What is the recommended treatment for an adult patient with syphilis who is allergic to penicillin (PCN)?

Treatment of Syphilis in Penicillin-Allergic Patients

For non-pregnant adults with syphilis who are allergic to penicillin, doxycycline 100 mg orally twice daily is the recommended alternative treatment: 14 days for early syphilis (primary, secondary, or early latent) and 28 days for late latent syphilis or syphilis of unknown duration. 1, 2, 3, 4

Formulation: Hyclate vs Monohydrate

• Either doxycycline hyclate or monohydrate at 100 mg is acceptable, as both formulations deliver equivalent bioavailable doxycycline and are used interchangeably in clinical practice 4
• The choice between formulations is based on tolerability rather than efficacy—monohydrate may cause less gastrointestinal upset in some patients, but both achieve the same therapeutic serum levels 4

Stage-Specific Dosing Algorithm

Early Syphilis (Primary, Secondary, or Early Latent <1 year)

• Doxycycline 100 mg orally twice daily for 14 days 1, 3, 4
• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold titer increase, symptoms within the past year, or partner with documented early syphilis 3

Late Latent Syphilis or Syphilis of Unknown Duration

• Doxycycline 100 mg orally twice daily for 28 days (4 weeks) 1, 2, 3, 4
• This extended duration is necessary because late-stage disease requires more prolonged treponemacidal levels 2

Tertiary Syphilis (Gummatous or Cardiovascular)

• Doxycycline 100 mg orally twice daily for 28 days 1, 2
• Critical caveat: CSF examination must be performed before initiating treatment to exclude neurosyphilis, as the treatment regimen differs entirely if CNS involvement is present 1, 2, 3

Absolute Contraindications and When Doxycycline Cannot Be Used

Pregnancy

• Pregnant patients with penicillin allergy MUST undergo penicillin desensitization followed by penicillin treatment—no exceptions 1, 2, 5, 3
• Doxycycline, tetracycline, erythromycin, azithromycin, and ceftriaxone are all inadequate in pregnancy because only penicillin has documented efficacy for preventing maternal transmission and treating fetal infection 2, 3
• Erythromycin specifically does not reliably cure fetal infection 3

Neurosyphilis

• Doxycycline is not adequately studied for neurosyphilis treatment 5
• Penicillin desensitization is strongly preferred for any patient with clinical evidence of neurologic involvement (cognitive dysfunction, motor/sensory deficits, ophthalmic/auditory symptoms, cranial nerve palsies, meningitis signs) 1, 2, 5, 3
• Syphilitic uveitis or other ocular manifestations are frequently associated with neurosyphilis and require IV penicillin therapy 1, 3

When Compliance Cannot Be Ensured

• If patient compliance with oral therapy or follow-up cannot be guaranteed, penicillin desensitization is strongly recommended 1, 5, 3
• This is particularly important because doxycycline requires 14-28 days of twice-daily dosing versus a single injection (or three weekly injections) of benzathine penicillin 2, 3

Alternative to Doxycycline: Tetracycline

• If doxycycline cannot be used, tetracycline 500 mg orally four times daily is the alternative: 14 days for early syphilis, 28 days for late latent syphilis 1, 5, 3
• Tetracycline has more gastrointestinal side effects and requires four-times-daily dosing, making compliance more challenging than doxycycline's twice-daily regimen 2, 5

Evidence Quality and Comparative Efficacy

• A 2006 comparative study found doxycycline had comparable serological response rates to benzathine penicillin for early syphilis, with 0% serological failure in the doxycycline group versus 5.5% in the penicillin group (not statistically significant, p=0.2) 6
• However, a 2022 retrospective study suggested doxycycline may have reduced success rates in late and undetermined syphilis infections compared to penicillin, though the difference was not statistically significant 7
• The CDC guidelines acknowledge that efficacy data from controlled trials for doxycycline are limited, and these therapies should be used only in conjunction with close serologic and clinical follow-up 1
• The efficacy of doxycycline in HIV-infected patients has not been well studied 1

Critical Pre-Treatment Evaluation

• All patients with syphilis must be tested for HIV infection 2, 3, 8
• CSF examination is mandatory before treating tertiary syphilis or when there are neurologic/ophthalmic signs, evidence of treatment failure, HIV infection with late latent syphilis, or nontreponemal titer ≥1:32 2, 3

Follow-Up Monitoring Requirements

• Quantitative nontreponemal serologic tests (RPR or VDRL) should be performed at 6 and 12 months after treatment for early syphilis 3
• For late latent syphilis, repeat testing at 6,12, and 24 months 2, 3
• A fourfold decline in nontreponemal test titers is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 2, 3
• HIV-infected patients require more frequent monitoring at 3-month intervals due to higher risk of treatment failure 2, 5, 3

Treatment Failure Criteria

• Treatment failure is defined as: persistent or recurring clinical signs/symptoms, sustained fourfold increase in nontreponemal titers, or failure of initially high titer to decline at least fourfold within the expected timeframe 2, 3
• If treatment failure occurs, re-evaluate for HIV infection and perform CSF examination to exclude neurosyphilis 2, 3
• Re-treatment typically consists of benzathine penicillin G 2.4 million units IM weekly for 3 weeks, unless CSF examination indicates neurosyphilis requiring IV penicillin 2, 3

Administration Considerations

• Administer doxycycline with adequate fluid to reduce risk of esophageal irritation and ulceration 4
• If gastric irritation occurs, doxycycline may be given with food or milk without significantly affecting absorption 4
• Counsel patients about Jarisch-Herxheimer reaction (acute fever, headache, myalgia occurring within 24 hours of treatment), which may occur particularly in patients with active lesions 2, 3

Common Pitfalls to Avoid

• Do not use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 3
• Do not rely solely on treponemal test antibody titers (FTA-ABS, TP-PA) to assess treatment response—these remain positive for life and do not correlate with disease activity 2, 3
• Do not switch between different nontreponemal testing methods (VDRL vs RPR) when monitoring serologic response, as results cannot be directly compared 3
• Remember that 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 3