What is the medication of choice for syphilis?

Medication of Choice for Syphilis

Benzathine penicillin G is the medication of choice for all stages of syphilis, with dosing determined by disease stage. 1, 2

First-Line Treatment by Stage

Early Syphilis (Primary, Secondary, and Early Latent)

• Benzathine penicillin G 2.4 million units intramuscularly as a single dose is the recommended treatment 1, 2, 3
• This regimen applies regardless of HIV status 4, 3
• Early latent syphilis is defined as infection acquired within the preceding year based on documented seroconversion, fourfold titer increase, history of symptoms, or having a sex partner with documented early syphilis 2

Late Latent Syphilis or Syphilis of Unknown Duration

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units intramuscularly at weekly intervals 1, 2, 3
• This same regimen applies to tertiary syphilis 1, 2

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units daily, administered as 3-4 million units intravenously every 4 hours for 10-14 days 3
• CSF examination is required to diagnose neurosyphilis in patients with neurological signs/symptoms, tertiary syphilis, or those whose serological titers fail to decline appropriately 2

Alternative Treatments for Penicillin-Allergic Patients

Doxycycline is the preferred alternative when penicillin cannot be used, though it should only be employed in non-pregnant patients 4, 1, 3

Dosing for Penicillin-Allergic Patients

• For early syphilis: Doxycycline 100 mg orally twice daily for 14 days 1, 3, 5
• For late latent syphilis: Doxycycline 100 mg orally twice daily for 28 days 1, 2, 5
• Tetracycline 500 mg orally four times daily is an alternative, though compliance is better with doxycycline due to less frequent dosing 3

Ceftriaxone as an Alternative

• Ceftriaxone 1 gram daily (intramuscular or intravenous) for 10 days is a reasonable alternative for early syphilis based on randomized trial data showing comparable efficacy to benzathine penicillin G 4, 3
• Optimal dosing is not well established, and this should be used with close clinical and serologic monitoring 3

Critical Caveats About Alternative Treatments

Azithromycin Should NOT Be Used

Azithromycin is not recommended for syphilis treatment in the United States despite some evidence of efficacy 4

• Treponema pallidum chromosomal mutations associated with macrolide resistance are highly prevalent in the United States 4
• Treatment failures with azithromycin have been documented in multiple geographic areas 4, 3
• While a single 2-gram oral dose showed comparable efficacy in some settings with low macrolide resistance, this cannot be relied upon in US practice 4

Amoxicillin Plus Probenecid

• Insufficient evidence exists to recommend oral amoxicillin plus probenecid for syphilis treatment 4
• A retrospective study suggested potential viability in HIV-infected patients, but had significant limitations including small sample size and lack of comparator group 4

Special Populations

Pregnant Women

Pregnant women must receive penicillin—it is the only therapy with documented efficacy for preventing maternal transmission 1, 2, 3

• Pregnant women with penicillin allergy should undergo desensitization and be treated with penicillin 1, 2, 3
• Alternative antibiotics are not adequately studied in pregnancy and should not be used 3
• Up to 40% of fetuses with in-utero exposure to syphilis are stillborn or die from infection during infancy, making proper treatment critical 6

HIV-Infected Patients

• Treatment regimens are identical to those for non-HIV-infected patients 4, 1, 2, 3
• Limited data suggest no benefit to multiple doses of benzathine penicillin G for early syphilis in HIV-infected patients compared to a single dose 4
• Closer follow-up is recommended: every 3 months rather than every 6 months 3
• HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment 2

Follow-Up and Treatment Monitoring

Serologic Monitoring

• Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 6,12, and 24 months 1, 2
• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 2
• Do not switch between different testing methods (e.g., VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 2

Treatment Failure Criteria

Treatment failure is defined as failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis 1, 2, 3

• Additional criteria include persistent or recurring signs/symptoms, or a sustained fourfold increase in nontreponemal test titers 3
• If treatment failure is suspected, patients should be re-evaluated for HIV infection and undergo CSF examination 2
• Re-treatment with weekly injections of benzathine penicillin G 2.4 million units intramuscularly for 3 weeks is recommended 1

Management of Sex Partners

Persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should be treated presumptively even if seronegative 1, 2

• Persons exposed more than 90 days before diagnosis should be treated presumptively if serologic test results are not immediately available and follow-up is uncertain 2
• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically 1

Important Clinical Considerations

Jarisch-Herxheimer Reaction

• An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis 2, 3
• Patients should be informed about this possible adverse reaction, which may include fever, headache, and myalgia 2, 3
• Some data suggest azithromycin may have lower rates of this reaction compared to benzathine penicillin G, though this does not outweigh concerns about resistance 4

Common Pitfalls to Avoid

• Do not use oral penicillin preparations for syphilis treatment—they are ineffective 2
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 2
• If a dose is missed during weekly therapy, an interval of 10-14 days between doses might be acceptable before restarting the sequence 2
• Administer adequate fluids with doxycycline to reduce risk of esophageal irritation and ulceration 5

Current Supply Challenges

• Benzathine penicillin G shortages have been documented, creating challenges in providing first-line therapy 7
• When benzathine penicillin G is unavailable, doxycycline serves as the primary alternative for non-pregnant patients 7
• Multiple facilities and pharmacies may need to be contacted to locate available doses during shortage periods 7