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[[Image:Syphilis-poster-wpa-cure.jpg|thumb|100px|Depression-era U.S. poster advocating early syphilis treatment]]
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[[Image:400Behandlung der Syphilis.jpg|thumb|100px|left|Application of mercury.]]
{{CMG}}{{AE}}{{AA}}; {{NRM}}
 
{{Syphilis}}
{{Syphilis}}
{{CMG}}
==Overview==
==Overview==
[[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.


==History==
==Medical Therapy==
There were originally no effective treatments for syphilis. The Spanish priest Francisco Delicado wrote ''El modo de adoperare el legno de India'' (Rome, 1525) about the use of ''[[Guaiacum]]'' in the treatment of syphilis. He himself suffered from syphilis. Another common remedy was [[mercury (element)|mercury]]: the use of which gave rise to the saying "A night in the arms of Venus leads to a lifetime on Mercury".<ref>{{cite web |url=http://www.dailymail.co.uk/pages/live/articles/news/news.html?in_article_id=460406&in_page_id=1770 |title=The magical properties of Mercury, the metal the EU wants to ban | the Daily Mail |format= |work=}}</ref>  It was administered multiple ways including by mouth and by rubbing it on the skin. One of the more curious methods was fumigation, in which the patient was placed in a closed box with his head sticking out. Mercury was placed in the box and a fire was started under the box which caused the mercury to vaporize. It was a grueling process for the patient and the least effective for delivering mercury to the body.
*[[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>
 
As the disease became better understood, more effective treatments were found. The first antibiotic to be used for treating disease was the [[arsenic]]-containing drug [[Arsphenamine|Salvarsan]], developed in 1908 by Sahachiro Hata while working in the laboratory of Nobel prize winner Paul Ehrlich. This was later modified into [[Neosalvarsan]]. Unfortunately, these drugs were not 100% effective, especially in late disease.  It had been observed that some who develop high fevers could be cured of syphilis. Thus, for a brief time [[malaria]] was used as treatment for tertiary syphilis because it produced prolonged and high fevers. This was considered an acceptable risk because the malaria could later be treated with [[quinine]] which was available at that time. This discovery was championed by [[Julius Wagner-Jauregg]], who won the 1927 [[Nobel Prize for Medicine]] for his work in this area. Malaria as a treatment for syphilis was usually reserved for late disease, especially neurosyphilis, and then followed by either Salvarsan or Neosalvarsan as adjuvant therapy. These treatments were finally rendered obsolete by the discovery of [[penicillin]], and its widespread manufacture after World War II allowed syphilis to be effectively and reliably cured.<ref name=Brown>{{cite book | author=Brown, Kevin| date=2006 | title=The Pox: The Life and Near Death of a Very Social Disease | location=Stroud | publisher=WSutton | pages=85-111, 185-91}}</ref>
 
==Current treatment==
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> 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.
 
Non-pregnant individuals who have severe allergic reactions to penicillin (e.g., [[anaphylaxis]]) may be effectively 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> If compliance and follow-up cannot be ensured, the [[Centers for Disease Control and Prevention|CDC]] recommends [[Desensitization (medicine)|desensitization]] with penicillin followed by penicillin treatment. 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.
 
====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====
:*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.  
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 [[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. 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.


===Alternative regimens===
:*Treatment for longer duration is required in patients with late latent, latent with unknown duration and tertiary syphilis.
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.
:*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.


==Jarisch-Herxheimer reaction==
:*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>
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> 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.


==Tuskegee syphilis study==
===Pharmacotherapy===
{{main|Tuskegee Study of Untreated Syphilis in the Negro Male}}
:'''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>
One of the best-documented cases of [[medical ethics|unethical human medical experimentation]] in the twentieth century was the [[Tuskegee syphilis study]]. The study took place in Tuskegee, Alabama and was supported by the Tuskegee Institute and the [[U.S. Public Health Service]] (PHS).<ref>{{cite web |url=http://www.pbs.org/wnet/aaworld/reference/articles/tuskegee_syphilis_study.html |title=A A World . Reference Room . Articles . Tuskegee Syphilis Study | PBS |format= |work=}}</ref>
::'''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
::'''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 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:<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>
:::*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
:::*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]].
:'''Syphilis Among HIV-Infected Persons'''
::'''Primary and Secondary Syphilis Among HIV-Infected Persons'''
::*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'''
:::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>
:::Late latent:
:::*Preferred regimen: [[Benzathine penicillin G]] 2.4 MU once a week for 3 weeks
::'''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
:'''Syphilis During Pregnancy'''
:*Pregnant women should be treated with the [[penicillin]] regimen appropriate for their stage of infection.
:*[[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.
::*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.
::*Preferred regimen: [[Benzathine penicillin G]] 50,000 U/kg/dose IM 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).
::*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'''
:*Preferred regimen: [[Aqueous crystalline penicillin G]] 50,000 U/kg q4–6h for 10 days


The study began in 1932 using a group of 600 black sharecroppers. Of these 600, 399 of the men had the disease and 201 were uninfected control patients. The PHS stated at first that treatment was supposed to be a part of the study, but they were unable to produce any useful data. It was then discovered that the PHS had decided to leave the men untreated and follow the course of the disease to these men's eventual deaths. They thought they were receiving experimental treatment for "bad blood" in exchange for free meals and a $50 death benefit. However, the study was designed to measure the progression of untreated syphilis and to determine whether syphilis caused [[cardiovascular]] damage more often than neurological damage, and to determine if the natural course of the disease was different in black men versus white men. By 1947 penicillin had become the standard treatment of syphilis. The men were never advised that they had syphilis, nor were they offered a treatment including Salvarsan or the other arsenical drugs that were in use at the beginning of the study.
==Approach to Diagnosis and Management of Syphilis==


The original study was meant to last six to nine months, but continued for 40 years, ending in 1972, long after wives and children had been infected, and many of the men had died of syphilis. It was estimated that more than one hundred men and women died as a result of this study. The study ended because of a story printed in the ''Washington Star''. A class-action lawsuit was then filed against the federal government for the study. This lawsuit was settled out of court and the living subjects and their descendants were awarded a total of ten million dollars. After the settlement was awarded, the government passed the [[National Research Act]], which required the government to review and approve all medical studies involving human subjects.
{{Family tree/start}}
{{Family tree | | | | | | | | | | | | | | A01 | | | | | | | | | | | | |A01=Positive syphilis screening test}}
{{Family tree | | | | | | | | | | | | | | |!| | | | | | | | | | | | | |}}
{{Family tree | | | | | | | | | | | | | | B01 | | | | | | | | | | | | |B01=Perform treponemal-specific test}}
{{Family tree | | | | | | | |,|-|-|-|-|-|-|^|-|-|-|-|-|-|.| | | | | | | }}
{{Family tree | | | | | | | C01 | | | | | | | | | | | | C02 | | | | | |C01=Positive treponemal-specific test|C02=Negative treponemal-specific test}}
{{Family tree | | | | | | | |!| | | | | | | | | | | |,|-|^|-|.| | | | |}}
{{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}}
{{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}}
{{Family tree | | |!| | |,|-|^|-|.| | | | | | | | | |!| | | | | | | | |}}
{{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>}}
{{Family tree | | |!| |!| | | | |!| | | |!| | | | | |!| | | | | | | | |}}
{{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}}
{{Family tree | | | | | | | | | | | | | |!| | | | | | | | | | | | | | }}
{{Family tree | | | | | | | | | |,|-|-|-|^|-|-|-|.| | | | | | | | | |}}
{{Family tree | | | | | | | | | H01 | | | | | | H02 | | | | | | | | |H01=Yes|H02=No}}
{{Family tree | | | | | | | |,|-|^|-|.| | | | | |!| | | | | | | | |}}
{{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>}}
{{Family tree | | | | | | | | |!| | |!| | | | | | | | | | | | | | |}}
{{Family tree | | | | | | | | |!| | J01 | | | | | | | | | | | | | |J01=Desensitization}}
{{Family tree | | | | | | | | |!| |!| | | | | | | | | | | | | | | |}}
{{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}}
{{Family tree/end}}


==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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