Syphilis medical therapy: Difference between revisions

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__NOTOC__
__NOTOC__
{{CMG}}
{{CMG}}{{AE}}{{AA}}; {{NRM}}
{{Syphilis}}
{{Syphilis}}
==Overview==
==Overview==
[[Penicillin#Benzylpenicillin (penicillin G)|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, [[Penicillin#Benzylpenicillin (penicillin G)|parenteral penicillin G]] is the only therapy with documented efficacy for syphilis.  
[[Penicillin#Benzylpenicillin (penicillin G)|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, [[Penicillin#Benzylpenicillin (penicillin G)|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==
==Medical Therapy==
*[[Penicillin#Benzylpenicillin (penicillin G)|Penicillin G]], administered parenterally, is the preferred drug for treating all stages of syphilis.  
*[[Penicillin#Benzylpenicillin (penicillin G)|Penicillin G]], administered [[parenterally]], is the preferred drug for treating all stage of syphilis.<ref name=cdcsyphilis>http://www.cdc.gov/std/tg2015/syphilis.htm Accessed on September 26, 2016</ref>


:*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.  
:*The preparation used (i.e., [[Benzathine penicillin G|benzathine]], aqueous [[Procaine penicillin G|procaine]], or [[Penicillin G potassium|aqueous crystalline]]), the dosage, and the length of treatment depend on the stage and clinical manifestations of the disease.  


:*Selection of the appropriate [[Penicillin#Benzylpenicillin (penicillin G)|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.  
:*Treatment for longer duration is required in patients with late latent, latent with unknown duration and tertiary syphilis.


:*Combinations of benzathine penicillin, procaine penicillin, and oral penicillin preparations are not considered appropriate for the treatment of syphilis.  
:*Selection of the appropriate [[Penicillin#Benzylpenicillin (penicillin G)|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.


*During pregnancy, [[Penicillin#Benzylpenicillin (penicillin G)|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
:*Combinations of benzathine penicillin, procaine penicillin, and oral penicillin preparations are not considered appropriate for the treatment of syphilis.<ref name=BCR>http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5409a1.htm</ref> 
 
*The [[Herxheimer reaction|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===
===Pharmacotherapy===
*The first-choice treatment for all manifestations of syphilis remains [[penicillin]] in the form of [[Penicillin#Benzylpenicillin .28penicillin G.29|penicillin G]].<ref name=CDC>{{cite journal | author=Centers for Disease Control | title=Sexually Transmitted Diseases Treatment Guidelines, 2006 | journal=MMWR | volume=55 | date=08-04-2006 | issue=RR-11 | pages=24-32}}</ref>  
:'''Syphilis Among non-HIV-Infected Persons'''<ref name="pmid26042815">{{cite journal |vauthors=Workowski KA, Bolan GA |title=Sexually transmitted diseases treatment guidelines, 2015 |journal=[[MMWR. Recommendations and Reports : Morbidity and Mortality Weekly Report. Recommendations and Reports / Centers for Disease Control]] |volume=64 |issue=RR-03 |pages=1–137 |year=2015 |pmid=26042815 |doi= |url=http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6403a1.htm |issn=}}</ref>
 
::'''Primary and Secondary Syphilis'''
*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.  
::*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
*[[Penicillin#Benzylpenicillin (penicillin G)|Parenteral penicillin G]] is the only therapy with documented effect during pregnancy. For early syphilis, one dose of penicillin is sufficient.
::'''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 and Infections of Unknown Duration=====
:::Late Latent Syphilis or Latent Syphilis of Unknown Duration:
*Late latent syphilis is defined as latency for greater than one year.
:::*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)
*If [[Syphilis laboratory findings#CSF analysis|CSF examination]] yields no evidence of [[neurosyphilis]], then [[Penicillin#Benzylpenicillin (penicillin G)|penicillin G]] is recommended as weekly doses for 3 weeks.  
::'''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
*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.
::'''Ocular syphilis'''
 
:::Pathogen-directed antimicrobial therapy:<ref>{{cite book | last = Bennett | first = John | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Elsevier/Saunders | location = Philadelphia, PA | year = 2015 | isbn = 978-1455748013 }}</ref>
=====Neurosyphilis=====
:::*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
*For patients diagnosed with [[neurosyphilis]] including ocular or auditory syphilis with or without [[Syphilis laboratory findings#CSF analysis|positive CSF results]], [[Penicillin#Benzylpenicillin (penicillin G)|aqueous crystalline penicillin G]] is the treatment of choice.  
:::*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 [[Human Immunodeficiency Virus (HIV)|HIV]], and all should have a [[lumbar puncture]] before starting therapy to exclude concurrent [[neurosyphilis]].
*The recommended regimen is intravenous treatment every 4 hours or continuously for 10-14 days.
:'''Syphilis Among HIV-Infected Persons'''
 
::'''Primary and Secondary Syphilis Among HIV-Infected Persons'''
*If intravenous administration is not possible, then [[Penicillin#Procaine benzylpenicillin|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.  
::*Preferred regimen: [[Benzathine penicillin G]] 2.4 MU IM single dose<ref name="pmid9235493">{{cite journal| author=Rolfs RT, Joesoef MR, Hendershot EF, Rompalo AM, Augenbraun MH, Chiu M et al.| title=A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. The Syphilis and HIV Study Group. | journal=N Engl J Med | year= 1997 | volume= 337 | issue= 5 | pages= 307-14 | pmid=9235493 | doi=10.1056/NEJM199707313370504 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9235493  }} </ref>
 
::'''Latent Syphilis Among HIV-Infected Persons'''
*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 [[Penicillin#Benzylpenicillin (penicillin G)|benzathine penicillin G]] after the completion of a 14-day course of aqueous crystalline or aqueous procaine penicillin G for [[neurosyphilis]].
:::Early latent:
 
:::*Preferred regimen: [[Benzathine penicillin G]] 2.4 MU IM single dose<ref name="pmid25286091">{{cite journal| author=Yang CJ, Lee NY, Chen TC, Lin YH, Liang SH, Lu PL et al.| title=One dose versus three weekly doses of benzathine penicillin G for patients co-infected with HIV and early syphilis: a multicenter, prospective observational study. | journal=PLoS One | year= 2014 | volume= 9 | issue= 10 | pages= e109667 | pmid=25286091 | doi=10.1371/journal.pone.0109667 | pmc=4186862 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25286091  }} </ref>
*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.
:::Late latent:
 
:::*Preferred regimen: [[Benzathine penicillin G]] 2.4 MU once a week for 3 weeks
=====HIV-Infected Patients=====
::'''Neurosyphilis Among HIV-Infected Persons'''
*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.
::*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
*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.
:'''Syphilis During Pregnancy'''
 
:*Pregnant women should be treated with the [[penicillin]] regimen appropriate for their stage of infection.
*The magnitude of these risks, however, although not precisely defined, is probably small.
:*[[Penicillin#Benzylpenicillin (penicillin G)|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 [[Herxheimer reaction|Jarisch-Herxheimer reaction]] is an acute febrile reaction.  
*Skin testing or [[desensitization]] is recommended in latent syphilis and neurosyphilis in other patients with HIV infection.
::*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.
===Pencillin Allergy===
::*The Jarisch-Herxheimer reaction occurs most frequently among patients who have early syphilis, presumably because bacterial burdens are higher during these stages.
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.<ref>{{cite journal|author=Salkind AR, Cuddy PG, Foxworth JW|title=Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy|journal=JAMA|year=2001|volume=285|issue=19|pages=2498&ndash;2505|url=http://jama.ama-assn.org/cgi/content/abstract/285/19/2498}}</ref> Nevertheless, penicillin is still the most common cause of severe allergic drug reactions.
::*[[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.
[[Allergy|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]].<ref>{{cite journal |author=Gruchalla RS, Pirmohamed M |title=Clinical practice. Antibiotic allergy |journal=N. Engl. J. Med. |volume=354 |issue=6 |pages=601-9 |year=2006 |pmid=16467547 |doi=10.1056/NEJMcp043986}}</ref> 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.
:'''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).
====Jarisch-Herxheimer Reaction====
::*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
*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.<ref>{{cite journal |author=Rolfs RT, Joesoef MR, Hendershot EF, et al |title=A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. The Syphilis and HIV Study Group |journal=N. Engl. J. Med. |volume=337 |issue=5 |pages=307-14 |year=1997 |pmid=9235493 |doi=}}</ref>
::*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.
*This reaction is characterized by fever, fatigue, and transient worsening of any mucocutaneous symptoms, and usually subsides within 24 hours.  
::'''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
*These symptoms can be alleviated with [[acetaminophen]] (paracetamol) and should not be mistaken for drug allergy.  
::*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
*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.
::*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.
====Penicillin Skin Test====
::*Preferred regimen: [[Benzathine penicillin G]] 50,000 U/kg/dose IM single dose
*[[Penicillin skin testing]] with the major and minor determinants of penicillin can reliably identify persons at high risk for penicillin reactions.<ref name="pmid3300459">{{cite journal |author=Saxon A, Beall GN, Rohr AS, Adelman DC |title=Immediate hypersensitivity reactions to beta-lactam antibiotics |journal=[[Annals of Internal Medicine]] |volume=107 |issue=2 |pages=204–15 |year=1987 |month=August |pmid=3300459 |doi= |url= |accessdate=2012-02-18}}</ref><ref name="pmid18589051">{{cite journal |author=Yates AB |title=Management of patients with a history of allergy to beta-lactam antibiotics |journal=[[The American Journal of Medicine]] |volume=121 |issue=7 |pages=572–6 |year=2008 |month=July |pmid=18589051 |doi=10.1016/j.amjmed.2007.12.005 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9343(08)00037-5 |accessdate=2012-02-18}}</ref> 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.  
::'''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
*Patients with history of penicillin reaction and negative skin-test negative can receive conventional penicillin therapy.  
::*[[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'''
*Skin-test-positive patients should be desensitized before initiating treatment.
:*Preferred regimen: [[Aqueous crystalline penicillin G]] 50,000 U/kg q4–6h for 10 days


*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.
==Approach to Diagnosis and Management of Syphilis==


=====Indication=====
{{Family tree/start}}
*Patients at high risk for [[anaphylaxis]], including those who have:
{{Family tree | | | | | | | | | | | | | | A01 | | | | | | | | | | | | |A01=Positive syphilis screening test}}
:*A history of [[penicillin]]-related anaphylaxis, [[asthma]], or other diseases that would make anaphylaxis more dangerous
{{Family tree | | | | | | | | | | | | | | |!| | | | | | | | | | | | | |}}
:*Been treated with [[Beta blockers|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.
{{Family tree | | | | | | | | | | | | | | B01 | | | | | | | | | | | | |B01=Perform treponemal-specific test}}
 
{{Family tree | | | | | | | |,|-|-|-|-|-|-|^|-|-|-|-|-|-|.| | | | | | | }}
*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|chlorpheniramine maleate]] or [[fexafenadine]] during the preceding 24 hours, [[diphenhydramine|diphenhydramine HCl]] during the preceding 4 days, or [[hydroxyzine]] or [[phenathiazines]] during the preceding 3 weeks).
{{Family tree | | | | | | | C01 | | | | | | | | | | | | C02 | | | | | |C01=Positive treponemal-specific test|C02=Negative treponemal-specific test}}
 
{{Family tree | | | | | | | |!| | | | | | | | | | | |,|-|^|-|.| | | | |}}
=====Procedures=====
{{Family tree | | | | | | | D01 | | | | | | | | | | D02 | | D03 | | | |D01=Establish stage of infection; obtain quantitative nontreponemal test titres|D02=Primary syphilis suspected|D03=False-positive test result suspected}}
*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).
{{Family tree | | |,|-|-|-|-|+|-|-|-|-|-|.| | | | | |!| | | |!| | | | |}}
 
{{Family tree | | E01 | | | E02 | | | | E03 | | | | E04 | | E05 | | | |E01=Signs or symptoms of primary or secondary syphilis|E02=No clinical signs or symptoms (latent syphilis)|E03=Signs or symptoms of tertiary (late) syphilis, or patient is HIC positive or otherwise immunocompromised|E04=Obtain quantitative nontreponemal test titres|E05=Consider other causes}}
*Epicutaneous (Prick) Tests:
{{Family tree | | |!| | |,|-|^|-|.| | | | | | | | | |!| | | | | | | | |}}
:*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.
{{Family tree | | |!| | F01 | | F02 | | F03 | | | | F04 | | | | | | | |F01=Early latent syphilis|F02=Late latent syphilis|F03=Lumbar puncture|F04=Penicillin G benzazthine, 2.4 million units IM (single dose)<sup>*</sup>}}
:*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.
{{Family tree | | |!| |!| | | | |!| | | |!| | | | | |!| | | | | | | | |}}
:*The [[histamine]] controls should be positive to ensure that results are not falsely negative because of the effect of [[antihistaminics|
{{Family tree | | | G01 | | | | G02 | | |!| | | | | G03 | | | | | | |G01=Penicillin G benzazthine, 2.4 million units IM (single dose)*|G02=Penicillin G benzazthine, 2.4 million units IM once a week for 3 weeks (three doses)<sup>**</sup>|G03=Signs, symptoms, or CSF findings consistent with neurosyphilis}}
antihistaminic drugs]].
{{Family tree | | | | | | | | | | | | | |!| | | | | | | | | | | | | | }}
 
{{Family tree | | | | | | | | | |,|-|-|-|^|-|-|-|.| | | | | | | | | |}}
*Intradermal Test:
{{Family tree | | | | | | | | | H01 | | | | | | H02 | | | | | | | | |H01=Yes|H02=No}}
:*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.
{{Family tree | | | | | | | |,|-|^|-|.| | | | | |!| | | | | | | | |}}
:*The margins of the wheals induced by the injections should be marked with a ball point pen.
{{Family tree | | | | | | | I01 | | I02 | | | | I03 | | | | | | | |I01=No penicillin allergy|I02=Penicillin allergy|I03=Unvolve appropriate subspecialists. Penicillin G benzazthine, 2.4 million units IM once a week for 3 weeks (three doses)<sup>**</sup>}}
:*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.
{{Family tree | | | | | | | | |!| | |!| | | | | | | | | | | | | | |}}
 
{{Family tree | | | | | | | | |!| | J01 | | | | | | | | | | | | | |J01=Desensitization}}
===Management of Patients with History of Penicillin Allergy===
{{Family tree | | | | | | | | |!| |!| | | | | | | | | | | | | | | |}}
=====CDC Recommendations <ref name="urlSexually Transmitted Diseases Treatment Guidelines, 2010">{{cite web |url=http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5912a1.htm |title=Sexually Transmitted Diseases Treatment Guidelines, 2010 |format= |work= |accessdate=2012-12-19}}</ref>=====
{{Family tree | | | | | | | | | K01 | | | | | | | | | | | | | | | |K01=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}}
{{cquote|
{{Family tree/end}}
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 [[Pencillin|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|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 management during pregnancy|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 [[IgE|immunoglobulin E (IgE)]]-mediated allergic response to [[penicillin]]<ref name="pmid3300459">{{cite journal |author=Saxon A, Beall GN, Rohr AS, Adelman DC |title=Immediate hypersensitivity reactions to beta-lactam antibiotics |journal=[[Annals of Internal Medicine]] |volume=107 |issue=2 |pages=204–15 |year=1987 |month=August |pmid=3300459 |doi= |url= |accessdate=2012-02-18}}</ref><ref name="pmid18589051">{{cite journal |author=Yates AB |title=Management of patients with a history of allergy to beta-lactam antibiotics |journal=[[The American Journal of Medicine]] |volume=121 |issue=7 |pages=572–6 |year=2008 |month=July |pmid=18589051 |doi=10.1016/j.amjmed.2007.12.005 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9343(08)00037-5 |accessdate=2012-02-18}}</ref>, 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 [[cephalosporin]]s 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.<ref name=Azith>{{cite journal | author=Lukehart SA, Godornes C, Molini BJ, et al | title=Macrolide resistance in Treponema pallidum in the United States and Ireland | journal=N Engl J Med. | volume=351 | pages=154-8 | date=2004 | PMID=15247355}}</ref>
 
*Because anaphylactic reactions to penicillin can be fatal, every effort should be made to avoid administering penicillin to penicillin-allergic patients, unless they undergo [[Pencillin desentization|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]].<ref name="pmid3300459">{{cite journal |author=Saxon A, Beall GN, Rohr AS, Adelman DC |title=Immediate hypersensitivity reactions to beta-lactam antibiotics |journal=[[Annals of Internal Medicine]] |volume=107 |issue=2 |pages=204–15 |year=1987 |month=August |pmid=3300459 |doi= |url= |accessdate=2012-02-18}}</ref><ref name="pmid18589051">{{cite journal |author=Yates AB |title=Management of patients with a history of allergy to beta-lactam antibiotics |journal=[[The American Journal of Medicine]] |volume=121 |issue=7 |pages=572–6 |year=2008 |month=July |pmid=18589051 |doi=10.1016/j.amjmed.2007.12.005 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9343(08)00037-5 |accessdate=2012-02-18}}</ref> 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 [[Syphilis medical therapy#Pencillin allergy: Penicillin skin test|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|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''' <ref name="pmid26042815">{{cite journal |vauthors=Workowski KA, Bolan GA |title=Sexually transmitted diseases treatment guidelines, 2015 |journal=[[MMWR. Recommendations and Reports : Morbidity and Mortality Weekly Report. Recommendations and Reports / Centers for Disease Control]] |volume=64 |issue=RR-03 |pages=1–137 |year=2015 |pmid=26042815 |doi= |url=http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6403a1.htm |issn=}}</ref>
:*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 IM
::* Note: Up to the adult dose of 2.4 MU in a 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 IM
:::* Note: Up to the adult dose of 2.4 MU in a 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==
==References==
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Latest revision as of 00:23, 30 July 2020

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

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Overview

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

  • 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

Syphilis Among non-HIV-Infected Persons[3]
Primary and Secondary Syphilis
Latent Syphilis
Early Latent Syphilis:
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]
Syphilis Among HIV-Infected Persons
Primary and Secondary Syphilis Among HIV-Infected Persons
Latent Syphilis Among HIV-Infected Persons
Early latent:
Late latent:
Neurosyphilis Among HIV-Infected Persons
Syphilis During Pregnancy
  • Pregnant women should be treated with the penicillin regimen appropriate for their stage of infection.
  • 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.
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

Approach to Diagnosis and Management of Syphilis

 
 
 
 
 
 
 
 
 
 
 
 
 
Positive syphilis screening test
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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

  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.
  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.


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