INTRODUCTION — Syphilis is an infection caused by the bacterium Treponema pallidum. During the initial phase of infection, the organism disseminates widely, setting the stage for subsequent manifestations. If untreated, syphilis can have a number of significant late adverse outcomes, including cardiovascular, gummatous, and neurologic complications. The management of syphilis is based upon its classification into stages of disease: early syphilis (includes primary, secondary, and early latent syphilis); late (includes late latent, cardiovascular, and gummatous syphilis); and neurosyphilis (includes central nervous system disease and ocular syphilis at any time).

The treatment of syphilis in nonpregnant adults and patient monitoring after treatment will be reviewed here. Other topics related to the treatment of syphilis are discussed elsewhere:

●(See "Syphilis: Screening and diagnostic testing".)

●(See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV".)

●(See "Neurosyphilis".)

●(See "Syphilis in patients with HIV".)

●(See "Syphilis in pregnancy".)

●(See "Congenital syphilis: Clinical features and diagnosis".)

●(See "Congenital syphilis: Evaluation, management, and prevention".)

GENERAL APPROACH TO ANTIMICROBIAL THERAPY — Our approach to the treatment of nonpregnant adults with syphilis are consistent with the 2015 guidelines from the United States Centers for Disease Control and Prevention (CDC) [1]. Discussions of the treatment of syphilis in the setting of HIV infection and pregnancy, as well as congenital syphilis, are found elsewhere. (See "Syphilis in patients with HIV" and "Congenital syphilis: Evaluation, management, and prevention" and "Syphilis in pregnancy", section on 'Maternal treatment'.)

Pre-treatment evaluation — Patients with signs and symptoms consistent with syphilis should undergo serologic testing to confirm the diagnosis. However, certain groups of patients can be treated empirically for early syphilis based upon clinical findings (eg, patients with a suspected chancre) or a known recent exposure, especially if they are unlikely to follow up. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Primary syphilis (chancre)' and 'Treatment of early syphilis' below.)

A nontreponemal serologic test should be obtained just before initiating therapy (ideally, on the first day of treatment) to establish the pre-treatment titer. Since nontreponemal titers can increase significantly between the date of diagnosis and the date of treatment, this test is critical to establishing the adequacy of the post-treatment serologic response. (See "Syphilis: Screening and diagnostic testing", section on 'Serologic tests' and 'Patient monitoring' below.)

Penicillin as the treatment of choice — Parenterally-delivered penicillin G is the treatment of choice for all stages of syphilis (table 1) [2]. Treatment recommendations are based upon the pharmacokinetics of the available drugs, the microbe's slow growth rate (penicillin is active against dividing organisms and requires prolonged antimicrobial exposure for effective killing), the in vitro activity of antimicrobial agents against T. pallidum, and more than 50 years of clinical experience [1,3].

In all types of syphilis, prolonged continuous levels of penicillin are necessary for the elimination of treponemes [4]. However, the dosage, formulation, and duration of treatment depend upon the stage of disease and whether or not infection involves "protected sites" that sequester T. pallidum (eg, ocular structures, the central nervous system) (table 1). As an example, long-acting penicillin G benzathine given intramuscularly (standard treatment of early syphilis) provides continuous levels of penicillin in all tissues except these protected sites. Thus, patients with syphilis involving these areas should be treated with intravenous (IV) penicillin G. (See 'Treatment of neurosyphilis' below.)

For patients without neurosyphilis, the appropriate formulation of parenteral penicillin is penicillin G benzathine, which is marketed under the trade name Bicillin L-A. This agent should only be given via the intramuscular (IM) route since IV administration has been associated with cardiopulmonary arrest and death [4]. IM administration of penicillin G benzathine produces detectable serum concentrations for up to 30 days.

Bicillin L-A must be distinguished from Bicillin C-R (which contains equal concentrations of procaine and benzathine penicillin), which should not be used to treat patients with syphilis. Bicillin C-R results in detectable serum drug levels for only seven days. Inadvertent use of this shorter-acting preparation in a Los Angeles sexually transmitted disease clinic led to a large-scale public health investigation and retesting and retreatment of a significant number of patients [5]. The Bicillin C-R product is now labeled with a warning: "not for the treatment of syphilis." This agent is typically used for the treatment of susceptible streptococci. (See "Treatment and prevention of streptococcal pharyngitis in adults and children", section on 'Antibiotic treatment'.)

Given periodic shortages of penicillin G benzathine, it is important to follow recommended dosing regimens (eg, a single dose of penicillin G benzathine for early syphilis) (table 1) [6]. In addition, use of penicillin G benzathine for syphilis treatment should be prioritized for pregnant women, and alternative regimens, such as doxycycline, may need to be utilized for nonpregnant adults if supplies are limited. (See 'Alternative regimens for early syphilis' below and 'Alternative regimens for late syphilis' below and "Syphilis in pregnancy", section on 'Maternal treatment'.)

Patients who are allergic to penicillin — If a patient is allergic to penicillin, the choice of agent is less clear. Options include:

●Testing for penicillin allergy and/or rechallenging with penicillin

●Desensitizing to penicillin if allergy testing is positive

●Using an alternative agent with close post-treatment monitoring

For patients with a documented history of a penicillin allergy, we typically initiate an alternative regimen if the patient has early disease or late latent syphilis and can be closely monitored after treatment. Alternative antimicrobial agents include tetracyclines and cephalosporins (table 1). Some patients who are allergic to penicillin may also be allergic to ceftriaxone (see "Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics"). However, if ceftriaxone is used, we typically prefer IV administration rather than IM injections, which are often painful. Azithromycin should be used only if other agents are not available due to reports of treatment failures associated with macrolide resistance. A more detailed discussion of how to choose an alternative agent is found below. (See 'Alternative regimens for early syphilis' below.)

Patients should generally be tested for allergy and desensitized to or rechallenged with penicillin if they are pregnant, or present with neurosyphilis, cardiovascular manifestations of late syphilis, and/or treatment failure. Patients with a history of an immediate-type hypersensitivity reaction require desensitization. For patients with a history of a delayed-type reaction, some can be rechallenged with penicillin, while others should have skin testing prior to being re-exposed. Detailed discussions of the management of patients with a penicillin allergy are found elsewhere. (See "Penicillin allergy: Immediate reactions" and "Penicillin allergy: Delayed hypersensitivity reactions".)

TREATMENT OF EARLY SYPHILIS — The goals of treatment for early syphilis are to prevent long-term adverse outcomes of infection and reduce transmission to others. Early syphilis refers to primary, secondary, and early latent syphilis. A diagnosis of early syphilis implies that T. pallidum infection occurred within the previous year.

●Primary – Following acquisition of T. pallidum, the initial clinical manifestations are termed primary syphilis and usually consist of a painless chancre at the site of inoculation, accompanied by regional adenopathy. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Primary syphilis (chancre)'.)

●Secondary – Approximately 25 percent of individuals with untreated primary infection will develop a systemic illness that represents secondary syphilis. Clinical manifestations are protean, but often include a disseminated rash, condylomata lata, lymphadenopathy, alopecia, and/or hepatitis. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Secondary syphilis'.)

●Early latent – Latent syphilis refers to the period when a patient is infected with T. pallidum, as demonstrated by serologic testing, but has no symptoms. Early latent syphilis by definition occurs within the first year of initial infection. Patients diagnosed with early latent syphilis should be considered to be potentially infectious. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Latent syphilis (asymptomatic)' and "Syphilis: Screening and diagnostic testing", section on 'Latent syphilis'.)

Preferred regimens for early syphilis — A single dose of penicillin G benzathine (2.4 million units intramuscularly [IM]) is standard therapy for most patients with primary, secondary, and early latent syphilis (table 1) [1,7]. Long-acting penicillin G benzathine should only be given via the IM route [4]. (See 'Penicillin as the treatment of choice' above.)

Patients with neurologic manifestations should be evaluated for neurosyphilis. The clinical manifestations, diagnosis, and treatment of neurosyphilis are discussed elsewhere. (See "Neurosyphilis", section on 'Early neurosyphilis' and 'Treatment of neurosyphilis' below.)

A persistent level >0.018 mcg/mL of penicillin for 7 to 10 days without interruption of >24 to 30 hours is needed in the blood to ensure killing of T. pallidum in early infection [8]. A single 2.4 million unit dose of penicillin G benzathine maintains this serum concentration for about three weeks [9]. Increasing the dose does not clear treponemes more quickly [10]. In addition, no resistance has been reported despite several decades of penicillin G use. However, sensitivity testing is not typically performed because the organism cannot be readily grown in the laboratory.

The use of single-dose treatment of early syphilis was supported in a systematic review, which included data from two large randomized clinical trials evaluating the efficacy of a single dose of 2.4 million units of IM penicillin G benzathine for the treatment of primary and secondary syphilis [2,11,12]. Clinical cure rates were 90 to 100 percent for both HIV-uninfected and HIV-infected persons. In addition, data from the 1950s suggested that long-acting depot penicillin therapy for early syphilis prevented subsequent development of late syphilis, including neurosyphilis [13,14]. Several studies have evaluated "enhanced" therapy with additional doses of penicillin G benzathine and found no additional benefit [15-17].

Alternative regimens for early syphilis — Alternative regimens are typically administered to patients who are unable to take penicillin. However, they may also be needed when penicillin G benzathine is unavailable (table 1) [6].

We prefer doxycycline as our first-line alternative agent in nonpregnant adults, even though it requires multiple doses. Such patients with early syphilis may be treated with 14 days of doxycycline (100 mg PO twice daily). Tetracycline (500 mg PO four times daily) can also be used, but few patients are able to adhere to this challenging regimen. Data from small, retrospective studies indicate serologic response rates of 83 to 100 percent when patients were treated with these agents [18-24].

For patients requiring an alternative regimen (such as when penicillin G benzathine is not available) who are not allergic to penicillin, oral amoxicillin with probenecid can be used (amoxicillin 3 g plus probenecid 500 mg orally, both given twice daily for 14 days). However, this regimen requires prolonged oral dosing in addition to probenecid. This regimen was evaluated in Japan (where penicillin G benzathine is not available) in a retrospective observational study of 286 HIV-infected persons presenting with all stages of syphilis [25]. The treatment duration was 14 to 30 days, and successful treatment was defined as at least a fourfold decline in nontreponemal titer. Approximately 95 percent of patients with early syphilis were successfully treated with this regimen.

Ceftriaxone can also be used to treat early syphilis [26,27]; however, some patients who are allergic to penicillin may also be allergic to ceftriaxone. Given the limited clinical data with this regimen [28], the optimal dose and duration of treatment have not been defined. Guidelines recommend 1 to 2 grams (IM or intravenously [IV]) daily for 10 to 14 days [1]. An additional discussion of the use of ceftriaxone is found above. (See 'Patients who are allergic to penicillin' above.)

A single 2-gram dose of azithromycin is another alternative, although it is generally not recommended unless no other alternative options are available. Azithromycin was found to be equivalent to penicillin G benzathine for the treatment of early syphilis in two randomized trials [11,29,30]; however, its use is greatly limited due to the rapid emergence of macrolide resistance in T. pallidum associated with treatment failure [29,31-33].

TREATMENT OF LATE SYPHILIS — Late syphilis includes tertiary syphilis and late latent syphilis, and such patients require a longer duration of treatment compared with those who have early syphilis. Patients with neurologic manifestations should be treated for neurosyphilis. (See 'Treatment of neurosyphilis' below.)

●Tertiary – Tertiary syphilis refers to patients with late syphilis who have symptomatic manifestations involving the cardiovascular system or gummatous diseases (usually of the skin and subcutaneous tissues). (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Late syphilis'.)

●Late latent – Latent syphilis refers to the period when a patient is infected with T. pallidum, as demonstrated by serologic testing, but has no symptoms. Late latent syphilis by definition occurs more than one year after initial infection. If the timing of an infection is not known, late latent syphilis is presumed [34]. Transmission is unlikely to occur in this stage of disease. (See "Syphilis: Screening and diagnostic testing", section on 'Latent syphilis' and "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Latent syphilis (asymptomatic)'.)

Preferred regimen for late syphilis — Penicillin G benzathine (2.4 million units intramuscularly [IM] once weekly for three weeks) is standard therapy for tertiary and late latent syphilis as it provides adequate and persistent serum levels of penicillin (table 1) [1,7,13,14]. While it has the advantage of not requiring daily patient adherence, it does require that the patient follow up consistently over the entire span of treatment to receive the full course of therapy. If a patient misses a dose, and if more than 14 days have elapsed since the prior dose, the course should be reinitiated [35].

●Tertiary syphilis – Patients with gummatous or cardiovascular infection should have a cerebrospinal fluid examination prior to initiation of therapy to assess for neurosyphilis. The management of neurosyphilis is described below. (See 'Treatment of neurosyphilis' below.)

If neurosyphilis is not present, we administer penicillin G benzathine (2.4 million units IM) once a week for three weeks [1]. Cutaneous gummas usually heal rapidly after penicillin therapy with little scarring. For those with cardiovascular disease, antibiotic therapy does not reverse the clinical manifestations of syphilis, but it may halt progression of disease.

Although we do not advocate for intravenous (IV) penicillin in the absence of neurosyphilis, some experts recommend using the same treatment regimen for cardiovascular syphilis as for neurosyphilis [1]. In addition, some experts recommend the administration of 40 to 60 mg of prednisolone daily for three days beginning 24 hours before treatment for any form of cardiovascular syphilis [36]. However, there are no data supporting the use of IV penicillin or glucocorticoids for patients with cardiovascular manifestations.

●Late latent syphilis – Patients with late latent syphilis should be treated with three doses of penicillin G benzathine (2.4 million units IM) once a week for three weeks (table 1) [1].

Alternative regimens for late syphilis — For patients without neurosyphilis who are allergic to penicillin, we test for penicillin allergy and then desensitize if testing is positive. If desensitization is not possible, we generally use doxycycline or ceftriaxone (if the patient can be safely treated with other beta-lactam drugs). (See "Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics".)

●For patients with gummatous or cardiovascular infection, we generally prefer doxycycline (100 mg PO twice daily for 28 days) if adherence to treatment seems likely. There have been no studies evaluating the use of extended released doxycycline 200 mg once daily for the treatment of syphilis. For patients whose adherence seems questionable, we administer ceftriaxone (2 g IV or IM daily for 10 to 14 days). (See 'Patients who are allergic to penicillin' above.)

●For those with late latent syphilis, doxycycline 100 mg PO twice daily for 28 days should be administered [1].

●We avoid azithromycin given concerns for resistance and subsequent treatment failure.

There are very limited data on the efficacy of these regimens in late syphilis, and therefore, we closely monitor the response to therapy [37,38]. (See 'Patient monitoring' below.)

TREATMENT OF NEUROSYPHILIS — Neurosyphilis can occur at any time during the course of infection. Patients with early neurosyphilis typically present with ocular disease, cranial nerve dysfunction (especially auditory or facial nerve involvement), or meningitis. Later in disease, the most common forms involve the brain and spinal cord parenchyma (general paresis and tabes dorsalis) (table 1). (See "Neurosyphilis", section on 'Clinical manifestations'.)

Patients with neurosyphilis should generally be treated with intravenous (IV) therapy. The rationale for using IV rather than intramuscular (IM) therapy includes:

●The dose of IM penicillin G benzathine that is administered for other stages of syphilis does not produce measurable cerebrospinal fluid (CSF) levels of the drug [39].

●Several case reports of patients with HIV treated with penicillin G benzathine who subsequently developed symptomatic neurosyphilis have been published; in some instances, viable T. pallidum were demonstrated in CSF after therapy [13,14,40,41].

We also administer IV therapy to patients strongly suspected of having CNS syphilis (eg, compatible clinical syndrome, reactive blood serology, and CSF pleocytosis) even if they have a nonreactive CSF-Venereal Disease Research Laboratory (VDRL) since the CSF-VDRL test may be falsely negative in as many as 70 percent of patients with neurosyphilis. A more detailed discussion of how to diagnose neurosyphilis is found elsewhere. (See "Neurosyphilis".)

Preferred regimens for neurosyphilis — Patients with neurosyphilis should be treated with IV penicillin G (3 to 4 million units IV every four hours, or 18 to 24 million units per day by continuous infusion) for 10 to 14 days (table 1) [1].

For patients with late disease, we generally administer a single dose of penicillin G benzathine (2.4 million units IM) after completion of IV penicillin since the duration of treatment for neurosyphilis is shorter than the regimens used for late syphilis. This approach is based upon the pathophysiology of the organism, the required drug levels needed to eradicate the organism in later stages of disease, and the overall safety of the drug. However, there are no clinical trial data to support any firm recommendations. Some specialists administer three weekly doses of penicillin G benzathine 2.4 million units IM after completion of the neurosyphilis regimen [1]. Although this approach is also reasonable, patient follow-up for the full course of therapy may be challenging. Shortages of the drug may also compromise this approach.

On rare occasion, we treat HIV-uninfected patients with mild neurologic symptoms and a questionable diagnosis of neurosyphilis the same way we treat those with other forms of late syphilis (ie, three weekly doses of penicillin G benzathine 2.4 million units IM). Such patients are typically elderly patients with mild cognitive deficits consistent with early dementia, where the risk and inconvenience of sampling CSF and/or administering IV therapy may exceed the risk of undertreated neurosyphilis. If symptoms are more specific for neurosyphilis, IV penicillin can be given even when CSF sampling cannot be done.

Alternative regimens for neurosyphilis — Patients should generally be desensitized to or rechallenged with penicillin if they present with neurosyphilis so they can receive the standard IV regimen rather than using an alternative regimen (table 1). (See "Penicillin allergy: Immediate reactions" and "Penicillin allergy: Delayed hypersensitivity reactions" and 'Preferred regimens for neurosyphilis' above.)

Alternatives to IV penicillin include:

●Penicillin G procaine (2.4 million units IM once daily) plus probenecid (500 mg orally four times a day) both for 10 to 14 days [1]. Although this combination provides higher serum levels than penicillin G benzathine, CSF levels of penicillin are often are not detectable, and this regimen has not been well studied for the treatment of neurosyphilis [42]. However, data from 150 persons with neurosyphilis treated with either IV penicillin G or IM penicillin G procaine plus probenecid in a nonrandomized study demonstrated comparable proportions of CSF abnormality normalization with both treatments [43]. Most participants in this study had HIV, but HIV status did not impact outcome.

●Ceftriaxone (2 g IV daily for 10 to 14 days) if the patient can be safely treated with other beta-lactam drugs. (See "Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics".)

Doxycycline (200 mg orally twice daily) for 21 days is also an alternative approach, but should be reserved for exceptional circumstances. This regimen has very limited supporting data [44] and is not recommended by the United States Centers for Disease Control and Prevention [34].

PATIENT MONITORING — Patients should be monitored clinically and with laboratory testing to ensure they are responding appropriately to therapy.

Jarisch-Herxheimer reaction — The Jarisch-Herxheimer reaction (JHR) is an acute, self-limited, febrile reaction that usually occurs within the first 24 hours after the patient receives therapy for any spirochetal infection, including syphilis. This reaction occurs in approximately 10 to 35 percent of cases [45]. It is seen most commonly after treatment of early syphilis.

The fever may be accompanied by systemic symptoms, including headache, myalgias, rigors, diaphoresis, hypotension, and worsening of rash if initially present. Uncommon manifestations include meningitis, respiratory distress, renal and/or hepatic dysfunction, mental status changes, stroke, seizures, and uterine contractions in pregnancy [46]. An additional discussion of the JHR in pregnancy is found elsewhere. (See "Syphilis in pregnancy", section on 'Potential complications of treatment: Jarisch-Herxheimer reaction'.)

The mechanism by which this reaction develops is not completely understood. However, it is thought to result from accelerated phagocytosis by polymorphonuclear leukocytes, followed by the release of lipoproteins, cytokines, and immune complexes from killed organisms [45,47,48].

There is no way to prevent this reaction. Patients should be informed of the possible signs and symptoms and advised to contact their clinicians if a severe reaction occurs. Although these symptoms often resolve without intervention within 12 to 24 hours, non-steroidal anti-inflammatory drugs (NSAIDS) or other antipyretics can be used if symptoms arise and they may reduce the severity of symptoms and the duration of the reaction.

Clinical assessment — Patients with early syphilis should be assessed clinically for resolution of symptoms (eg, rash, ulcer). However, for patients with late stage cardiovascular or noncutaneous gummatous disease, a significant change in symptoms is unlikely. For individuals with symptomatic neurosyphilis, serial neurological examinations should be performed every six months.

Serologic testing — Nontreponemal (rapid plasma reagin [RPR] or Venereal Disease Research Laboratory) titers should be monitored after treatment. The frequency of serologic monitoring is described below. (See 'How often to monitor' below.)

Since T. pallidum cannot be cultured in the laboratory, the success of treatment must be inferred through this indirect measure. Although definitive criteria for cure or failure have not been established, the United States Centers for Disease Control and Prevention has suggested definitions to assess the patient's response to treatment [1]. A description of the types of serologic tests used to diagnose and monitor syphilis is found elsewhere. (See "Syphilis: Screening and diagnostic testing", section on 'Serologic tests'.)

Adequate response — A fourfold decline in the nontreponemal titer, equivalent to a change of two dilutions (eg, from 1:16 to 1:4 or from 1:32 to 1:8), is considered to be an acceptable response to syphilis therapy. Over time, most patients successfully treated for syphilis experience seroreversion; however, some remain serofast. In a systematic review that included data from 20 studies, a fourfold or greater decline in nontreponemal titers was associated with younger age, higher baseline nontreponemal titers, and earlier syphilis stage [49].

Seroreversion — The loss of antibodies over time (seroreversion) in a patient who has been successfully treated for syphilis is considered to be consistent with clinical cure. The majority of patients who are treated for early syphilis will experience seroreversion over time. Although seroreversion is typically seen with nontreponemal antibodies, seroreversion of treponemal tests has also been reported, with rates as high as 24 percent (particularly in patients treated early during primary syphilis) [50,51]. In the rare instance in which treatment is initiated prior to any detectable serologic response (eg, primary syphilis diagnosed clinically or by direct spirochete detection), serologic testing may remain nonreactive.

Serofast state — Patients who have had an adequate (≥fourfold) decline in titers, but whose nontreponemal titers do not serorevert or continue to fall after 24 months of monitoring, are considered serofast. The serofast state is seen in approximately 15 to 20 percent of patients with early syphilis and has been reported to be as high as 35 percent in patients with late latent syphilis [52-54]. Generally the nontreponemal titer stabilizes at a low level (eg, a titer of <1:8), but higher serofast titers are occasionally seen, particularly in HIV-infected patients. Individuals who are serofast should be tested for HIV infection, since the serofast state can be the result of immunodysregulation of antibody production [1].

Treatment failure — Persons with syphilis are considered to have treatment failure if nontreponemal titers do not decline fourfold or greater or if there is a documented fourfold increase after initial decline. Treatment failure should be distinguished from reinfection. (See 'Management of treatment failure' below.)

How often to monitor — A nontreponemal titer should be obtained just before initiating therapy (ideally, on the first day of treatment) since titers can increase significantly over a few days between diagnosis of syphilis and treatment initiation. The subsequent frequency of monitoring depends upon the stage of disease and presence of HIV coinfection.

●In patients with early syphilis, serologic testing should be performed 6 and 12 months following treatment and at any time if clinical symptoms recur. In general, such patients should experience an adequate response by 12 months. (See 'Adequate response' above.)

●Patients with late syphilis (including late latent syphilis) should undergo follow-up serologic testing at 6, 12, and 24 months, as some patients with late syphilis may not have an adequate response for up to two years following treatment.

●Patients with HIV are typically monitored more frequently. The management of HIV-infected patients with syphilis is discussed elsewhere. (See "Syphilis in patients with HIV".)

Once the nontreponemal titer has become nonreactive (seroreversion), additional testing is not needed unless it is being done based on concerns for a new infection. (See 'Seroreversion' above.)

Patients who have had an adequate response to therapy may still have a detectable nontreponemal titer following treatment. For such patients, we continue to monitor the nontreponemal titer every six months until seroreversion of the nontreponemal test has occurred, or the patient is considered to be serofast (see 'Serofast state' above). After identifying a patient as serofast, we generally repeat nontreponemal tests every six months for one to two years to assess for stability, and then at increasing intervals (eg, annually) to assess for possible late failure or reinfection.

Antibody titers decline at varying rates following treatment, depending upon the stage of infection and the magnitude of the pre-treatment titer. Patients with early syphilis may experience more rapid relative declines in RPR titers than patients with late syphilis. As an example, in a systematic review, serologic response to treatment was typically seen by six months in patients with early syphilis, but generally demonstrated a slower decline (12 to 24 months) in patients with late latent disease [2]. Other factors that may slow the rate at which titers decline following therapy include prior episodes of syphilis, the duration of infection prior to therapy, and the presence of HIV coinfection [37,50,55].

Patients with neurosyphilis — Patients with neurosyphilis should undergo clinical and serologic monitoring at the same frequency as patients without neurosyphilis. In addition, monitoring of cerebrospinal fluid abnormalities may also be warranted. A discussion of monitoring after treatment for neurosyphilis is found elsewhere. (See "Neurosyphilis", section on 'Monitoring'.)

MANAGEMENT OF TREATMENT FAILURE — Persons with syphilis are suspected of treatment failure if nontreponemal titers do not decline fourfold or greater, or if there is a documented fourfold increase after an initial decline. Additional discussions of treatment failure in patients with neurosyphilis and HIV are found elsewhere. (See 'Serologic testing' above and 'How often to monitor' above and "Neurosyphilis", section on 'Monitoring' and "Syphilis in patients with HIV", section on 'Approach to treatment failure'.)

If a patient has not had an adequate response to treatment, it is important to determine if the individual has been reinfected, is experiencing a slow response to treatment, or has failed treatment. Since drug resistance to penicillin has not been described, treatment failure is likely due to poor adherence with the treatment regimen, treatment with an alternative agent, immunocompromised status, or undiagnosed central nervous system disease.

Our approach to patients with possible treatment failure is as follows:

●We first assess the patient to see if there is a history of possible new exposure or clinical evidence of a new infection (eg, chancre, rash). In addition, we repeat testing for HIV.

●If there is no evidence of new infection, we then assess for evidence of potential neurosyphilis. We perform a lumbar puncture (LP) in HIV-uninfected patients with the following:

•Neurologic symptoms

•Signs or symptoms of syphilis that persist or recur

•A fourfold or greater increase in nontreponemal test titers persisting for >2 weeks

•Persons treated for late latent syphilis with an initially high titer (≥1:32) that fails to decline at least fourfold within 12 to 24 months of treatment

If the cerebrospinal fluid (CSF) is abnormal, then the patient needs a treatment course for neurosyphilis. (See 'Treatment of neurosyphilis' above.)

If the CSF is unremarkable, but there continues to be concern for treatment failure, we retreat the patient with another course of therapy. This should be accomplished with a regimen recommended for late syphilis, even if the initial presentation was early syphilis. Such patients who failed an alternative regimen should be reassessed to see if penicillin can be administered. In the case of reported penicillin allergy, testing for true allergy should be pursued, and if present, the patient should undergo desensitization.

After the patient has been retreated, we continue close clinical and serologic follow-up (eg, every six months) and determine the need for additional evaluation and management based upon subsequent changes in nontreponemal titers.

When an alternative regimen has been used because of a reported penicillin allergy and treatment response is inadequate (ie, nontreponemal titers fail to decline fourfold within 12 months of treatment), it is reasonable to test for penicillin allergy and consider treatment with penicillin G benzathine in those whose allergy testing is negative. If treatment with penicillin is not possible, the management plan should be formulated on a case-by-case basis; the primary options are to continue monitoring nontreponemal titers closely (and retreat if the titer increases) or to perform an LP to evaluate for neurosyphilis. An additional discussion of the treatment of patients who are allergic to penicillin is found above. (See 'Patients who are allergic to penicillin' above.)

For patients with neurosyphilis and evidence of treatment failure, retreatment usually requires 14 days of intravenous penicillin G. There is no evidence that longer courses of treatment or use of different antibiotics changes the outcome.

TREATMENT AFTER AN EXPOSURE — There is no vaccine for syphilis. Thus, persons exposed sexually to a partner who has syphilis in any stage should be evaluated clinically and serologically for evidence of infection.

●If the patient has clinical evidence of syphilis, treatment is tailored to the specific manifestation as summarized in the table (table 1) and described in more detail above. (See 'Treatment of early syphilis' above and 'Treatment of neurosyphilis' above.)

●For those who are asymptomatic, we treat empirically for early syphilis if the patient had condomless oral, anal, or vaginal sex with:

•A sex partner who was diagnosed with primary, secondary, or early latent syphilis within the preceding 90 days.

•A sex partner who was diagnosed with late latent syphilis within the preceding 90 days if the partner had a high nontreponemal titer (eg, >1:32). A high serologic titer is often associated with early infection, and the patient may have been misdiagnosed with late disease when in fact infection occurred more recently.

For such patients, baseline serologic testing is performed at the time of presentation, although we do not withhold treatment pending serology results. Serologic testing may be negative in those with incubating or early disease. However, if nontreponemal testing is positive, it should be used to monitor the response to therapy. (See 'Serologic testing' above.)

●For asymptomatic patients who were exposed to a sex partner with syphilis more than 90 days preceding their partner’s diagnosis, we generally determine the need for treatment based upon the results of baseline serologic testing. However, if serologic testing is not readily available, or if follow up is uncertain, we treat empirically. The specific treatment regimen depends upon when the patient was exposed (ie, early versus late latent syphilis). In general, we prefer to treat persons in this setting whose exposure is uncertain since the risk of undertreatment typically exceeds that of overtreatment. (See 'Treatment of early syphilis' above and 'Treatment of late syphilis' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sexually transmitted infections".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Syphilis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Syphilis is an infection caused by the bacterium Treponema pallidum. During the initial phase of infection, the organism disseminates widely, setting the stage for subsequent manifestations. If untreated, syphilis can have a number of significant late manifestations, including cardiovascular, gummatous, and neurologic complications. (See 'Introduction' above.)

●A nontreponemal titer should be obtained just before initiating therapy (ideally, on the first day of treatment) since titers can increase significantly over a few days between diagnosis of syphilis and treatment initiation. (See 'Pre-treatment evaluation' above.)

●Penicillin is the treatment of choice for all stages of syphilis (table 1). For patients who are allergic to penicillin, alternative agents include tetracyclines, ceftriaxone, and azithromycin. However, we only use azithromycin if no other options are available due to concerns of treatment failure associated with macrolide resistance. (See 'General approach to antimicrobial therapy' above.)

●For nonpregnant adults with early syphilis (primary, secondary, and early latent syphilis) without evidence of neurosyphilis, we recommend a single dose of penicillin G benzathine (2.4 million units intramuscularly [IM]) rather than an extended course of penicillin therapy (Grade 2B). For patients who are allergic to penicillin, we suggest doxycycline for 14 days rather than another agent (Grade 2C). (See 'Treatment of early syphilis' above.)

●For patients with tertiary syphilis (gummatous or cardiovascular disease) or late latent syphilis without evidence of neurosyphilis, we suggest IM penicillin G benzathine rather than intravenous (IV) therapy (Grade 2C). An IM injection of 2.4 million units penicillin G benzathine should be given once weekly for three weeks. If a patient misses a dose, and if more than 14 days have elapsed since the prior dose, the course should be reinitiated. (See 'Treatment of late syphilis' above.)

●For patients with neurosyphilis, we recommend IV penicillin G rather than IM therapy (Grade 1B). Penicillin G should be administered as 3 to 4 million units IV every four hours (or 18 to 24 million units per day by continuous infusion) for 10 to 14 days. For patients with late disease, we generally administer a single dose of IM penicillin G benzathine after the IV course has been completed, since the duration of treatment for neurosyphilis is shorter than the regimens used for late syphilis. (See 'Treatment of neurosyphilis' above.)

●Patients should be monitored clinically and with serologic testing after treatment to ensure they are responding appropriately to therapy. A fourfold decline in the nontreponemal titer, equivalent to a change of two dilutions (eg, from 1:16 to 1:4 or from 1:32 to 1:8), is considered to be an acceptable response. Over time, most patients successfully treated for syphilis experience seroreversion; however, some remain serofast. (See 'Clinical assessment' above and 'Serologic testing' above.)

●The frequency of serologic monitoring depends upon the stage of disease and presence of HIV coinfection (see 'How often to monitor' above):

•In HIV-uninfected patients with early syphilis, serologic testing should be performed 6 and 12 months following treatment and at any time if clinical symptoms recur. In general, such patients should experience an adequate response by 12 months.

•HIV-uninfected patients with late syphilis should undergo follow-up serologic testing at 6, 12, and 24 months, as some patients with late syphilis may not have an adequate response for up to two years following treatment.

•Patients with HIV are typically monitored more frequently. This is discussed in a separate topic review. (See "Syphilis in patients with HIV".)

●Patients with neurosyphilis should undergo clinical and serologic monitoring at the same frequency as patients without neurosyphilis. Monitoring of cerebrospinal fluid abnormalities may also be warranted. (See "Neurosyphilis", section on 'Monitoring'.)

●Persons with syphilis are suspected of treatment failure if nontreponemal titers do not decline fourfold or greater, or if there is a documented fourfold increase after an initial decline. If a patient has not had an adequate response to treatment, it is important to determine if the individual has been reinfected, is experiencing a slow response to treatment, or has failed treatment. Since drug resistance to penicillin has not been described, treatment failure is likely due to poor adherence with the treatment regimen, treatment with an alternative agent, immunocompromised status, or undiagnosed central nervous system disease. (See 'Management of treatment failure' above.)

●Persons exposed sexually to a partner who has syphilis should be evaluated clinically and serologically for evidence of infection. The need for empiric treatment depends primarily upon when the exposure occurred and the stage of their partner’s infection. (See 'Treatment after an exposure' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge P Frederick Sparling, MD, who contributed to an earlier version of this topic review.