Syphilis medical therapy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Overview

Penicillin G, administered parenterally, is the preferred drug for treating all stages of syphilis. If allergic, then tetracycline or doxycycline may also be used. During pregnancy, parenteral penicillin G is the only therapy with documented efficacy for syphilis.

Medical Therapy

• Penicillin G, administered parenterally, is the preferred drug for treating all stages of syphilis.

• 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.

• 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.

• During pregnancy, 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.

Pharmacotherapy

1. Syphilis Among non-HIV-Infected Persons [123]

1.1 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

1.2 Latent Syphilis

1.2.1 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

1.2.2 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)

1.3 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

1.4 Neurosyphilis and ocular syphilis

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

2. Syphilis Among HIV-Infected Persons

2.1 Primary and Secondary Syphilis Among HIV-Infected Persons

Preferred regimen: Benzathine penicillin G 2.4 MU IM single dose

2.2 Latent Syphilis Among HIV-Infected Persons

2.2.1 early latent

Preferred regimen: Benzathine penicillin G 2.4 MU IM single dose

2.2.2 late latent

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

2.3 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

3. Syphilis During Pregnancy

Pregnant women should be treated with the penicillin regimen appropriate for their stage of infection

4. Congenital Syphilis in neonates

4.1 condition1: 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.

4.2 condition2: Infants who have a normal physical examination and a serum quantitive 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 nonpenicillin 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

4.3 condition3: 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

4.4 condition4: 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.

5. Congenital Syphilis in infants and children

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

Pencillin Allergy

Although penicillin is still the most commonly reported allergy, less than 20% of all patients who believe that they have a penicillin allergy are truly allergic to penicillin. Nevertheless, penicillin is still the most common cause of severe allergic drug reactions.

Allergic reactions to any β-lactam antibiotic may occur in up to 10% of patients receiving that agent. Anaphylaxis will occur in approximately 0.01% of patients. There is about a 5% cross-sensitivity between penicillin-derivatives, cephalosporins and carbapenems. This risk warrants extreme caution with all β-lactam antibiotics in patients with a history of severe allergic reactions (urticaria, anaphylaxis, interstitial nephritis) to any β-lactam antibiotic.

Jarisch-Herxheimer Reaction

• Before administering any treatment, clinicians should warn all patients about the possibility of a Jarisch-Herxheimer reaction, which occurs most often in secondary syphilis and with penicillin therapy, and may be more common in HIV-infected patients.

• This reaction is characterized by fever, fatigue, and transient worsening of any mucocutaneous symptoms, and usually subsides within 24 hours.

• These symptoms can be alleviated with acetaminophen (paracetamol) and should not be mistaken for drug allergy.

• In addition, clinicians should inform HIV-infected patients that currently recommended regimens may be less effective for them than for patients without HIV infection and that close serologic follow-up is therefore essential.

Penicillin Skin Test

• Penicillin skin testing with the major and minor determinants of penicillin can reliably identify persons at high risk for penicillin reactions. Although these reagents are easily generated and have been available for more than 30 years, only benzylpenicilloyl poly-L-lysine (Pre-Pen which is the major determinant) and penicillin G have been available commercially. These two tests identify an estimated 90%-97% of the currently allergic patients. However, because skin testing without the minor determinants would still miss 3%-10% of allergic patients and because serious or fatal reactions can occur among these minor-determinant--positive patients, caution should be exercised when the full battery of skin-test reagents is not available.

• Patients with history of penicillin reaction and negative skin-test negative can receive conventional penicillin therapy.

• Skin-test-positive patients should be desensitized before initiating treatment.

• All patients with a history suggesting IgE- mediated reactions to penicillin (e.g., anaphylaxis, angioedema, bronchospasm, or urticaria) should be desensitized in a hospital setting. In patients with reactions not likely to be IgE-mediated, outpatient-monitored test doses can be considered.

Indication

• Patients at high risk for anaphylaxis, including those who have:

• A history of penicillin-related anaphylaxis, asthma, or other diseases that would make anaphylaxis more dangerous
• Been treated with beta-adrenergic blocking agents, should be tested with 100-fold dilutions of the full-strength skin-test reagents before being tested with full-strength reagents.

• In these situations, patients should be tested in a monitored setting in which treatment for an anaphylactic reaction is available. If possible, the patient should not have taken antihistamines recently (e.g., chlorpheniramine maleate or fexafenadine during the preceding 24 hours, diphenhydramine HCl during the preceding 4 days, or hydroxyzine or phenathiazines during the preceding 3 weeks).

Procedures

• Dilute the antigens either 100-fold for preliminary testing (if the patient has had a life-threatening reaction to penicillin) or 10-fold (if the patient has had another type of immediate, generalized reaction to penicillin within the preceding year).

• Epicutaneous (Prick) Tests:

• Duplicate drops of skin-test reagent are placed on the volar surface of the forearm. The underlying epidermis is pierced with a 26-gauge needle without drawing blood.
• An epicutaneous test is positive if the average wheal diameter after 15 minutes is greater than or equal to 4 mm larger than that of negative controls; otherwise, the test is negative.
• The histamine controls should be positive to ensure that results are not falsely negative because of the effect of antihistaminic drugs.

• Intradermal Test:

• If epicutaneous tests are negative, duplicate 0.02-mL intradermal injections of negative control and antigen solutions are made into the volar surface of the forearm by using a 26- or 27-gauge needle on a syringe.
• The margins of the wheals induced by the injections should be marked with a ball point pen.
• An intradermal test is positive if the average wheal diameter 15 minutes after injection is greater than 2 mm larger than the initial wheal size and also is greater than 2 mm larger than the negative controls. Otherwise, the tests are negative.

Management of Patients with History of Penicillin Allergy

CDC Recommendations

“

1. If the full battery of skin-test reagents is available, including both major and minor determinants, patients who report a history of penicillin reaction and who are skin-test negative can receive conventional penicillin therapy. Skin-test positive patients should be desensitized before initiating treatment. 2. If the full battery of skin-test reagents, including the minor determinants, is not available, the patient should be skin tested using benzylpenicilloyl poly-L-lysine (i.e., the major determinant) and penicillin G. Patients who have positive test results should be desensitized. One approach suggests that persons with a history of allergy who have negative test results should be regarded as possibly allergic and desensitized. Another approach in those with negative skin-test results involves test-dosing gradually with oral penicillin in a monitored setting in which treatment for anaphylactic reaction can be provided. 3. If the major determinant (Pre-Pen) is not available for skin testing, all patients with a history suggesting IgE-mediated reactions to penicillin (e.g., anaphylaxis, angioedema, bronchospasm, or urticaria) should be desensitized in a hospital setting. In patients with reactions not likely to be IgE-mediated, outpatient-monitored test doses can be considered.

”

Pencillin Allergy: Non-pregnant Individuals

• No proven alternatives to penicillin are available for treating neurosyphilis, congenital syphilis, or syphilis in pregnant women. Penicillin also is recommended for use, whenever possible, in HIV-infected patients.

• Of the adult U.S. population, 3%-10% have experienced an immunoglobulin E (IgE)-mediated allergic response to penicillin, such as urticaria, angioedema, or anaphylaxis (i.e., upper airway obstruction, bronchospasm, or hypotension). Readministration of penicillin to these patients can cause severe, immediate reactions.

• Non-pregnant individuals who have severe allergic reactions to penicillin (e.g., anaphylaxis) may be treated with oral tetracycline or doxycycline although data to support this is limited. Ceftriaxone may be considered as an alternative therapy, although the optimal dose is not yet defined. However, cross-reactions in penicillin-allergic patients with cephalosporins such as ceftriaxone are possible. Azithromycin was suggested as an alternative. However, there have been reports of treatment failure due to resistance in some areas.

• Because anaphylactic reactions to penicillin can be fatal, every effort should be made to avoid administering penicillin to penicillin-allergic patients, unless they undergo acute desensitization to eliminate anaphylactic sensitivity.

• Although an estimated 10% of persons who report a history of severe allergic reactions to penicillin continue to remain allergic their entire lives, with the passage of time, most persons who have had a severe reaction to penicillin stop expressing penicillin-specific IgE. These persons can then be treated safely with penicillin.

Pencillin Allergy: Pregnant Individuals

All pregnant women with syphilis should be desensitized and treated with penicillin. Follow-up includes clinical evaluation at 1 to 2 weeks followed by clinical and serologic evaluation at 3, 6, 9, 12, and 24 months after treatment.

Pencillin Allergy: Desensitization

• Patients who have a positive skin test to one of the penicillin determinants can be desensitized.

• This is a straightforward, relatively safe procedure that can be performed orally or IV.

• Although the two approaches have not been compared, oral desensitization is regarded as safer and easier to perform.

• Patients should be desensitized in a hospital setting because serious IgE-mediated allergic reactions can occur.

• Desensitization usually can be completed in approximately 4-12 hours, after which time the first dose of penicillin is administered.

• After desensitization, patients must be maintained on penicillin continuously for the duration of the course of therapy.

Treatment

Antimicrobial regimen

• 1. Syphilis Among non-HIV-Infected Persons

• 1.1 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

• 1.2 Latent Syphilis

• 1.2.1 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

• 1.2.2 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)

• 1.3 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

• 1.4 Neurosyphilis and ocular syphilis

• 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

• 2. Syphilis Among HIV-Infected Persons

• 2.1 Primary and Secondary Syphilis Among HIV-Infected Persons

• Preferred regimen: Benzathine penicillin G 2.4 MU IM single dose

• 2.2 Latent Syphilis Among HIV-Infected Persons

• 2.2.1 early latent

• Preferred regimen: Benzathine penicillin G 2.4 MU IM single dose

• 2.2.2 late latent

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

• 2.3 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

• 3. Syphilis During Pregnancy

• Pregnant women should be treated with the penicillin regimen appropriate for their stage of infection

• 4. Congenital Syphilis in neonates

• 4.1 condition1: 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.

• 4.2 condition2: Infants who have a normal physical examination and a serum quantitive 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 nonpenicillin 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

• 4.3 condition3: 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

• 4.4 condition4: 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.

• 5. Congenital Syphilis in infants and children

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

References

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