Syphilis Treatment: How Many Injections and RPR Follow-Up Tests
Syphilis is curable with penicillin injections matched to the stage of disease. Just as important as the injections are follow-up RPR tests until the titre falls as expected, and treating partners at the same time.
Key points
- The main medicine is benzathine penicillin G: one injection for primary, secondary and early latent syphilis, and one injection a week for 3 weeks for late latent syphilis.
- After treatment, repeat RPR/VDRL at 6 and 12 months (more often in some cases). The titre should fall at least fourfold.
- Pregnant women must be treated with penicillin only, and partners exposed in the previous 90 days should be treated even if their blood test is still negative.
Once people learn they have syphilis, the first questions I hear are "How many injections do I need?" and "Will it definitely go away?" The short answer is that syphilis is curable. The number of injections depends on the stage, but treatment does not end with the last injection. You need follow-up blood tests for at least 1–2 years to confirm the infection has really cleared. This article summarizes the US CDC 2021 guidelines, the WHO 2024 recommendations and the guidelines of Thailand's Department of Disease Control, so you can understand the plan your doctor makes for you.
Treatment by stage (non-pregnant adults)
| Stage | Main treatment | Alternative if allergic to penicillin or during shortages |
|---|---|---|
| Primary, secondary and early latent (within 1 year) | Benzathine penicillin G 2.4 million units, one intramuscular injection | Doxycycline by mouth twice a day for 14 days |
| Late latent (over 1 year) or unknown duration | Benzathine penicillin G 2.4 million units once a week for 3 weeks | Doxycycline twice a day for 28 days |
| Neurosyphilis, ocular or otic syphilis | Aqueous crystalline penicillin G intravenously for 10–14 days (in hospital) | Procaine penicillin with probenecid, or ceftriaxone, at the doctor's discretion |
More things to know:
- For late latent syphilis needing 3 injections, the doses should be given exactly 7 days apart. If a dose is delayed too long (more than 9 days in pregnancy, or more than about 14 days for others according to CDC guidance), the doctor may need to restart the series.
- People living with HIV receive the same regimen as everyone else for their stage, but are followed up more closely.
- Azithromycin is no longer used to treat syphilis, because almost all strains are now resistant.
Syphilis in pregnancy
Pregnant women must be treated with penicillin only, because it is the only medicine proven to prevent congenital syphilis in the baby. If a pregnant woman is allergic to penicillin, she is desensitized in hospital and then given the standard regimen. Doxycycline must not be used in pregnancy. A pregnant woman with a positive syphilis test should be cared for together with an obstetrician straight away.
Penicillin shortages
Very few manufacturers in the world make benzathine penicillin G, so shortages happen from time to time. In the United States, after a recall of some batches in July 2025, health authorities said production might not return to normal until around late 2027. The guidance during shortages is to reserve penicillin for pregnant women, babies with suspected congenital syphilis, and people who cannot take doxycycline. Non-pregnant adults can use doxycycline for their stage instead, but must finish the full course.
In Thailand, availability varies over time and between hospitals and clinics. Your doctor will choose the most suitable regimen available and arrange especially close follow-up if you are on tablets.
Fever and chills after the injection: is that normal?
Within the first 24 hours after starting treatment, some people get fever, chills, aches, headache, or a rash that temporarily looks worse. This is called the Jarisch–Herxheimer reaction. It happens because dying bacteria release substances that trigger inflammation. It is common in primary and secondary syphilis, it is not a drug allergy, and it usually settles within a day. You can take a fever reducer. But hives, facial swelling or difficulty breathing may be a true allergic reaction, and you need to go to the emergency department immediately (in Thailand call 1669, the medical emergency number). A pregnant woman with these symptoms together with a tightening belly or reduced baby movements must go to hospital straight away.
During and after treatment
- Avoid sex for at least 7 days after completing treatment, and until any sores or rash have fully healed.
- Sexual partners exposed in the 90 days before a diagnosis of primary, secondary or early latent syphilis should be treated straight away, even if their blood test is still negative. Partners exposed longer ago should have a blood test first. For help with the conversation, read When your partner has an STI.
- Get tested for HIV and other sexually transmitted infections at the same time. If your HIV test is negative and you have ongoing risk, consider PrEP.
Follow-up RPR/VDRL blood tests
After treatment, follow-up uses the RPR or VDRL titre (not TPHA, which usually stays positive for life). Ideally use the same test at the same laboratory each time, because RPR and VDRL results cannot be compared directly.
| Stage | Repeat test at | Sign that treatment worked |
|---|---|---|
| Primary and secondary | 6 and 12 months | Titre falls at least fourfold within 12 months |
| Latent | 6, 12 and 24 months | Titre falls at least fourfold within 12–24 months, if the starting titre was high |
| People living with HIV | Every 3 months in the first year, and at 24 months | Same criteria |
A fourfold fall means dropping two dilution steps, for example from 1:32 to 1:8, or from 1:16 to 1:4.
If the titre does not fall, or goes back up
- A fourfold rise, for example from 1:4 to 1:16, usually means reinfection or treatment failure. You need a new assessment, an HIV test, and possibly a lumbar puncture if there are indications.
- A titre that falls but never reaches zero and stays low, such as 1:1 to 1:4 for a long time, is called serofast. CDC data show that about 15–20% of people correctly treated for primary or secondary syphilis do not reach the expected fall within 12 months. This does not always mean infection is still present. Your doctor will keep monitoring it together with your risk history.
- Testing too early, for example 1 month after the injection, may show no fall yet. There is no need to panic.
- First 24 hPossible fever, chills
Jarisch–Herxheimer reaction, not a drug allergy; usually gone in a day
- ≥ 7 daysNo sex
After finishing treatment and until sores or rash have fully healed
- 6 monthsFirst RPR/VDRL
Same method, same lab if possible
- 12 monthsTitre should fall ≥ 4-fold
Primary and secondary criterion, e.g. 1:32 down to 1:8
- 24 monthsRetest in latent stage
With HIV: test every 3 months in year 1 and at 24 months
Summarised from CDC 2021. Actual timing is as your doctor schedules.
Retreatment is decided by the titre trend and new risk, not a single result.
Preventing reinfection
Reinfection is very common in people with ongoing risk. Testing every 3–6 months, using condoms and, for some groups, Doxy-PEP all help reduce the chances. To review symptoms and testing, see Syphilis: symptoms, stages and blood tests.
When to see a doctor urgently, and how the clinic can help
Go to hospital immediately if you have blurred vision, a painful red eye, sudden hearing loss or ringing in the ears, severe headache or weakness. These may be signs of ocular syphilis or neurosyphilis, which need intravenous treatment.
At Dr. Kris Clinic, I assess the stage of disease, plan treatment according to current guidelines, arrange your follow-up RPR tests on schedule, and help care for your partner at the same time in confidence, as well as planning long-term prevention. English-speaking consultations are available.
Medicines and services your doctor may consider
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Frequently asked questions
Is one syphilis injection enough?
Yes, for primary, secondary and early latent syphilis acquired within the past year. For late latent syphilis or syphilis of unknown duration, you need one injection a week for a total of 3 injections.
My RPR is still not negative after treatment. Do I need another injection?
Not necessarily. If the titre has fallen at least fourfold within the expected time, treatment has worked. Some people keep a low titre (serofast). Your doctor will consider retreatment if the titre rises again or does not fall as expected.
I am allergic to penicillin. Can syphilis still be treated?
Yes. People who are not pregnant can take doxycycline for 14 or 28 days depending on the stage, under a doctor's care. Pregnant women need desensitization and then penicillin.
When can I have sex again after treatment?
At least 7 days after completing treatment, once sores or rash have healed and your partner has also been treated, so you do not pass it back and forth.
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การรักษาซิฟิลิส ฉีดกี่เข็ม และการติดตามผลเลือด RPR หลังรักษา →
References
- Workowski KA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021: Syphilis. MMWR Recomm Rep 2021;70(4).
- World Health Organization. Updated recommendations for the treatment of Neisseria gonorrhoeae, Chlamydia trachomatis and Treponema pallidum (syphilis), and new recommendations on syphilis testing and partner services. 2024.
- NYC Department of Health and Mental Hygiene. 2026 Health Advisory #7: Ongoing shortage of benzathine penicillin G (Bicillin L-A). April 2026.
- Department of Disease Control, Ministry of Public Health. Guidelines for the diagnosis, treatment and prevention of sexually transmitted infections, 2021 (in Thai).
This article is for education and does not replace diagnosis or treatment by a doctor. If you have symptoms or concerns, please see a doctor.
