What is the recommended treatment for syphilis using Benzathine penicillin G (Bicillin)

Benzathine Penicillin G Treatment for Syphilis

Benzathine penicillin G remains the definitive treatment of choice for all stages of syphilis, with dosing determined by disease stage: a single 2.4 million unit IM injection for early syphilis (primary, secondary, and early latent) and three weekly 2.4 million unit IM injections for late latent or unknown duration syphilis. 1, 2

Treatment Regimens by Stage

Early Syphilis (Primary, Secondary, and Early Latent <1 Year)

• Single dose of benzathine penicillin G 2.4 million units IM is the standard treatment, supported by over 40 years of clinical experience and achieving 90-100% treatment success rates 3, 1, 4
• 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 2
• This single-dose regimen applies regardless of HIV status, though HIV-infected patients may be at increased risk for neurologic complications and treatment failure 3

Late Latent Syphilis or Unknown Duration

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at 1-week intervals 3, 1, 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
• Treatment completion rates for the three-dose regimen are notably low in real-world practice (42.9% in one study), highlighting the importance of ensuring patient follow-up 5

Tertiary Syphilis

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at 1-week intervals 3, 1, 2
• Patients with symptomatic late syphilis should have CSF examination before therapy is initiated 3

Special Populations

HIV-Infected Patients

• Use the same treatment regimens as HIV-negative patients for early syphilis (single 2.4 million unit dose) 3, 1, 2
• Some specialists recommend additional treatments (three weekly doses instead of one) for early syphilis in HIV-infected patients, though evidence supporting this intensified approach is limited 3
• For late latent syphilis in HIV-infected persons, CSF examination should be performed before treatment to exclude neurosyphilis 3
• HIV-infected patients require more intensive follow-up at 3,6,9,12, and 24 months after therapy 3
• Treatment response is not affected by CD4 count, and a single dose remains effective even in immunocompromised patients 6

Pregnant Women

• Only penicillin G is proven effective for preventing maternal transmission and treating fetal infection 1, 2, 7
• Pregnant women with penicillin allergy must undergo desensitization and be treated with penicillin—no alternatives are acceptable 3, 1, 2
• All pregnant women should be screened for syphilis at the first prenatal visit, during the third trimester, and at delivery 7
• Up to 40% of fetuses with in-utero exposure to syphilis are stillborn or die from infection during infancy, making appropriate treatment critical 7
• Treatment completion rates are higher in pregnant women (68.7%) compared to the general population, likely due to increased monitoring 5

Pediatric Patients

• For children with acquired primary or secondary syphilis: Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose 1
• For late latent syphilis: Benzathine penicillin G 50,000 units/kg IM at 1-week intervals for three doses (total 150,000 units/kg up to 7.2 million units) 3
• Children should have CSF examination to exclude neurosyphilis, and birth/maternal records should be reviewed to distinguish congenital from acquired syphilis 3

Penicillin-Allergic Patients

Early Syphilis (Non-Pregnant)

• Doxycycline 100 mg orally twice daily for 14 days is the recommended alternative 1, 2, 7
• Ceftriaxone may be effective but optimal dose and duration have not been definitively established 3
• Azithromycin shows promise but is most useful for incubating syphilis rather than established disease 3

Late Latent Syphilis (Non-Pregnant)

• Doxycycline 100 mg orally twice daily for 28 days 3, 1, 2
• Tetracycline 500 mg orally four times daily for 28 days is an alternative 3
• These therapies should be used only with close serologic and clinical follow-up 3
• Critical caveat: The effectiveness of non-penicillin alternatives has not been well documented, and these should be considered suboptimal 3

Pregnant Patients with Penicillin Allergy

• No alternatives to penicillin are acceptable—patients must undergo penicillin desensitization 3, 1, 2

Monitoring Treatment Response

Expected Serologic Response

• Quantitative nontreponemal tests (RPR or VDRL) should be repeated at 6,12, and 24 months 1, 2
• For primary/secondary syphilis: A fourfold decline in titer (two dilutions) is expected within 6 months 1, 2, 8
• For late syphilis: A fourfold decline is expected within 12-24 months 1, 2
• Approximately 15% of patients with early-stage syphilis do not meet standard criteria for serologic cure at 12 months despite appropriate treatment 3

Treatment Failure Criteria

Treatment failure is defined by any of the following 3, 1:

• Failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis
• Titers increase fourfold at any time
• An initially high titer (≥1:32) fails to decline at least fourfold within 12-24 months
• Signs or symptoms attributable to syphilis develop

Management of Treatment Failure

• Re-evaluate for HIV infection and perform CSF examination 2
• Re-treat with benzathine penicillin G 2.4 million units IM weekly for 3 weeks if CSF is normal 3

The "Serofast State"

• A significant proportion of patients remain seropositive after treatment (the "serofast state") 4
• The relationship between serologic and clinical response remains unclear in these cases 3
• Treponemal tests remain positive for life in most patients and should not be used to monitor treatment response 8

Critical Pitfalls to Avoid

Diagnostic Errors

• Do not treat based solely on positive RPR without treponemal confirmation—biological false positives are common 8
• Do not use different testing methods (switching between VDRL and RPR) when monitoring response—results cannot be directly compared 2

Treatment Errors

• Do not use oral penicillin preparations—they are ineffective for syphilis treatment 2
• Do not use non-penicillin alternatives in pregnant women—only penicillin prevents maternal transmission 1, 2
• Do not rely on treponemal antibody titers to assess treatment response—they correlate poorly with disease activity 2

Supply Chain Considerations

• Benzathine penicillin G shortages have occurred, creating significant treatment challenges 9
• When BPG is unavailable, doxycycline can be used as a temporary alternative for non-pregnant patients, but efforts should continue to locate BPG 9
• The shortage particularly impacts pregnant women and patients requiring the three-dose regimen 9

Management of Sexual Partners

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

Jarisch-Herxheimer Reaction

• An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis 2
• Symptoms include headache, myalgia, fever, and other constitutional symptoms 2
• Patients should be counseled about this expected reaction before treatment 2