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
- 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
- The first-choice treatment for all manifestations of syphilis remains penicillin in the form of penicillin G.[1]
- The effect of penicillin on syphilis was widely known before randomized clinical trials were used; as a result, treatment with penicillin is largely based on case series, expert opinion, and years of clinical experience.
- Parenteral penicillin G is the only therapy with documented effect during pregnancy. For early syphilis, one dose of penicillin is sufficient.
Late latent and Infections of Unknown Duration
- Late latent syphilis is defined as latency for greater than one year.
- If CSF examination yields no evidence of neurosyphilis, then penicillin G is recommended as weekly doses for 3 weeks.
- If allergic, then tetracycline or doxycycline may also be used for this stage, but for 28 days instead of the normal 14. As with before, the data to support use of tetracycline and ceftriaxone are limited.
Neurosyphilis
- For patients diagnosed with neurosyphilis including ocular or auditory syphilis with or without positive CSF results, aqueous crystalline penicillin G is the treatment of choice.
- The recommended regimen is intravenous treatment every 4 hours or continuously for 10-14 days.
- If intravenous administration is not possible, then procaine penicillin is an alternative (administered daily with probenecid for two weeks). Procaine injections are painful, however, and patient compliance may be difficult to ensure.
- To approximate the 21-day course of therapy for late latent disease and to address concerns about slowly dividing treponemes, most experts now recommend 3 weekly doses of benzathine penicillin G after the completion of a 14-day course of aqueous crystalline or aqueous procaine penicillin G for neurosyphilis.
- No oral antibiotic alternatives are recommended for the treatment of neurosyphilis. The only alternative that has been studied and shown to be effective is intramuscular ceftriaxone daily for 14 days.
HIV-Infected Patients
- Alternative regimens such as tetracyclines are not well studied in HIV infection and a careful follow-up is recommended. Tetra-cyclines are contraindicated in pregnancy.
- HIV-infected patients with early syphilis may have a higher risk of neurological complications and a higher rate of treatment failure with currently recommended regimens.
- The magnitude of these risks, however, although not precisely defined, is probably small.
- Skin testing or desensitization is recommended in latent syphilis and neurosyphilis in other patients with HIV infection.
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.[2] 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.[3] 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.[4]
- 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.[5][6] 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 [7]
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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.
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. |
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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[5][6], 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.[8]
- 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.[5][6] 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
- Syphilis Among non-HIV-Infected Persons[9]
- Primary and Secondary Syphilis
- Preferred regimen (adult): Benzathine penicillin G 2.4 million units IM in a single dose
- Preferred regimen (pediatric): Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose
- Latent Syphilis
- Early Latent Syphilis
- Preferred regimen: Benzathine penicillin G 2.4 million units IM in a single dose
- Pediatric regimen: Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose
- Late Latent Syphilis or Latent Syphilis of Unknown Duration
- Preferred regimen: Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervalspediatric
- Pediatric regimen: Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units, administered as 3 doses at 1-week intervals (total 150,000 units/kg up to the adult total dose of 7.2 million units)
- Tertiary Syphilis
- Preferred regimen: Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals
- Neurosyphilis and ocular syphilis
- Preferred regimen: 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
- Alternative regimen: Procaine penicillin 2.4 million units IM once daily AND Probenecid 500 mg orally four times a day, both for 10--14 days
- Syphilis Among HIV-Infected Persons
- Primary and Secondary Syphilis Among HIV-Infected Persons
- Preferred regimen: Benzathine penicillin G 2.4 million units IM in a single dose.
- Latent Syphilis Among HIV-Infected Persons
- early latent
- Preferred regimen: Benzathine penicillin G 2.4 million units IM in a single dose.
- late latent
- Preferred regimen: Benzathine penicillin G at weekly doses of 2.4 million units for 3 weeks.
- Neurosyphilis Among HIV-Infected Persons
- Preferred regimen: 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
- Alternative regimen: Procaine penicillin 2.4 million units IM once daily AND Probenecid 500 mg orally four times a day, both for 10--14 days
- Syphilis During Pregnancy
- Preferred regimen: Pregnant women should be treated with the penicillin regimen appropriate for their stage of infection
- 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: Aqueous crystalline penicillin G 100,000--150,000 units/kg/day, administered as 50,000 units/kg/dose IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days OR Procaine penicillin G 50,000 units/kg/dose IM in a single daily dose 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 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: Aqueous crystalline penicillin G 100,000--150,000 units/kg/day, administered as 50,000 units/kg/dose IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days OR Procaine penicillin G 50,000 units/kg/dose IM in a single daily dose for 10 days OR Benzathine penicillin G 50,000 units/kg/dose IM in a 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 units/kg/dose IM in a 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).
- Preferred regimen: No treatment is required; however, benzathine penicillin G 50,000 units/kg as a single IM injection 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
References
- ↑ Centers for Disease Control (08-04-2006). "Sexually Transmitted Diseases Treatment Guidelines, 2006". MMWR. 55 (RR-11): 24–32. Check date values in:
|date=(help) - ↑ Salkind AR, Cuddy PG, Foxworth JW (2001). "Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy". JAMA. 285 (19): 2498&ndash, 2505.
- ↑ Gruchalla RS, Pirmohamed M (2006). "Clinical practice. Antibiotic allergy". N. Engl. J. Med. 354 (6): 601–9. doi:10.1056/NEJMcp043986. PMID 16467547.
- ↑ Rolfs RT, Joesoef MR, Hendershot EF; 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. PMID 9235493.
- ↑ 5.0 5.1 5.2 Saxon A, Beall GN, Rohr AS, Adelman DC (1987). "Immediate hypersensitivity reactions to beta-lactam antibiotics". Annals of Internal Medicine. 107 (2): 204–15. PMID 3300459. Unknown parameter
|month=ignored (help);|access-date=requires|url=(help) - ↑ 6.0 6.1 6.2 Yates AB (2008). "Management of patients with a history of allergy to beta-lactam antibiotics". The American Journal of Medicine. 121 (7): 572–6. doi:10.1016/j.amjmed.2007.12.005. PMID 18589051. Retrieved 2012-02-18. Unknown parameter
|month=ignored (help) - ↑ "Sexually Transmitted Diseases Treatment Guidelines, 2010". Retrieved 2012-12-19.
- ↑ Lukehart SA, Godornes C, Molini BJ; et al. (2004). "Macrolide resistance in Treponema pallidum in the United States and Ireland". N Engl J Med. 351: 154–8. PMID 15247355.
- ↑ 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.