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  • STIs including syphilis are increasing across the US, including Nebraska!
  • Use our ASAP resources to:
    • Review appropriate syphilis treatment
    • Manage the nationwide injectable penicillin shortage
    • Better manage a patient with a history of reported penicillin allergy

Section I: Syphilis Treatment


Penicillin G, administered parenterally, is the preferred drug for treating patients in all stages of syphilis. The preparation used (i.e., benzathine, aqueous procaine, or aqueous crystalline), dosage, and length of treatment depend on the stage and clinical manifestations of the disease. Treatment for late latent syphilis (>1 years’ duration) and tertiary syphilis requires a longer duration of therapy. Longer treatment duration is required for persons with latent syphilis of unknown duration to ensure that those who did not acquire syphilis within the preceding year are adequately treated.

Primary, Secondary, or Early Latent (<1 year)

Benzathine penicillin G 2.4 million units IM in a single dose

Late Latent (>1 year), Latent Syphilis of Unknown Duration, or Tertiary Syphilis with Normal CSF Examination

Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals

Neurosyphilis, Ocular Syphilis

Aqueous crystalline penicillin G 18-24 million units per day, administered as 3-4 million units IV every 4 hours or continuous infusion, for 10-14 days

  • Additional doses of benzathine penicillin are not indicated in patients with HIV infection
  • Additional doses of penicillin in pregnant women with early syphilis may be indicated if evidence of fetal syphilis on ultrasound

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 certain forms of penicillin. Combinations of benzathine penicillin, procaine penicillin, and oral penicillin preparations are not considered appropriate for syphilis treatment. Reports have indicated that practitioners have inadvertently prescribed combination long- and short-acting benzathine-procaine penicillin (Bicillin C-R) instead of the standard benzathine penicillin product (Bicillin L-A) recommended in the United States for treating primary, secondary, and latent syphilis. Practitioners, pharmacists, and purchasing agents should be aware of the similar names of these two products to avoid using the incorrect combination therapy agent for treating syphilis.

Penicillin’s effectiveness for treating syphilis was well established through clinical experience even before the value of randomized controlled clinical trials was recognized. Therefore, approximately all recommendations for treating syphilis are based not only on clinical trials and observational studies, but on many decades of clinical experience.

Special Considerations


Parenteral penicillin G is the only therapy with documented efficacy for syphilis during pregnancy. Pregnant women with syphilis at any stage who report penicillin allergy should be desensitized and treated with penicillin (see section on Managing Patients with a History of Penicillin Allergy).

Jarisch-Herxheimer Reaction

The Jarisch-Herxheimer reaction is an acute febrile reaction frequently accompanied by headache, myalgia, and fever that can occur within the first 24 hours after the initiation of any syphilis therapy; it is a reaction to treatment and not an allergic reaction to penicillin. Patients should be informed about this possible adverse reaction and how to manage it if it occurs. The Jarisch-Herxheimer reaction occurs most frequently among persons who have early syphilis, presumably because bacterial loads are higher during these stages. Antipyretics (such as acetaminophen) can be used to manage symptoms; however, they have not been proven to prevent this reaction. The Jarisch-Herxheimer reaction might induce early labor or cause fetal distress in pregnant women; however, this should not prevent or delay therapy.

Management of Sex Partners

Sexual transmission of T. pallidum is thought to occur only when mucocutaneous syphilitic lesions are present. Such manifestations are uncommon after the first year of infection. Persons exposed through sexual contact with a person who has primary, secondary, or early latent syphilis should be evaluated clinically and serologically and treated according to CDC recommendations Syphilis – STI Treatment Guidelines (

Section II: Penicillin Drug Shortage

Bicillin L-A® Shortage

The FDA has listed penicillin G benzathine injectable suspension on their Drug Shortages webpage, noting limited supply due to increased demand.

Bicillin L-A® is the first-line recommended treatment for syphilis and the only recommended treatment option for some patients.

During the shortage, clinics and hospitals should:

  • Continue to follow CDC’s treatment recommendations. Penicillin G benzathine (Bicillin L-A®) is the only recommended treatment for pregnant people infected with or exposed to syphilis.
  • Doxycycline 100mg PO BID for two weeks (for early syphilis) or for four weeks (for late latent or syphilis of unknown duration) is an alternative for the treatment of non-pregnant people with a penicillin allergy.
  • Prioritize the use of Bicillin L-A® to treat pregnant people and babies with congenital syphilis.
    • Avoid use of Bicillin L-A® for treatment of infections other than syphilis (i.e. pharyngitis, skin and soft tissue infections)
  • To help CDC continue to monitor the situation, notify DSTDP ( of:
    • Shortages or stock-outs of Bicillin L-A® in the jurisdiction.
    • Situations in which patients diagnosed with syphilis are not being treated due to the inability to procure Bicillin L-A® in the jurisdiction.
    • Report any shortages to the Pfizer Supply Continuity Team at 844-646-4398 (select 1 and then select 3).

Section III: Managing Patients with a History of Penicillin Allergy

Treatment Guidelines

Penicillin is recommended for all clinical stages of syphilis, and no proven alternatives exist for treating neurosyphilis, congenital syphilis, or syphilis during pregnancy.

Penicillin allergy is one of the most frequently reported antibiotic allergies. It is often overreported, and the majority of patients who report penicillin allergy are able to tolerate the medication. Patients often are incorrectly labeled as allergic to penicillin and are therefore denied the benefit of a ß-lactam therapy. The presence of a penicillin allergy label considerably reduces prescribing options for affected patients. Moreover, penicillin allergy labels lead to the use of more expensive and less effective drugs and can result in adverse consequences, including longer length of hospital stay and increased risk for infection.

The overreported prevalence of penicillin allergy is secondary to imprecise use of the term “allergy” by families and clinicians and lack of clarity to differentiate between immunoglobulin E (IgE)-mediated hypersensitivity reactions, drug intolerances, and other idiosyncratic reactions that can occur days after exposure. Approximately 80% of patients with a true IgE-mediated allergic reaction to penicillin have lost the sensitivity after 10 years. Thus, patients with recent reactions are more likely to be allergic than patients with remote reactions, and patients who had allergic reactions in the distant past might no longer be reactive.

In a Baltimore, Maryland, STI clinic study, only 7.1% of the patients who reported allergy to penicillin or to another ß-lactam antibiotic had an objective positive test for penicillin allergy. Moreover, in studies that have incorporated penicillin skin testing and graded oral challenge among persons with reported penicillin allergy, the true rates of allergy are low, ranging from 1.5% to 6.1%. In hospitalized patients and other populations with comorbidities, the typical rates of validated penicillin allergy among patients who report a history of penicillin allergy are 2.5%–9.0%.

Patients at Low Risk for Oral Challenge

If the patient gives only a low-risk history of IgE-mediated penicillin allergy that includes symptoms such as those listed below, an oral challenge (oral one-time dose of amoxicillin 250 mg) can be administered to document the absence of allergy. If the reaction occurred in the distant past (>10 years), the likelihood is reduced even further. The risk for severe amoxicillin-mediated anaphylaxis has decreased over time and is rare.

Low risk history in patients who report Penicillin allergy (Give Oral Challenge)

  • Gastrointestinal Symptoms
  • Headache
  • Pruritis without rash
  • Localized rash
  • Delayed onset rash (>24 hours)
  • Symptoms unknown
  • Family history of penicillin or other drug allergy
  • Patient denies allergy, but it is on the medical record

Skin Testing for Penicillin Allergy

Skin testing for penicillin allergy should be performed if any indication exists that the symptoms were secondary to an IgE-mediated hypersensitivity. Testing is also indicated as a potential diagnostic procedure to definitively rule out penicillin allergy and document a negative allergy status in the medical record (i.e., delabeling). Penicillin skin testing has become a clinically significant element in antibiotic stewardship programs, and the procedure has been increasingly used by hospital-based pharmacists, hospitalists, and infectious disease physicians as part of overall antibiotic stewardship interventions. When integrated into stewardship, the rates of ß-lactam antibiotic use increased substantially.

Persons with negative results of a penicillin skin test, followed by an amoxicillin oral challenge, can receive conventional penicillin therapy safely if needed. Persons with positive skin test results and for whom no other clinical options exist (e.g., neurosyphilis and syphilis in a pregnant woman) should be referred to an allergist and desensitized before initiating treatment.


Desensitization is required for persons who have a documented penicillin allergy and for whom no therapeutic alternatives exist (e.g., syphilis during pregnancy and persons with neurosyphilis). Modified protocols might be considered on the basis of the clinical syndrome, drug of choice, and route of administration. Patients might require referral to a specialty center where desensitization can be performed.

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