Syphilis medical therapy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]Muhammad Saad, M.B.B.S.[3]; Nate Michalak, B.A.

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## Overview

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Penicillin G, administered parenterally, is the preferred drug for treating all stages of syphilis. If the patient is allergic, then Tetracycline or doxycycline may also be used. During pregnancy, parenteral penicillin G is the only therapy with documented efficacy for syphilis. The Jarisch-Herxheimer reaction is an acute adverse febrile reaction that may occur after initiation of therapy for syphilis.

## Medical Therapy

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* Penicillin G, administered parenterally, is the preferred drug for treating all stage of syphilis.[1]

* The preparation used (i.e., benzathine, aqueous procaine, or aqueous crystalline), the dosage, and the length of treatment depend on the stage and clinical manifestations of the disease.

* Treatment for longer duration is required in patients with late latent, latent with unknown duration and tertiary syphilis.

* Selection of the appropriate penicillin preparation is important, because T. pallidum can reside in sequestered sites (e.g., the CNS and aqueous humor) that are poorly accessed by some forms of penicillin.

* Combinations of benzathine penicillin, procaine penicillin, and oral penicillin preparations are not considered appropriate for the treatment of syphilis.[2]

### Pharmacotherapy

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Syphilis Among non-HIV-Infected Persons[3]

Primary and Secondary Syphilis

* Preferred regimen: Benzathine penicillin G 2.4 MU IM single dose
* Pediatric regimen: Benzathine penicillin G 50,000 U/kg (Maximum, 2.4 MU) IM single dose

Latent Syphilis

Early Latent Syphilis:

* Preferred regimen: Benzathine penicillin G 2.4 MU IM in a single dose
* Pediatric regimen: Benzathine penicillin G 50,000 U/kg (Maximum, 2.4 MU) IM single dose

Late Latent Syphilis or Latent Syphilis of Unknown Duration:

* Preferred regimen: Benzathine penicillin G 7.2 MU total, administered as 3 doses of 2.4 MU IM each at 1 week intervals
* Pediatric regimen: Benzathine penicillin G 50,000 U/kg IM (Maximum, 2.4 MU), administered as 3 doses at 1 week intervals (total 150,000 U/kg up to the adult total dose of 7.2 MU)

Tertiary Syphilis

* Preferred regimen: Benzathine penicillin G 7.2 MU total, administered as 3 doses of 2.4 MU IM each at 1 week intervals

Ocular syphilis

Pathogen-directed antimicrobial therapy:[4]

* Preferred regimen (1): Penicillin 4 MU IV q4h for 10-14 days AND Benzathine penicillin G 2.4 MU IM once weekly for 3 weeks
* Note (1): Corticosteroids (Prednisone 60-80 mg PO qd) are co-administered to decrease intraocular inflammation and prevent rebound inflammation from Jarisch-Herxheimer reaction.
* Note (2): All patients with presumed ocular syphilis should be tested for HIV, and all should have a lumbar puncture before starting therapy to exclude concurrent neurosyphilis.

Syphilis Among HIV-Infected Persons

Primary and Secondary Syphilis Among HIV-Infected Persons

* Preferred regimen: Benzathine penicillin G 2.4 MU IM single dose[5]

Latent Syphilis Among HIV-Infected Persons

Early latent:

* Preferred regimen: Benzathine penicillin G 2.4 MU IM single dose[6]

Late latent:

* Preferred regimen: Benzathine penicillin G 2.4 MU once a week for 3 weeks

Neurosyphilis Among HIV-Infected Persons

* Preferred regimen: Aqueous crystalline penicillin G 18-24 MU per day, administered as 3-4 MU IV q4h or continuous infusion, for 10-14 days
* Alternative regimen: Procaine penicillin 2.4 MU IM q24h AND Probenecid 500 mg PO qid for 10-14 days

Syphilis During Pregnancy[7]

* Pregnant women should be treated with the penicillin regimen appropriate for their stage of infection as follows:
* Primary, secondary, and early latent syphilis: BPG 2.4 million units intramuscularly once daily.
* Late latent or unknown duration: BPG administered as 3 doses of 2.4 million units intramuscularly, given at 1 week intervals.
* Neuro, ocular, and otic syphilis: Aqueous crystalline penicillin G, 18-24 million units daily given as 3-4 units intravenously every 4 hours.
* Parenteral penicillin G is the only therapy with documented efficacy for syphilis. Pregnant women with syphilis in any stage who report penicillin allergy should be desensitized and treated with penicillin
* The Jarisch-Herxheimer reaction is an acute febrile reaction.

* Frequently accompanied by headache, myalgia, fever, and other symptoms that usually occur within the first 24 hours after the initiation of any therapy for syphilis.
* Patients should be informed about this possible adverse reaction.
* The Jarisch-Herxheimer reaction occurs most frequently among patients who have early syphilis, presumably because bacterial burdens are higher during these stages.
* Antipyretics can be used to manage symptoms, but they have not been proven to prevent this reaction.
* The Jarisch-Herxheimer reaction might induce early labor or cause fetal distress in pregnant women, but this should not prevent or delay therapy.

Congenital Syphilis in Neonates

Condition 1: Infants with proven or highly probable disease and (1) an abnormal physical examination that is consistent with congenital syphilis;（2）a serum quantitative nontreponemal serologic titer that is fourfold higher than the mother's titer; or （3）a positive darkfield test of body fluid(s).

* Preferred regimen (1): Aqueous crystalline penicillin G 100,000-150,000 U/kg/day, administered as 50,000 U/kg/dose IV q12h during the first 7 days of life and q8h thereafter for a total of 10 days
* Preferred regimen (2): Procaine penicillin G 50,000 U/kg/dose IM q24h for 10 days
* Note: If more than 1 day of therapy is missed, the entire course should be restarted. Data are insufficient regarding the use of other antimicrobial agents (e.g., ampicillin). When possible, a full 10-day course of penicillin is preferred, even if ampicillin was initially provided for possible sepsis. The use of agents other than penicillin requires close serologic follow-up to assess adequacy of therapy. In all other situations, the maternal history of infection with T. pallidum and treatment for syphilis must be considered when evaluating and treating the infant.

Condition 2: Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the (1) mother was not treated, inadequately treated, or has no documentation of having received treatment; (2) mother was treated with erythromycin or another non-penicillin regimen; or (3) mother received treatment <4 weeks before delivery.

* Preferred regimen (1): Aqueous crystalline penicillin G 100,000-150,000 U/kg/day, administered as 50,000 U/kg/dose IV q12h during the first 7 days of life and q8h thereafter for a total of 10 days
* Preferred regimen (2): Procaine penicillin G 50,000 U/kg/dose IM q24h for 10 days
* Preferred regimen (3): Benzathine penicillin G 50,000 U/kg/dose IM single dose
* Note: If the mother has untreated early syphilis at delivery, 10 days of parenteral therapy can be considered

Condition 3: Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the (1) mother was treated during pregnancy, treatment was appropriate for the stage of infection, and treatment was administered >4 weeks before delivery; and (2) mother has no evidence of reinfection or relapse.

* Preferred regimen: Benzathine penicillin G 50,000 U/kg/dose IM single dose

Condition 4: Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the (1) mother's treatment was adequate before pregnancy; and (2) mother's nontreponemal serologic titer remained low and stable before and during pregnancy and at delivery (VDRL <1:2; RPR <1:4).

* No treatment is required
* Benzathine penicillin G 50,000 U/kg IM single dose might be considered, particularly if follow-up is uncertain.

Congenital Syphilis in infants and children

* Preferred regimen: Aqueous crystalline penicillin G 50,000 U/kg q4–6h for 10 days

## Approach to Diagnosis and Management of Syphilis

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| Positive syphilis screening test|

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| Perform treponemal-specific test|

| Positive treponemal-specific test|

| Negative treponemal-specific test|

| Establish stage of infection; obtain quantitative nontreponemal test titres|

| Primary syphilis suspected|

| False-positive test result suspected|

| Signs or symptoms of primary or secondary syphilis|

| No clinical signs or symptoms (latent syphilis)|

| Signs or symptoms of tertiary (late) syphilis, or patient is HIC positive or otherwise immunocompromised|

| Obtain quantitative nontreponemal test titres|

| Consider other causes|

| Early latent syphilis|

| Late latent syphilis|

| Lumbar puncture|

| Penicillin G benzazthine, 2.4 million units IM (single dose)*|

| Penicillin G benzazthine, 2.4 million units IM (single dose)*|

| Penicillin G benzazthine, 2.4 million units IM once a week for 3 weeks (three doses)**|

| Signs, symptoms, or CSF findings consistent with neurosyphilis|

| Yes|

| No|

| No penicillin allergy|

| Penicillin allergy|

| Unvolve appropriate subspecialists. Penicillin G benzazthine, 2.4 million units IM once a week for 3 weeks (three doses)**|

| Desensitization|

| Aqueous crystalline penicillin G, 3 to 4 million units IV every 4 hours for 10 to 14 days; or penicillin G procaine, 2.4 million units once daily, plus 500 mg of probenecid orally four times daily for 10 to 14 days|

## References

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1. ↑ http://www.cdc.gov/std/tg2015/syphilis.htm Accessed on September 26, 2016
2. ↑ http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5409a1.htm
3. ↑ Workowski KA, Bolan GA (2015). "Sexually transmitted diseases treatment guidelines, 2015". MMWR. Recommendations and Reports : Morbidity and Mortality Weekly Report. Recommendations and Reports / Centers for Disease Control. 64 (RR-03): 1–137. PMID 26042815.
4. ↑ Bennett, John (2015). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Elsevier/Saunders. ISBN 978-1455748013.
5. ↑ Rolfs RT, Joesoef MR, Hendershot EF, Rompalo AM, Augenbraun MH, Chiu M; et al. (1997). "A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. The Syphilis and HIV Study Group". N Engl J Med. 337 (5): 307–14. doi:10.1056/NEJM199707313370504. PMID 9235493.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
6. ↑ Yang CJ, Lee NY, Chen TC, Lin YH, Liang SH, Lu PL; et al. (2014). "One dose versus three weekly doses of benzathine penicillin G for patients co-infected with HIV and early syphilis: a multicenter, prospective observational study". PLoS One. 9 (10): e109667. doi:10.1371/journal.pone.0109667. PMC 4186862. PMID 25286091.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
7. ↑ "Syphilis: A Review | Pediatrics | JAMA | JAMA Network".

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