What is the recommended treatment for a patient with latent syphilis, considering factors such as Human Immunodeficiency Virus (HIV) status and history of previous syphilis treatment?

Treatment for Latent Syphilis

For early latent syphilis, administer benzathine penicillin G 2.4 million units IM as a single dose; for late latent syphilis or latent syphilis of unknown duration, administer benzathine penicillin G 7.2 million units total as three doses of 2.4 million units IM at weekly intervals. 1, 2

Defining the Stage of Latent Syphilis

Before initiating treatment, you must determine whether the patient has early versus late latent syphilis, as this fundamentally changes the treatment regimen:

• Early latent syphilis is defined as syphilis acquired within the preceding year, documented by: 3, 1, 2

  • Documented seroconversion within the past year
  • Fourfold or greater increase in nontreponemal titer within the past year
  • Unequivocal symptoms of primary or secondary syphilis within the past year
  • A sex partner with documented primary, secondary, or early latent syphilis

• Late latent syphilis or latent syphilis of unknown duration includes all other cases that do not meet the above criteria 3, 1

Pre-Treatment Evaluation: When to Perform Lumbar Puncture

You must perform CSF examination before treatment if the patient meets any of the following criteria: 3, 1, 2

• Neurologic signs or symptoms (cognitive dysfunction, motor or sensory deficits, meningismus)

• Ophthalmic manifestations (uveitis, iritis, vision changes)

• Evidence of active tertiary syphilis (aortitis, gumma)

• Treatment failure from prior therapy

• HIV infection with late latent syphilis or syphilis of unknown duration

• Serum nontreponemal titer ≥1:32, unless duration of infection is definitively known to be <1 year

• Nonpenicillin therapy is planned, unless duration is known to be <1 year

• If CSF shows abnormalities consistent with neurosyphilis, treat as neurosyphilis with aqueous crystalline penicillin G 18-24 million units per day IV for 10-14 days instead of the latent syphilis regimen 1, 4

Standard Treatment Regimens

Early Latent Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose 3, 1, 2

Late Latent Syphilis or Latent Syphilis of 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 patient misses a dose during weekly therapy, an interval of 10-14 days between doses may be acceptable before restarting the sequence 3, 2

• Critical exception: Pregnant patients who miss any dose must repeat the full course of therapy—no exceptions 3

Management of Penicillin Allergy

Non-Pregnant Patients

For penicillin-allergic patients, alternative regimens should only be used after CSF examination has excluded neurosyphilis: 3, 1

• Early latent syphilis:

  • Doxycycline 100 mg orally twice daily for 14 days 3, 1, 5
  • OR Tetracycline 500 mg orally four times daily for 14 days 3, 1

• Late latent syphilis or unknown duration:

  • Doxycycline 100 mg orally twice daily for 28 days 3, 1, 5
  • OR Tetracycline 500 mg orally four times daily for 28 days 3, 1

• These alternative regimens require close serologic and clinical follow-up, and their efficacy in HIV-infected persons has not been adequately studied 3, 1

• Ceftriaxone (1 gram IM or IV daily for 10-14 days) may be considered as an alternative, though data are limited and the optimal dose and duration have not been definitively established 3, 2

  • Do not use ceftriaxone in patients with severe penicillin allergy (e.g., Stevens-Johnson syndrome) due to cross-reactivity between beta-lactam antibiotics 2

• Do not use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 2

Pregnant Patients

Pregnant patients who are allergic to penicillin MUST be desensitized and treated with penicillin—there are no acceptable alternatives. 3, 1, 2, 4

• Penicillin is the only therapy with documented efficacy for preventing maternal transmission to the fetus and treating fetal infection 2
• Tetracycline, doxycycline, erythromycin, azithromycin, and ceftriaxone are inadequate—erythromycin does not reliably cure fetal infection 2
• Women treated during the second half of pregnancy are at risk for premature labor and/or fetal distress from Jarisch-Herxheimer reaction and should seek immediate medical attention if they notice contractions or changes in fetal movements 2

HIV-Infected Patients

Treatment Approach

• HIV-infected patients with early latent syphilis should be treated with the same regimen as HIV-negative patients: benzathine penicillin G 2.4 million units IM as a single dose 3, 1

  • Some experts recommend additional treatments (e.g., three weekly doses as for late syphilis) or supplemental antibiotics, though this is not universally agreed upon 3

• HIV-infected patients with late latent syphilis or syphilis of unknown duration should have a CSF examination before treatment 3, 1

  • If CSF is normal, treat with benzathine penicillin G 7.2 million units total as three weekly doses of 2.4 million units IM 3, 1, 2
  • If CSF shows neurosyphilis, treat as neurosyphilis 3

• Penicillin regimens should be used for all stages of syphilis in HIV-infected patients; if penicillin-allergic, perform skin testing and desensitization, then treat with penicillin 3, 2

Enhanced Follow-Up

• HIV-infected patients require more intensive monitoring: evaluate clinically and serologically at 3,6,9,12,18, and 24 months after therapy 3, 1
• Some experts recommend CSF examination after therapy (at 6 months) even if asymptomatic, though this is of unproven benefit 3
• If nontreponemal titer does not decrease fourfold within 6-12 months, strongly consider CSF examination and re-treatment 3

Follow-Up Protocol

Standard Monitoring

• Repeat quantitative nontreponemal serologic tests (RPR or VDRL) at 6,12, and 24 months after treatment 3, 1, 4

Criteria for Re-Treatment

Re-treat the patient if any of the following occur: 3, 1

• Nontreponemal titers increase fourfold (two dilutions) at any time

• 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

• Before re-treatment, perform CSF examination to evaluate for neurosyphilis 3

• Re-treatment typically involves three weekly injections of benzathine penicillin G 2.4 million units IM, unless CSF indicates neurosyphilis 2

Pediatric Considerations

After the newborn period, children diagnosed with syphilis require special evaluation:

• Perform CSF examination to exclude neurosyphilis 3, 1, 2
• Review birth and maternal medical records to assess whether the child has congenital or acquired syphilis 3

Pediatric Dosing (for acquired latent syphilis with normal CSF)

• Early latent syphilis: Benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose 3, 1, 2

• Late latent syphilis or unknown duration: Benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) administered as three doses at 1-week intervals (total 150,000 units/kg up to adult total dose of 7.2 million units) 3, 1, 2

Management of Sex Partners

• Persons exposed within 90 days preceding the diagnosis of primary, secondary, or early latent syphilis should be treated presumptively, even if seronegative 2
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic test results are not immediately available and follow-up is uncertain 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

Critical Pitfalls to Avoid

• Never use oral penicillin preparations for syphilis treatment—they are ineffective 2
• Do not switch between different nontreponemal tests (e.g., VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 2
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 2
• Remember that 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 2
• All patients with syphilis should be tested for HIV infection 3, 2