> Table of Contents > Syphilis
Melissa Badowski, PharmD
Mahesh C. Patel, MD
image BASICS
  • A chronic, systemic infectious disease caused by Treponema pallidum
  • Transmitted sexually, vertically (maternal-fetal) by direct contact with an active lesion, and via blood transfusions
  • Untreated disease includes four overlapping stages.
    • Primary: single (usually) painless chancre at point of entry; appears in 10 to 90 days; chancre heals without treatment in 3 to 6 weeks
    • Secondary: appears 2 to 8 weeks after primary chancre. Nonpruritic rash on palms or soles of feet, mucous membrane lesions, headache, fever, lymphadenopathy, alopecia
    • Latent: seroreactive without evidence of disease
      • Early latent: acquired within the last year
      • Late latent: exposure >12 months prior to diagnosis
    • Tertiary (late): Serology may be negative (fluorescent treponemal antibody absorption [FTA-ABS] test typically positive).
      • Gumma, cardiovascular, and late neurosyphilis; may be fatal
    • Neurosyphilis: any type of CNS involvement; can occur at any stage
      • Psychosis, delirium, dementia
  • Syphilis can affect nearly every organ/tissue in the body leading to moniker “the great imitator.”
Pediatric Considerations
In noncongenital cases, consider child abuse.
Pregnancy Considerations
  • All pregnant patients should be screened with VDRL or rapid plasma reagin (RPR) test early in pregnancy. If high exposure risk, repeat at 28 weeks and at delivery (1,2)[A].
  • The same nontreponemal test used for initial screening should be used for follow-up (1,2)[A].
  • Syphilis rate decreased until 2000; has increased (primarily in men) since then (3)[A].
  • In 2013: 5.3/100,000. Highest for men aged 25 to 29 years and women aged 20 to 24 years (3)[A]
    • Men: 9.8/100,000
    • Women: 0.9/100,000
  • Congenital: 8.7 cases/100,000 live births (4)[A]
  • Race/ethnicity (3)[A]
    • Male (per 100,000 population)
      • White, non-Hispanic: 5.4
      • Black, non-Hispanic: 27.9
      • Hispanic: 11.6
      • Asian/Pacific Islander: 4.6
      • American Indian/Alaska native: 4.7
    • Female (per 100,000 population)
      • White, non-Hispanic: 0.3
      • Black, non-Hispanic: 4.0
      • Hispanic: 0.8
      • Asian/Pacific Islander: 0.2
      • American Indian/Alaska native: 1.0
  • Predominant sex: male (91%) > female (9%) (3)[A]
  • Greatest increase in men having sex with men (MSM) (3)[A]
T. pallidum subspecies pallidum, spirochete: can enter through intact mucous membranes or breaks in skin. Highly infectious; exposure to as few as 60 spirochetes is associated with ˜50% chance of infection
MSM, multiple sexual partners, exposure to infected body fluids, IV drug use, transplacental transmission, adult inmates, high-risk sexual behavior, HIV positive
Education regarding safe sex; condoms reduce but do not eliminate transmission (5)[A]
HIV infection, hepatitis B, other STIs
Signs/symptoms depend on stage
  • Primary: single (occasionally multiple), usually painless ulcer (chancre) in groin or at other point of entry. Regional adenopathy.
  • Secondary
    • Rash: skin/mucous membranes
      • Rough, red-brown macules, usually on palms and soles
      • May appear with chancre or after it has healed
      • Condyloma lata
      • Alopecia
    • Nonspecific symptoms: fever, adenopathy, malaise, headache, hair loss
  • Tertiary
    • Focal neurologic findings (hearing loss, visual loss)
    • Gummas (skin, mucous membranes, other organ systems)
  • Primary: chancroid, lymphogranuloma venereum, granuloma inguinale, condyloma acuminata, herpes simplex, Behçet syndrome, trauma, carcinoma, mycotic infection, lichen planus, psoriasis, fungal infection
  • Secondary: pityriasis rosea, drug eruption, psoriasis, lichen planus, viral exanthema, Stevens-Johnson syndrome
  • Positive serology, asymptomatic: previously treated syphilis/other spirochetal disease (yaws, pinta)
Initial Tests (lab, imaging)
  • Dark-field microscopy demonstrating T. pallidum spirochetes in lesion exudate/tissue biopsy: gold standard but difficult and not very sensitive (6)[A]
  • Nontreponemal tests (VDRL/RPR) (3,6)[A]
    • Primary screening test: positive within 7 days of exposure
    • Nonspecific, false-positive results common; must confirm diagnosis with treponemal tests
    • Positive test should be quantified and titers followed regularly after treatment.
      • Titers usually correlate with disease activity; 4-fold change is clinically significant.
      • Titers decrease with time/treatment; following adequate treatment for primary/secondary disease, a 4-fold decline is typically seen after 6 to 12 months.
      • Absence of a 4-fold decline suggests potential treatment failure.
      • ˜15% of appropriately treated patients do not have a 4-fold decline in titer 12 months after treatment. Management is unclear, repeat HIV testing and/or CSF examination and continue to follow titers.
      • With appropriate treatment, titers should become negative (see serofast reaction).
      • Titers of patients treated in latent stages decline more gradually.
    • Prozone phenomenon: negative results from high titers of antibody; test with diluted serum
    • Serofast reaction: persistently positive results years after successful treatment; new infection diagnosed by 4-fold rise in titer
    • Conditions that may alter treponemal testing (all stages of syphilis can have a false-negative RPR result, especially in primary syphilis)
      • Pregnancy, autoimmune disease, mononucleosis, malaria, leprosy, viral pneumonia, cardiolipin antigens, injection drug use, acute febrile illness, HIV infection; elderly can have false-positive results.
  • Treponemal tests (confirmatory test after positive nontreponemal screening test): FTA-ABS, TP-PA (T. pallidum particle agglutination) (6)[A]:
    • Confirmatory test; not used for screening
    • Usually positive for life after treatment
    • Titers of no benefit
    • 15-25% of patients treated during primary stage revert to serologic nonreactivity after 2 to 3 years.
  • Lumbar puncture indicated for (6)[A]:
    • Neurologic, ocular, or auditory manifestations
    • Some experts advise in all secondary and early latent cases—even without neurologic symptoms
    • HIV-positive patients with late latent/latent of unknown duration
    • In patients with late latent/latent of unknown duration if nonpenicillin therapy planned
    • In treatment failures
    • If other evidence of active tertiary syphilis is present (e.g., aortitis, gumma, iritis)
    • In children to rule out neurosyphilis
    • VDRL, not RPR, used on CSF; may be negative in neurosyphilis; highly specific but insensitive
    • Send CSF for protein, glucose, and cell count.
    • Monitor resolution by cell count at 6 months along with serologies (see “Patient Monitoring”).
    • Negative FTA-ABS or microhemagglutination (MHA)-TP on CSF excludes neurosyphilis (highly sensitive).
    • Positive FTA-ABS or MHA-TP on CSF is not diagnostic because of high false-positive rate.
    • Traumatic tap, tuberculosis (TB), pyogenic/aseptic meningitis can all result in false-positive VDRL.

  • Advise patients to avoid intercourse until treatment is complete, and notify partners (6)[A].
  • Test for HIV (3,6)[A].
  • Management of sexual contacts (6)[A]
    • Presumptively treat partners exposed within 90 days of diagnosis.
    • Treat those exposed >90 days before diagnosis presumptively if serologic results are not available immediately and follow-up is uncertain.
    • Presumptively treat those exposed to a patient diagnosed with syphilis of unknown duration who have high treponemal titers (>1:32).
    • Long-term sex partners of patients with latent infection should be evaluated clinically and serologically and treated accordingly.
First Line
Parenteral penicillin G is the drug of choice. The particular formulation is determined by the disease stage and clinical presentation.
  • Primary, secondary, and early latent <1 year (6)[A]
    • Benzathine penicillin G 2.4 million U IM × 1 dose
    • Penicillin-allergic patients: doxycycline 100 mg PO BID for 2 weeks, or tetracycline 500 mg PO QID for 2 weeks, or ceftriaxone 1 to 2 g IM or IV daily for 10 to 14 days
      • Azithromycin 2 g PO × 1 dose (early syphilis only; should not be used in HIV, MSM, or pregnancy)
      • Resistance and treatment failures have been noted in several U.S. regions.
  • Late latent/latent of unknown duration and tertiary without evidence of neurosyphilis (6)[A]
    • Benzathine penicillin G 2.4 million U IM weekly × 3 doses
    • Penicillin-allergic patients: Attempt desensitization and treatment with penicillin or doxycycline 100 mg PO 2 BID for 28 days, or tetracycline 500 mg PO QID for 28 days; compliance may be an issue.
  • Ocular or neurosyphilis (6)[A]
    • Aqueous crystalline penicillin G 3 to 4 million U IV q4h as continuous infusion for 10 to 14 days
    • Alternative: Procaine penicillin G 2.4 million U IM daily in conjunction with probenecid 500 mg PO QID for 10 to 14 days (if compliance can be ensured)
    • Penicillin-allergic patients: Attempt desensitization and treat with penicillin; ceftriaxone 2 g/day IM or IV for 10 to 14 days.
    • If late latent, latent of unknown duration, or tertiary in addition to neurosyphilis, consider also treating as recommended for late latent after completion of neurosyphilis treatment.
  • Congenital (6)[A]
    • Aqueous crystalline penicillin G 50,000 U/kg/dose IV q12h for the first 7 days of life and q8h thereafter for a total of 10 days, or procaine penicillin G 50,000 U/kg/dose IM daily for 10 days
    • If negative CSF serologies, normal physical exam, and titer: Maternal titer, then 50,000 U/kg benzathine penicillin G IM in single dose is also an alternative.
    • If >1 day of drug is missed, restart course.
    • Children (after newborn period): aqueous crystalline penicillin G 50,000 U/kg/dose IV q4-6h for 10 days; late latent, 50,000 U/kg IM as 3 doses at 1-week intervals
    • For contacts without symptoms: Treat as primary after serologies are obtained.
    • HIV-infected and pregnant patients may show poor response to recommended IM doses. Use IV therapy for all treatment failures in these patients.
    • Do not give benzathine or procaine penicillins IV.
  • Children (after newborn period) (6)[A]: aqueous crystalline penicillin G 50,000 U/kg/dose IV q4-6h for 10 days; late latent, 50,000 U/kg IM as 3 doses at 1-week intervals
  • Pregnancy (6)[A]
    • Treatment is the same as for nonpregnant patients
    • Some recommend 2nd dose of 2.4 million units benzathine penicillin G 1 week after initial dose in 3rd trimester or with primary, secondary, or early latent syphilis.
    • Penicillin sensitivity: No proven alternatives to penicillin available for treatment during pregnancy.
    • Penicillin-allergic patients: Desensitize and treat with penicillin.
    • HIV-infected pregnant patients may show poor response to recommended IM doses. Use IV therapy for all treatment failures in these patients.
  • Treat contacts without symptoms as primary after serologies.
  • History of penicillin allergy:
    • Confirmed IgE-mediated reaction: desensitization
    • Questionable history of IgE-mediated hypersensitivity: penicillin skin testing if major and minor penicillin determinants available
  • Precautions (6)[A]
    • HIV-infected and pregnant patients may show poor response to recommended IM doses. Use IV therapy for all treatment failures in these patients.
    • Do not give benzathine or procaine penicillins IV.
  • Clinical and serologic evaluation between 6 and 12 months after treatment; if >1 year duration, check at 24 months (6)[A].
  • In HIV-infected persons, clinical and serologic evaluation at 3, 6, 9, 12, and 24 months after therapy (6)[A]
Patient Monitoring
  • Use VDRL or RPR test to monitor therapy: 4-fold rise (two dilutions) in titer indicates new infection, whereas failure to decrease 4-fold (two dilutions) in 6 to 12 months may indicate treatment failure (although definitive criteria for cure not established); always use same test (preferably same lab) for initial screening (6)[A].
  • Strongly consider retreatment for persistent clinical signs or recurrence, 4-fold rise in titers, or failure of initially high titer to decrease 4-fold by 6 to 12 months.
  • Neurosyphilis: repeat lumbar puncture every 6 months to check for normalization of CSF cell count (± CSF-VDRL and protein evaluation) (6)[A]
No intimate contacts until 4-fold titer drop
  • Excellent in all cases except patients with late syphilis complications and with HIV infection
  • Syphilis in HIV-infected patient
    • Treatment same as for HIV-negative patients
    • More often false-negative treponemal and nontreponemal tests or unusually high titers
    • Response to therapy less predictable
    • Early syphilis: increased risk of neurosyphilis and higher rates of treatment failure
    • Late neurosyphilis: harder to treat; can occur up to 20+ years after infection
1. Gomez GB, Kamb ML, Newman LM, et al. Untreated maternal syphilis and adverse outcomes of pregnancy: a systematic review and meta-analysis. Bull World Health Organ. 2013;91(3):217-226.
2. U.S. Preventive Services Task Force. Screening for syphilis infection in pregnancy: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med. 2009;150(10):705-709.
3. Patton ME, Su JR, Nelson R, et al. Primary and secondary syphilis—United States, 2005-2013. MMWR Morb Mortal Wkly Rep. 2014;63(18): 402-406.
4. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2012. Atlanta, GA: U.S. Department of Health and Human Services; 2013.
5. Koss CA, Dunne EF, Warner L. A systematic review of epidemiologic studies assessing condom use and risk of syphilis. Sex Transm Dis. 2009;36(7):401-405.
6. Workowski KA, Berman S. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59(RR-12):1-110.
See Also
Chlamydia Infection (Sexually Transmitted); Gonococcal Infections
  • A53.9 Syphilis, unspecified
  • A51.0 Primary genital syphilis
  • A53.0 Latent syphilis, unspecified as early or late
Clinical Pearls
  • Screen all HIV-positive patients and patients with high-risk sexual behaviors for syphilis.
  • Penicillin remains the treatment of choice for syphilis.
  • Syphilis rates are rising—particularly among MSM.