A. Family Spirochaetaceae

1. Treponema
   1. T. pallidum, the causative agent of syphilis
   2. T. carateum (pinta)
2. Borrelia
   1. B. burgdorferei (Lyme disease)
   2. B. recurrentis
3. Leptospira (Leptospirosis)

B. Serologic Tests for Syphilis

1. Non-Treponemal
   1. RPR - rapid plasma reagin test. Detects anti-phospholipid antibodies
   2. VDRL - venereal disease research laboratory
   3. These tests measure antibodies against a cardiolipin-lecithin-cholesterol antigen
   4. Tests are very sensitive except early in primary infection, but are nonspecific
   5. Always follow positive non-treponemal test with a treponemal assay (confirmatory)
   6. These tests usually become unreactive with treatment
   7. The RPR often remains positive for longer in patients with HIV and syphilis
2. False Positive Non-Treponemal Tests (VDRL / RPR)
   1. Bacterial infection: Pneumococcus, Endocarditis, Mycoplasma, Relapsing Fever, Leprosy
   2. Viral Infections: Vaccinia, Chicken pox, HIV, Measles, Infectious mononucleosis, Mumps
   3. Chronic Liver Disease, Viral Hepatitis
   4. Collagen-Vascular Disease
   5. Malignancy: Multiple Myeloma, Advanced Cancers
3. Confirmatory (Treponemal) Tests
   1. FTA-ABS - fluorescent treponemal antigen
   2. MHA-TP - microhemagglutination assay for T. pallidum
   3. Note that B. burgdorfori (Lyme Disease agent) may cause false positive FTA
   4. Anti-treponemal IgM Assays are under development
4. False Positive Treponemal Tests
   1. Lyme Disease
   2. Leprosy
   3. Infectious Mononucleosis
   4. Leptospirosis
   5. Systemic Lupus Erythematosus (SLE)
   6. HIV - usually later disease

C. Natural History

1. Spread through contact with infectious lesions
2. Usually requires disrupted epithelium
   1. These occur at sites of minor trauma
   2. Most common during sexual activity
3. Primary Skin Lesions
   1. Called "Chancre" - painless, raised skin lesion
   2. Usually develop ~21 days after exposure. Range 10-90 days dependent on inoculum
   3. The chancre is found only locally since dissemination has not yet occurred
   4. Resolve spontaneously
4. Secondary Stage
   1. Hematogenous dissemination of T. pallidum with distant physical findings
   2. Rashes: macular, papular, annular or follicular [3], keratoderma blenorrhagica [8]
   3. Condylomata lata - grayish, raised, broad, flat papules in moist areas
   4. Systemic signs and symptoms: fever, malaise, generalized lymphadenopathy
   5. Cholestatic liver disease [3]
   6. Alopecia
   7. May resolve spontaneously
5. Latent Stage
   1. Primary and secondary syphilis resolve spontaneously
   2. Disease enters latent stage
   3. Tertiary syphilis may then occur
   4. Latent syphilis is syphilis with seroreactivity without other evidence of disease
6. Tertiary Syphilis
   1. Gumma
   2. Cardiovascular disease - aortitis is prominant, may involve coronary ostia [1,5]
   3. Neurosyphilis: most commonly general paresis and tabes dorsalis
   4. Occurs in ~30% of untreated patients
7. Syphilis with HIV Infection
   1. Patients present more often with 2° than 1° syphilis
   2. Patients with HIV and 2° syphilis have persistent chancres more than HIV- patients
   3. Loss of RPR titers with therapy does not differ with HIV+ or HIV-
   4. However, patients with HIV disease probably require long therapy to prevent relapse
   5. Penicillin (PCN) high dose for neurosyphilis may be insufficient in HIV patients
   6. Azithromycin 2gm po x 1 as effective as high dose PCN in HIV+ patients [4]
   7. All patients with syphilis should be tested for HIV status
8. Congenital Syphilis: all neonates born to syphilitic mothers should be given PCN

D. Treatment [2]

1. Jarisch-Herxheimer Reaction
   1. Common reaction after treatment of syphilis
   2. Shaking chills, fever, myalgias, headache, tachycardia, possible rash
   3. Occurs in 50% of 1°, 75% of 2°, 30% of 3° syphilis following treatment
   4. Due to massive release of treponemal lipopolysaccharides; transient reaction
2. Primary or Secondary
   1. Adults: PCN G 2.4 million units (MU) intramuscular (IM) x 1
   2. Alternative in adults: azithromycin 2gm po (including in HIV+ persons) [4]
   3. Children: PCN 50,000 units/kg IM, up to maximum of 2.4 MU
3. Latent Syphilis (normal CSF if performed)
   1. Early Latent: PCN 2.4 MU IM x 1
   2. Late Latent or Syphilis of Unknown Duration: PCN 2.4 MU IM q week x 3 doses
   3. Tertiary syphilis is treated in same way as late latent syphilis
4. Allergy to PCN
   1. Azithromycin 2gm x 1 po as effective as PCN including in HIV+ persons [4]
   2. Doxycycline 100mg bid po x 14 days (early disease)
   3. Doxycycline 100mg bid x 4 weeks for latent disease
   4. Alternative: Ceftriaxone 1gm qd IM or IV for 8-10 days
   5. Pregnant women allergic to PCN should be desensitized and treated with PCN
5. Neurosyphilis
   1. Aqueous crystalline PCN G 18-24 MU (3-4 MU q4 hours) x 10-14 days OR
   2. Procaine PCN 2.4 MU qd IM + probenecid 500mg po qid x 10-14 days
   3. Ceftriaxone may be considered in HIV infected patients as PCN may fail
6. HIV
   1. PCN 2.4 MU IM x 1 was sufficient in HIV+ and HIV- persons [6]
   2. Some experts advocated increased doses of antibiotics for prolonged duration
   3. Adding amoxicillin+probenicid to HIV+ persons had no clinical effect [6]
   4. Azithromycin 2gm po x 1 dose as ffective as PCN [4]
   5. Azithromycin resistance has been reported in USA and should be considered
7. Pregnant Women: only PCN reliably protects the fetus (? cephalosporins)
8. Monitoring Laboratory Changes
   1. In HIV- persons, RPR should slowly fall by >2 dilutions (>75%)
   2. In HIV+ persons, RPR can remain elevated with clinical manifestations [6]
   3. FTA/MHA remain positive even after therapy
9. Trace and Treat Partners
10. Prevention of Transmission [7]
    1. PCN G benzathine 2.4 million units IM x 1
    2. Azithromycin 1gm po x 1 dose (as effective as IM penicillin)
    3. Doxycyclin 200mg po bid x 14 days

References

1. Sexually Transmitted Disease Treatment Guidelines. 2002. MMWR. 51(RR6):1
2. Ryan ET, Felsenstein D, Aquino SL, et al. 2005. NEJM. 353(25):2697 (Case Record)
3. Greenstone CL, Saint S, Moseley RH. 2007. NEJM. 356(23):2407 (Case Discussion)
4. Riedner G, Rusizoka M, Todd J, et al. 2005. NEJM. 353(12):1236
5. Vlahakes GJ, Hanna GJ, Marks EJ. 1998. NEJM. 338(13):897 (Case Record)
6. Rolfs RT, Joesoef MR, Hendershot EF, et al. 1997. NEJM. 337(5):307
7. Hook EW III, Stephens J, Ennis DM. 1999. Ann Intern Med. 131(6):434
8. Tonna I and Laing RB. 2008. NEJM. 358(20):2160