In a non‑pregnant adult with a documented penicillin allergy, can ceftriaxone be used to treat syphilis and what are the recommended dosing regimens for early syphilis versus late latent or neurosyphilis?

Ceftriaxone for Syphilis in Penicillin-Allergic Patients

In non-pregnant adults with documented penicillin allergy, ceftriaxone 1 gram IM or IV daily for 10-14 days is an acceptable alternative for early syphilis (primary, secondary, or early latent), but penicillin desensitization remains the gold standard when feasible. 1, 2

Critical First Step: Exclude Pregnancy and Neurosyphilis

Before considering ceftriaxone, you must:

• Confirm the patient is not pregnant – ceftriaxone is absolutely contraindicated in pregnancy; all pregnant patients require penicillin desensitization without exception 1, 3
• Perform CSF examination if any of the following are present: neurologic or ophthalmic symptoms, evidence of tertiary syphilis, treatment failure, HIV infection with late latent disease, or nontreponemal titer ≥1:32 1, 4
• If neurosyphilis is present, ceftriaxone 2 grams IV daily for 10-14 days may be considered, but data are extremely limited and penicillin desensitization is strongly preferred 5, 1

Dosing Regimens by Stage

Early Syphilis (Primary, Secondary, or Early Latent ≤1 Year)

Ceftriaxone 1 gram IM or IV daily for 10-14 days 1, 2

• A 2017 multicenter randomized trial in 301 immunocompetent adults demonstrated that ceftriaxone 1 gram IV daily for 10 days achieved a 90.2% serological response rate at 6 months versus 78.0% with benzathine penicillin (p=0.01) 2
• For secondary syphilis specifically, ceftriaxone showed superior response rates (95.8% vs 76.2%, p<0.01) 2
• Single-dose ceftriaxone is completely ineffective – the full 10-14 day course is mandatory 5, 1

Late Latent Syphilis or Syphilis of Unknown Duration

Evidence for ceftriaxone in late latent disease is extremely limited 1

• The optimal approach is doxycycline 100 mg orally twice daily for 28 days after CSF examination excludes neurosyphilis 1, 3
• If doxycycline is contraindicated, consider penicillin desensitization rather than ceftriaxone, as there are no adequate data supporting ceftriaxone for late latent disease 1

Neurosyphilis (If Desensitization Not Feasible)

Ceftriaxone 2 grams IV daily for 10-14 days 5, 1

• This regimen has very limited supporting data from small case series only 5, 1
• The standard remains aqueous crystalline penicillin G 18-24 million units IV daily for 10-14 days 1, 4
• Critical caveat: 10-15% cross-reactivity exists between penicillin and ceftriaxone due to shared beta-lactam structure 1

Key Limitations and Warnings

Cross-Reactivity Risk

• Patients with severe penicillin reactions (Stevens-Johnson syndrome, anaphylaxis) may also react to ceftriaxone 1, 6
• One case report documented successful use of ceftriaxone in a pregnant woman with penicillin-induced Stevens-Johnson syndrome, but this required intensive monitoring and is not standard practice 6

Insufficient Evidence for Specific Populations

• Late latent syphilis: Optimal dose and duration not established; very limited data 5, 1
• Tertiary syphilis: No adequate evidence base 1
• HIV-infected patients: Limited data, though one retrospective study of 49 HIV-positive patients showed comparable efficacy to penicillin 7

Follow-Up Requirements

Because ceftriaxone data are limited compared to penicillin, more intensive monitoring is essential:

• Quantitative nontreponemal tests (RPR or VDRL) at 6,12, and 24 months 1, 4
• For HIV-infected patients: add testing at 3 and 9 months 1, 4
• Treatment success = ≥4-fold decline in titer within 6 months for early syphilis or 12-24 months for late latent disease 1, 4

Treatment Failure Indicators

• Persistent or recurrent symptoms 1, 4
• Sustained 4-fold increase in nontreponemal titers 1, 4
• Failure of initially high titer to decline 4-fold within expected timeframe 1, 4
• If failure occurs: perform CSF examination and retreat with IV penicillin regimen for neurosyphilis 1, 4

Alternative to Ceftriaxone: Doxycycline

For non-pregnant, penicillin-allergic patients without neurosyphilis, doxycycline is often preferred over ceftriaxone:

• Early syphilis: Doxycycline 100 mg orally twice daily for 14 days 1, 3
• Late latent syphilis: Doxycycline 100 mg orally twice daily for 28 days (after CSF examination) 1, 3
• Doxycycline has more extensive clinical experience than ceftriaxone and avoids beta-lactam cross-reactivity 1, 3

Common Pitfalls to Avoid

1. Never use ceftriaxone in pregnancy – desensitization to penicillin is mandatory 1, 3
2. Never use single-dose ceftriaxone – it is completely ineffective 5, 1
3. Never skip CSF examination before treating late latent syphilis with non-penicillin regimens – undiagnosed neurosyphilis will not respond 1, 4
4. Never assume ceftriaxone is safe in patients with severe penicillin reactions – cross-reactivity can occur 1, 6
5. Never use azithromycin – widespread macrolide resistance makes it unreliable 1

When Penicillin Desensitization Is Preferred

Despite ceftriaxone being an option, penicillin desensitization followed by standard penicillin therapy is preferred when:

• The patient is pregnant 1, 3
• Neurosyphilis is present 5, 1
• Late latent or tertiary syphilis requires treatment 1
• Patient compliance with oral doxycycline is uncertain 1
• Severe penicillin allergy raises concern about ceftriaxone cross-reactivity 1