7 Things to Know About Syphilis


The CDC has recently reported increasing antibiotic resistant Treponema pallidum strains and ocular syphilis incidence.

The CDC and the World Health Organization released new guidelines in June 2015 and August 2016 reflecting new prescribing trends caused by increasing antibiotic resistance, drug shortages, and drug allergies that jeopardize providers’ ability to cure syphilis. 1

1. Preferred Regimens

A single benzathine penicillin G 2.4 million unit intramuscular injection is the preferred early syphilis treatment overall, and it’s the only CDC recommended treatment for pregnant women. Providers should give pediatric patients 50,000 units per kg up to the adult dose (equal to 48 kg).1

Providers have 2 penicillin-based regimen options to treat proven or likely congenital syphilis. The first regimen is aqueous crystalline penicillin G 50,000 units/kg intravenously every 12 hours for the first 7 days and every 8 hours for the next 3 days. The second regimen is a once daily intramuscular dose of procaine penicillin G 50,000 units/kg for 10 days. Providers should restart either regimen if the newborn misses multiple days’ dose(s).1

The CDC recommends 3 weekly intramuscular injections of benzathine penicillin G 2.4 million units for late-stage patients and patients with unknown infection timing.1

The preferred neuro-, otic, and ocular syphilis treatment is crystalline penicillin G 18 to 24 million units (total daily dose) either as 3 to 4 million units IV every 4 hours or by continuous IV infusion for 10 to 14 days. Follow-up with 1 to 3 intramuscular benzathine penicillin G 2.4 million units is optional.2

2. Benzathine penicillin G shortage

However, benzathine penicillin G (Bicillin-LA) supplies are short nationwide (as of October 2016).1 Pfizer has Bicillin LA 600,000 unit/ 1 mL syringes, 1,200,000 unit/ 2 mL syringes, and 2,400,000 unit/ 4 mL syringes on allocation. Providers should ration Bicillin-LA by favoring use in pregnant women and avoiding use for non-syphilis infections (eg, streptococcal pharyngitis).

Bicillin-CR is a distinct product, and providers should NOT substitute this product for Bicillin-LA. Providers should not substitute the penicillin G benzathine with procaine penicillin G combination product for Bicillin-CR because the penicillin quantity is insufficient.

Procaine penicillin G, indicated for congenital syphilis, is also on shortage nationwide and the manufacturer estimates the supply will resume in early April 2017.1

3. Alternative regimens

Alternative regimens in early syphilis patients with penicillin allergies include doxycycline 100 mg orally twice daily for 14 days or tetracycline 500 mg 4 times daily for 14 days.1,2 There’s limited evidence for variable ceftriaxone regimens (eg, 1 to 2 g daily either IM or IV for 10 to 14 days).

Providers should desensitize pregnant penicillin-allergic women and treat with benzathine penicillin G 2.4 million units IM once or twice. Administering a second dose 1 week later is optional in early syphilis, but organization rationing may restrict patients to a single dose if quantities are limited.

The CDC notes with caution that providers may use weight-based ceftriaxone in penicillin-allergic patients or when either penicillin is unavailable. The CDC recommends re-testing for syphilis cure at 6 months.2 Ceftriaxone-calcium precipitates can occlude neonates’ IV lines and veins and ceftriaxone alone can cause hyperbilirubinemia-induced kernicterus in neonates.

Doxycycline 100 mg by mouth twice daily for 28 days is the sole recommended alternative for penicillin-allergic late latent patients.1 Providers should desensitize and give penicillin to patients with low chance of follow-up or suspected poor adherence.

Providers should desensitize and give the preferred penicillin regimen to penicillin-allergic neuro-, otic, or ocular syphilis patients when possible. The other CDC supported regimen is 2 g intramuscular or intravenous daily ceftriaxone injections for 10 to 14 days.2

4. An allergy-like reaction

The Jarisch-Herxheimer reaction can be confused for an allergic reaction. Patients often experience headache, myalgia, fever, and other flu-like symptoms within 24 hours of starting antibiotics. The risk is greatest during early syphilis due to the high bacterial burden. Antipyretics (eg, acetaminophen) are effective at minimizing, but not preventing, symptoms.1 This reaction can induce early labor in pregnant women, but treatment delay poses a greater risk to the unborn child because of congenital syphilis concerns.

5. Antibiotic resistance

The CDC reserves a single 2-gram azithromycin oral dose for cases in which doxycycline use is not feasible.3 Extensive macrolide resistance in Treponema pallidum strains across the United States drives this guidance. The CDC recommends avoiding azithromycin use in MSM, HIV-infected, or pregnant patients.2 Macrolide resistance is more common in MSM and HIV-infected patients and providers should use caution in pregnant patients due to cerebral palsy and epilepsy concerns (see Lin 2013).

6. Dating apps, casual sex, and managing sex partners

Multiple organizations, such as the AIDS Healthcare Foundation, have blamed dating mobile applications (“dating apps”) like Tinder and Grindr for the recent increase in syphilis and other sexually transmitted infections.4

Young people are less sexually active, less likely to become pregnant, and more likely to begin engaging in sexual contact later in life than past generations, yet dating apps make anonymous casual sex easier. Promiscuity increases the chance of contracting an infection and anonymous sexual contact stymies notifying the patients’ partners of a diagnosis.2

Public health organizations’ success combatting HIV has created a false sense of security among the highest risk individuals. Syphilis is less scary than HIV (which is incurable), other bacterial infections with worse acute symptoms (eg, herpes), or oncoviruses (eg, human papillomavirus species) because its worst symptoms manifests years to decades after initial infection.

7. Ocular syphilis and its relationship to HIV

The November 4, 2016, CDC Morbidity and Mortality Weekly Report detailed the recent 50% increase in ocular syphilis since 2000.5 Ocular syphilis is a rare, although serious, syphilis manifestation especially common among HIV-infected MSM. Half of ocular syphilis patients are HIV-negative though. The epidemiology of ocular syphilis is similar to syphilis’ overall epidemiology (93% of patients were male, 69% MSM, and half HIV infected).

However, ocular syphilis still represents less than 1% of all syphilis cases. Eye pain, blurry vision, or vision loss are symptoms consistent with ocular syphilis warranting an ophthalmic examination.

Primary and secondary syphilis patients in HIV endemic areas should receive a, HIV test at syphilis diagnosis and 3 months later if the result is negative.1 Contracting syphilis doubles to triples the risk of contracting another sexually transmitted infection such as HIV. The penetration opportunity through the broken skin on syphilitic sores and the shared sexual method of transmission drive this relationship. Immunocompromised HIV-infected patients are at increased risk of poor syphilis outcomes (eg, ocular syphilis).

Syphilis treatment is complicated by crucial drug shortages, frequent penicillin allergy among patients, teratogenicity concerns, and Treponema pallidum’s burgeoning resistance to multiple antibiotics. Fewer patients receive the one-time benzathine penicillin G injection at a clinic. Pharmacists’ medication knowledge helps providers choose the best patient-specific option among the other syphilis treatment options. More patients rely on pharmacists to acquire their antibiotics and would benefit from adherence counseling.


  • Syphilis. CDC website cdc.gov/std/tg2015/syphilis.htm. Published June 4, 2015. Updated July 27, 2016. Accessed November 7, 2016.
  • Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. AIDSinfo website. aidsinfo.nih.gov/guidelines/html/4/ adult-and-adolescent-oi-prevention-and-treatment-guidelines/330/syphilis. Published on December 17, 2015. Accessed November 7, 2016.
  • Growing antibiotic resistance forces updates to recommended treatment for sexually transmitted infections. World Health Organization website. who.int/mediacentre/news/releases/2016/antibiotics-sexual-infections/en. Accessed November 7, 2016.
  • Schaefer Riley N. Tinder might be to blame for rise in syphilis among millennials. New York Post. October 29, 2016. nypost.com/2016/10/29/tinder-might-be-to-blame-for-rise-in-syphilis-among-millennials. Accessed November 7, 2016.
  • Oliver SE, Aubin M, Atwell L, et al. Ocular syphilis eight jurisdictions, United States, 2014—2015. Weekly. 2016;65(43):1185—1188.

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