What is the recommended treatment for a patient with syphilis, considering the stage of the disease and potential penicillin allergy?

Syphilis Treatment

Benzathine penicillin G is the only acceptable treatment for all stages of syphilis, with dosing and duration determined by disease stage—penicillin-allergic patients (except pregnant women) may receive doxycycline, but pregnant patients must undergo desensitization and receive penicillin. 1

Treatment by Stage

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose is the recommended treatment 1, 2
• For penicillin-allergic non-pregnant adults: doxycycline 100 mg orally twice daily for 14 days 1, 3
• Tetracycline 500 mg orally four times daily for 14 days is an alternative for penicillin-allergic patients 2

Early Latent Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose 1
• Early latent is defined as syphilis acquired within the preceding year, documented by seroconversion, fourfold titer increase, symptoms within the past year, or sex partner with documented early syphilis 1
• For penicillin-allergic non-pregnant adults: doxycycline 100 mg orally twice daily for 14 days 1, 3

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 IM at weekly intervals 1, 2
• CSF examination should be performed before treatment in patients with neurologic/ophthalmic signs, evidence of tertiary syphilis, treatment failure, HIV infection with late latent disease, or nontreponemal titer ≥1:32 1
• For penicillin-allergic non-pregnant adults: doxycycline 100 mg orally twice daily for 28 days 1, 3

Tertiary Syphilis

• Perform CSF examination first to exclude neurosyphilis—if neurosyphilis is present, the treatment regimen changes entirely 4
• If CSF is normal: benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals 4, 2
• Some specialists treat all cardiovascular syphilis cases with neurosyphilis regimens due to concern about CNS involvement 4

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
• Alternative regimen if compliance assured: procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily, both for 10-14 days 2
• Some specialists add benzathine penicillin 2.4 million units IM weekly for 3 weeks after completing neurosyphilis treatment to provide comparable total duration 2
• Syphilitic uveitis or other ocular manifestations should be treated as neurosyphilis with CSF examination 2

Special Populations

HIV-Infected Patients

• Use the same penicillin regimens as HIV-negative patients for all stages 1, 2
• A 2017 randomized trial showed no benefit to three doses versus single dose of benzathine penicillin for early syphilis in HIV-infected patients 5
• HIV-infected patients with late latent syphilis or syphilis of unknown duration should have CSF examination before treatment 2
• More frequent follow-up is mandatory (at 6,12,18, and 24 months) to detect treatment failure 2
• If treatment failure occurs, perform CSF examination and manage accordingly 2

Pregnant Women

• All pregnant women must receive penicillin regardless of allergy status—those with penicillin allergy must undergo desensitization followed by penicillin treatment 1, 2
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission and treating fetal infection 2, 1
• Some experts recommend a second dose of benzathine penicillin 2.4 million units IM one week after the initial dose for primary, secondary, or early latent syphilis in pregnancy 2
• Screen all pregnant women at first prenatal visit, during third trimester (28 weeks), and at delivery 1
• Women treated during the second half of pregnancy are at risk for premature labor/fetal distress from Jarisch-Herxheimer reaction—they should seek immediate medical attention if contractions or changes in fetal movements occur 1, 2
• Never use tetracycline, doxycycline, erythromycin, azithromycin, or ceftriaxone in pregnancy—erythromycin does not reliably cure fetal infection 1

Pediatric Patients

• Benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose for primary, secondary, or early latent syphilis 1
• For late latent syphilis: benzathine penicillin G 50,000 units/kg IM for three total doses at weekly intervals (total 150,000 units/kg up to 7.2 million units) 1
• Children require CSF examination to exclude neurosyphilis before treatment 1

Alternative Treatments and Important Caveats

Ceftriaxone

• Ceftriaxone 1 gram IM/IV daily for 10-14 days may be considered based on randomized trial data showing comparable efficacy to benzathine penicillin 1
• For neurosyphilis: ceftriaxone 2 grams IV daily for 10-14 days (limited data) 1
• Patients with severe penicillin allergy (Stevens-Johnson syndrome) may also be allergic to ceftriaxone as both are beta-lactams 1
• Evidence for late latent and tertiary syphilis is extremely limited 1

Azithromycin

• Do not use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 1
• While a 2002 pilot study showed promise with azithromycin 2.0 g as a single dose 6, subsequent resistance has made this regimen obsolete 1

Follow-Up Protocol

Primary and Secondary Syphilis

• Perform quantitative nontreponemal tests (RPR or VDRL) at 6 and 12 months after treatment 1
• Expect a fourfold decline in titer within 6 months 1

Latent Syphilis

• Repeat quantitative nontreponemal tests at 6,12, and 24 months 1
• Expect fourfold decline within 12-24 months 1

Treatment Failure Criteria

• Persistent or recurring signs/symptoms 1
• Sustained fourfold increase in nontreponemal titers 1
• Failure of initially high titer to decline at least fourfold within 6-12 months for early syphilis or 12-24 months for late syphilis 1
• If treatment failure occurs: re-evaluate for HIV, perform CSF examination, and re-treat with three weekly injections of benzathine penicillin G 2.4 million units IM unless neurosyphilis is diagnosed 1

Neurosyphilis Follow-Up

• If CSF pleocytosis was present initially, repeat CSF examination every 6 months until cell count normalizes 2

Management of Sex Partners

• Treat presumptively with benzathine penicillin G 2.4 million units IM if exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis, even if seronegative 7, 1
• 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 1
• Repeat serologic testing at 6 weeks, 3 months, and 6 months to detect seroconversion in those treated presumptively who were initially seronegative 7

Critical Pitfalls to Avoid

• Never use oral penicillin preparations—they are completely ineffective for any stage of syphilis 1, 4
• Do not use different serologic test methods (RPR vs VDRL) when monitoring response—results cannot be directly compared 1, 4
• Do not skip CSF examination before treating tertiary syphilis—this may miss neurosyphilis requiring different treatment 4
• Procaine penicillin without probenecid does not achieve adequate CSF levels and is inadequate for neurosyphilis 1
• If a dose is missed during weekly therapy, an interval of 10-14 days between doses might be acceptable before restarting the sequence 1
• 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 1

Jarisch-Herxheimer Reaction

• An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis 1, 4
• Symptoms include headache, myalgia, fever, and other constitutional symptoms 1
• Continue penicillin therapy and provide supportive care including antipyretics 7
• In pregnancy during second half, this reaction may precipitate premature labor or fetal distress 1