What are the oral treatment options for syphilis when parenteral penicillin G benzathine (Penicillin G benzathine) is not feasible, such as in patients with a confirmed penicillin allergy?

Oral Treatment of Syphilis

For penicillin-allergic patients with early syphilis (primary, secondary, or early latent), doxycycline 100 mg orally twice daily for 14 days is the preferred oral treatment, with tetracycline 500 mg orally four times daily for 14 days as an alternative if doxycycline cannot be tolerated. 1, 2

First-Line Oral Alternatives for Penicillin-Allergic Patients

Early Syphilis (Primary, Secondary, Early Latent)

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative treatment recommended by the CDC for non-pregnant penicillin-allergic patients 3, 1, 2, 4

• Tetracycline 500 mg orally four times daily for 14 days is an effective alternative, though compliance is typically better with doxycycline due to less frequent dosing and fewer gastrointestinal side effects 3, 1, 2

• Clinical data support doxycycline's efficacy: a 2006 study demonstrated 0% serological failure rate with doxycycline versus 5.5% with benzathine penicillin G, with median time to serological response of 106 days versus 137 days respectively 5

• More recent data from 2017 confirmed continued effectiveness, showing no statistically significant difference in serological response rates between doxycycline and penicillin at 6 months (69.52% vs. 75.00%) or 12 months (92.38% vs. 96.17%) 6

Late Latent Syphilis or Syphilis of Unknown Duration

• Doxycycline 100 mg orally twice daily for 28 days is recommended for late latent syphilis or syphilis of unknown duration in penicillin-allergic patients 1, 4

• Tetracycline 500 mg orally four times daily for 28 days is the alternative if doxycycline cannot be tolerated 3

• A 2022 retrospective study noted that doxycycline may have a reduced success rate in late and undetermined syphilis infections compared to early infections, with higher serofast rates observed 7

Second-Line Oral Options (When Compliance Can Be Assured)

Ceftriaxone

• Ceftriaxone 1 g daily (IM or IV) for 8-10 days may be considered as an alternative, though optimal dosing is not well established 3, 2

• The CDC notes that pharmacologic and bacteriologic considerations suggest ceftriaxone should be effective, but clinical experience is insufficient to identify late failures 3

• Single-dose ceftriaxone is NOT effective for treating syphilis 3

Erythromycin (Less Effective)

• Erythromycin 500 mg orally four times daily for 14 days is an option only for non-pregnant patients whose compliance with therapy and follow-up can be ensured 3

• Erythromycin is less effective than other recommended regimens and should be used only when other alternatives are not feasible 3

Azithromycin (NOT Recommended)

• Despite a 2002 pilot study showing promising results with azithromycin (94% response rate with single 2.0-g dose) 8, macrolide resistance in T. pallidum is now widespread in the United States, making azithromycin unsuitable 2

Critical Special Populations

Pregnant Patients

• Pregnant patients with penicillin allergy MUST be desensitized and treated with penicillin - alternative oral treatments are not recommended during pregnancy 3, 1, 2

• This is non-negotiable: up to 40% of fetuses with in-utero exposure to syphilis are stillborn or die from infection during infancy 9

HIV-Infected Patients

• HIV-infected patients should receive the same oral regimens (doxycycline or tetracycline) as HIV-negative patients if penicillin-allergic 2

• However, more frequent monitoring is required: serologic follow-up every 3 months instead of every 6 months 3, 1, 2

Patients with Uncertain Compliance

• If compliance with therapy or follow-up cannot be ensured, desensitization and treatment with penicillin is mandatory rather than using oral alternatives 3, 1, 2

• Skin testing for penicillin allergy may be useful to determine if desensitization is truly necessary 3

Follow-Up Requirements for Oral Treatment

• Clinical and serologic evaluation at 6 and 12 months after treatment is required 2

• For early syphilis, quantitative nontreponemal serologic tests should be repeated at 6,12, and 24 months 1

• Treatment failure is defined as: persistent or recurring signs/symptoms, sustained fourfold increase in nontreponemal test titers, or failure of titers to decline fourfold within 6 months after therapy for primary or secondary syphilis 3, 1, 2

• HIV-infected patients require evaluation every 3 months rather than every 6 months 3, 1, 2

Common Pitfalls and Caveats

• Jarisch-Herxheimer reaction (fever, headache, myalgia) may occur within 24 hours after treatment, especially in early syphilis 2

• Serologic tests may decline more slowly in patients who have had previous syphilis infections 3, 2

• Ensure adequate fluid intake with doxycycline or tetracycline to reduce risk of esophageal irritation and ulceration 4

• Doxycycline absorption is not significantly affected by food or milk, so it can be given with food if gastric irritation occurs 4

• For patients who fail oral treatment or show inadequate serologic response, re-treatment with three weekly injections of benzathine penicillin G 2.4 million units IM is recommended, unless CSF examination indicates neurosyphilis 3