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Syphilis is a spirochetal infection that has resurged since 2001, the nadir year since 1996. Syphilis infection rates are highest in men who have sex with men. Syphilis is much less common than the other STIs, with an infection rate of 5.6 per 100,000 population in the United States (vs. 496 per 100,000 for Chlamydia).

Syphilis presents in several stages. The primary phase of syphilis is a painless ulcer called a chancre (Figure 16-4). The chancre may be visible on the genitals, although it can also be inside the vagina, mouth, or rectum, making it difficult to find. This lesion will appear within 3 weeks of transmission and will last for several weeks untreated. The secondary phase of infection is disseminated and involves a diffuse macular rash, typically with palm and sole lesions, generalized lymphadenopathy, fever, and condyloma latum (smooth, moist lesions on genitals without cauliflower appearance of condyloma acuminatum). Tertiary syphilis is often asymptomatic but affects the heart, eyes, and auditory system and can be associated with gumma formation. Gummas are soft, granulomatous growths in organs that can cause mechanical obstruction and weakening of blood vessel walls. Latent infection often involves the CNS.

Diagnosis of primary syphilis is challenging. The test of choice is darkfield microscopy, which is not readily available. Direct fluorescent (monoclonal) antibody (DFA) testing may be available. Antibody tests for syphilis, such as the rapid plasma reagin (RPR) and the less frequently used Venereal

Table 16-8 Treatment Guidelines for Herpes Simplex Infection


Initial Outbreak




400 mg tid for 7-10 days

days 800 mg bid for 5

days 800 mg tid for 2 days


1.0 g bid for 7-10 days

500 mg once daily 1.0 g once daily

500 mg bid for 3

days 1.0 g once daily for 5 days


250 mg tid for 7-10 days

days 1.0 g bid for 1 day

Data from Centers for Disease Control and Prevention. Sexually transmitted disease treatment guidelines, 2010. MMWR 2010;59(No. RR-12). tid, Three times daily; bid, twice daily.

Figure 16-4 Primary chancre of syphilis.

(From glans.thumbnail.jpg.)

Figure 16-4 Primary chancre of syphilis.

(From glans.thumbnail.jpg.)

Disease Research Laboratories (VDRL), are often not positive early in infection and thus cannot be used to rule out primary syphilis based on a single reading. Treponemal antigen testing (EIA) may be available in some laboratories. The fluorescent treponemal antibody absorption (FTA-ABS) test may also be negative in the early infection. Direct PCR for primary syphilis lesions has been tested but is not yet FDA approved. A physician may choose to treat presumptively if a painless chancre and risk factors are present and may then do a convalescent RPR test in 1 to 2 weeks to confirm the infection by the appearance of a positive reaction. One would expect a fourfold change in titer of either test to indicate the presence of disease.

Primary and secondary syphilis are treated with a single injection of penicillin G, 2.5 million units. Other regimens do not have proven effectiveness but can be used in the penicillin-allergic patient, including doxycycline, 100 mg twice daily for 14 days; ceftriaxone, 500 mg to 1 g intramuscularly (IM) daily for 8 to 10 days; or azithromycin, 2 g as a single oral dose, although resistance to azithromycin has been observed. Patients treated for primary syphilis should have periodic clinical follow-up and serologic testing to determine a fourfold decrease in RPR reactivity within 6 months.

Latent syphilis can be either early, meaning infection within the last year, or late, meaning infection beyond a year. Early latent syphilis is treated with a single injection of penicillin G, 2.4 million units. Syphilis of late latency or unknown duration is treated with three injections of penicillin G, 2.4 million units, in 3 consecutive weeks. For penicillin-allergic patients, doxycycline, 100 mg twice daily for 28 days, is required. Those with latent syphilis should have ophthalmic examination as well as evaluation for vascular gumma formation. Suspected neurologic involvement of latent syphilis must be evaluated with cerebrospinal fluid (CSF) examination and treatment with aqueous penicillin G, 3-4 million units intravenously (IV) every 4 hours for 10 to 14 days.

Partners of patients with newly diagnosed syphilis are at risk for infection. Partners within 90 days of a diagnosis of primary syphilis should be tested, but treated presumptively even if serologic testing is negative. For partners prior to 90 days before diagnosis, serology is generally reliable in detecting presence of infection and may guide treatment. Patients with secondary syphilis should inform partners within 6 months before diagnosis, or 12 months for those diagnosed with tertiary syphilis (Table 16-9).

Table 16-9 Diagnosis and Treatment of Syphilis


Clinical Manifestations

Diagnosis (Sensitivity)


Primary syphilis


Darkfield microscopy of skin lesion (80%) Nontreponemal tests (78%-86%)

Treponemal-specific tests (76%-84%)

Penicillin G benzathine, 2.4 million units IM (single dose) Alternatives in nonpregnant patients with penicillin allergy: doxycycline (Vibramycin), 100 mg PO bid for 2 weeks; tetracycline, 500 mg PO four times daily for 2 weeks; ceftriaxone (Rocephin), 1 g IM or IV once daily for 8-10 days; or azithromycin (Zithromax), 2 g PO (single dose)

Secondary syphilis

Skin and mucous membranes: diffuse rash, condyloma latum, other lesions Renal system: glomerulonephritis, nephrotic syndrome Liver: hepatitis

CNS: headache, meningismus, cranial neuropathy, iritis, uveitis Constitutional symptoms: fever, malaise, generalized lymphadenopathy, arthralgias, weight loss, others

Darkfield microscopy of skin lesion (80%)

Nontreponemal tests (100%) Treponemal-specific tests (100%)

Same treatments as for primary syphilis

Latent syphilis


Nontreponemal tests (95%-100%)

Treponemal-specific tests (97%-100%)

Early latent syphilis: same treatments as for primary and secondary syphilis

Late latent syphilis: penicillin G benzathine, 2.4 million units IM once weekly for 3 weeks Alternatives in nonpregnant patients with penicillin allergy: doxycycline, 100 mg PO bid for 4 weeks, or tetracycline, 500 mg PO four times daily for 4 weeks

Tertiary (late) syphilis

Gummatous disease, cardiovascular disease

Nontreponemal tests (71%-73%) Treponemal-specific tests (94%-96%)

Same treatment as for late latent syphilis


Seizures, ataxia, aphasia, paresis, hyperreflexia, personality changes, cognitive disturbance, visual changes, hearing loss, neuropathy, loss of bowel or bladder function, others

Cerebrospinal fluid examination

Aqueous crystalline penicillin G, 3-4 million units IV q4h for 10-14 days, or penicillin G procaine, 2.4 million units IM once daily, plus probenecid, 500 mg PO four times daily, both drugs given for 10-14 days

Data from Brown DL, Frank JE. Diagnosis and management of syphilis. Am Fam Physician , 2003;68:283-290. IM, Intramuscularly; IV, intravenously, PO, orally; q4h, every 4 hours; CNS, central nervous system.

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