Reexamining Syphilis: An Update on Epidemiology, Clinical Manifestations, and Management

Molly E Kent, PharmD; Frank Romanelli, PharmD MPH BCPS

The Annals of Pharmacotherapy. 2008;42(2):226-236.

Summary

Syphilis rates have increased dramatically in recent years, with a large percentage of this increase occurring among MSM and patients coinfected with HIV. Penicillin remains the treatment of choice today with different dosage forms and duration of therapy recommended for the 4 distinct stages of this disease. There are limited therapeutic options for patients with penicillin allergies. Diagnosis and management of patients infected with both syphilis and HIV are challenging due to the altered presentation of syphilis and the unique interplay between the 2 disease processes. To continue to combat the increasing prevalence of this disease, increased clinical vigilance is needed to identify patients at risk for syphilis and to screen, diagnose, and treat them appropriately.

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Reprint Address

Dr. Romanelli, College of Pharmacy, University of Kentucky, 725 Rose St., Lexington, KY 40536, fax 859/323-0069. E-mail: froma2@email.uky.edu .

Cite this: Reexamining Syphilis: An Update on Epidemiology, Clinical Manifestations, and Management - Medscape - Feb 01, 2008.

Table 1. Tests for the Diagnosis of Syphilis ^{[1,2,13,22,23,24,44,45,46,47,48,49,50]}
Test	Test Type	Specimen	Comments
Darkfield microscopy and direct fluorescent antibody stains	direct detection	ulcer exudates, lymph node aspirate, tissue biopsies	limited availability, rarely used, low sensitivity, unable to distinguish pathogenic Treponema spp.
VDRL and RPR	nontreponemal modified Wasserman reaction	blood	standard initial screening test; high sensitivity; 1-2% rate of false-positives associated with increased age, autoimmune disease, malignancy, injection drug use, vaccinations, pregnancy, Epstein-Barr virus, HIV infection, rickettsial infection, mycoplasmal infection, spirochetal infection
TP-PA and FTA-abs	treponemal	blood	confirmatory test; high sensitivity and specificity; rare false-positives associated with malaria, autoimmune disease, pregnancy, leprosy, viral infection, spirochetal infections; unable to distinguish pathogenic Treponema spp.
VDRL-CSF	nontreponemal	CSF	high specificity, low sensitivity positive = CNS syphilis negative = ?
CSF FTA-abs	treponemal	CSF	high sensitivity, low specificity, negative = no CNS syphilis, false-positives common and may be due to passive diffusion of the treponemal antibodies from the blood to CSF

CNS = central nervous system; CSF = cerebrospinal fluid; FTA-abs = fluorescent treponemal antibody absorption test; RPR = Rapid Plasma Reagin; TP-PA = T. pallidum particle agglutination; VDRL = Venereal Disease Research Laboratory.

Table 2. Treatment Regimens for Syphilis in Non-HIV-Infected and HIV ^a-Infected Patients ^[24]
Stage	Patients Not Allergic to Penicillin	Patients Allergic to Penicillin
Primary, secondary, early latent	benzathine PCN G 2.4 million units im once	doxycycline 100 mg po bid for 10 days or tetracycline 500 mg 4 times daily for 14 days or ceftriaxone 1 g iv or im daily for 8-10 days
Primary, secondary, early latent	HIV: consider 3 wk	HIV: ceftriaxone; consider desensitization
Late latent or of unknown duration	benzathine PCN G 2.4 million units im every week for 3 wk	doxycycline 100 mg po bid for 28 days or tetracycline 500 mg po 4 times daily for 28 days
Late latent or of unknown duration	benzathine PCN G 2.4 million units im every week for 3 wk	HIV: ceftriaxone; consider desensitization
Tertiary syphilis gumma or cardiovascular	benzathine PCN G 2.4 million units im every week for 3 wk	doxycycline 100 mg po bid for 28 days or tetracycline 500 mg po 4 times daily for 28 days
Tertiary syphilis gumma or cardiovascular	benzathine PCN G 2.4 million units im every week for 3 wk	HIV: no recommendations
Neurosyphilis (any stage)	aqueous crystalline PCN G 3-4 million units iv every 4 h or 18-24 million units/day iv infusion for 10-14 days or procaine PCN 2.4 million units im once daily plus probenecid 500 mg po 4 times daily for 10-14 days	ceftriaxone 2 g iv or im daily for 10-14 days
Neurosyphilis (any stage)		HIV: no recommendations
Neurosyphilis (late stage)	above regimen followed by benzathine PCN G 2.4 million units im every week for up to 3 wk

PCN = penicillin.
^aOnly differences are highlighted for treating HIV-infected patients.

Table 2. Treatment Regimens for Syphilis in Non-HIV-Infected and HIV ^a-Infected Patients ^[24]
Stage	Patients Not Allergic to Penicillin	Patients Allergic to Penicillin
Primary, secondary, early latent	benzathine PCN G 2.4 million units im once	doxycycline 100 mg po bid for 10 days or tetracycline 500 mg 4 times daily for 14 days or ceftriaxone 1 g iv or im daily for 8-10 days
Primary, secondary, early latent	HIV: consider 3 wk	HIV: ceftriaxone; consider desensitization
Late latent or of unknown duration	benzathine PCN G 2.4 million units im every week for 3 wk	doxycycline 100 mg po bid for 28 days or tetracycline 500 mg po 4 times daily for 28 days
Late latent or of unknown duration	benzathine PCN G 2.4 million units im every week for 3 wk	HIV: ceftriaxone; consider desensitization
Tertiary syphilis gumma or cardiovascular	benzathine PCN G 2.4 million units im every week for 3 wk	doxycycline 100 mg po bid for 28 days or tetracycline 500 mg po 4 times daily for 28 days
Tertiary syphilis gumma or cardiovascular	benzathine PCN G 2.4 million units im every week for 3 wk	HIV: no recommendations
Neurosyphilis (any stage)	aqueous crystalline PCN G 3-4 million units iv every 4 h or 18-24 million units/day iv infusion for 10-14 days or procaine PCN 2.4 million units im once daily plus probenecid 500 mg po 4 times daily for 10-14 days	ceftriaxone 2 g iv or im daily for 10-14 days
Neurosyphilis (any stage)		HIV: no recommendations
Neurosyphilis (late stage)	above regimen followed by benzathine PCN G 2.4 million units im every week for up to 3 wk

PCN = penicillin.
^aOnly differences are highlighted for treating HIV-infected patients.

Table 3. Recommendations for Monitoring Treatment Response ^[24]
Disease Stage	Definition of Failure	Non-HIV-Infected Patients Follow-Up	HIV-Infected Patients Follow-Up
Primary/secondary	<4-fold drop in nontreponemal titers within 6 mo (6-12 mo in pts. with HIV); 4-fold increase in nontreponemal titers; signs/symptoms of syphilis return	clinical and serological evaluation at 6, 12 mo	clinical and serological evaluation at 3, 6, 9, 12, 24 mo
Latent/tertiary	<4-fold drop in high (>1:32) nontreponemal titers within 12-24 mo; 4-fold increase in nontreponemal titers; signs/symptoms of syphilis return	clinical and serological evaluation at 6, 12, 24 mo	clinical and serological evaluation at 6, 12, 18, 24 mo
Neurosyphilis (any stage)	failure of CSF to normalize within 2 y; lack of pleocytosis decrease within 6 mo	CSF analysis every 6 mo until cell count normal

CSF = cerebrospinal fluid.

Table 2. Treatment Regimens for Syphilis in Non-HIV-Infected and HIV ^a-Infected Patients ^[24]
Stage	Patients Not Allergic to Penicillin	Patients Allergic to Penicillin
Primary, secondary, early latent	benzathine PCN G 2.4 million units im once	doxycycline 100 mg po bid for 10 days or tetracycline 500 mg 4 times daily for 14 days or ceftriaxone 1 g iv or im daily for 8-10 days
Primary, secondary, early latent	HIV: consider 3 wk	HIV: ceftriaxone; consider desensitization
Late latent or of unknown duration	benzathine PCN G 2.4 million units im every week for 3 wk	doxycycline 100 mg po bid for 28 days or tetracycline 500 mg po 4 times daily for 28 days
Late latent or of unknown duration	benzathine PCN G 2.4 million units im every week for 3 wk	HIV: ceftriaxone; consider desensitization
Tertiary syphilis gumma or cardiovascular	benzathine PCN G 2.4 million units im every week for 3 wk	doxycycline 100 mg po bid for 28 days or tetracycline 500 mg po 4 times daily for 28 days
Tertiary syphilis gumma or cardiovascular	benzathine PCN G 2.4 million units im every week for 3 wk	HIV: no recommendations
Neurosyphilis (any stage)	aqueous crystalline PCN G 3-4 million units iv every 4 h or 18-24 million units/day iv infusion for 10-14 days or procaine PCN 2.4 million units im once daily plus probenecid 500 mg po 4 times daily for 10-14 days	ceftriaxone 2 g iv or im daily for 10-14 days
Neurosyphilis (any stage)		HIV: no recommendations
Neurosyphilis (late stage)	above regimen followed by benzathine PCN G 2.4 million units im every week for up to 3 wk

PCN = penicillin.
^aOnly differences are highlighted for treating HIV-infected patients.

Table 3. Recommendations for Monitoring Treatment Response ^[24]
Disease Stage	Definition of Failure	Non-HIV-Infected Patients Follow-Up	HIV-Infected Patients Follow-Up
Primary/secondary	<4-fold drop in nontreponemal titers within 6 mo (6-12 mo in pts. with HIV); 4-fold increase in nontreponemal titers; signs/symptoms of syphilis return	clinical and serological evaluation at 6, 12 mo	clinical and serological evaluation at 3, 6, 9, 12, 24 mo
Latent/tertiary	<4-fold drop in high (>1:32) nontreponemal titers within 12-24 mo; 4-fold increase in nontreponemal titers; signs/symptoms of syphilis return	clinical and serological evaluation at 6, 12, 24 mo	clinical and serological evaluation at 6, 12, 18, 24 mo
Neurosyphilis (any stage)	failure of CSF to normalize within 2 y; lack of pleocytosis decrease within 6 mo	CSF analysis every 6 mo until cell count normal

CSF = cerebrospinal fluid.

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Reexamining Syphilis: An Update on Epidemiology, Clinical Manifestations, and Management

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