Syphilis

Clinical Snapshot

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]

Recognize the Condition

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Staging Determines Everything

Syphilis is staged by clinical presentation and known or estimated duration — the stage determines the entire treatment plan.

Primary syphilis

A chancre: classically a single, large, painless genital ulcer. Genital herpes ulcers, by contrast, are typically multiple, small, painful, and vesiculoulcerative — but there is real overlap in presentation, so do not rule out syphilis just because an ulcer looks atypical.

Secondary syphilis

A systemic stage: rash (classically involving the palms and soles), lymphadenopathy, and sometimes serious end-organ involvement including ocular syphilis or neurosyphilis. Both primary and secondary syphilis can present with ulcerative lesions.

Early latent syphilis

Asymptomatic infection of under 1 year's duration, confirmed serologically.

Late latent syphilis / unknown duration

Asymptomatic infection of over 1 year's duration, or duration that cannot be established.

Tertiary and neurosyphilis

Cardiovascular syphilis, gummatous disease, and neurosyphilis (which can occur at any stage, not only late disease). Ocular syphilis and neurosyphilis, especially with acute presentation, need urgent specialist consultation.

Risk Factors

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.

Red Flags & Refer

Refer for any of the following:

Suspected ocular syphilis or neurosyphilis, especially with an acute presentation — needs specialist consultation, not routine outpatient management.
Suspected or confirmed tertiary syphilis.
Penicillin required (pregnancy, neurosyphilis) but the patient has a genuine penicillin allergy — refer for specialist-directed penicillin desensitization.

Assessment & Diagnosis

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]

Treatment Targets

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.

Choose Initial Treatment

Direct treatment rule — stage determines the regimen

Primary, secondary, or early latent syphilis (under 1 year's duration): benzathine penicillin G 2.4 million units IM as a single dose (consider a second dose 1 week later if the patient is pregnant).

Late latent syphilis, syphilis of unknown duration, cardiovascular syphilis, or tertiary syphilis not involving the CNS: benzathine penicillin G 2.4 million units IM weekly for 3 doses.

Neurosyphilis (any stage): benzylpenicillin (aqueous penicillin G) 3-4 million units IV every 4 hours (16-24 million units/day) for 10-14 days — a different drug and route from the other stages; do not substitute benzathine penicillin, which does not achieve adequate CNS penetration.^[2]

Do not confuse: benzathine penicillin G (long-acting IM) with benzylpenicillin/aqueous penicillin G (short-acting IV) — they are used for different stages and are not interchangeable.

No longer recommended

Azithromycin is not recommended for syphilis — treatment failures and resistance have been reported.^[3]

Non-Pharmacologic Treatment

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.

Pharmacologic Treatment Options

Drug / intervention	Role	Dose / use	Important adverse effects	Teaching points
Benzathine penicillin G Preferred	Primary/secondary/early latent (under 1 year)	2.4 million units IM as a single dose (2nd dose at 1 week if pregnant)	Jarisch-Herxheimer reaction (fever, chills, resolving under 24h) — not a drug allergy	Supplied as 2 mL prefilled syringes containing 1.2 million units — 2 injections needed for a single dose.
Benzathine penicillin G (late latent) Preferred	Late latent, unknown duration, cardiovascular, tertiary non-CNS	2.4 million units IM weekly for 3 doses	Jarisch-Herxheimer reaction, as above	Consider penicillin desensitization first in a penicillin-allergic patient rather than defaulting to doxycycline.
Benzylpenicillin (aqueous penicillin G) Preferred	Neurosyphilis, any stage	3-4 million units IV every 4 hours (16-24 million units/day) for 10-14 days	Jarisch-Herxheimer reaction, as above	Benzathine penicillin does not reach adequate CNS levels — use this formulation, not the IM one, for neurosyphilis.
Doxycycline Alternative	Non-neurosyphilis, penicillin-allergic, not pregnant	100 mg PO BID for 14 days (early) or 28 days (late/unknown/cardiovascular/tertiary)	GI upset, rash, photosensitivity	Contraindicated in pregnancy and breastfeeding — desensitization is required in that situation instead.
Ceftriaxone Special situation	Last-resort alternative, exceptional circumstances	1 g IV/IM daily for 10 days (2 g daily for 10-14 days if neurosyphilis)	GI upset, hypersensitivity reactions	Not a satisfactory alternative to penicillin in pregnancy.

Not recommended: azithromycin is not recommended for syphilis at any stage — treatment failures and resistance have been reported.^[3]

Special Populations

Pregnancy: a penicillin-based regimen is the only consistently effective treatment in pregnancy. Refer to a specialist for penicillin desensitization if the patient is allergic — do not substitute doxycycline (contraindicated in pregnancy) or ceftriaxone (not a satisfactory alternative in pregnancy). Consider a second benzathine penicillin dose 1 week after the first for primary/secondary/early latent disease. Untreated syphilis can cause systemic disease in the patient, congenital syphilis in the newborn, and fetal loss; maternal treatment substantially reduces vertical transmission risk, but the newborn may still need empiric therapy with follow-up to exclude congenital syphilis — particularly if the patient was treated less than 4 weeks before delivery. Transmission during breastfeeding is theoretically possible during secondary syphilis specifically.^[2]

Partner trace-back windows

Diagnosis	Trace-back period	Action
Primary syphilis	3 months	Refer all partners for testing; refer all partners within the previous 3 months for empiric treatment even if their test is negative.
Secondary syphilis	6 months	Same approach — test all partners; empirically treat partners within the trace-back window even if seronegative.
Early latent syphilis	1 year	Same approach, extended to a 1-year window.
Late latent syphilis	Not time-limited	Test all long-term partners, and any of their children who may have been exposed during pregnancy.

Monitoring & Follow-Up

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.

Treatment Failure / Next Step

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

Common Errors to Avoid

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.

Clinical Decision Algorithm

Syphilis: stage-based treatment selection

Syphilis confirmed by serology ± direct detection

Neurosyphilis or ocular syphilis suspected (any stage)

Refer urgently. Benzylpenicillin 3-4 million units IV Q4H (16-24 million units/day) x 10-14 days

Primary, secondary, or early latent (under 1 year)

Benzathine penicillin G 2.4 million units IM single dose (2nd dose at 1 week if pregnant)

True penicillin allergy: not pregnant — doxycycline 100 mg PO BID x 14 days. Pregnant — refer for penicillin desensitization, do not substitute doxycycline

Late latent, unknown duration, cardiovascular, or tertiary (non-CNS)

Benzathine penicillin G 2.4 million units IM weekly x 3 doses

True penicillin allergy: consider desensitization first. If not pursued and not pregnant — doxycycline 100 mg PO BID x 28 days

Test all partners within the stage-specific trace-back window; empirically treat partners within that window even if seronegative

Follow serologic titres to confirm treatment response

Drug Tables

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.

Drug	Dosage	Adverse effects	Comments
Benzathine penicillin G — primary/secondary/early latent Bicillin L-A	2.4 million units IM as a single dose (consider a 2nd dose 1 week later if the patient is pregnant).	Jarisch-Herxheimer reaction (fever, chills, rigors, sweating, resolving within 24 hours) — not a drug allergy.	Supplied as 2 mL prefilled syringes containing 1.2 million units each — 2 injections are needed to give the full single dose. Do not confuse with benzylpenicillin. Tetracyclines may decrease penicillin efficacy — avoid combining.
Benzathine penicillin G — late latent/unknown duration/cardiovascular/tertiary non-CNS Bicillin L-A	2.4 million units IM weekly x 3 doses.	Jarisch-Herxheimer reaction, as above.	Consider penicillin desensitization in a penicillin-allergic patient rather than defaulting to doxycycline, particularly at this stage.
Benzylpenicillin (aqueous penicillin G) — neurosyphilis generics	3-4 million units IV every 4 hours (16-24 million units/day) x 10-14 days.	Jarisch-Herxheimer reaction, as above.	The preferred regimen specifically for neurosyphilis — benzathine penicillin does not achieve adequate CNS levels. Can be used in pregnancy and breastfeeding.

Cephalosporins — Last-Resort Alternative

Use only in exceptional circumstances, generally alongside desensitization planning.

Drug	Dosage	Adverse effects	Comments
Ceftriaxone generics	All stages except neurosyphilis: 1 g IV/IM daily x 10 days. Neurosyphilis: 2 g IV/IM daily x 10-14 days.	GI upset, hypersensitivity reactions.	Last-resort alternative, including for patients undergoing penicillin desensitization. Not a satisfactory alternative to penicillin in pregnancy. Do not reconstitute or co-administer with calcium-containing IV solutions.

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

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

Drug	Dosage	Adverse effects	Comments
Doxycycline — primary/secondary/early latent generics	100 mg PO BID x 14 days.	GI upset, rash, candidal vaginitis, photosensitivity.	Useful for a genuinely penicillin-allergic patient who is not pregnant and does not have neurosyphilis. Decreased levels with antacids, iron, bismuth, carbamazepine, phenytoin. May decrease penicillin efficacy if combined.
Doxycycline — late latent/unknown duration/cardiovascular/tertiary non-CNS generics	100 mg PO BID x 28 days.	Same as above.	Consider penicillin desensitization first, even in a penicillin-allergic patient, given the stakes of undertreating this stage.

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]

References

Recommendations on screening for syphilis in non-pregnant adults and adolescents — Canada Communicable Disease Report (National Advisory Committee on Sexually Transmitted and Blood-Borne Infections). CCDR 2024;50(7/8)
Syphilis guide: Key information and resources — Public Health Agency of Canada. Canadian Guidelines on Sexually Transmitted Infections
Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis — New England Journal of Medicine (Riedner G, Rusizoka M, Todd J, et al.). N Engl J Med 2005;353(12):1236-1244

Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.