The treatment of syphilis infection is curative with appropriate antibiotics. Prompt diagnosis and antibiotic therapy is important because of the possibility of long-term complications, either from untreated infection or from prolonged infection of unknown duration. Parenteral benzylpenicillin is the first-line drug treatment for all stages of syphilis, as recommended by the US Centers for Disease Control and Prevention (CDC).[5] The preparation (i.e., benzathine, procaine, aqueous), dose, and length of treatment are determined by the stage and clinical manifestations of the disease.[5][3][95][96]

Without neurosyphilis

Treatment may follow diagnostic test results or may be empirical. Empirical therapy may be considered in those with suspected early infection (a rash or ulceration) before results of serology are available. This approach may be appropriate if there are concerns regarding re-attendance. Sexual contacts of patients with confirmed syphilis should be screened and offered presumptive treatment if follow-up may be problematic. The benefits of empirical therapy (prompt therapy) and risks (potentially unnecessary treatment) should be discussed with the patient.

The first-line treatment for primary, secondary, and early latent syphilis (without neurosyphilis) is intramuscular benzathine benzylpenicillin as a single dose.[5] If the patient is allergic to penicillin and is not pregnant, oral doxycycline may be offered as a first-line treatment. Adherence and patient compliance may influence treatment outcome if oral therapy is administered. Single-dose azithromycin is used in some centres, but is not recommended by the CDC due to concerns regarding macrolide resistance.[97][98][99]

Treatment of latent syphilis is intended to prevent late complications. The first-line treatment of late latent and tertiary (gummatous and cardiovascular) syphilis (without neurosyphilis) is intramuscular benzathine benzylpenicillin given as three doses over 2 weeks (days 0, 7, 14). Oral doxycycline may be offered as a first-line treatment to patients with penicillin allergy. Patients who have symptomatic gummatous syphilis or cardiovascular syphilis should undergo cerebrospinal fluid (CSF) examination before treatment is started.

Untreated cardiovascular (latent) syphilis may be asymptomatic, or cause aortic aneurysm (mainly thoracic), aortic regurgitation, angina, or stenosis of coronary ostia. Antibiotic therapy for cardiovascular syphilis does not reverse cardiovascular disease, which may continue to progress after treatment. This is because the underlying pathology of medial necrosis of the aortic wall has been established. Discussion with a cardiologist is advised.


Central nervous system involvement can occur at any stage of syphilis, and can range from asymptomatic meningeal involvement to dementia and sensory neuropathy. First-line treatment for neurosyphilis is intravenous aqueous benzylpenicillin. Second-line treatment is intramuscular procaine benzylpenicillin plus oral probenecid. Some specialists administer intramuscular benzathine benzylpenicillin once weekly for up to 3 weeks after the treatment regimen for neurosyphilis has been completed, to ensure that the duration of treatment is comparable with that of late syphilis in the absence of neurosyphilis. 

Penicillin desensitisation is recommended for all patients with penicillin hypersensitivity and neurosyphilis. The evidence for the use of non-penicillin regimens is relatively weak. However, high-dose doxycycline is used by some clinicians in this situation.[100]

Penicillin allergy skin testing identifies patients at high risk for penicillin reactions. Skin reagents used should include major and minor allergens.[101] Patients who are skin-test negative can receive penicillin therapy. However, some clinicians perform desensitisation without skin testing, particularly if the skin reagents for both minor and major determinants of penicillin allergy are not available. Acute desensitisation can be performed in patients who have a positive skin test to one of the penicillin determinants, and should be performed in a hospital setting. Oral or intravenous desensitisation can be performed, and is usually completed in 4 hours, following which the first dose of penicillin is administered.[102]

Infection in pregnancy

Parenteral benzylpenicillin is the only recommended treatment in pregnancy. Pregnant patients who are allergic to penicillin should be desensitised and treated with penicillin. Pregnant women should receive penicillin-based treatment according to their stage of syphilis, although some specialists recommend that women presenting in the third trimester with early syphilis should receive two injections of benzathine benzylpenicillin rather than one.

Sonographic fetal assessment for congenital syphilis is performed. The presence of fetal or placental syphilis (e.g., hepatomegaly, ascites, and hydrops fetalis) indicates a greater risk of treatment failure for congenital syphilis.[70] Pregnant women should be advised of the possibility of the Jarisch-Herxheimer reaction. Jarisch-Herxheimer reaction may be complicated by fetal distress and premature labour. Specialist care by an obstetrician is recommended.

Co-infection with HIV

Syphilis is an important facilitator of HIV transmission. Most clinicians treat HIV-positive and HIV-negative patients with the same penicillin regimens, according to the stage of syphilis. For example, first-line treatment of primary and secondary syphilis among patients with HIV co-infection is with a single dose of intramuscular benzathine benzylpenicillin.[5] However, duration of therapy may be prolonged in patients with HIV and neurosyphilis. 

People with HIV infection and primary or secondary syphilis should be assessed clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy.[5] Although of unconfirmed benefit, some specialists recommend performing CSF analysis 6 months after therapy either routinely or if non-treponemal titres do not decrease fourfold within 6-12 months of therapy. Patients with primary or secondary syphilis and HIV co-infection who are allergic to penicillin should receive antibiotic therapy as recommended for penicillin-allergic, HIV-negative patients.

Congenital syphilis

All infants born to mothers with reactive non-treponemal and treponemal tests should have non-treponemal serology (Venereal Disease Research Laboratory [VDRL] or rapid plasma reagin [RPR] tests) performed on infant serum. False-positive results may occur if umbilical cord blood is sampled, due to contamination of umbilical cord blood with maternal blood.

When infants aged >1 month test positive for syphilis, clinicians should review maternal records and serology results to determine if the infection is congenital or acquired.[5] 

If there is evidence of effective treatment (and no re-infection) of the mother, a normal physical examination of the infant, and the infant’s VDRL/RPR is less than fourfold higher than the mother’s, then no treatment is indicated. Infants with an abnormal physical examination or a VDRL/RPR that is fourfold or greater than the mother’s titre should be fully evaluated and treated.

First-line treatment of congenital syphilis is intravenous aqueous benzylpenicillin or intramuscular procaine benzylpenicillin.[5][103] Intramuscular benzathine benzylpenicillin is recommended if a non-treponemal test in the infant is non-reactive and there is low likelihood of infectivity.[5]  Discussion with an obstetric specialist and neonatologist is recommended. Intramuscular benzathine benzylpenicillin is infrequently used in resource-rich countries. Close clinical and serological follow-up by a paediatric specialist is recommended.

Potential adverse effects of therapy

Patients should be warned of possible reactions to treatment, such as the Jarisch-Herxheimer reaction and iatrogenic procaine reaction.

Jarisch-Herxheimer reaction is an acute febrile illness that can occur within the first 24 hours after initiation of antibiotic treatment for syphilis. Symptoms include acute fever, headache, and myalgia, usually in patients with early syphilis. Corticosteroid therapy may be considered to prevent potential serious consequences of Jarisch-Herxheimer reaction in non-pregnant patients with cardiovascular syphilis or neurosyphilis.[3] However, evidence of effectiveness is unclear and it is not routinely recommended in some countries.

Iatrogenic procaine reaction (procaine psychosis, procaine mania, Hoigné syndrome) may occur if intramuscular procaine benzylpenicillin is mistakenly administered intravenously. Patients may develop penicillin allergic responses, including anaphylactic shock.[104]

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