Treatment Guidelines

Syphilis is a sexually transmitted disease caused by the spirochete Treponema pallidum. The risk of infection is 30-50% in persons who engage in sexual contact with a partner suffering multiple syphilitic lesions; however, the rate of infection resulting from a single sexual exposure is unknown. Transmission of syphilis can occur by kissing a person who has an active oral lesion or transplacentally from mother to fetus. Blood transfusion is no longer a significant method of transmission now that all donated blood is routinely screened.

Infection occurs in stages, and each stage manifests its own symptoms. Treatment dosages and length of therapy vary with the different stages of disease.

The initial stage is termed incubating syphilis and this covers the time from infection with the spirochete to the onset of clinical manifestations or conversion of serologic tests. This period routinely lasts 2 weeks but may be as brief as 10 days or as long as 2 months. During this time, the diagnosis can not be made clinically or serologically. Therefore, a patient who has had sexual contact with an infected individual may have an undetectable syphilitic infection for up to 90 days. These persons should be treated empirically.

The next phase is termed primary syphilis and is characterized by the development of a papule at the site of inoculation. This papule ulcerates and develops a raised and indurated border. This painless lesion is referred to as a chancre. After the chancre appears, patients usually manifest painless regional adenopathy. The chancre heals in about 4 to 6 weeks and the patient then enters the phase termed secondary syphilis.

Secondary syphilis occurs 6 to 8 weeks after resolution of the above-mentioned chancre. This phase often begins with such nonspecific symptoms as headache, pharyngitis, and fever. A moderate leukocytosis with a relative lymphocytosis is common. The characteristic lesion of this stage is a macular or papular rash. Classically, the rash is located on the palms and soles; however, it may begin on the trunk and spread to the extremities. The rash is usually bilateral, symmetric, and may be pruritic. Hematogenous dissemination of spirochetes to moist areas, especially the anus or vagina, results in the development of condylomata lata, which are flat, hypertrophic wart-like lesions. Adenopathy is a common manifestation of secondary syphilis and often occurs in the inguinal, suboccipital, postauricular, and cervical regions. Epitrochlear lymphadenopathy is considered pathognomonic and warrants an aggressive workup.

If patients do not receive therapy during the secondary stage, they enter the latent stage. During the latent stage, patients are asymptomatic, and the diagnosis of syphilis can only be made serologically. During this stage patients may suffer relapses of secondary syphilis. Approximately 35% of these patients will progress, if untreated, to tertiary syphilis based on the data from the Oslo and Tuskegee studies.

Tertiary syphilis represents a progressive, inflammatory disorder affecting multiple organ systems. Ten percent of these patients manifest cardiovascular syphilis (aortitis of the thoracic aorta with resultant aortic regurgitation, saccular aneurysms, or coronary ostial stenosis), 10% manifest neurosyphilis (which may be asymptomatic or symptomatic---diagnosis is confirmed by finding a positive VDRL on examination of the CSF although a negative result does not exclude the diagnosis), and 15% manifest gummatous syphilis. Gummatous tertiary syphilis refers to the development of destructive granulomas usually of the skin or bone. Biopsy of these lesions are nonspecific and organisms are rarely recovered by this method.

Symptomatic neurosyphilis is divided into parenchymal or meningovascular disease. Meningovascular disease results from endarteritis and should be suspected in persons suffering from strokes or seizures. Parenchymal syphilis results in tabes dorsalis (loss of vibratory sense and proprioception with resultant broad-based gait and a positive Romberg test), personality changes, dementia and delusional states. The Argyll Robertson pupil (pupil constricts to accommodation but unreactive toward light) is a common manifestation of parenchymal syphilis. A lumbar puncture should be performed in any patient with syphilis infection of unknown duration and suspected neurologic involvement. The cerebral spinal fluid should be subjected to VDRL testing; however, a negative result does not exclude neurosyphilis.

Darkfield microscopy is the most accurate means to exclusively diagnose primary syphilis. The primary lesion should be cleansed with saline and gauze and then exudative material from the lesion is placed on a glass slide and the specimen is examined under a microscope with a dark field condenser. This method requires skill on the part of the examiner and is often unavailable to the primary care physician.

Serologic tests are of two types. The first type of tests are screening tests that detect nontreponemal antibodies directed against a lipoidal antigen produced by host tissues in reaction to contact with the infecting spirochete. The nontreponemal tests (VDRL and RPR) and syphilis IgG titers are screening tests. These tests are 78-85% sensitive for primary syphilis. However, false-positive results are encountered with a number of disease states. Antibody quantity varies with the stage of infection (antibodies are first detected during the primary phase and peak during secondary syphilis). The antibody titers may become negative in the late stages of disease even without effective therapy. When the nontreponemal tests are positive, they must be confirmed with treponemal tests. A positive nontreponemal test in the presence of a negative treponemal test is indicative of a biologically false-positive result and another disease process should be suspected.

The fluorescent treponemal antibody absorption test (FTA-ABS) and the microhemagglutination T. pallidum assay (MHA-TP) are the more commonly used confirmatory treponemal tests. Unlike the screening tests, FTA-ABS and MHA-TP are not quantitative and are either reactive or nonreactive. These tests do not yield false-positive results and usually remain positive for the life of the patient.

One area of much controversy in medicine is regarding the interpretation of a persistently positive VDRL in a patient who has received adequate therapy for syphilis. Three possibilities exist in this instance: a biologically false-positive reaction, persistent active infection, or reinfection. Reinfection should be strongly suspected when the titer is greater than 1:4. A persistently high titer of the VDRL or RPR is commonly seen in HIV-infected individuals secondary to the polyclonal antibody stimulation seen in these persons. When interpreting the RPR after therapy, one must remember that the length of time required for this test to become nonreactive is dependent on the length of infection prior to the administration of appropriate therapy. The RPR should turn nonreactive 1 year after therapy for primary syphilis and 2 years after treatment for secondary syphilis. Patients who had progressed to late syphilis before receiving therapy often require 5 years for the RPR to become nonreactive. A positive RPR after the appropriate time span to allow conversion to a nonreactive status should be considered indicative of either persistent infection, reinfection, or a biologically false-positive reaction.

Therapy for incubating syphilis, primary, secondary, or early latent syphilis entails benzathine penicillin G 2.4 million units intramuscularly for one single dose, or in penicillin allergic patients, tetracycline 500 mg PO QID for 15 days or doxycycline 100 mg PO BID for 14 days or erythromycin 500 mg PO QID for 14 days. Syphilitic infections of greater than 1-year duration including latent, late benign, and cardiovascular syphilis are treated with benzathine penicillin G 2.4 million units intramuscularly every week for 2 weeks, or in penicillin allergic patients, tetracycline 500 mg PO QID or doxycycline 100 mg PO BID for 4 weeks. Treatment of neurosyphilis is accomplished with aqueous crystalline penicillin G 2-4 million units IV Q 4 hours for 10 days followed by benzathine penicillin G 2.4 million units intramuscularly every week for 2 weeks or procaine penicillin G 2.4 million units intramuscularly daily plus probenecid 500 mg PO QID for 10 days followed by weekly penicillin G 2.4 million units intramuscularly for 2 weeks. Penicillin-allergic patients with neurosyphilis should be treated with the tetracycline therapy outlined for the treatment of cardiovascular syphilis or ceftriaxone 1 gram IM/IV daily for 14 days. Pregnant women are given the above-mentioned therapy appropriate for the stage of maternal syphilis. In penicillin-allergic pregnant patients therapy entails skin testing followed by desensitization if necessary and then appropriate therapy.

Effective therapy of syphilis may result in the Jarisch-Herxheimer reaction, which includes fever, chills, myalgias, and headache. This reaction may begin 1 to 2 hours after therapy has been instituted. Patients should be warned about this reaction upon receiving therapy for syphilis. Aspirin or NSAIDs are effective therapy and no other treatment in required.