Syphilis Treatment: Options for Each Stage of Infection

Syphilis treatment is done with antibiotics, such as benzathine penicillin G (Bicillin L-A), ceftriaxone, or doxycycline. The goal of treatment is to eliminate the bacterium Treponema pallidum.

Syphilis is a sexually transmitted infection (STI) that spreads through sexual contact with a person who has the infection. It can also be passed from a pregnant person to their baby and affect fetal development.

Syphilis treatment should be guided by an infectious disease specialist, gynecologist, urologist, or primary care provider, depending on the stage of infection. In the case of neurosyphilis, hospital admission may be needed.

Syphilis treatment by stage

According to the CDC, syphilis treatment in nonpregnant adults depends on the stage of infection and may follow these recommendations:

1. Primary, secondary, and early latent syphilis

Treatment for primary, secondary, and early latent syphilis is done with antibiotics.

Treatment standard:

The standard or first-choice treatment for primary, secondary, and early latent syphilis is:

• Benzathine penicillin G (Bicillin L-A), 1 single-dose injection of 2.4 million units, given into the muscle.

Benzathine penicillin G should be given as 2 divided doses of 1.2 million units, with 1 dose in each gluteal muscle, to reduce side effects at the injection site.

After the penicillin injection, it is common to have a reaction that causes fever, muscle pain, headache, fast heartbeat, shallow breathing, and low blood pressure. These symptoms can last 12 to 24 hours and should only be treated with acetaminophen.

Alternative treatment:

For people with a penicillin allergy, alternative treatment may include:

• Doxycycline 100 mg, twice a day, by mouth, for 14 days; or

• Tetracycline 500 mg, 4 times a day, by mouth, for 14 days; or

• Ceftriaxone 1 g per day, as an injection into the muscle or vein, for 10 days.

The type of antibiotic should be prescribed by an infectious disease specialist, gynecologist, urologist, or other healthcare provider. It is important to complete treatment exactly as prescribed to ensure the infection is fully treated and to reduce the risk of complications.

2. Late latent syphilis and tertiary syphilis

Treatment for late latent syphilis, latent syphilis of unknown duration, or tertiary syphilis is done with the following antibiotics:

Treatment standard:

For the standard treatment of late latent syphilis, latent syphilis of unknown duration, or tertiary syphilis, the following is recommended:

• Benzathine penicillin G (Bicillin L-A), 1 injection of 2.4 million units, once a week, for 3 weeks, given into the muscle.

Benzathine penicillin G doses should also be given as 2 divided doses of 1.2 million units, with 1 dose in each gluteal muscle.

The recommended interval between each benzathine penicillin G dose is 7 days, for a total treatment period of 3 weeks.

Alternative treatment:

Alternative treatment is usually recommended when the person has a penicillin allergy.

For late latent syphilis or latent syphilis of unknown duration, alternative treatment may include:

• Doxycycline 100 mg, twice a day, by mouth, for 28 days; or

• Tetracycline 500 mg, 4 times a day, by mouth, for 28 days.

For tertiary syphilis, anyone with a penicillin allergy should be treated in consultation with an infectious disease specialist.

3. Neurosyphilis

Neurosyphilis treatment is done with antibiotics such as:

Treatment standard:

The standard treatment for neurosyphilis is:

• Aqueous crystalline penicillin G, 18 to 24 million units per day, given into the vein as 3 to 4 million units every 4 hours or as a continuous infusion, for 10 to 14 days; or

• Procaine penicillin G 2.4 million units, once a day, given into the muscle, plus probenecid 500 mg, 4 times a day, by mouth, both for 10 to 14 days.

When procaine penicillin G and probenecid are used, treatment with both medications should be done for 10 to 14 days. This may be followed by 1 injection of benzathine penicillin G 2.4 million units, once a week, for 1 to 3 weeks, given into the muscle.

Alternative treatment:

Alternative treatment for neurosyphilis may include:

• Ceftriaxone 1 to 2 g per day, as an injection into the muscle or vein, for 10 to 14 days.

Neurosyphilis treatment should be completed for the full amount of time recommended by the doctor.

Penicillin allergy

In case of a penicillin allergy, penicillin desensitization may be recommended, especially because there are no proven alternatives for treating neurosyphilis, congenital syphilis, or syphilis during pregnancy.

However, in some nonpregnant people with a penicillin allergy, the doctor may prescribe doxycycline, tetracycline, or ceftriaxone as an alternative, depending on the stage of syphilis and the person’s health status.

Treatment during pregnancy

The first-choice treatment for syphilis during pregnancy is benzathine penicillin G. When a pregnant person has a penicillin allergy, desensitization is usually recommended so they can receive penicillin G.

The recommended dose depends on the stage of syphilis. For primary, secondary, or early latent syphilis, the commonly recommended dose is 2.4 million units of benzathine penicillin G (Bicillin L-A), given into the muscle in a single dose.

For late latent syphilis or syphilis of unknown duration during pregnancy, treatment usually involves benzathine penicillin G 2.4 million units, given into the muscle once a week for 3 weeks.

According to the CDC, penicillin G is the only known effective antimicrobial for treating syphilis during pregnancy and preventing congenital syphilis. When desensitization is not possible, the obstetrician should discuss the case with an infectious disease specialist.

Treatment for congenital syphilis

Congenital syphilis is syphilis that is passed from an infected mother to her baby during pregnancy.

In these cases, treatment should be guided by a pediatrician. It is usually started soon after birth with penicillin given directly into the vein every 12 hours during the first 7 days of life, then every 8 hours for a total of 10 days, depending on the baby’s age and clinical condition.

After treatment for congenital syphilis is started, it is normal for some newborns to develop symptoms such as fever, rapid breathing, or an increased heart rate. These symptoms can be controlled with other medications, such as acetaminophen.

Care during treatment

Important precautions during syphilis treatment include:

• Informing sexual partners so they can be tested and start treatment if needed
• Avoiding sexual contact during treatment, even with a condom
• Getting tested for HIV, as Treponema pallidum infection can increase the risk of HIV infection

Regular follow-up testing, such as a VDRL or RPR test, is also important to check whether treatment is working. This is usually done every 3 months, or as recommended by a healthcare provider.

If follow-up tests show that treatment was not effective, a new treatment plan may be recommended.

Even after treatment, a person can get syphilis again. For this reason, it is important to continue using condoms during all intimate contact to reduce the risk of syphilis and other sexually transmitted infections (STIs).

Signs of improvement or worsening

Signs that syphilis treatment is working usually appear about 3 to 4 days after treatment starts. These signs may include feeling better overall, reduction in swollen lymph nodes, and healing sores.

When treatment is not completed as prescribed, syphilis can worsen. Signs of worsening may include fever above 100.4°F, joint and muscle pain, reduced muscle strength, and progressive paralysis.

In these cases, the risk of complications may also increase. Possible complications include meningitis, hepatitis, joint deformities, and paralysis.