Syphilis

After an incubation period of 3 to 4 weeks (range 1 to 13 weeks), a primary lesion (chancre) develops at the site of inoculation. The initial red papule quickly forms a chancre, usually a painless ulcer with a firm base; when rubbed, it produces clear fluid containing numerous spirochetes. Nearby lymph nodes may be enlarged, firm, and nontender. The chancre may also develop a yellow or gray color over time.

Chancres can occur anywhere but are most common on the following:

• Penis, anus, and rectum in men

• Vulva, cervix, rectum, and perineum in women

• Lips or mouth

About half of infected women and one-third of infected men are unaware of the chancre because it causes few symptoms. Chancres in the rectum or mouth, usually occurring in men, are often unnoticed.

The chancre usually heals in 3 to 12 weeks. Then, people appear to be completely healthy.

Images of Primary Syphilis

Primary Syphilis (Genital Chancre) (1)

Syphilitic chancres may appear on or around the genitals.

Image courtesy of Drs. Gavin Hart and N. J. Flumara via the Public Health Image Library of the Centers for Disease Control and Prevention.

Primary Syphilis (Genital Chancre) (2)

Syphilitic chancres may appear on or around the genitals.

Photo courtesy of Karen McKoy, MD.

Primary Syphilis (Anal Chancre)

Syphilitic chancres may appear on or around the anus.

Image courtesy of Dr. Susan Lindsley via the Public Health Image Library of the Centers for Disease Control and Prevention.

Primary Syphilis (Mouth Chancre)

Syphilitic chancres may appear on or around the mouth.

Image courtesy of the Public Health Image Library of the Centers for Disease Control and Prevention.

Primary Syphilis (Digital Chancre)

Syphilitic chancres may appear on or around the digits or ostomy sites.

Image courtesy of the Public Health Image Library of the Centers for Disease Control and Prevention.

Primary Syphilis (Extragenital Chancre)

Syphilitic chancres may appear in extragenital locations.

Photo courtesy of Karen McKoy, MD.

Primary Syphilis (Genital Chancre) (1)

Syphilitic chancres may appear on or around the genitals.

Image courtesy of Drs. Gavin Hart and N. J. Flumara via the Public Health Image Library of the Centers for Disease Control and Prevention.

Primary Syphilis (Genital Chancre) (2)

Syphilitic chancres may appear on or around the genitals.

Photo courtesy of Karen McKoy, MD.

Primary Syphilis (Anal Chancre)

Syphilitic chancres may appear on or around the anus.

Image courtesy of Dr. Susan Lindsley via the Public Health Image Library of the Centers for Disease Control and Prevention.

Primary Syphilis (Mouth Chancre)

Syphilitic chancres may appear on or around the mouth.

Image courtesy of the Public Health Image Library of the Centers for Disease Control and Prevention.

Primary Syphilis (Digital Chancre)

Syphilitic chancres may appear on or around the digits or ostomy sites.

Image courtesy of the Public Health Image Library of the Centers for Disease Control and Prevention.

Primary Syphilis (Extragenital Chancre)

Syphilitic chancres may appear in extragenital locations.

Photo courtesy of Karen McKoy, MD.

The spirochete spreads in the bloodstream, producing widespread mucocutaneous lesions, lymph node swelling, and, less commonly, symptoms in other organs. Symptoms typically begin 6 to 12 weeks after the chancre appears; some patients still have a chancre. Fever, loss of appetite, nausea, and fatigue are common. Headache (due to meningitis), hearing loss (due to otitis), balance problems (due to labyrinthitis), visual disturbances (due to retinitis or uveitis), and bone pain (due to periostitis) can also occur.

Most patients have mucocutaneous lesions; a wide variety of rashes and lesions occurs, and any body surface can be affected. Without treatment, lesions may disappear in a few days to weeks, persist for months, or return after healing, but all eventually heal, usually without scarring.

Syphilitic dermatitis is usually symmetric and more marked on the palms and soles. The individual lesions are round, often scale, and may coalesce to form larger lesions, but they generally do not itch or hurt. After lesions resolve, the affected areas may be lighter or darker than normal. If the scalp is involved, alopecia areata often occurs.

Condyloma lata are hypertrophic, flattened, dull pink, white-gray, or tan papules (colors vary by skin color, location of the lesions, and accompanying inflammation) at mucocutaneous junctions and in moist areas of the skin (eg, in the perianal area, under the breasts); lesions are extremely infectious. Lesions of the mouth, throat, larynx, penis, vulva, or rectum are usually circular, raised, and often gray to white with a red border. Condyloma lata are typically painless unless they cause discomfort because of their location.

Secondary syphilis can affect many other organs:

• Lymphadenopathy, usually generalized, with nontender, firm, discrete nodes, and often hepatosplenomegaly

• Eyes (uveitis), bones (periostitis), joints, meninges, kidneys (glomerulitis), liver (hepatitis), or spleen

• Mild meningitis, rarely with meningeal symptoms, which can include headache, neck stiffness, cranial nerve lesions, deafness, and eye inflammation (eg, optic neuritis, retinitis)

However, acute or subacute meningitis is more common among patients with HIV infection and may manifest as meningeal symptoms or strokes due to intracranial vasculitis (1).

Images of Secondary Syphilis

Secondary Syphilis (Body)

Secondary syphilis mimics many other dermatoses, causing a diffuse rash that may be macular, papular, or pustular, with discrete or confluent lesions.

... read more

Image courtesy of the Public Health Image Library of the Centers for Disease Control and Prevention.

Secondary Syphilis (Back)

Secondary syphilis mimics many other dermatoses, causing a diffuse rash that may be macular, papular, or pustular, with discrete or confluent lesions.

... read more

Image courtesy of the Public Health Image Library of the Centers for Disease Control and Prevention.

Secondary Syphilis (Condyloma Lata) (1)

This photo shows hypertrophic papules known as condylomata lata on the genitals of a woman with secondary syphilis.

SCIENCE PHOTO LIBRARY

Secondary Syphilis (Condyloma Lata) (2)

This photo shows condylomata lata, seen here as gray, raised lesions in the region of the vulva and anus.

CDC

Secondary Syphilis (Elbow)

A complete skin examination may detect localized sites of secondary syphilis rash; in this case, condyloma lata.

Photo courtesy of Karen McKoy, MD.

Secondary Syphilis (Palms)

A maculopapular rash on the palms is characteristic of secondary syphilis.

Image courtesy of the Public Health Image Library of the Centers for Disease Control and Prevention.

Secondary Syphilis (Sole)

A maculopapular rash on the sole is characteristic of secondary syphilis.

Image courtesy of Susan Lindsley via the Public Health Image Library of the Centers for Disease Control and Prevention.

Secondary Syphilis (Mucous Patch)

Mucous patches in the mouth are characteristic of secondary syphilis.

Photo courtesy of Karen McKoy, MD.

Secondary Syphilis (Facial Lesions)

Syphilis rash can occur at any body site.

Photo courtesy of Karen McKoy, MD.

Secondary Syphilis (Body)

Secondary syphilis mimics many other dermatoses, causing a diffuse rash that may be macular, papular, or pustular, with discrete or confluent lesions.

... read more

Image courtesy of the Public Health Image Library of the Centers for Disease Control and Prevention.

Secondary Syphilis (Back)

Secondary syphilis mimics many other dermatoses, causing a diffuse rash that may be macular, papular, or pustular, with discrete or confluent lesions.

... read more

Image courtesy of the Public Health Image Library of the Centers for Disease Control and Prevention.

Secondary Syphilis (Condyloma Lata) (1)

This photo shows hypertrophic papules known as condylomata lata on the genitals of a woman with secondary syphilis.

SCIENCE PHOTO LIBRARY

Secondary Syphilis (Condyloma Lata) (2)

This photo shows condylomata lata, seen here as gray, raised lesions in the region of the vulva and anus.

CDC

Secondary Syphilis (Elbow)

A complete skin examination may detect localized sites of secondary syphilis rash; in this case, condyloma lata.

Photo courtesy of Karen McKoy, MD.

Secondary Syphilis (Palms)

A maculopapular rash on the palms is characteristic of secondary syphilis.

Image courtesy of the Public Health Image Library of the Centers for Disease Control and Prevention.

Secondary Syphilis (Sole)

A maculopapular rash on the sole is characteristic of secondary syphilis.

Image courtesy of Susan Lindsley via the Public Health Image Library of the Centers for Disease Control and Prevention.

Secondary Syphilis (Mucous Patch)

Mucous patches in the mouth are characteristic of secondary syphilis.

Photo courtesy of Karen McKoy, MD.

Secondary Syphilis (Facial Lesions)

Syphilis rash can occur at any body site.

Photo courtesy of Karen McKoy, MD.

Latent syphilis can be early (< 1 year after infection) or late (≥ 1 year after infection).

Symptoms and signs are absent, but antibodies, detected by serologic tests for syphilis, persist. Because symptoms of primary and secondary syphilis are often minimal or ignored, patients frequently are first diagnosed during the latent stage when routine blood tests for syphilis are performed.

Syphilis may remain latent permanently, but relapses with contagious skin or mucosal lesions may occur during the early latent period.

Patients are often given antibiotics for other disorders, which may cure latent syphilis and may account for the rarity of late-stage disease in high-resource countries.

About one-third of untreated people develop late syphilis, although not until years to decades after the initial infection. Lesions may be clinically classified as

• Benign tertiary syphilis

• Cardiovascular syphilis

• Neurosyphilis

Benign tertiary gummatous syphilis usually develops within 3 to 10 years of infection and may involve the skin, bones, and internal organs. Gummas are soft, destructive, inflammatory masses that are typically localized but may diffusely infiltrate an organ or tissue; they grow and heal slowly and leave scars.

Syphilis (Gumma)

Image

BSIP, SIDEA REVUZ/SCIENCE PHOTO LIBRARY

Tertiary Syphilis (Gumma)

Image

CDC/ Susan Lindsley

Benign tertiary syphilis of bone results in either inflammation or destructive lesions that cause a deep, boring pain, characteristically worse at night.

Cardiovascular syphilis usually manifests 10 to 25 years after the initial infection as any of the following:

• Aneurysmal dilation of the ascending aorta

• Insufficiency of the aortic valve

• Narrowing of the coronary arteries

Pulsations of the dilated aorta may cause symptoms by compressing or eroding adjacent structures in the chest. Symptoms include brassy cough and obstruction of breathing due to pressure on the trachea, hoarseness due to vocal cord paralysis resulting from compression of the left laryngeal nerve, and painful erosion of the sternum and ribs or spine.

Neurosyphilis has several forms:

• Asymptomatic neurosyphilis

• Meningovascular neurosyphilis

• Parenchymatous neurosyphilis

• Tabes dorsalis

Asymptomatic neurosyphilis with mild meningitis develops in patients with latent , secondary, or tertiary syphilis. Without treatment, it can evolve to symptomatic neurosyphilis. If cerebrospinal fluid examination does not detect evidence of meningitis 2 years after the initial infection, neurosyphilis is unlikely to develop.

Meningovascular neurosyphilis results from inflammation of large- to medium-sized arteries of the brain or spinal cord; symptoms typically occur 5 to 10 years after infection and range from none to strokes. Initial symptoms may include headache, neck stiffness, dizziness, behavioral abnormalities, poor concentration, memory loss, lassitude, insomnia, and blurred vision. Spinal cord involvement may cause weakness and wasting of shoulder-girdle and arm muscles, slowly progressive leg weakness with urinary or fecal incontinence or both, and, rarely, sudden paralysis of the legs due to thrombosis of spinal arteries.

Parenchymatous neurosyphilis (general paresis, or dementia paralytica) results when chronic meningoencephalitis causes destruction of cortical parenchyma. It usually develops 15 to 20 years after initial infection and typically does not affect patients before their 40s or 50s. Behavior progressively deteriorates, sometimes mimicking a mental disorder or dementia. Irritability, difficulty concentrating, deterioration of memory, defective judgment, headaches, insomnia, fatigue, and lethargy are common; seizures, aphasia, and transient hemiparesis are possible. Hygiene and grooming deteriorate. Patients may become emotionally unstable and depressed and have delusions of grandeur with lack of insight; wasting may occur. Tremors of the mouth, tongue, outstretched hands, and whole body may occur; other signs include pupillary abnormalities, dysarthria, hyperreflexia, and, in some patients, extensor plantar responses. Handwriting is usually shaky and illegible.

Tabes dorsalis (locomotor ataxia) involves slow, progressive degeneration of the posterior columns and nerve roots. It typically develops 20 to 30 years after initial infection; mechanism is unknown. Usually, the earliest, most characteristic symptom is an intense, stabbing (lightning) pain in the back and legs that recurs irregularly with loss of vibratory sense, proprioception, and reflexes in the lower extremities. Gait ataxia, hyperesthesia, and paresthesia may cause a sensation of walking on foam rubber. Loss of bladder sensation leads to urine retention, incontinence, and recurrent infections. Erectile dysfunction is common.

Many patients with tabes dorsalis have Argyll Robertson pupils (pupils that accommodate for near vision but do not respond to light). Optic atrophy may occur.

Examination of the legs detects hypotonia, hyporeflexia, impaired vibratory and joint position sense, ataxia in the heel-shin test, absence of deep pain sensation, and Romberg sign.

Tabes dorsalis tends to be intractable even with treatment.

Visceral crises (episodic pain) are a variant of tabes dorsalis; paroxysms of pain occur in various organs, most commonly in the stomach (causing vomiting) but also in the rectum, bladder, and larynx.

Syphilitic ocular and otic manifestations can occur at any stage of the disease.

Ocular syndromes can affect virtually any part of the eye; they include interstitial keratitis, uveitis (anterior, intermediate, and posterior), chorioretinitis, retinitis, retinal vasculitis, and cranial nerve and optic neuropathies. Cases of ocular syphilis have occurred among men with HIV infection who have sex with men. Several cases resulted in significant morbidity, including blindness. Patients with ocular syphilis are at risk of neurosyphilis.

Otosyphilis may affect the cochlea (causing hearing loss and tinnitus) or vestibular system (causing vertigo and nystagmus).

Trophic lesions, secondary to hypoesthesia of the skin or periarticular tissues due to nerve damage from syphilis, may develop in the later stages, after injury or skin breakdown goes unnoticed. Trophic ulcers may develop on the soles of the feet and penetrate deeply, in some cases to the underlying bone.

Neurogenic arthropathy (Charcot joints), a painless joint degeneration with bony swelling and abnormal range of movement, is a classic manifestation of neuropathy.

1. 1. Ropper AH. Neurosyphilis [published correction appears in N Engl J Med. 2019 Oct 31;381(18):1789. doi: 10.1056/NEJMx190030.] [published correction appears in N Engl J Med. 2023 Nov 9;389(19):1828. doi: 10.1056/NEJMx230008.]. N Engl J Med. 2019;381(14):1358-1363. doi:10.1056/NEJMra1906228

Tests consist of:

• Screening (a reaginic, or nontreponemal) tests

• Confirmatory (treponemal) tests

• Darkfield microscopy

Nontreponemal and treponemal tests, collectively, are known as serologic tests for syphilis (STS).

T. pallidum cannot be grown in vitro. Traditionally, reaginic tests have been performed first, and positive results are confirmed by a treponemal test. Some laboratories now reverse this sequence; they do newer, inexpensive treponemal tests first and confirm positive results using a nontreponemal test.

Nontreponemal (reaginic) tests use lipid antigens (cardiolipin from bovine hearts) to detect reagin (human antibodies that bind to lipids). The Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests are sensitive, simple, and inexpensive reaginic tests that are used for screening but are not completely specific for syphilis. Results may be presented qualitatively (eg, reactive, weakly reactive, borderline, or nonreactive) and quantitatively as titers (eg, positive at 1:16 dilution).

In addition to treponemal infections, the following can produce a positive (biologically false-positive) reagin test result:

• Systemic infections unrelated to syphilis (such as tuberculosis, rickettsial diseases, and endocarditis)

• Immunization (specifically COVID-19 or smallpox vaccines)

• Systemic lupus erythematosus

• Antiphospholipid antibody syndromes

• Pregnancy

Treponemal tests detect antitreponemal antibodies qualitatively and are very specific for syphilis. They include the following:

• Fluorescent treponemal antibody absorption (FTA-ABS) test

• Microhemagglutination assay for antibodies to T. pallidum (MHA-TP)

• T. pallidum hemagglutination assay (TPHA)

• T. pallidum enzyme immunoassay (TP-EIA)

• Chemoluminescence immunoassays (CLIA)

If these tests do not confirm treponemal infection after a positive reaginic test, the reaginic result is deemed biologically false-positive.

Cerebrospinal fluid (CSF) nontreponemal tests are reasonably sensitive for early disease but less so for late neurosyphilis. CSF reaginic tests can be used to diagnose neurosyphilis or to monitor response to treatment by measuring antibody titers. In cases of a clinical picture suggestive of neurosyphilis with a negative nontreponemal test, a treponemal test has high sensitivity for neurosyphilis (3).

Neither reaginic nor treponemal tests become positive until 3 to 6 weeks after the initial infection. Thus, a negative result is common in early primary syphilis and does not exclude syphilis until after 6 weeks. Reaginic titers decrease at least 4-fold after effective treatment, typically becoming negative by 1 year in primary and by 2 years in secondary syphilis; however, low titers (≤ 1:8) may persist in some patients, a response referred to as the "serofast reaction." Treponemal tests usually remain positive for many decades despite effective treatment and thus cannot be used to assess the success of treatment (3).

Choice of tests and interpretation of test results depend on various factors, including previous syphilis, possible exposure to syphilis, and results of testing.

If patients have had syphilis, a reaginic test is performed. A 4-fold increase in titer suggests new infection or failed treatment.

If patients have not had syphilis, treponemal and reaginic tests are performed. Test results determine the next steps:

• Positive results on both tests: These results suggest new infection.

• Positive results on the treponemal test, but negative results on the reaginic test: A second treponemal test is performed to confirm the positive test. If reaginic test results are repeatedly negative, treatment is not indicated.

• Positive results on treponemal test, negative results on the reaginic test, but history suggests recent exposure: A reaginic test is repeated 2 to 4 weeks after exposure to make sure any new infection is detected.

Darkfield microscopy directs light obliquely through a slide of exudate from a chancre or lymph node aspirate to directly visualize spirochetes. Although the skills and equipment required are not usually available, darkfield microscopy is the most sensitive and specific test for early primary syphilis; it can also be used in secondary syphilis. The spirochetes appear against a dark background as bright, motile, narrow coils that are about 0.25 micrometers wide and 5 to 20 micrometers long. They must be distinguished morphologically from nonpathogenic spirochetes, which may be part of the normal flora, especially of the mouth. Therefore, darkfield examination of intraoral specimens for syphilis is not performed.

Primary syphilis is usually suspected based on relatively painless genital (but occasionally extragenital) ulcers. Syphilitic ulcers should be differentiated from other sexually transmitted genital lesions (see table Differentiating Common Sexually Transmitted Genital Lesions). Coinfections with 2 ulcer-causing pathogens (eg, herpes simplex virus plus T. pallidum) are not rare (4).

Darkfield microscopy of exudate from a chancre or lymph node aspirate may be diagnostic. If results are negative or the test is unavailable, a reaginic STS is performed. If results are negative or the test cannot be performed immediately but a skin lesion has been present for < 3 weeks (before the STS becomes positive) and an alternate diagnosis seems unlikely, treatment may be instituted, and the STS is repeated in 2 to 4 weeks.

Patients with syphilis should be tested for other sexually transmitted infections (STIs), including HIV infection, at diagnosis and 6 months later.

Because syphilis can mimic many diseases, it should be considered when any cutaneous eruption or mucosal lesion is undiagnosed, particularly if patients have any of the following:

• Generalized lymphadenopathy

• Lesions on the palms or soles

• Condyloma lata

• Risk factors (eg, HIV infection, multiple sex partners)

Clinically, secondary syphilis may be mistaken for a medication eruption, rubella, infectious mononucleosis, erythema multiforme, pityriasis rubra pilaris, fungal infection, or, particularly, pityriasis rosea. Condyloma lata may be mistaken for warts, hemorrhoids, or pemphigus vegetans; scalp lesions may be mistaken for ringworm or idiopathic alopecia areata.

Secondary syphilis is excluded by a negative reaginic STS, which is virtually always reactive during this stage, often with a high titer. A compatible syndrome with a positive STS (reaginic or treponemal) warrants treatment. Uncommonly, this combination represents latent syphilis coexisting with another skin disease. Patients with secondary syphilis should be tested for other STIs.

Asymptomatic, latent syphilis is diagnosed when reaginic and treponemal STS are positive in the absence of symptoms or signs of active syphilis. Such patients should have a thorough examination, particularly genital, skin, neurologic, and cardiovascular examinations, to exclude secondary and tertiary syphilis.

Criteria for early latent syphilis include during the prior year a documented conversion from negative to positive treponemal test, a newly positive nontreponemal test, or a sustained (> 2 weeks) 4-fold or greater increase in reaginic test titers plus any of the following:

• Unequivocal symptoms of primary or secondary syphilis

• A sex partner with documented primary, secondary, or early latent syphilis

• No possible exposure except during the previous 12 months

Patients who have latent syphilis but do not fulfill the above criteria have late latent syphilis.

Treatment and serologic follow-up for up to several years may be needed to ensure the success of therapy because reaginic STS titers decrease slowly.

Latent acquired syphilis must be differentiated from latent congenital syphilis, latent yaws, and other treponemal infections.

Patients with symptoms or signs of tertiary syphilis (particularly unexplained neurologic abnormalities) require STS. If the tests are reactive, the following should be done:

• Lumbar puncture for CSF examination (including reaginic STS)

• Imaging of the brain and aorta

• Screening of any other organ systems clinically suspected to be involved

At this stage of syphilis, a reaginic STS is nearly always positive, except in a few cases of tabes dorsalis.

In benign tertiary syphilis, differentiation from other inflammatory mass lesions or ulcers may be difficult without biopsy.

Cardiovascular syphilis is suggested by symptoms and signs of aneurysmal compression of adjacent structures, particularly stridor or hoarseness.

Syphilitic aortic aneurysm is suggested by aortic insufficiency without aortic stenosis and, on chest radiograph, by widening of the aortic root and linear calcification on the walls of the ascending aorta. Diagnosis of aneurysm is confirmed with aortic imaging (transesophageal echocardiography, CT, or MRI).

In neurosyphilis, most symptoms and signs except for Argyll Robertson pupil are nonspecific, so that diagnosis relies heavily on a high index of clinical suspicion. In parenchymatous neurosyphilis, the CSF reaginic and serum treponemal tests are reactive, and CSF typically has lymphocytic pleocytosis and elevated protein. In tabes dorsalis, serum reaginic tests may be negative if patients have been previously treated, but serum treponemal tests are usually positive. CSF usually has lymphocytic pleocytosis and elevated protein, and sometimes reaginic or treponemal test results are positive; however, in many treated patients, CSF is normal.

CSF findings can be found at any stage of syphilis. If a lumbar puncture is performed without neurologic symptoms or signs, a diagnosis of asymptomatic neurosyphilis is made based on abnormal CSF (typically, lymphocytic pleocytosis and elevated protein) and a reactive CSF reaginic test (in the absence of grossly bloody contamination of the CSF). If present, HIV may confound the diagnosis because it causes mild pleocytosis and various other neurologic symptoms. Asymptomatic neurosyphilis does not require any different treatments than those recommended for the stage of syphilis.

If ocular syphilis is diagnosed, CSF testing for neurosyphilis should be performed. Patients with ocular symptoms and reactive syphilis serology need a full eye examination, including cranial nerve evaluation. If cranial nerve dysfunction or other focal neurologic findings are present, a lumbar puncture should be performed. Patients with reactive syphilis serology and isolated ocular findings but no cranial nerve dysfunction or neurologic findings do not need CSF examination before treatment.

Hearing loss can occur at any stage of syphilis and also can be isolated or associated with neurosyphilis. With isolated auditory symptoms and normal neurologic examination, CSF examination is not recommended before treatment. Otosyphilis should be treated using the same regimen as for neurosyphilis.

1. 1. US Preventive Services Task Force, Mangione CM, Barry MJ, et al. Screening for Syphilis Infection in Nonpregnant Adolescents and Adults: US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA. 2022;328(12):1243-1249. doi:10.1001/jama.2022.15322

2. 2. US Preventive Services Task Force (USPSTF), Bibbins-Domingo K, Grossman DC, et al. Screening for Syphilis Infection in Nonpregnant Adults and Adolescents: US Preventive Services Task Force Recommendation Statement. JAMA. 2016;315(21):2321-2327. doi:10.1001/jama.2016.5824

3. 3. Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187. Published 2021 Jul 23. doi:10.15585/mmwr.rr7004a1. Erratum: Vol. 70, No. RR-4. MMWR Morb Mortal Wkly Rep. 2023;72(4):107-108. Published 2023 Jan 27. doi:10.15585/mmwr.mm7204a5

4. 4. Li D, Yang X, Zhang Z, et al. Incidence of Co-Infections of HIV, Herpes Simplex Virus Type 2 and Syphilis in a Large Cohort of Men Who Have Sex with Men in Beijing, China. PLoS One. 2016;11(1):e0147422. Published 2016 Jan 28. doi:10.1371/journal.pone.0147422

Penicillin G benzathine 2.4 million units IM given once produces blood levels that are sufficiently high for 2 weeks to cure primary, secondary, and early (Penicillin G benzathine 2.4 million units IM given once produces blood levels that are sufficiently high for 2 weeks to cure primary, secondary, and early (< 1 year) latent syphilis. Doses of 1.2 million units are usually given in each buttock to reduce local reactions.

Additional doses of 2.4 million units should be given 7 and 14 days after the first (total of 3 doses) for late (> 1 year) latent syphilis or latent syphilis of unknown duration because treponemes occasionally persist in the cerebrospinal fluid (CSF) after single-dose regimens. Treatment is the same regardless of HIV status.

For nonpregnant patients with a significant penicillin allergy (anaphylactic, bronchospastic, or urticarial), the first alternative is doxycycline 100 mg orally twice a day for 14 days (28 days for late latent syphilis or latent syphilis of unknown duration). Azithromycin 2 g orally in a single dose is effective for primary, secondary, or early latent syphilis caused by susceptible strains. However, a single mutation that increases resistance is increasingly common in many parts of the world, including the United States, and results in unacceptably high failure rates. For nonpregnant patients with a significant penicillin allergy (anaphylactic, bronchospastic, or urticarial), the first alternative is doxycycline 100 mg orally twice a day for 14 days (28 days for late latent syphilis or latent syphilis of unknown duration). Azithromycin 2 g orally in a single dose is effective for primary, secondary, or early latent syphilis caused by susceptible strains. However, a single mutation that increases resistance is increasingly common in many parts of the world, including the United States, and results in unacceptably high failure rates.

Azithromycin should not be used to treat pregnant patients or late latent syphilis. Pregnant patients with a penicillin allergy should be hospitalized and desensitized to penicillin.

Ceftriaxone 1 g IM or IV once/day for 10 to 14 days has been effective in some patients with early syphilis and may be effective at later stages, but optimal dose and duration of therapy are unknown.Ceftriaxone 1 g IM or IV once/day for 10 to 14 days has been effective in some patients with early syphilis and may be effective at later stages, but optimal dose and duration of therapy are unknown.

Late latent syphilis can be treated with penicillin G benzathine 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals.can be treated with penicillin G benzathine 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals.

Benign or cardiovascular tertiary syphilis can be treated in the same way as late latent syphilis.

For ocular syphilis, otic syphilis, or neurosyphilis, one of the following is recommended:

• Aqueous penicillin 4 million units IV every 4 hours (penetrates the central nervous system best but may be impractical)

• Penicillin G procaine 2.4 million units IM once/day plus 500 mg probenecid orally 4 times a day Penicillin G procaine 2.4 million units IM once/day plus 500 mg probenecid orally 4 times a day

Both regimens are given for 10 to 14 days, followed by penicillin G benzathine 2.4 million units IM once/week for 1 to 3 weeks after completion of these neurosyphilis treatment regimens to provide a total duration of therapy comparable to that for late latent syphilis. Both regimens are given for 10 to 14 days, followed by penicillin G benzathine 2.4 million units IM once/week for 1 to 3 weeks after completion of these neurosyphilis treatment regimens to provide a total duration of therapy comparable to that for late latent syphilis.

For patients who have penicillin allergies, ceftriaxone 2 g IM or IV once/day for 14 days can be effective, but cross-sensitivity with cephalosporins may be a concern. The alternative is penicillin desensitization because For patients who have penicillin allergies, ceftriaxone 2 g IM or IV once/day for 14 days can be effective, but cross-sensitivity with cephalosporins may be a concern. The alternative is penicillin desensitization becauseazithromycin and doxycycline have not been adequately evaluated in patients with neurosyphilis.

Patients with tabes dorsalis and lightning pains should be given analgesics as needed; oral carbamazepine sometimes helps.and lightning pains should be given analgesics as needed; oral carbamazepine sometimes helps.

Patients with primary or secondary syphilis, especially those with secondary syphilis, can have a JHR within 6 to 12 hours of initial treatment. It typically manifests as malaise, fever, headache, sweating, rigors, anxiety, or a temporary exacerbation of the syphilitic lesions. The mechanism is not understood, and JHR may be misdiagnosed as an allergic reaction.

JHR usually subsides within 24 hours and poses no danger. However, patients with general paresis or a high CSF cell count may have a more serious reaction, including seizures or strokes, and should be warned and observed accordingly.

Unanticipated JHR may occur if patients with undiagnosed syphilis are given antitreponemal antibiotics for other infections.

After treatment, patients should have

• Examinations and reaginic tests at 6 and 12 months and annually thereafter until the test is nonreactive or until a durable 4-fold reduction in titer is achieved

• For neurosyphilis, CSF testing every 6 months until CSF cell count is normal

The importance of repeated tests to confirm cure should be explained to patients before treatment. Examinations and reaginic tests should be performed at 6 and 12 months after treatment and annually thereafter until the test is nonreactive. Failure of titers to decline by 4-fold at 6 months suggests treatment failure. After successful treatment, primary lesions heal rapidly, and plasma reaginic titers fall and usually become qualitatively negative within 9 to 12 months.

In approximately 15 to 25% of patients with primary or secondary syphilis treated as recommended, the reaginic titer does not decrease by 4-fold, which is the criterion used to define response at 1 year after treatment. These patients should be followed clinically and serologically; they should also be evaluated for HIV infection.

If neurologic symptoms or signs are identified, a CSF evaluation is recommended, with findings guiding management. If follow-up cannot be ensured, CSF should be checked for neurosyphilis (because unrecognized neurosyphilis may be the cause of treatment failure), or patients should be retreated with penicillin G benzathine 2.4 million units IM once/week for 3 weeks.If neurologic symptoms or signs are identified, a CSF evaluation is recommended, with findings guiding management. If follow-up cannot be ensured, CSF should be checked for neurosyphilis (because unrecognized neurosyphilis may be the cause of treatment failure), or patients should be retreated with penicillin G benzathine 2.4 million units IM once/week for 3 weeks.

Treponemal tests may remain positive for decades or permanently and should not be measured to monitor progress. Serologic or clinical relapse, usually affecting the nervous system, may occur after 6 to 9 months, but the cause may be reinfection rather than relapse.

Patients with neurosyphilis without HIV infection or those with HIV infection who are on effective antiretroviral therapy and who exhibit serologic (normalization of the serum rapid plasma reagin titer) and clinical responses after treatment do not need repeated CSF examinations. In patients with HIV infection, persisting CSF pleocytosis may represent effects of HIV rather than persisting neurosyphilis. Normal CSF cell count, negative CSF and serum reaginic test results, and negative neurologic examination findings for 2 years indicate probable cure. If any of the following is present, retreatment with a more intensive regimen of antibiotics is indicated:

• CSF cell count that remains abnormal for > 2 years

• A serum reaginic test that remains reactive for > 2 years

• An increasing serum reaginic test titer

• Clinical relapse

1. 1. Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187. Published 2021 Jul 23. doi:10.15585/mmwr.rr7004a1. Erratum: Vol. 70, No. RR-4. MMWR Morb Mortal Wkly Rep. 2023;72(4):107-108. Published 2023 Jan 27. doi:10.15585/mmwr.mm7204a5

2. 2. Bachmann LH, Barbee LA, Chan P, et al. CDC Clinical Guidelines on the Use of Doxycycline Postexposure Prophylaxis for Bacterial Sexually Transmitted Infection Prevention, United States, 2024. MMWR Recomm Rep. 2024;73(2):1-8. Published 2024 Jun 6. doi:10.15585/mmwr.rr7302a1