Key principles for the treatment of syphilis include the following: 
Penicillin is the drug of choice to treat syphilis.
Doxycycline is the best alternative for treating early and late latent syphilis. Syphilis associated with HIV infection does not require any enhanced antimicrobial therapy.
In the treatment of late syphilis by weekly injections, missing a dose of penicillin for a period of 10-14 days does not require restarting the entire course of injections.
The exception to this is in the case of pregnant women in whom there is no latitude for missing a dose of penicillin.
There is evidence that an interval of 7-9 days between doses may produce better results.
CSF testing to detect neurosyphilis is strongly recommended in patients with tertiary syphilis or with neurological signs or symptoms consistent with neurosyphilis and in patients without symptoms whose serologic titers do not decline appropriately after being treated with recommended therapy.
Reinfection rates among MSM are high, so frequent serological testing in this group is recommended.
CDC recommends the use of the RPR-based screening algorithm. When there is a low epidemiologic risk or clinical probability of syphilis, the positive predictive value of an isolated unconfirmed reactive treponemal chemoluminescence test or enzyme immunoassay is low.
Penicillin was established as an effective treatment for syphilis before the widespread use of randomized clinical trials.  The treatment guidelines published by the CDC (see current CDC recommendations) are based largely on uncontrolled trials and expert opinion. Guidelines are based on staging, with later stages requiring longer courses of treatment due to the slower rate of bacterial replication. 
Penicillin remains the mainstay of treatment and the standard by which other modes of therapy are judged.  The 2015 CDC STD treatment guidelines support the use of penicillin as the preferred drug for treating all stages of syphilis.  Penicillin is the only recommended therapy for neurosyphilis, congenital syphilis, or syphilis during pregnancy. Rarely, T pallidum has been found to persist following adequate penicillin therapy; however, there is no indication that the organism has acquired resistance to penicillin.
The following regimens are recommended for penicillin treatment:
Primary or secondary syphilis - Benzathine penicillin G 2.4 million units intramuscularly (IM) in a single dose
Early latent syphilis - Benzathine penicillin G 2.4 million units IM in a single dose
Late latent syphilis or latent syphilis of unknown duration - Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals
Pregnancy - Treatment appropriate to the stage of syphilis is recommended.
Clinicians should be aware that only benzathine penicillin product (Bicillin L-A) should be used, not benzathine-procaine penicillin (Bicillin C-R). In addition, oral penicillin is never appropriate for the treatment of syphilis.
If the patient arrives late for subsequent doses, clinical experience suggests that an interval of 10-14 days between doses of benzathine penicillin for latent syphilis might be acceptable before restarting the sequence of injections; however, according to pharmacokinetics/pharmacodynamics, an interval of 7-9 days between doses is more optimal. [29, 30, 31] In pregnancy, missed doses are not acceptable. Pregnant patients must repeat the full course of therapy. 
In patients with a history of penicillin allergy, desensitization may be necessary in cases of pregnancy, neurosyphilis, congenital syphilis, or tertiary syphilis.
According to the 2015 CDC STD guidelines, no treatment regimens for syphilis have been shown to be more effective in preventing neurosyphilis in patients who are HIV positive than the syphilis regimens recommended for patients who are HIV negative. Careful monitoring after therapy is required, as patients with HIV infection are at higher risk for reinfection and have a slower serologic response than patients without HIV infection. 
Alternatives to penicillin
As stated in the 2015 CDC guidelines, several therapies exist that might be effective in nonpregnant, penicillin-allergic patients with primary or secondary syphilis. 
Tetracycline, erythromycin, and ceftriaxone  have shown antitreponemal activity in clinical trials; however, they currently are recommended only as alternative treatment regimens in patients allergic to penicillin. A 10- to 14-day trial of ceftriaxone is effective for treating early syphilis, although the optimal dose and duration have not been established. Doxycycline and tetracycline for 28 days have been used for many years and are the only acceptable alternatives to penicillin for the treatment of latent syphilis. Doxycycline is the preferred alternative to penicillin owing to its tolerability. 
Azithromycin has also been studied. A meta-analysis of randomized clinical trials comparing azithromycin to benzathine penicillin G for early syphilis was published in 2008 showing favorable results for azithromycin.  A 2010 study by Hook et al showed a single dose of azithromycin (2 g PO) to be equivalent to the treatment of choice, benzathine penicillin G (2.4 million units IM) in patients with early syphilis without HIV. Serological cure after 6 months of follow-up was not significant between the 2 treatments, although azithromycin recipients had a higher incidence of adverse effects (mostly self-limited gastrointestinal symptoms).  Although azithromycin is effective, resistance is increasing in the United States, with some areas reporting up to 84% resistance; therefore, azithromycin should be used only in areas of low resistance or in early syphilis with close clinical follow-up. [19, 36]
Following the initiation of treatment, the dying treponemes release inflammatory molecules that trigger a cytokine cascade possibly leading to a response known as the Jarisch-Herxheimer reaction. Symptoms include myalgias, fever, headache, and tachycardia, sometimes with exacerbation of whatever current syphilitic lesions are manifested (eg, rash or chancre).
The reaction is common, develops within several hours after beginning antibiotic treatment, and usually clears within 24 hours after onset. Its exact etiology is unclear, although it may be due to an immunological reaction to the rupture of spirochetes.
Management of this reaction often involves symptomatic treatment (eg, with antipyretics and analgesics) and observation. In pregnant women, treatment may induce early labor or cause fetal distress. Patients should be informed of the possibility of this reaction before undergoing antibiotic therapy. As stated in the CDC 2015 STD treatment guidelines, although the Jarisch-Herxheimer reaction might induce obstetric complications such as early labor or fetal distress, this risk should not preclude or delay therapy for syphilis. Women are advised to seek obstetric care after treatment if they notice any fever, uterine contractions, or a decrease in fetal movement. 
Some patients experience severe anxiety and other psychological disturbances after the administration of procaine penicillin. Fever, hallucinations, hyperventilation, and convulsions characterize the reaction. Circulatory collapse is occasionally reported.
Resuscitation and supportive care are necessary in severe cases; however, most reactions are mild, requiring only reassurance or symptomatic relief. Symptoms usually dissipate within 30 minutes.
Surgical care is reserved for treating the complications of tertiary syphilis (eg, aortic valve replacement).
Prevention of Syphilis
The primary goal of prevention is to limit the spread of syphilis. This entails counseling patients to use safe sex practices and advising patients who abuse intravenous (IV) drugs to never share needles and to use clean needles. Notification and treatment of sexual partners and exposed drug partners are paramount. Prevention also entails educating health care workers to use universal precautions when treating all patients.
Empiric treatment with one dose of benzathine penicillin G 2.4 million units intramuscularly (IM) is recommended in all patients who have had sexual contact with a partner who has tested positive for primary, secondary, or early latent syphilis within the preceding 90 days. 
Studies of primary screening for syphilis in clinics and emergency departments are favorable for screening of high-risk, urban populations. Routine screening is advocated for all at-risk mothers.
Two reports from 2009 indicate that circumcision does not help prevent the transmission of syphilis, although circumcision may help reduce the transmission of other STDs such as HIV infection. [37, 38]
Consultation with an infectious diseases specialist may be required for difficult or complex cases of syphilis. Consult with a dermatologist, vascular surgeon, ophthalmologist, or neurologist should also be obtained as necessary to assist with the variable presentations of syphilis.
Additionally, the CDC, the World Health Organization (WHO), and Morbidity and Mortality Weekly Report (MMWR) are excellent updated references. Syphilis may be reportable to public health authorities in some jurisdictions.
Monitor patients with syphilis to ensure adequacy of treatment. Patients with early syphilis should be monitored with repeat RPR or VDRL at 6- and 12-month intervals. Patients with HIV infection and patients treated with a nonpenicillin regimen should be seen at 3, 6, 9, and 12 months. Patients with latent syphilis should be monitored with RPR or VDRL at 6-, 12-, and 24-month intervals.
Generally speaking, therapy is considered a failure if the signs and symptoms of syphilis return or fail to improve. This occurs when the titer of the nontreponemal test increases 4-fold or a 4-fold decrease from the initial VDRL titer does not occur within 1 year.
However, clearly defined criteria regarding treatment failure are lacking. In their literature review, Augenbraun and Rolfs found that 15-25% of patients treated for syphilis do not have a 4-fold decrease in titers over a 3-month period, and some do not have a decrease for 6 months or longer.  Information is lacking on whether these patients are at higher risk for progression. Currently accepted guidelines are as follows:
Any reappearance of symptoms is defined as a relapse.
More than a double-dilution increase (ie, a 4-fold titer increase) in serologic tests is a relapse.
Patients with latent syphilis who have initially high titers (≥1:32) and fail to have a double-dilution decrease (4-fold titer decline) 12-24 months after therapy should be reevaluated for neurosyphilis and possible retreatment.
Some treponemal test results may remain positive for life despite effective treatment. Individuals in this circumstance require proper documentation to avoid unnecessary retreatment.
Supervise retreatment to ensure compliance.
Recommendations for specific patient subsets are as follows.
Patients with treated primary or secondary syphilis
Patients treated for primary and secondary syphilis should have follow-up VDRL testing at 6, and 12 months after treatment. Patients with HIV infection should be monitored at 3, 6, 9, and 12 months, as they are known to have more rapid progression of disease. Most patients with primary syphilis who are treated adequately have a nonreactive VDRL within 1 year, and almost all patients treated for secondary syphilis have a negative VDRL result within 2 years. A small minority of patients remain seropositive in spite of successful treatment. If all clinical and serologic examinations remain satisfactory for 2 years following treatment, the patient can be reassured that cure is complete, and no further follow-up care is needed.
Patients with latent syphilis
Perform quantitative RPR/VDRL testing for up to 2 years. Schedule annual follow-up visits for an indefinite period of time for patients with persistently positive serologic tests.
The 2010 CDC STD treatment guidelines state that HIV-infected individuals with latent syphilis should receive the same stage-specific treatment as recommended for HIV-negative individuals. 
Patients with benign tertiary or cardiovascular syphilis
Patients should be observed by the physician for the rest of their lives to monitor for complications.
Patients with neurosyphilis
Patients with neurosyphilis should have follow-up at 6-month intervals for at least 3 years with physical examinations, CSF evaluation (eg, cell count, protein, VDRL), and serologic testing.
Go to Neurosyphilis for complete information on this topic.
Pregnant patients with syphilis
Pregnant women treated for syphilis should have monthly VDRL testing for the duration of their pregnancy.
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