Can ceftriaxone (a third-generation cephalosporin) administered intramuscularly (IM) be used as a treatment for syphilis infection in patients allergic to penicillin?

Ceftriaxone IM for Syphilis Treatment

Ceftriaxone 1 gram IM daily for 10-14 days can be used as an alternative treatment for syphilis in penicillin-allergic patients, though it remains a second-line option with limited data compared to penicillin, and should be reserved for situations where penicillin desensitization is not feasible. 1, 2

Primary Treatment Remains Penicillin

• Benzathine penicillin G is the gold standard for all stages of syphilis and should be the first-line treatment whenever possible 3, 2
• For penicillin-allergic patients, penicillin desensitization followed by penicillin therapy is the strongly preferred approach, particularly when compliance cannot be ensured 2, 4
• Skin testing can help clarify true penicillin allergy status before proceeding with alternatives 4

When Ceftriaxone Can Be Used

Dosing and Duration

• The recommended ceftriaxone regimen is 1 gram daily (IM or IV) for 10-14 days for early syphilis 1, 2, 4
• For neurosyphilis, ceftriaxone 2 grams daily IV for 10-14 days has limited supporting data but may be considered 1
• Single-dose ceftriaxone is not effective and should never be used 4

Supporting Evidence

• A 2022 network meta-analysis showed ceftriaxone had a higher serological response rate than penicillin at 6-month follow-up (RR 1.12,95% CI 1.02-1.23) 5
• Multiple observational studies in HIV-infected patients demonstrated comparable efficacy between ceftriaxone and penicillin, with ≥4-fold decline in VDRL titers in 91% of patients 6, 7
• A randomized trial from 1989 showed equivalent clinical and serological response between ceftriaxone and penicillin for primary and secondary syphilis 8

Critical Limitations and Caveats

Cross-Reactivity Warning

• Patients with severe penicillin allergy (such as Stevens-Johnson syndrome) may also be allergic to ceftriaxone, as both are beta-lactam antibiotics 1, 9
• Exercise extreme caution and consider alternative non-beta-lactam options (doxycycline or tetracycline) in patients with severe penicillin reactions 4

Data Gaps

• The optimal dose and duration of ceftriaxone have not been definitively established 1
• Evidence for ceftriaxone in late latent syphilis and tertiary syphilis is extremely limited 1
• Efficacy data in HIV-infected patients, while promising, remain limited compared to penicillin 1

Alternative Non-Beta-Lactam Options

First-Line Alternatives (Non-Pregnant)

• Doxycycline 100 mg orally twice daily is the preferred non-penicillin alternative: 14 days for early syphilis, 28 days for late latent syphilis 3, 2, 4
• Tetracycline 500 mg orally four times daily (same duration as doxycycline) is effective but has more gastrointestinal side effects affecting compliance 2, 4

When These Cannot Be Used

• If both penicillin and doxycycline allergies exist, tetracycline becomes the primary alternative 4
• Erythromycin 500 mg orally four times daily for 14 days is less effective and should only be used when compliance can be absolutely ensured 4

Mandatory Follow-Up for Ceftriaxone-Treated Patients

• Close serologic monitoring is required due to limited efficacy data for alternative therapies 2, 4
• Quantitative nontreponemal tests (RPR or VDRL) should be performed at 6 and 12 months for early syphilis 3, 2
• For HIV-infected patients, increase monitoring frequency to 3-month intervals (at 3,6,9, and 12 months) 3, 4
• Treatment success is defined as a fourfold decline in nontreponemal titer within 6 months for early syphilis 3, 2

Absolute Contraindications to Ceftriaxone Use

Pregnancy

• Ceftriaxone is inadequate for treating syphilis in pregnancy and does not reliably prevent congenital syphilis 2
• All pregnant women with penicillin allergy must undergo desensitization followed by penicillin treatment—no exceptions 2, 4
• Only penicillin has documented efficacy for preventing maternal transmission to the fetus 2
• One case report showed successful prevention of congenital syphilis with ceftriaxone in a woman with Stevens-Johnson syndrome to penicillin, but this remains experimental and not guideline-recommended 9

Neurosyphilis

• Alternative regimens for neurosyphilis are not adequately studied 4
• Penicillin desensitization is strongly preferred for neurosyphilis treatment 1, 4
• If ceftriaxone must be used for neurosyphilis, the dose is 2 grams daily IV (not IM) for 10-14 days, with very limited supporting data 1

Common Pitfalls to Avoid

• Do not use oral penicillin preparations—they are completely ineffective for syphilis 2
• Do not switch between different nontreponemal tests (VDRL vs RPR) when monitoring response, as results cannot be directly compared 2
• Do not use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 1, 2
• Do not rely on treponemal antibody tests (FTA-ABS, TP-PA) to monitor treatment response—they remain positive for life 3
• Remember that 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 1, 3, 2