remains the mainstay of treatment and the standard by which other modes of therapy are judged.^[26] The 2010 CDC STD treatment guidelines support the use of penicillin as the preferred drug for treating all stages of syphilis.^[18] Penicillin is the only therapy used widely for neurosyphilis, congenital syphilis, or syphilis during pregnancy. Rarely, T pallidum has been found to persist following adequate penicillin therapy; however, there is no indication that the organism has acquired resistance to penicillin.

The following regimens are recommended for penicillin treatment:

• Primary or secondary syphilis - Benzathine penicillin G 2.4 million units intramuscularly (IM) in a single dose
• Early latent syphilis - Benzathine penicillin G 2.4 million units IM in a single dose
• Late latent syphilis or latent syphilis of unknown duration - Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals
• Pregnancy - Treatment appropriate to the stage of syphilis is recommended.^[20]

In patients with a history of penicillin allergy, skin testing is recommended. Patients who are skin test negative can receive conventional treatment with penicillin; skin test positive patients should be desensitized in the hospital. Make every effort to document penicillin allergy before choosing an alternative treatment, because the efficacy of alternative regimens is questionable in all stages of syphilis. Many treatment failures have been reported.

According to the 2010 CDC STD guidelines, no treatment regimens for syphilis have been shown to be more effective in preventing neurosyphilis in patients who are HIV positive than the syphilis regimens recommended for patients who are HIV negative. Careful monitoring after therapy is required.^[18]

Alternatives to penicillin

As stated in the 2010 CDC guidelines, several therapies exist that might be effective in nonpregnant, penicillin-allergic patients with primary or secondary syphilis.^[18]

Tetracycline, erythromycin, and ceftriaxone^[27] have shown antitreponemal activity in clinical trials; however, they currently are recommended only as alternative treatment regimens in patients allergic to penicillin. The 2010 CDC guidelines suggest that a 10- to 14-day trial of ceftriaxone is effective for treating early syphilis, although the optimal dose and duration have not been established. Doxycycline and tetracycline have been used for many years.^[18]

Azithromycin has also been studied. A meta-analysis of randomized clinical trials comparing azithromycin to benzathine penicillin G for early syphilis was published in 2008 showing favorable results for azithromycin.^[28] The CDC 2010 STD treatment guidelines cite the effectiveness of azithromycin in treating early syphilis. However, there are documented cases of treatment failure due to azithromycin-resistant mutations in T pallidum in several areas of the United States. Therefore, azithromycin should be used only when the use of penicillin or doxycycline is not feasible. Its use in men who have sex with men (MSM) or pregnant women is contraindicated.^[18] A 2010 study by Hook et al showed a single dose of azithromycin (2 g PO) to be equivalent to the treatment of choice, benzathine penicillin G (2.4 million units IM) in patients with early syphilis without HIV. Serological cure after 6 months of follow-up was not significant between the 2 treatments, although azithromycin recipients had a higherincidence of adverse effects (mostly self-limited gastrointestinal symptoms).^[29]

A larger, multicenter trial is needed to confirm these results before this treatment can be recommended. Azithromycin treatment failures have been reported by the CDC.^[30]

Jarisch-Herxheimer reaction

Following the initiation of treatment, the dying treponemes release inflammatory molecules that trigger a cytokine cascade possibly leading to a response known as the Jarisch-Herxheimer reaction. Symptoms include myalgias, fever, headache, and tachycardia, sometimes with exacerbation of whatever current syphilitic lesions are manifested (eg, rash or chancre).

The reaction is common, develops within several hours after beginning antibiotic treatment, and usually clears within 24 hours after onset. Its exact etiology is unclear, although it may be due to an immunological reaction to the rupture of spirochetes.

Management of this reaction often involves symptomatic treatment (eg, with antipyretics and analgesics) and observation. In pregnant women, treatment may induce early labor or cause fetal distress. Patients should be informed of the possibility of this reaction before undergoing antibiotic therapy. As stated in the CDC 2010 STD treatment guidelines, although the Jarisch-Herxheimer reaction might induce obstetric complications such as early labor or fetal distress, this risk should not preclude or delay therapy for syphilis.^[18] Women are advised to seek obstetric care after treatment if they notice any fever, uterine contractions, or a decrease in fetal movement.^[18]

Procaine toxicity

Some patients experience severe anxiety and other psychological disturbances after the administration of procaine penicillin. Fever, hallucinations, hyperventilation, and convulsions characterize the reaction. Circulatory collapse is occasionally reported.

Resuscitation and supportive care are necessary in severe cases; however, most reactions are mild, requiring only reassurance or symptomatic relief. Symptoms usually dissipate within 30 minutes.

Surgical care is reserved for treating the complications of tertiary syphilis (eg, aortic valve replacement).

The primary goal of prevention is to limit the spread of syphilis. This entails counseling patients to use safe sex practices and advising patients who abuse intravenous (IV) drugs to never share needles and to use clean needles. Notification and treatment of sexual partners and exposed drug partners are paramount. Prevention also entails educating health care workers to use universal precautions when treating all patients.

Studies of primary screening for syphilis in clinics and emergency departments are favorable for screening of high-risk, inner-city populations. Routine screening is advocated for all at-risk mothers.

Two reports from 2009 indicate that circumcision does not help prevent the transmission of syphilis, although circumcision may help prevent the transmission of viral sexually transmitted diseases.^{[31, 32]}

Consultation with an infectious diseases specialist may be required for difficult or complex cases of syphilis. Consult with a dermatologist, vascular surgeon, ophthalmologist, or neurologist should also be obtained as necessary to assist with the variable presentations of syphilis.

Additionally, the CDC, the World Health Organization (WHO), and Morbidity and Mortality Weekly Report (MMWR) are excellent updated references. Syphilis may be reportable to public health authorities in some jurisdictions.

Inpatient care is generally reserved for complications of late syphilis.

Monitor patients with syphilis to ensure adequacy of treatment. The Clinical Effectiveness Group notes that follow-up visits in patients with syphilis should be performed at 3-, 6-, and 12-month intervals. Patients with HIV infection or patients treated with a nonpenicillin regimen should be monitored for life.

Generally speaking, therapy is considered a failure if the signs and symptoms of syphilis return. This occurs when the titer of the nontreponemal test increases 4-fold or a 4-fold decrease from the initial VDRL titer does not occur within 1 year.

However, clearly defined criteria regarding treatment failure are lacking. In their literature review, Augenbraun and Rolfs found that 15-25% of patients treated for syphilis do not have a 4-fold decrease in titers over a 3-month period, and some do not have a decrease for 6 months or longer.^[33] Information is lacking on whether these patients are at higher risk for progression. Currently accepted guidelines are as follows:

• Any reappearance of symptoms is defined as a relapse.
• More than a double-dilution increase (ie, a 4-fold titer increase) in serologic tests is a relapse.
• Patients with latent syphilis who have initially high titers (≥1:32) and fail to have a double-dilution decrease (4-fold titer decline) 12-24 months after therapy should be reevaluated for neurosyphilis and possible retreatment.
• Some treponemal test results may remain positive for life despite effective treatment. Individuals in this circumstance require proper documentation to avoid unnecessary retreatment.
• Supervise retreatment to ensure compliance.

Recommendations for specific patient subsets are as follows.

Patients with treated primary or secondary syphilis

Patients treated for primary and secondary syphilis should have follow-up VDRL testing at 3, 6, and 12 months after treatment. Patients with HIV should be monitored closely, as they are known to have more rapid progression of disease. Most patients with primary syphilis who are treated adequately have a nonreactive VDRL within 1 year, and almost all patients treated for secondary syphilis have a negative VDRL result within 2 years. A small minority of patients remain seropositive in spite of successful treatment.

According to the 2010 CDC STD guidelines, HIV-infected individuals should be assessed clinically and serologically for treatment failure at 3, 4, 9, 12, and 24 months post therapy.^[18]

If the VDRL titer of 1:8 or more fails to fall at least 4 fold within 12 months or if the titer starts to rise, consider more intensive retreatment, and examine the cerebrospinal fluid (CSF). If all clinical and serologic examinations remain satisfactory for 2 years following treatment, the patient can be reassured that cure is complete, and no further follow-up care is needed.

Patients with latent syphilis

Perform quantitative reagin testing for up to 2 years. Schedule annual follow-up visits for an indefinite period of time for patients with persistently positive serologic tests.

The 2010 CDC STD treatment guidelines state that HIV-infected individuals with latent syphilis should receive the same stage-specific treatment as recommended for HIV-negative individuals.^[18]

Patients with benign tertiary or cardiovascular syphilis

Patients should be observed by the physician for the rest of their lives to monitor for complications.

Patients with neurosyphilis

Patients with neurosyphilis should have follow-up at 6-month intervals for at least 3 years with physical examinations, CSF evaluation (eg, cell count, protein, reagin titer), and serologic testing.

Go to Neurosyphilis for complete information on this topic.

Pregnant patients with syphilis

Pregnant women treated for syphilis should have monthly VDRL testing for the duration of their pregnancy.