Antibiotics used to treat syphilis

Diagnosis and Management of Syphilis

Stage-Specific Diagnosis and Treatment

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TREATMENT GUIDELINES

Guidelines from the Centers for Disease Control and Prevention (CDC) recommend parenterally administered penicillin G for the treatment of all stages of syphilis (Figure 1).9 Alternative regimens may be used in patients who are allergic to penicillin. However, pregnant women and patients with neuro-syphilis require treatment with penicillin even if they are allergic to the drug. In these patients, desensitization is necessary before penicillin therapy is initiated.

Treatment of Syphilis

FIGURE 1.

Recommended approach to the treatment of syphilis. (IM = intramuscular; HIV = human immunodeficiency virus; CSF = cerebrospinal fluid; IV = intravenous)

*–Alternative treatments for nonpregnant penicillin-allergic patients: doxycycline (Vibramycin), 100 mg taken orally twice daily for 2 weeks, or tetracycline, 500 mg taken orally four times daily for 2 weeks; limited data support efficacy for ceftriaxone (Rocephin), 1 g once daily IM or IV for 8 to 10 days, or azithromycin (Zithromax), 2 g orally (single dose).

†–Alternative treatments for nonpregnant penicillin-allergic patients: doxycycline, 100 mg taken orally twice daily for 4 weeks, or tetracycline, 500 mg taken orally four times daily for 4 weeks.

Information from reference 9.

FIGURE 1.

Recommended approach to the treatment of syphilis. (IM = intramuscular; HIV = human immunodeficiency virus; CSF = cerebrospinal fluid; IV = intravenous)

*–Alternative treatments for nonpregnant penicillin-allergic patients: doxycycline (Vibramycin), 100 mg taken orally twice daily for 2 weeks, or tetracycline, 500 mg taken orally four times daily for 2 weeks; limited data support efficacy for ceftriaxone (Rocephin), 1 g once daily IM or IV for 8 to 10 days, or azithromycin (Zithromax), 2 g orally (single dose).

†–Alternative treatments for nonpregnant penicillin-allergic patients: doxycycline, 100 mg taken orally twice daily for 4 weeks, or tetracycline, 500 mg taken orally four times daily for 4 weeks.

Information from reference 9.

The treatment of syphilis is similar in HIV-positive and HIV-negative patients. However, HIV-positive patients require more frequent follow-up because of an increased risk of treatment failure. In addition, a higher index of suspicion for central nervous system (CNS) involvement must be maintained.9

Treatment of syphilis in any stage should take into account the risks of acquiring other STDs. HIV testing should be considered in the initial evaluation of all patients with syphilitic infection.9Screening for hepatitis B and C, gonorrhea, and chlamydial infection also should be considered.

After appropriate treatment has been administered, patients should be followed with quantitative nontrepone-mal test titers to establish treatment response. Typically, nontreponemal test titers should become at least four times lower within six months after treatment of primary or secondary syphilis, and within 12 to 24 months after treatment of latent or late infection.10

PRIMARY SYPHILIS

Primary syphilis is most often associated with a single, painless chancre, although it can manifest in other ways (i.e., multiple chancres, painful papules or ulcers, or no lesions).4 The chancre is most commonly found on the external genitalia and develops 10 to 90 days (average: 21 days) after infection.11 Associated regional lymphadenopathy is common. The chancre usually resolves spontaneously in one to four months.

Lesions that can be confused with the chancre of primary syphilis include herpes simplex virus infection, chancroid, fixed drug eruption, lymphogranuloma venereum, granuloma inguinale (donovanosis), traumatic ulcer, furuncle (boil), and aphthous ulcer.12 A selected differential diagnosis is provided in Table 1.12,13

TABLE 1

Selected Differential Diagnosis of Genital Lesions

Disorder or disease Characteristics of genital lesion Etiology

Primary syphilis: chancre

Solitary, painless ulcer with indurated border

Treponema pallidum

Secondary syphilis: condyloma latum

Slightly raised or flat, round or oval papules covered by gray exudate

T. pallidum

Genital herpes

Cluster of shallow, small, painful ulcers on a red base

Herpes simplex virus

Chancroid

Painful ulcer with sharp, undermined borders

Haemophilus ducreyi

Venereal warts

Soft, usually painless skin-colored or red papules

Human papillomavirus

Lymphogranuloma venereum: primary stage

Painless papule, shallow erosion, or ulcer; may be multiple or single

Chlamydia trachomatis

Information from references 12 and 13.

TABLE 1

Disorder or disease Characteristics of genital lesion Etiology

Primary syphilis: chancre

Solitary, painless ulcer with indurated border

Treponema pallidum

Secondary syphilis: condyloma latum

Slightly raised or flat, round or oval papules covered by gray exudate

T. pallidum

Genital herpes

Cluster of shallow, small, painful ulcers on a red base

Herpes simplex virus

Chancroid

Painful ulcer with sharp, undermined borders

Haemophilus ducreyi

Venereal warts

Soft, usually painless skin-colored or red papules

Human papillomavirus

Lymphogranuloma venereum: primary stage

Painless papule, shallow erosion, or ulcer; may be multiple or single

Chlamydia trachomatis

Information from references 12 and 13.

Primary syphilis is diagnosed by dark-field microscopy of a suspected lesion or by serologic testing (Table 2).2,9 Either technique can have a false-negative result early in the course of the disease. Thus, if clinical suspicion is high, treatment for syphilis should be initiated.

TABLE 2

Stages of Syphilitic Infection

Stage Clinical manifestations Diagnosis (sensitivity) Treatment

Primary syphilis

Chancre

Dark-field microscopy of skin lesion (80%) Nontreponemal tests (78% to 86%) Treponemal-specific tests (76% to 84%)

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

Secondary syphilis

Skin and mucous membranes: diffuse rash, condyloma latum, other lesions Renal system: glomerulonephritis, nephrotic syndrome Liver: hepatitis Central nervous system: headache, meningismus, cranial neuropathy, iritis and uveitis Constitutional symptoms: fever, malaise, generalized lymphadenopathy, arthralgias, weight loss, others

Dark-field microscopy of skin lesion (80%) Nontreponemal tests (100%) Treponemal-specific tests (100%)

Same treatments as for primary syphilis

Latent syphilis

None

Nontreponemal tests (95% to 100%) Treponemal-specific tests (97% to 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 orally twice daily for 4 weeks; or tetracycline, 500 mg orally four times daily for 4 weeks

Tertiary (late) syphilis

Gummatous disease, cardiovascular disease

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

Same treatment as for late latent syphilis

Neurosyphilis

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 to 4 million units IV every 4 hours for 10 to 14 days; or penicillin G procaine, 2.4 million units IM once daily, plus probenecid, 500 mg orally four times daily, with both drugs given for 10 to 14 days

IM = intramuscular; IV = intravenous.

Information from references 2 and 9.

TABLE 2

Stage Clinical manifestations Diagnosis (sensitivity) Treatment

Primary syphilis

Chancre

Dark-field microscopy of skin lesion (80%) Nontreponemal tests (78% to 86%) Treponemal-specific tests (76% to 84%)

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

Secondary syphilis

Skin and mucous membranes: diffuse rash, condyloma latum, other lesions Renal system: glomerulonephritis, nephrotic syndrome Liver: hepatitis Central nervous system: headache, meningismus, cranial neuropathy, iritis and uveitis Constitutional symptoms: fever, malaise, generalized lymphadenopathy, arthralgias, weight loss, others

Dark-field microscopy of skin lesion (80%) Nontreponemal tests (100%) Treponemal-specific tests (100%)

Same treatments as for primary syphilis

Latent syphilis

None

Nontreponemal tests (95% to 100%) Treponemal-specific tests (97% to 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 orally twice daily for 4 weeks; or tetracycline, 500 mg orally four times daily for 4 weeks

Tertiary (late) syphilis

Gummatous disease, cardiovascular disease

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

Same treatment as for late latent syphilis

Neurosyphilis

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 to 4 million units IV every 4 hours for 10 to 14 days; or penicillin G procaine, 2.4 million units IM once daily, plus probenecid, 500 mg orally four times daily, with both drugs given for 10 to 14 days

IM = intramuscular; IV = intravenous.

Information from references 2 and 9.

Primary syphilis is treated with 2.4 million units of penicillin G benzathine delivered intramuscularly in a single dose. In nonpregnant patients who are allergic to penicillin, alternative regimens include doxycycline (Vibramycin), in a dosage of 100 mg taken orally twice daily for two weeks, or tetracycline, in a dosage of 500 mg taken orally four times daily for two weeks. Limited evidence indicates that ceftriaxone (Rocephin), in a dosage of 1 g delivered intramuscularly or intravenously once daily for eight to 10 days, or azithromycin (Zithromax), in a single 2-g dose taken orally, may be effective for the treatment of primary syphilis, although close follow-up is warranted to assess treatment efficacy.9

At six and 12 months after treatment, patients with primary syphilis should be reexamined and undergo repeat serologic testing. Treatment failure is defined as recurrent or persistent symptoms or a sustained fourfold increase in nontreponemal test titers despite appropriate treatment. Patients with treatment failure should be tested for HIV infection and evaluated for neurosyphilis with a cerebrospinal fluid (CSF) examination.9

SECONDARY SYPHILIS

Secondary syphilis develops several weeks to months after the chancre appears.4 The skin is most often affected. Patients may present with macular, maculopapular, or even pustular lesions, beginning on the trunk and proximal extremities. The rash of secondary syphilis may involve all skin surfaces, including the palms and soles. Condyloma latum also is associated with secondary syphilis. Involving mainly warm, moist areas such as the perineum and perianal skin, this soft, verrucous plaque is painless but highly infectious.

Other organs and systems that can be affected in secondary syphilis include the renal system (glomerulonephritis, nephrotic syndrome), the liver (hepatitis), the CNS (headache, meningitis, cranial neuropathy, iritis, and uveitis), and the musculoskeletal system (arthritis, osteitis, periostitis).4 Patients also may have constitutional symptoms such as fever, malaise, generalized lymphadenopathy, arthralgias, and weight loss.

The diagnosis of secondary syphilis is confirmed by nontreponemal and treponemal-specific tests. Treatment employs the same antibiotic regimens used for primary syphilis. Follow-up is the same as that for primary syphilis (Figure 2).9

Follow-up of Primary or Secondary Syphilis

FIGURE 2.

An approach to follow-up in patients treated for primary or secondary syphilis. (IM = intramuscular; HIV = human immunodeficiency virus)

*–See text for alternative treatment recommendations for nonpregnant penicillin-allergic patients.

†–See text for recommended treatments for neurosyphilis.

Information from reference 9.

FIGURE 2.

An approach to follow-up in patients treated for primary or secondary syphilis. (IM = intramuscular; HIV = human immunodeficiency virus)

*–See text for alternative treatment recommendations for nonpregnant penicillin-allergic patients.

†–See text for recommended treatments for neurosyphilis.

Information from reference 9.

LATENT SYPHILIS

It is important to distinguish between early and late latent syphilis, because relapse to secondary syphilis and recurrent infectivity are possible during the early latent stage. Early latent syphilis encompasses the first year after infection. This stage can be established only in patients who have seroconverted within the past year, who have had symptoms of primary or secondary syphilis within the past year, or who have had a sexual partner with primary, secondary, or early latent syphilis within the past year. Patients who do not meet any of these criteria should be presumed to have late latent syphilis.

CNS involvement may be asymptomatic. Therefore, the possibility of neurosyphilis should be considered in patients with early or late latent syphilis.

Early latent syphilis is treated in the same way as primary and secondary syphilis. Late latent syphilis is treated with 2.4 million units of penicillin G benzathine administered intramuscularly once a week for three weeks. Alternative regimens in nonpregnant patients with penicillin allergy include doxycycline, in a dosage of 100 mg taken orally twice daily for four weeks, or tetracycline, in a dosage of 500 mg taken orally four times daily for four weeks.9

After treatment of early or late latent syphilis, quantitative nontreponemal titers should be measured at six, 12, and 24 months. Neurosyphilis should be strongly considered in patients who show a fourfold increase in titers, patients who have an initially high titer (1:32 or greater) that fails to decline at least fourfold, patients who have HIV infection, and patients who develop signs or symptoms of neurosyphilis.9

TERTIARY SYPHILIS

Tertiary or late syphilis is classified into gummatous syphilis, cardiovascular syphilis, and neurosyphilis. Gummas are granulomatous-like lesions; they are clinically significant because they cause local destruction.4 These lesions may affect any organ system but most commonly occur in the skin, mucous membranes, and bones.

Cardiovascular syphilis results from destruction of the elastic tissue of the aorta, which leads to aortitis and the formation of aneurysms that rarely rupture. The ascending aorta is most often affected, with the potential complications of aortic valve insufficiency and coronary artery stenosis. A diagnostic clue is the presence of linear calcifications of the aorta on a chest radiograph. Approximately 11 percent of untreated patients progress to cardiovascular syphilis.14

Antibiotic therapy for gummatous and cardiovascular syphilis is the same as that for late latent syphilis, provided no evidence of neurologic involvement is present. Consensus is lacking on the appropriate follow-up in patients who have tertiary syphilis with no CNS involvement. Clinical response to treatment varies and depends on the type and location of gummatous or cardiovascular lesions.9

NEUROSYPHILIS AT ANY STAGE OF SYPHILIS

Neurologic involvement occurs in up to 10 percent of patients with untreated syphilis.14 Neurosyphilis should be considered in patients with signs or symptoms of neurologic involvement at any stage of T. pallidum infection and in all patients with late latent or tertiary syphilis, although asymptomatic neurosyphilis is the most common presentation.4 Neurologic involvement also should be suspected in patients who previously have been treated for neurosyphilis, patients who have not responded to treatment for primary, secondary, or latent syphilis, and patients who have HIV infection or other conditions that compromise immune status.

Lumbar puncture is required to establish the diagnosis of neurosyphilis. The CSF should be tested for white blood cell count and protein level, and for reactivity on a VDRL test.5,15 Although a positive CSF VDRL test result is specific for neurosyphilis, a negative result does not exclude the possibility of this infection, because sensitivity is less than 100 percent. A CSF white blood cell count greater than 10 per mm3(10 × 106per L) or a CSF protein level greater than 50 mg per dL (0.50 g per L) indicates possible neurosyphilis.

Treponemal-specific testing (e.g., TPHA) is helpful only when the result is negative (i.e., it rules out neurosyphilis). Because IgG can cross the blood-brain barrier, a positive test may falsely imply CNS involvement.5 TPHA testing to compare serum and CSF values (TPHA index) may prove beneficial in establishing the diagnosis of neurosyphilis. Testing for spirochete DNA via poly-merase chain reaction methods is an evolving technique that may be helpful because it detects organisms, rather than antibodies, in the CSF.16

In late neurosyphilis, both vascular lesions (meningo-vascular neurosyphilis) and neuronal degeneration (parenchymatous neurosyphilis) are possible.4 The clinical manifestations of neurosyphilis include seizures, ataxia, aphasia, paresis, hyperreflexia, personality and cognitive changes, visual changes, hearing loss, neuropathy, and loss of bowel and bladder functions.

Penicillin is the only drug that has proved effective in the treatment of neurosyphilis. The CDC endorses two regimens.9 The first is aqueous crystalline penicillin G, in a dosage of 3 to 4 million units administered intravenously every four hours for 10 to 14 days. The second regimen consists of penicillin G procaine, in a dosage of 2.4 million units administered intramuscularly once daily, plus probenecid, in a dosage of 500 mg orally four times daily, with both drugs given for 10 to 14 days.

Follow-up of patients treated for neurosyphilis depends on the initial CSF findings.9 If pleocytosis was present, the CSF should be reexamined every six months until the white blood cell count is normal. Retreatment should be considered if the CSF white blood cell count does not decline after six months or completely normalize after two years.9

The CSF also can be reexamined to look for serial decreases in antibodies on the VDRL test or serial decreases in protein levels, although the management of persistent abnormalities is not well established. It is expected that CSF parameters will normalize within two years. Failure to normalize may warrant retreatment. Most treatment failures occur in immunocompromised patients.

Syphilis Treatment and Care

There are no home remedies or over-the-counter drugs that will cure syphilis, but syphilis is easy to cure in its early stages. A single intramuscular injection of long acting Benzathine penicillin G (2.4 million units administered intramuscularly) will cure a person who has primary, secondary or early latent syphilis. Three doses of long acting Benzathine penicillin G (2.4 million units administered intramuscularly) at weekly intervals is recommended for individuals with late latent syphilis or latent syphilis of unknown duration. Treatment will kill the syphilis bacterium and prevent further damage, but it will not repair damage already done.

Selection of the appropriate penicillin preparation is important to properly treat and cure syphilis. Combinations of some penicillin preparations (e.g., Bicillin C-R, a combination of benzathine penicillin and procaine penicillin) are not appropriate treatments for syphilis, as these combinations provide inadequate doses of penicillin.

Although data to support the use of alternatives to penicillin is limited, options for non-pregnant patients who are allergic to penicillin may include doxycycline, tetracycline, and for neurosyphilis, ceftriaxone. These therapies should be used only in conjunction with close clinical and laboratory follow-up to ensure appropriate serological response and cure.

Persons who receive syphilis treatment must abstain from sexual contact with new partners until the syphilis sores are completely healed. Persons with syphilis must notify their sex partners so that they also can be tested and receive treatment if necessary.

Treatment Guidelines and Updates

  • 2015 STD Treatment Guidelines – Syphilis (June 4, 2015)
    • Syphilis During Pregnancy
    • Congenital Syphilis
  • Clinical Advisory: Ocular Syphilis in the United States (Updated April 16, 2015)

Resources for Clinicians

  • The Diagnosis, Management and Prevention of Syphilis: An Update and Reviewpdf iconexternal icon – A clinical guidance document for use in the diagnosis and management of syphilis. Based on content from the 2015 CDC STD Treatment Guidelines, and developed by the NYC Department of Health and Mental Hygiene Bureau of Sexually Transmitted Infections and the NYC STD Prevention Training Center. (March 2019)
  • Syphilis Pocket Guide for Providerspdf icon – Updated booklet for providers containing need-to-know details on the diagnosis, treatment, and prevention of syphilis. (November 30, 2017)
  • Syphilis Self-Study Moduleexternal icon – An online learning experience that helps users learn how to manage syphilis. It is continuously updated and integrates the most recent STD Treatment Guidelines. Free CME/CNE available. (November 1, 2017)
  • The Rising Tide of Syphilis: Coming to a Patient Near Youexternal icon (July 18, 2017)
  • Congenital Syphilis Is on the Rise? Reviewing Prevention Stepsexternal icon (July 19, 2016)
  • Suggested Reporting Language for Syphilis Serology Testingpdf iconexternal icon (May 19, 2016)
  • Medscape Commentary: Keep an Eye Out for Ocular Syphilisexternal icon (added February 11, 2016)

Related Content

  • STD & Pregnancy Treatment

In This Section

  • Syphilis
  • What are the symptoms of syphilis?
  • Should I get tested for syphilis?
  • How do I get treated for syphilis?
  • How is syphilis prevented?

Syphilis can be easily cured with antibiotics. Your sexual partners need to be treated, too. If you don’t treat syphilis, it can lead to very serious health problems.

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Want to get tested for syphilis?

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What is the treatment for syphilis?

Syphilis is usually super easy to get rid of in the early stages. Your nurse or doctor will prescribe antibiotics to treat the infection — usually penicillin, unless you’re allergic or can’t take it for other reasons.

If you’re having syphilis treatment, it’s really important for your sexual partners to get treated also. Otherwise, you may pass the infection back and forth, or to other people.

What do I need to know if I get treated for syphilis?

If you’re getting treated for syphilis:

  • Take all of your medicine the way your doctor tells you to, even if your symptoms go away sooner.

  • Your partner(s) should also get tested and treated for syphilis so you don’t re-infect each other or anyone else.

  • Don’t have any kind of sex (vaginal, anal, oral) until you and your partners have finished your treatments, and any sores are totally healed.

  • Don’t share your medicine with anyone. If your partner needs treatment, you should each get your own separate doses of antibiotics. Make sure you both take all of the medicine prescribed to you.

  • Even if you finish your treatment and the syphilis is totally gone, it’s still possible to get a new syphilis infection again if you’re exposed in the future. Syphilis isn’t a one-time-only deal. So use condoms and/or dental dams and get tested regularly.

What happens if I don’t get treated for syphilis?

Even though syphilis is common and has mild symptoms in the beginning, it can become a really big deal if it’s not treated. You can also easily pass it to other people.

Syphilis is easily cured in the early stages. But if you don’t treat syphilis early on, it can get worse and do serious harm to your body in the future. Late stage syphilis can lead to health problems that can’t be reversed or healed, like blindness or paralysis.

Syphilis can also cause problems if you’re pregnant. Syphilis can be passed to your fetus during pregnancy or to your baby at birth. This is called congenital syphilis, and it’s very dangerous. Congenital syphilis can lead to stillbirth, birth defects, or infant death. You should be tested for syphilis if you’re pregnant to make sure this doesn’t happen.

Having syphilis also increases your chances of getting or spreading HIV, the virus that causes AIDS.

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Which antibiotic are useful to treat newborns with congenital syphilis?

Review question

To assess the effectiveness and safety of antibiotic treatment for newborns with congenital syphilis.

Background

Pregnant women with syphilis can transmit it through the placenta to the fetus or at birth to the neonate; in such cases the baby is said to have congenital syphilis. This continues to be a substantial public health problem in many countries. In 2007, the World Health Organization launched a global initiative for the elimination of mother-to-child transmission of syphilis.

Trial characteristics

We identified only two clinical trials following extensive searches of medical databases carried out up to 23 May 2018 and involved two main formulations of penicillin, long-acting benzathine penicillin and procaine benzylpenicillin. Both trials recruited infants with asymptomatic (no symptoms) congenital syphilis. The first with 22 newborns was undertaken in South Africa and compared benzathine penicillin with no treatment. The second trial was carried out in USA and recruited 169 infants and compared the effectiveness of benzathine penicillin and procaine benzylpenicillin.

Key results

The first study showed there was not difference in the rate of neonatal death due to any cause, moreover results suggested a possible reduction into the proportion of neonates with clinical manifestations of congenital syphilis. Also penicillin administration increase the number of patients who experience a favourable response in terms of the test used to monitor disease activity (serological cure). This trial was stopped early after there were four cases of congenital syphilis found in the no-treatment group and none in the penicillin group.

The second trial showed that both benzathine penicillin and procaine benzylpenicillin were probably equally effective in treating congenital syphilis for the outcomes absence of clinical manifestations of congenital syphilis and serological cure. None of the studies assessed the side effects of treatment.

Quality of the evidence

The quality of the evidence for the first trial was low due to poor reporting of study methods. For the second trial, there was high-quality evidence for the absence of clinical manifestations of congenital syphilis on neonates, but moderate-quality evidence for serological cure due to few data.

Conclusions

Compared with no intervention, treatment with benzathine penicillin may increase rates of serological cure by the age of three months and possibly reduce the the clinical manifestation of congenital syphilis. There is probably no difference between long-acting benzathine penicillin and procaine benzylpenicillin for treating newborns with congenital syphilis.

“We already use Zithromax for penicillin-allergic patients. There are also logistical benefits to a pill. It’s actually a little bit less expensive, because you don’t have to have a pharmacist mix it, and a nurse to administer it. It’s also easier to keep a pill stored on a shelf,” he said.

But, he added, “The difficulty is, with large-scale distribution, we worry about a resistance pattern.”

“The presence of resistance in North America and Ireland makes the routine use of azithromycin a very risky proposition,” said Sheila Lukehart, a professor of medicine at the University of Washington in Seattle.

Last year, Lukehart published a study in the New England Journal of Medicine that found almost 90 percent of samples taken in Dublin, Ireland, and nearly 40 percent of samples of T. pallidum taken in San Francisco contained a genetic mutation making it resistant to azithromycin.

“The decision about using azithromycin needs to be based carefully on what you know about the strains in that community, which means we need to be doing surveillance. So far, there’s no concerted surveillance effort ongoing in most of this country and worldwide,” she explained.

“There are macrolide-resistant T. pallidum spreading along the West Coast right now. We don’t know whether this was a single resistant strain that is now spreading, or if it’s new resistance that is developing. We don’t know which of those two is occurring,” she added.”If it’s a new resistance that is developing, it could doom azithromycin for treatment of syphilis,” Lukehart said. “If it’s a limited number of already-resistant strains traveling through sexual networks, and if you know that these strains are rarely present in your community, it’s probably fine to use azithromycin. Again, this requires surveillance and careful follow-up.”

For someone with syphilis, Lukehart said, what’s most important is consistent monitoring with your physician.

“When you’re asked by a physician to come back for follow-up, you need to be very reliable, particularly if you’ve been given non-penicillin therapy. Report back to your doctor quickly if your sores don’t heal,” Lukehart.

More information

The U.S. Centers for Disease Control and Prevention explains what syphilis is and how to prevent the infection.

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Doxycycline Compared with Benzathine Penicillin for the Treatment of Early Syphilis

Kaplan-Meier curves were generated by comparing the time to treatment failure between the doxycycline treatment and BPG treatment groups. There was no statistically significant difference between the 2 curves (log-rank test, P = .2). Among patients who had a serological response to treatment (figure 2), the median times to serological response in the doxycycline treatment and BPG treatment groups were 106 days (95% CI, 75–149) and 137 days (95% CI, 111–172), respectively (log-rank test, P = .6 ).

Figure 2

Kaplan-Meier curves summarizing the time to serological response for the doxycycline (DOXY) treatment group (n = 34) and the benzathine penicillin G (BPG) treatment group (n = 67).

Figure 2

Kaplan-Meier curves summarizing the time to serological response for the doxycycline (DOXY) treatment group (n = 34) and the benzathine penicillin G (BPG) treatment group (n = 67).

Discussion

“The evidence upon which recommendations for syphilis therapy are based remains inadequate for such a complicated disease” is the oft-quoted conclusion that Rolfs wrote in his exhaustive 1995 review of the data on which the CDC recommendations for the treatment of syphilis were based. Little has changed since then. Both the United States and European guidelines for the treatment of syphilis list doxycycline as the preferred alternate drug for the treatment of early syphilis if a patient is allergic to penicillin or refuses parenteral therapy . The basis for this recommendation largely relies on the efficacy of other tetracyclines in treating syphilis and the lack of more-convenient alternatives. This reasoning is no doubt supported by the felicitous pharmacokinetic properties of doxycycline.

Our study suggests that doxycycline is a reasonable alternative when treating patients with early syphilis who cannot be safely treated with BPG. None of the patients in our study had evidence of treatment failure 270–400 days after treatment with doxycycline. Our findings are consistent with the findings of Harshan et al. , who found no treatment failures among the 20 patients with primary and secondary syphilis who were treated with one-half the dosage of doxycycline used in the current study. Similarly, in the study by Onoda , only 1 patient among 15 with early syphilis had serological evidence of nonresponse to treatment 4 months after doxycycline therapy. Because the patient had been lost to follow up, it is unclear whether a serological response might have been achieved with a longer follow-up time. Overall, our data, along with these reports, provide a basis for the use of doxycycline as an alternative therapeutic option in the treatment of early syphilis.

The serological failure rate among the patients who received BPG was 5.5%, which is consistent with the 2%–12% range of treatment failure reported in other studies evaluating penicillin efficacy . The broad range of the estimates may be related to variations in formulations and dosing of penicillin, in addition to the different methods adopted by each study. Not surprisingly, the 4 patients who experienced treatment failure in our study were beyond the primary stage of syphilis, and one-half were known to have HIV infection. Most studies suggest a higher probability of serological failures for patients with more-advanced syphilis, HIV infection, and a history of syphilis . Of note, the BPG treatment group had nearly twice as many HIV-infected patients as the doxycycline treatment group. Although our study was not large enough for HIV infection to be statistically significant, if those with HIV infection had increased risk of serological failure, this may have increased the failure rate in the group receiving BPG.

The time to a 4-fold titer decrease was also evaluated in this study. Although the data were not collected prospectively, both groups had similar follow-up times and a similar number of follow-up serological titers. We were interested in whether patients treated with doxycycline experienced a delay in documented serological response, compared with patients treated with BPG. The median time to achieving an adequate serological response was similar in both groups. Because of the retrospective nature of the analyses, the measured time may be an overestimate of the actual time it takes to achieve a 4-fold drop in titers. However, the ∼75% response rate at 6 months in our study is in agreement with previously published data on serological response to therapy in early syphilis .

This study has several other limitations. As is the case for all retrospective studies, especially those in which the final, eligible study population is a fraction of the original population, both selection and information biases must be acknowledged. The 107 patients included in this study were those who had documented follow-up serological tests. They may not be representative of the population at large. However, our main result would only be confounded by a differential loss to follow up on the basis of treatment type. Because the proportion lost to follow up in both the doxycycline treatment and BPG treatment groups was similar, it seems unlikely that differential losses would have biased the results.

Despite the statewide database that captures all reactive syphilis serological test results obtained in both private and public settings in the state of Maryland, nearly 60% of treated patients did not have any evidence of follow-up serological testing after therapy. Some syphilis patients may have seroreverted, others may have moved out of the jurisdiction, and some may have used aliases upon initial diagnosis, and there also may have been incomplete reporting of some reactive serological results to the state health department. This, however, still suggests that at least a significant number of patients treated at our clinics are not returning to document therapeutic effectiveness, which requires long-term follow up for assessment of complications. In addition, our study did not evaluate cases of clinical failure. Among the 4 patients who experienced serological failure, 2 followed up at a clinic, and neither had evidence of clinical failure. As is the case for all studies evaluating therapeutic responses in patients with syphilis, whether prospective or retrospective, the issue of treatment failure versus reinfection can never be fully ascertained. We reviewed the field records of all patients with serological failure to try to minimize outcome identification bias. Because none of the patients in the doxycycline group had treatment failure, this bias is less of a cause of concern. Finally, the relatively small number of patients and the lack of any treatment failure in the doxycycline group rendered any attempt to use multivariable models meaningless.

The issue of whether doxycycline is superior to BPG can only be addressed by a large clinical trial. However, the relatively good efficacy data with single-dose BPG would make such a costly trial superfluous. In summary, although small, this study suggests that the recommendation of doxycycline as a preferred alternate agent in the treatment of early syphilis is a reasonable one.

Acknowledgments

We would like to thank the Baltimore City Health Department staff for coordinating access for the abstraction of data.

Financial support. National Institutes of Health (5R01AI045724 to A.M.R.).

Potential conflicts of interest. All authors: no conflicts.

1 Centers for Disease Control Prevention (CDC) Sexually transmitted diseases treatment guidelines 2002, MMWR Recomm Rep, 2002, vol. 51 RR-6(pg. 1-78) 2 Centers for Disease Control Prevention (CDC) Azithromycin treatment failures in syphilis infections—San Francisco, California, 2002–2003, MMWR Morb Mortal Wkly Rep, 2004, vol. 53 (pg. 197-8) 3 Lukehart SA , Godornes C , Molini BJ , et al. Macrolide resistance in Treponema pallidum in the United States and Ireland, N Engl J Med, 2004, vol. 351 (pg. 154-8) 4 Hendricks FD , Greaves AB , Olansky S , et al. Terramycin in the treatment of venereal disease; a preliminary report, J Am Med Assoc, 1950, vol. 143 (pg. 4-5) 5 Kierland RR , Herrell WE , O’Leary PA . Treatment of syphilis with aureomycin administered by mouth, Arch Derm Syphilol, 1950, vol. 61 (pg. 185-95) 6 Montgomery CH , Knox JM . Antibiotics other than penicillin in the treatment of syphilis, N Engl J Med, 1959, vol. 261 (pg. 277-80) 7 Rajam RV , Rangiah RN , Somini C , Krishnamoorthy C . Tetracycline (achromycin) in venereal diseases, Antiseptic Madras, 1956, vol. 53 (pg. 9-19) 8 Onoda Y . Therapeutic effect of oral doxycycline on syphilis, Br J Vener Dis, 1979, vol. 55 (pg. 110-5) 9 Harshan V , Jayakumar W . Doxycycline in early syphilis: a long term follow up, Indian J Dermatol, 1982, vol. 27 (pg. 119-24) 10 Wharton M , Chorba TL , Vogt RL , Morse DL , Buehler JW . Case definitions for public health surveillance, MMWR Recomm Rep, 1990, vol. 39 RR-13(pg. 1-43) 11 Kaplan EL , Meier P . Non-parametric estimation from incomplete observations, J Am Stat Assoc, 1958, vol. 3 (pg. 457-81) 12 Rolfs RT . Treatment of syphilis, 1993, Clin Infect Dis, 1995, vol. 20 Suppl 1(pg. S23-38) 13 Parkes R , Renton A , Meheus A , Laukamm-Josten U . Review of current evidence and comparison of guidelines for effective syphilis treatment in Europe, Int J STD AIDS, 2004, vol. 15 (pg. 73-88) 14 Rolfs RT , Joesoef MR , Hendershot EF , et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection: the Syphilis and HIV Study Group, N Engl J Med, 1997, vol. 337 (pg. 307-14) 15 Romanowski B , Sutherland R , Fick GH , Mooney D , Love EJ . Serologic response to treatment of infectious syphilis, Ann Intern Med, 1991, vol. 114 (pg. 1005-9) Presented in part: 2005 International Society for Sexually Transmitted Diseases Research meeting, Amsterdam, Netherlands (abstract WP-057). © 2006 by the Infectious Diseases Society of America

Antibiotic therapy for adults with neurosyphilis

Review Question

We reviewed the clinical effectiveness and safety of antibiotic therapy for adults with neurosyphilis.

Background

Syphilis is a condition caused by a micro-organism called Treponema pallidum. At any stage of syphilis an individual can acquire neurosyphilis, which is an infection of the central nervous system (brain and spinal cord). The infection can be spread throughout the central nervous system, causing complications in the brain and spine. It may occur during early or late syphilis and it can have severe consequences for patients. Research has shown that people who are also infected with HIV are more likely to get neurosyphilis. Antibiotics are used to treat neurosyphilis. The first option is aqueous crystalline penicillin. However, in some cases, such as penicillin allergy, other antibiotics can be used.

Study characteristics

We searched the medical literature up to April 2019 for trials that evaluated the effectiveness and safety of drugs proposed for the management of neurosyphilis in adults. We found only one randomised clinical trial that met our criteria (patients are randomly put into groups to receive different treatments). This trial involved 36 adults with both syphilis and HIV, who were mainly men, with a median age of 34 years. The trial compared two drugs: ceftriaxone (2 g once daily), and penicillin G (4 million units every 4 hours for 10 days). It was funded by a pharmaceutical company.

Key findings

The trial reported serological cure, which is a decrease in the levels of the infection shown by laboratory analysis of fluids in the brain and spinal cord (known as cerebrospinal fluids), and clinical cure, which is the absence of signs or symptoms of neurosyphilis. Only three of 18 participants receiving ceftriaxone and two of 18 participants receiving penicillin G achieved serological cure; and eight of 18 participants receiving ceftriaxone and two of 18 participants receiving penicillin G achieved clinical cure.

There was not enough evidence to allow us to state if there is a difference between treatment with ceftriaxone or Penicillin G for neurosyphilis in adults. The outcomes evaluated could change when trials with a better design become available. Additionally, we did not identify any evidence related to the effectiveness and safety of other drugs proposed to manage this condition.

Quality of evidence

The quality of the evidence was very low for the outcomes serological cure and clinical cure due to problems with the trial’s design and methods, and because there was only a small number of participants.

What to know about syphilis

Doctors categorize the stage of syphilis as either primary, secondary, latent, or tertiary. A variety of symptoms define each stage.

The disease can be contagious during the primary and secondary stages and, occasionally, the early latent phase. Tertiary syphilis is not contagious, but it has the most severe symptoms.

Primary symptoms

The symptoms of primary syphilis include one or more painless, firm, and round syphilitic sores, or chancres. These appear 10 days to 3 months after the bacteria enter the body.

Chancres resolve within 2–6 weeks. However, without treatment, the disease may remain in the body and progress to the next phase.

Secondary symptoms

Secondary syphilis symptoms include:

  • sores that resemble oral, anal, and genital warts
  • a nonitchy, rough, red or red-brown rash that starts on the trunk and spreads to the entire body, including the palms and soles
  • muscle aches
  • fever
  • a sore throat
  • swollen lymph nodes
  • patchy hair loss
  • headaches
  • unexplained weight loss
  • fatigue

These symptoms may resolve a few weeks after they first appear. They might also return several times over a longer period.

Without treatment, secondary syphilis can progress to the latent and tertiary stages.

Read more about secondary syphilis.

Latent syphilis

The latent phase can last for several years. During this time, the body will harbor the disease without symptoms.

However, the T. pallidum bacteria remain dormant in the body, and there is always a risk of recurrence. Doctors still recommend treating syphilis at this stage, even if symptoms do not occur.

After the latent phase, tertiary syphilis may develop.

Tertiary syphilis, or late syphilis

Tertiary syphilis can occur 10–30 years after the onset of the infection, usually after a period of latency during which there are no symptoms.

At this stage, syphilis damages the following organs and systems:

  • heart
  • blood vessels
  • liver
  • bones
  • joints

Gummas may also develop. These are soft tissue swellings that can occur anywhere on the body.

Organ damage means that tertiary syphilis can often lead to death. Treating syphilis before it reaches this stage is, therefore, critical.

Neurosyphilis

Neurosyphilis is a condition that develops when T. pallidum bacteria have spread to the nervous system. It often has links to latent and tertiary syphilis. However, it can occur at any time after the primary stage.

A person with neurosyphilis may be asymptomatic for a long time. Alternatively, symptoms might develop gradually.

Symptoms include:

  • dementia or altered mental status
  • abnormal gait
  • numbness in the extremities
  • problems with concentration
  • confusion
  • headache or seizures
  • vision problems or vision loss
  • weakness

Congenital syphilis

Congenital syphilis is severe and frequently life threatening. T. pallidum bacteria can transfer from a pregnant woman to a fetus through the placenta and during the birth process.

Data suggest that without screening and treatment, about 70% of women with syphilis will have an adverse outcome in pregnancy.

Adverse outcomes include early fetal or neonatal death, preterm birth or low birth weight, and infection in infants.

Symptoms in newborns include:

  • saddle nose, in which the bridge of the nose is missing
  • fever
  • difficulty gaining weight
  • a rash of the genitals, anus, and mouth
  • small blisters on the hands and feet that change to a copper colored rash, which may be bumpy or flat, and spread to the face
  • watery nasal fluid

Older infants and young children may experience:

  • Hutchinson teeth, or abnormal, peg shaped teeth
  • bone pain
  • vision loss
  • hearing loss
  • joint swelling
  • saber shins, a bone problem in the lower legs
  • scarring of the skin around the genitals, anus, and mouth
  • gray patches around the outer vagina and anus

In 2015, the World Health Organization (WHO) confirmed Cuba as the first country in the world to have entirely eradicated congenital syphilis.

Learn how to recognize different STDs here.

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