Approach
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 penicillin G is the first-line drug treatment for all stages of syphilis, as recommended by the Centers for Disease Control and Prevention (CDC).[8] The preparation (i.e., benzathine, procaine, aqueous), dose, and length of treatment are determined by the stage and clinical manifestations of the disease.[4][8][93][94]
Without neurosyphilis
Treatment may follow diagnostic test results or may be empiric. Empiric 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 empiric 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 penicillin G as a single dose.[8] 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 centers, but is not recommended by the CDC due to concerns regarding macrolide resistance.[95][96][97]
Treatment of latent syphilis is intended to prevent late complications. The first-line treatment of late latent and tertiary (gummatous, cardiovascular, psychiatric manifestations, late neurosyphilis) syphilis with normal cerebrospinal fluid (CSF) examination is intramuscular benzathine penicillin G (once weekly for 3 weeks). Oral doxycycline may be offered as a first-line treatment to patients with penicillin allergy. Patients who have tertiary syphilis should undergo CSF examination before treatment is started. Patients with abnormal CSF findings should be treated with a neurosyphilis regimen.[8]
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.
Neurosyphilis
Central nervous system involvement can occur at any stage of syphilis, and can range from asymptomatic meningeal involvement to dementia and sensory neuropathy.[16] First-line treatment for neurosyphilis is intravenous aqueous penicillin G. Second-line treatment is intramuscular procaine penicillin plus oral probenecid. Some specialists administer intramuscular benzathine penicillin G once weekly for up to 3 weeks after the treatment regimen for neurosyphilis has been completed, to ensure the duration of treatment is comparable with that of late syphilis in the absence of neurosyphilis.[8]
Penicillin desensitization is recommended for all patients with penicillin hypersensitivity and neurosyphilis. The evidence for the use of nonpenicillin regimens is relatively weak. However, high-dose doxycycline is used by some clinicians in this situation.[7][16]
Penicillin allergy skin testing identifies patients at high risk for penicillin reactions. Skin reagents used should include major and minor allergens.[98] Patients who are skin-test negative can receive penicillin therapy. However, some clinicians perform desensitization without skin testing, particularly if the skin reagents for both minor and major determinants of penicillin allergy are not available. Acute desensitization 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 desensitization can be performed, and is usually completed in 4 hours, following which the first dose of penicillin is administered.[99]
Infection in pregnancy
Parenteral penicillin G is the only recommended treatment in pregnancy.[63] Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin. Pregnant women should receive penicillin-based treatment according to their stage of syphilis. For pregnant women with primary, secondary, or early latent syphilis, certain evidence suggests that administering two injections of intramuscular benzathine penicillin G, rather than one, can help prevent congenital syphilis. Pregnant women with late latent or tertiary syphilis with normal CSF examination should receive three injections of intramuscular benzathine penicillin G, as per the guidance for nonpregnant individuals.[8]
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.[68] Pregnant women should be advised of the possibility of the Jarisch-Herxheimer reaction. Jarisch-Herxheimer reaction may be complicated by fetal distress and premature labor. Specialist care by an obstetrician is recommended.[8]
Coinfection with HIV
Syphilis is an important facilitator of HIV transmission.[15] 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 coinfection is with a single dose of intramuscular benzathine penicillin G. There are no data to suggest that additional doses of benzathine penicillin G or other antibiotics enhance efficacy in patients with HIV.[8]
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. Although of unconfirmed benefit, some specialists recommend performing CSF analysis 6 months after therapy either routinely or if nontreponemal titers do not decrease fourfold within 6-12 months of therapy. Patients with primary or secondary syphilis and HIV coinfection who are allergic to penicillin should receive antibiotic therapy as recommended for penicillin-allergic, HIV-negative patients.[8]
Congenital syphilis
Decisions about management of congenital syphilis are made on the basis of whether infection is confirmed or suspected (highly probable, possible, less likely or unlikely) by considering various factors, including:[8]
Identification of syphilis in the mother
Adequacy of maternal treatment
Presence of clinical, laboratory, or radiographic evidence of syphilis in the infant (testing should include paired maternal and neonatal non-treponemal serological titres using the same test, preferably conducted at the same laboratory).
See Classification.
All infants born to mothers with reactive nontreponemal and treponemal tests should have nontreponemal 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.[8]
When infants ages >1 month test positive for syphilis, clinicians should review birth and maternal records and serology results to determine if the infection is congenital or acquired.[8] Infants and children ages >1 month with acquired primary or secondary syphilis should be managed by a pediatric infectious disease specialist and evaluated for sexual abuse.[8] See Sexual abuse and assault.
If there is evidence of effective treatment (and no reinfection) of the mother, a normal physical exam of the infant, and the infant’s VDRL/RPR is less than fourfold higher than the mother’s, then no treatment is indicated; however, close serologic follow-up is recommended every 2 to 3 months for 6 months. Infants with an abnormal physical exam or a VDRL/RPR that is fourfold or greater than the mother’s titer should be fully evaluated and treated.[8]
First-line treatment for confirmed proven or highly probable congenital syphilis is intravenous aqueous penicillin G or intramuscular procaine penicillin G.[8][100]
Possible congenital syphilis is treated with intravenous aqueous penicillin G, intramuscular procaine penicillin G, or intramuscular benzathine penicillin G.[8][100] If a nontreponemal test in the infant is nonreactive and the mother’s risk for untreated syphilis is low, or if complete evaluation (CSF examination, long-bone radiographs, and complete blood count with platelets) is normal and follow-up is certain, a single dose of intramuscular benzathine penicillin G may be given.[8][100] If the mother had untreated early syphilis at the time of delivery, the neonate is at increased risk for congenital syphilis and the 10-day course of penicillin G should be considered, even if investigations are normal, nontreponemal test is nonreactive, and follow-up is assured.[8]
If congenital syphilis is less likely (i.e., if a nontreponemal test in the infant is nonreactive, physical exam of the infant is normal, and the mother was successfully treated during pregnancy), a single dose of intramuscular benzathine penicillin G is the recommended treatment.[8] If the mother was adequately treated before pregnancy, a nontreponemal test in the infant is nonreactive, and physical exam of the infant is normal, congenital syphilis is unlikely and no treatment is required. However, a single dose of intramuscular benzathine penicillin G can be considered if subsequent follow-up of the infant is uncertain and they have a reactive nontreponemal test.[8]
Infants with a penicillin allergy or those who develop an allergic reaction presumed secondary to penicillin should be desensitized and treated with penicillin.[8] Skin testing is not possible in infants with congenital syphilis as the procedure has not been standardized in this age group.[8] Skin testing may be used in children ages ≥2 years. Discussion with an obstetric specialist and neonatologist is recommended. Neonates with reactive nontreponemal tests should be followed up to ensure that the nontreponemal test returns to negative.[8] Close clinical and serologic follow-up by a pediatric 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.[8] Corticosteroid therapy may be considered to prevent potential serious consequences of Jarisch-Herxheimer reaction in nonpregnant patients with cardiovascular syphilis or neurosyphilis.[4] However, evidence of effectiveness is unclear and it is not routinely recommended in the US.
Iatrogenic procaine reaction (procaine psychosis, procaine mania, Hoigné syndrome) may occur if intramuscular procaine penicillin G is mistakenly administered intravenously. Patients may develop penicillin allergic responses, including anaphylactic shock.[21]
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