Syphilis

Syphilis is caused by Treponema pallidum, a bacterium that penetrates broken skin or mucous membranes, almost always through sexual contact. Canadian syphilis rates have risen sharply enough that screening recommendations were formally updated in 2024 — screening is now recommended for every sexually active person with a new or multiple partners, or on patient request, with repeat screening every 3-6 months for anyone with ongoing multiple partners.^[1] Benzathine penicillin G is the only consistently effective treatment at every stage — there is no equally effective non-penicillin alternative, which makes penicillin allergy a genuine management problem rather than a simple substitution.^[2]

• New sexual partner or multiple sexual partners — this is now itself sufficient to recommend syphilis screening, independent of symptoms.^[1]
• A partner with confirmed or suspected syphilis.
• Men who have sex with men, and other populations with higher background prevalence.
• Pregnancy — universal screening is recommended, given the severity of untreated congenital syphilis.
• Other genital-ulcer STIs increase the risk of acquiring and transmitting HIV — consider HIV testing alongside syphilis testing.

Direct detection

Swab an anogenital or oral lesion for PCR where available; darkfield microscopy or direct immunofluorescence antibody testing on lesion fluid is an option where available for anogenital lesions specifically.

Serology

Serologic testing is the mainstay for staging and follow-up: a nontreponemal test (used for initial screening and for monitoring treatment response by titre) is paired with a treponemal test (used to confirm the diagnosis, and which typically remains positive for life even after successful treatment). Use your laboratory's specific testing algorithm and sequence, and interpret results in the context of prior treatment history when known.^[2]

• Cure the infection with an effective penicillin regimen matched to the correct stage.
• Prevent progression to tertiary disease, neurosyphilis, or ocular syphilis.
• Prevent transmission to sexual partners.
• Prevent vertical transmission and congenital syphilis when the patient is pregnant.

• Test and treat all sexual contacts within the relevant trace-back window (see Special Populations and Drug Tables).
• Advise abstaining from sexual contact until the patient and any recently treated partner(s) have completed treatment.
• Counsel specifically on the Jarisch-Herxheimer reaction (see Monitoring) before treatment, so the patient is not alarmed if it occurs.

Partner trace-back windows

• Follow every treated patient serologically (nontreponemal titres) to confirm an adequate treatment response and to detect possible treatment failure.
• Counsel patients about the Jarisch-Herxheimer reaction before treatment: fever, chills, rigors, and sweating that can occur at any stage but is most common in early syphilis, resolving within 24 hours. This is not a drug allergy and does not mean penicillin should be avoided in future.
• Refer for ongoing follow-up of a newborn whose parent was treated less than 4 weeks before delivery, to exclude congenital syphilis.

1. Confirm the correct stage-specific regimen, dose, and full number of doses were given.
2. Reassess serologic titres for the expected treatment response.
3. Confirm partners were tested and treated within the correct trace-back window.
4. If treatment failure or reinfection is suspected, evaluate for neurosyphilis specifically before retreating, since this changes the regimen entirely.
5. Refer to an infectious disease or sexual health specialist for confirmed treatment failure or diagnostic uncertainty.

• Confusing benzathine penicillin G (long-acting IM, used for primary/secondary/latent/cardiovascular/tertiary non-CNS disease) with benzylpenicillin/aqueous penicillin G (short-acting IV, used for neurosyphilis) — these are not interchangeable.
• Treating the Jarisch-Herxheimer reaction as a penicillin allergy and avoiding penicillin in the future as a result.
• Using azithromycin for syphilis — it is no longer recommended.
• Substituting doxycycline or ceftriaxone for penicillin in a pregnant patient instead of arranging desensitization.
• Treating a genital ulcer as herpes without adequately considering syphilis, given the real overlap in how the two can present.

How to use this table: Doses are adult doses and require patient-specific confirmation. Test and treat sexual contacts within the stage-specific window. Select any drug name to open its complete Pharmasist Drug Database page.

Penicillins — Preferred at Every Stage

Benzathine penicillin G and benzylpenicillin (aqueous penicillin G) are different formulations used for different stages — do not interchange them.

Cephalosporins — Last-Resort Alternative

Use only in exceptional circumstances, generally alongside desensitization planning.

Tetracyclines — Alternative for Non-Neurosyphilis, Non-Pregnant Patients

Contraindicated in pregnancy and breastfeeding — not an option in that population.

Not recommended: azithromycin is not recommended for syphilis at any stage — treatment failures and resistance have been reported.

Evidence note: Drug inventory, dosing, adverse effects, and comments reflect standard Canadian practice per current PHAC guidance.^[2]