What is the drug of choice for treating syphilis?

Drug of Choice for Syphilis

Parenteral penicillin G is the drug of choice for treating all stages of syphilis, with benzathine penicillin G being the preferred formulation for most cases. 1, 2

Treatment by Stage

Early Syphilis (Primary, Secondary, and Early Latent)

• Benzathine penicillin G 2.4 million units IM as a single dose is the recommended treatment 2, 3, 4
• This single-dose regimen has been proven effective through 50 years of clinical experience 1
• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold titer increase, recent symptoms, or exposure to a partner with documented early syphilis 2

Late Latent Syphilis and Latent Syphilis of Unknown Duration

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals 2, 3
• This extended regimen is necessary due to the longer duration of infection 2

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days 2, 3
• This is the only acceptable regimen for neurosyphilis, which can occur at any stage of infection 4

Alternative Treatments for Penicillin-Allergic Patients

Non-Pregnant Adults

• For early syphilis (primary, secondary, early latent): Doxycycline 100 mg orally twice daily for 14 days 2, 5, 6
• For late latent syphilis: Doxycycline 100 mg orally twice daily for 28 days 2, 3, 6
• Ceftriaxone 1 gram IV/IM daily for 10 days is a reasonable alternative based on randomized trial data showing comparable efficacy to benzathine penicillin 2
• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures 2

Critical Exception: Pregnancy and Neurosyphilis

• Penicillin is the ONLY therapy with documented efficacy for preventing maternal transmission and treating fetal infection 1, 2, 5
• Pregnant women and neurosyphilis patients who report penicillin allergy MUST undergo desensitization followed by penicillin treatment—no alternatives are acceptable 1, 2, 5
• This is non-negotiable because no other antibiotic has been proven to prevent congenital syphilis 2

Special Populations

HIV-Infected Patients

• Use the same treatment regimens as HIV-negative patients for all stages of syphilis 2, 5
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose 2
• However, closer follow-up is mandatory to detect potential treatment failure or disease progression 2
• HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment 1, 2

Critical Pitfalls to Avoid

• Never use oral penicillin preparations—they are completely ineffective for syphilis treatment 1, 5
• Never substitute inadequate alternatives in pregnancy—only penicillin prevents congenital syphilis 2
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 1, 2
• Never switch between different nontreponemal test methods (RPR vs VDRL) when monitoring response—results cannot be directly compared 2, 5
• Never skip CSF examination before treating tertiary syphilis—missing neurosyphilis leads to treatment failure 5

Important Clinical Considerations

Jarisch-Herxheimer Reaction

• An acute febrile reaction frequently accompanied by headache and myalgia may occur within 24 hours after any syphilis therapy 1, 2, 3
• This reaction occurs most often in patients with early syphilis 1
• In pregnant women, this reaction may precipitate premature labor or fetal distress during the second half of pregnancy 2
• Patients should be informed about this possible adverse reaction, though antipyretics have not been proven to prevent it 1

Follow-Up Protocol

• Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 3,6,12, and 24 months after treatment 2, 5
• For primary/secondary syphilis: Expect a fourfold decline in titer within 6 months 2, 5
• For late syphilis: Expect a fourfold decline in titer within 12-24 months 2, 5
• Treatment failure is defined as failure of nontreponemal test titers to decline fourfold within these timeframes 2, 3

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
• Time periods for at-risk partners: 3 months plus duration of symptoms for primary syphilis, 6 months plus duration of symptoms for secondary syphilis, and 1 year for early latent syphilis 2