What is the recommended treatment for a patient diagnosed with syphilis when penicillin (PCN) G is not available?

Treatment of Syphilis When Penicillin G is Unavailable

For non-pregnant patients with syphilis when penicillin G is unavailable, doxycycline is the recommended alternative treatment: 100 mg orally twice daily for 14 days for early syphilis (primary, secondary, or early latent) or 28 days for late latent syphilis or syphilis of unknown duration. 1, 2, 3

Treatment Algorithm by Stage

Early Syphilis (Primary, Secondary, or Early Latent)

• Doxycycline 100 mg orally twice daily for 14 days 1, 2, 3
• This regimen is preferred over tetracycline due to better compliance with twice-daily versus four-times-daily dosing 2
• Early latent syphilis is defined as infection acquired within the preceding year based on documented seroconversion, fourfold increase in titer, history of symptoms, or having a sex partner with documented early syphilis 4

Late Latent Syphilis or Syphilis of Unknown Duration

• Doxycycline 100 mg orally twice daily for 28 days 1, 2, 3
• Tetracycline 500 mg orally four times daily for 28 days is an alternative, though less preferred 1

Neurosyphilis

• Doxycycline is NOT adequate for neurosyphilis 1
• These patients require IV aqueous crystalline penicillin G (18-24 million units daily for 10-14 days) or procaine penicillin with probenecid 1
• If penicillin allergy exists, penicillin desensitization is preferred, though ceftriaxone 2 g IV daily for 10-14 days may be considered in consultation with a specialist 1

Tertiary Syphilis

• Patients should be managed in consultation with an infectious disease specialist 1
• CSF examination should be performed to rule out neurosyphilis before initiating therapy 1

Evidence Supporting Doxycycline Efficacy

The effectiveness of doxycycline for early syphilis is supported by clinical data, though the evidence base is more limited than for penicillin:

• A comparative study showed no serological failures in the doxycycline group (0%; 95% CI, 0%-10.3%) versus 5.5% in the benzathine penicillin group, with median times to successful serological response of 106 days versus 137 days respectively 5
• A more recent study found doxycycline had slightly lower success rates in late and undetermined syphilis infections compared to penicillin, though differences were not statistically significant for early syphilis 6
• Another retrospective study showed no statistically significant differences in serological response between doxycycline and penicillin at 6 months (69.52% vs. 75.00%) or 12 months (92.38% vs. 96.17%) 7

Critical Management Considerations

Close Follow-Up is Mandatory

• All patients treated with doxycycline require close serologic and clinical monitoring 1, 2
• Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 6,12, and 24 months 1, 2
• For HIV-infected patients, monitoring should occur at 3-month intervals instead of 6-month intervals 2

Treatment Failure Criteria

Re-treatment should be initiated if: 1, 2

• Titers increase fourfold
• An initially high titer (≥1:32) fails to decline at least fourfold within 12-24 months of therapy
• Signs or symptoms attributable to syphilis develop

Special Populations

HIV-Infected Patients:

• Use the same doxycycline regimens as HIV-negative patients 1
• Require closer monitoring with follow-up at 3,6,9,12, and 24 months 1
• Alternative nonpenicillin regimens have not been sufficiently evaluated in HIV-infected persons to warrant use as first-line treatment 1

Pregnant Patients:

• Doxycycline is contraindicated in pregnancy 1
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission 4
• Pregnant patients with penicillin allergy must undergo penicillin desensitization 1, 4

Important Caveats and Pitfalls

When Doxycycline is NOT Appropriate:

• Neurosyphilis or ocular syphilis - requires IV penicillin or desensitization 1
• Pregnancy - requires penicillin desensitization 1, 4
• Children under 8 years of age - doxycycline contraindicated due to tooth discoloration risk 3

Ceftriaxone Considerations:

• Ceftriaxone might be effective based on biologic plausibility, but optimal dose and duration have not been defined 1
• Treatment decisions should be discussed in consultation with a specialist 1
• Some patients allergic to penicillin may also be allergic to ceftriaxone 1

Azithromycin Warning:

• Molecular resistance of T. pallidum to macrolides and clinical treatment failures with azithromycin have been reported 1
• Should only be used with close clinical and serologic monitoring to detect treatment failure 1

Administration Recommendations

• Administer adequate amounts of fluid with doxycycline to reduce risk of esophageal irritation and ulceration 3
• If gastric irritation occurs, doxycycline may be given with food or milk without significantly affecting absorption 3
• Patients should be informed about the possibility of Jarisch-Herxheimer reaction within 24 hours after therapy, especially in early syphilis 4