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 in patients with HIV".)
●(See "Syphilis in pregnancy".)
GENERAL APPROACH TO ANTIMICROBIAL THERAPY — Our approach to the treatment of nonpregnant adults with syphilis are consistent with the 2021 guidelines from the United States Centers for Disease Control and Prevention (CDC) . 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: Management and outcome" and "Syphilis in pregnancy", section on 'Maternal treatment'.)
Pretreatment 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. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Primary syphilis (chancre)' and 'Treatment of early syphilis' below and 'Treatment after an exposure' below.)
A nontreponemal serologic test should be obtained just before initiating therapy (ideally on the first day of treatment) to establish the pretreatment 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 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 . 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 2). As an example, long-acting penicillin G benzathine given intramuscularly (IM; 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 neuro/ocular/otic syphilis' 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 IM route since IV administration has been associated with cardiopulmonary arrest and death . 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 . 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 2) . 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 "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
Who should be desensitized to penicillin — Certain patients should be tested for penicillin allergy and desensitized to or rechallenged with penicillin rather than using an alternative agent. This includes those who are pregnant; those with ocular, otic, or neurosyphilis; those with cardiovascular manifestations of late syphilis; and/or those with 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 be evaluated by an allergist 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".)
Alternative agents — For some patients (eg, nonpregnant person with early syphilis), it is reasonable to use an alternative agent rather than attempt desensitization or rechallenge with penicillin. Detailed information on regimen selection in specific patient populations is discussed below. (See 'Treatment based on disease manifestation' below.)
Alternative antimicrobial agents include tetracyclines (eg, doxycycline) and cephalosporins (table 2), although some patients who are allergic to penicillin may also be allergic to cephalosporins. (See "Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics".)
In general, we prefer doxycycline rather than other alternative agents. If a cephalosporin is used, most of the experience has been with ceftriaxone ; we prefer IV administration rather than IM injections, which are often painful. Oral cefixime has also been evaluated for treatment of early syphilis; however, data are limited. In an unblinded randomized trial of 58 patients with early syphilis in which patients received cefixime (400 mg orally twice daily) or penicillin G benzathine (2.4 million units IM), a ≥4-fold decrease in the rapid plasma reagin (RPR) titer was achieved in 56 and 81 percent of those who received cefixime or penicillin, respectively .
A single 2 g dose of azithromycin had previously been considered an alternative agent for early syphilis since it was found to be equivalent to penicillin G benzathine in clinical trials [8-10]. However, it is now recommended only if other agents are not available, given reports of treatment failures associated with macrolide resistance [1,9,11-13].
All patients who receive an alternative agent should be closely monitored after treatment. (See 'Patient monitoring' below.)
TREATMENT BASED ON DISEASE MANIFESTATION — For most patients, the treatment of syphilis depends upon the specific disease manifestation. Special considerations for the treatment of syphilis during pregnancy and in patients with HIV infection are presented separately. (See "Syphilis in pregnancy" and "Syphilis in patients with HIV".)
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. A diagnosis of early syphilis implies that T. pallidum infection occurred within the previous year.
Early syphilis refers to primary, secondary, and early latent syphilis.
●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'.)
If the timing of an infection is not known, a person is presumed to have late latent syphilis. The treatment of late latent syphilis is discussed below. (See 'Late latent syphilis' below.)
Preferred regimens for early syphilis — Patients with neurologic, ocular, or otic manifestations of early syphilis require intravenous (IV) therapy. The management of these conditions are discussed below. (See 'Treatment of neuro/ocular/otic syphilis' below.)
For others, a single dose of penicillin G benzathine (2.4 million units intramuscularly [IM]) is standard therapy for primary, secondary, and early latent syphilis (table 2) [1,14]. Long-acting penicillin G benzathine should only be given via the IM route . Appropriate treatment for early syphilis requires persistent concentrations of penicillin to be sustained over a relatively long period of time, a requirement that is achieved in most patients with a single dose of penicillin G benzathine. A single 2.4 million unit dose of penicillin G benzathine maintains this serum concentration for about three weeks . Increasing the dose does not clear treponemes more quickly .
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 [2,8,17]. Clinical cure rates were 90 to 100 percent for both persons uninfected with HIV and persons infected with HIV. In addition, data from the 1950s suggested that long-acting depot penicillin therapy for early syphilis prevented subsequent development of late syphilis, including neurosyphilis [18,19]. Several studies have evaluated "enhanced" therapy with additional doses of penicillin G benzathine and found no additional benefit [20-24].
Alternative regimens for early syphilis — Alternative regimens for early syphilis are generally avoided in patients with neurologic, ocular, or otic manifestations and during pregnancy. The management of these patients is discussed separately. (See 'Treatment of neuro/ocular/otic syphilis' below and "Syphilis in pregnancy".)
For other patients, it is reasonable to use an alternative regimen in those with a penicillin allergy. Alternative regimens may also be needed when penicillin G benzathine is unavailable . In general, we prefer doxycycline (100 mg orally twice daily for 14 days) as our first-line alternative agent in nonpregnant adults (table 2). Tetracycline (500 mg orally four times daily for 14 days) can also be used, but adherence to this regimen may be challenging. Data from small, retrospective studies indicate serologic response rates of 83 to 100 percent when patients were treated with these agents [25-31]. Minocycline may also be used for treatment of early syphilis; however, in a retrospective study evaluating the use of minocycline, a 28-day course was administered, which is longer than the 14-day course used with doxycycline .
Ceftriaxone can also be used to treat early syphilis [33-35]; however, some patients who are allergic to penicillin may also be allergic to ceftriaxone. The regimen frequently studied and recommended by guidelines is 1 g (IM or IV) daily for 10 to 14 days . Additional information on the use of cephalosporins is discussed above. (See 'Patients who are allergic to penicillin' above.)
For patients who are not allergic to penicillin, oral amoxicillin with probenecid is an option. Oral amoxicillin (3 g) plus probenecid (500 mg) are both given twice daily for 14 days. This regimen was evaluated in Japan (where penicillin G benzathine is not available) in a retrospective observational study of 286 persons with HIV who presented with all stages of syphilis . 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.
Treatment of late syphilis — Late syphilis includes late latent syphilis and tertiary syphilis. For most patients, penicillin G benzathine (2.4 million units IM once weekly for three weeks) provides adequate and persistent serum levels of penicillin (table 2) [1,14,18,19]. However, patients with evidence of neurologic, otic, or ocular syphilis should be treated with IV therapy, as discussed below. (See 'Treatment of neuro/ocular/otic syphilis' below.)
There are limited data evaluating treatment regimens for late syphilis. Compared with early syphilis, longer duration of treatment should generally be administered since organisms might be dividing more slowly .
Late latent syphilis — 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, is present for more than one year after initial infection. If the timing of an infection is not known, a person is presumed to have late latent syphilis (versus early latent syphilis, as discussed above) . Transmission is unlikely to occur in this stage of disease; thus, the goal of therapy is to prevent complications of untreated syphilis. (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)'.)
Patients with late latent syphilis should be treated with 2.4 million units of IM penicillin G benzathine once a week for three weeks (7.2 million units total) (table 2) . While this regimen 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 dose is delayed and more than 14 days have elapsed since the prior dose, the course should be reinitiated .
For nonpregnant patients with late latent syphilis who are penicillin allergic, doxycycline (100 mg orally twice daily) can be administered for 28 days . Tetracycline or ceftriaxone are other alternatives (table 2). However, there are very limited data on the efficacy of these alternative regimens for treatment of late syphilis; thus, we closely monitor the response to therapy [39,40]. (See 'Patient monitoring' below.)
Tertiary syphilis — 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'.)
Patients with gummatous or cardiovascular infection should have a cerebrospinal fluid (CSF) examination prior to initiation of therapy to assess for neurosyphilis. The management of neurosyphilis is described below. (See 'Treatment of neuro/ocular/otic syphilis' below.)
●Preferred antimicrobial regimen – If neurosyphilis is not present, we administer penicillin G benzathine (2.4 million units IM) once a week for three weeks . Cutaneous gummas usually heal rapidly after penicillin therapy although with some scarring [41-43]. For those with cardiovascular disease, antibiotic therapy does not reverse the clinical manifestations of syphilis, but it may halt progression of disease. Similar to the treatment of late latent syphilis, if a patient misses a dose, and if more than 14 days have elapsed since the prior dose, the course should be reinitiated . This approach is consistent with guideline recommendations from the United States Centers for Disease Control and Prevention (CDC) .
●Alternative antimicrobial regimens – For penicillin-allergic patients with tertiary syphilis, we desensitize or rechallenge with penicillin, if possible. More detailed discussions of how to evaluate patients for penicillin allergy are presented elsewhere. (See 'Who should be desensitized to penicillin' above and "Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics".)
If desensitization is not possible, treatment options include doxycycline (100 mg orally twice daily for 28 days) or ceftriaxone (2 g IV or IM daily for 10 to 14 days) if the patient can be safely treated with other beta-lactam drugs. There are no data to support one approach over the other; however, we generally prefer ceftriaxone to ensure the full duration of treatment is completed.
Treatment of neuro/ocular/otic syphilis — Neurosyphilis, ocular syphilis, and otic syphilis can occur at any time during the course of infection (table 2). (See "Neurosyphilis", section on 'Clinical manifestations' and "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Clinical manifestations'.)
The treatment of ocular and otic syphilis is the same as that for neurosyphilis, even if there is no evidence of central nervous system involvement on CSF testing. Indications for CSF testing are discussed separately. (See "Syphilis: Screening and diagnostic testing", section on 'Patients with ocular/otic symptoms'.)
Long-acting IM penicillin G benzathine does not penetrate "protected sites" that sequester T. pallidum (eg, ocular structures, the central nervous system). (See 'Penicillin as the treatment of choice' above.)
Preferred regimens — Patients with ocular, otic, or 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 2) . The dose of IM penicillin G benzathine that is used for treatment of other stages of syphilis does not produce measurable CSF levels of the drug . In addition, there are several case reports of patients with HIV who were treated with penicillin G benzathine and subsequently developed symptomatic neurosyphilis; in some of these cases, viable T. pallidum were demonstrated in CSF after IM therapy [18,19,45,46].
For patients with late disease (ie, infection felt to be present for more than a year, such as general paresis or tabes dorsalis), we typically suggest a single dose of penicillin G benzathine (2.4 million units IM) be administered after the course of IV penicillin is completed since the duration of treatment for neurosyphilis is shorter than the regimens used for other forms of 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, some patients and providers may prefer to defer this additional dose since the benefit is theoretical, and there are no data to support any firm recommendations .
●Patients with penicillin allergy – Patients with neurosyphilis and a penicillin allergy should be evaluated to see if they can be desensitized to or rechallenged with penicillin. This way they can receive the standard IV regimen rather than using an alternative regimen (table 2). The approach to patients with a penicillin allergy is discussed elsewhere. (See "Penicillin allergy: Immediate reactions" and "Penicillin allergy: Delayed hypersensitivity reactions" and 'Preferred regimens' above.)
If desensitization or rechallenge with penicillin is not feasible, ceftriaxone (2 g IV daily for 10 to 14 days) is a reasonable alternative for those who are able to tolerate cephalosporins. The United States CDC states the dose of ceftriaxone for treatment of neurosyphilis is 1 to 2 g ; however, we prefer the 2 g dose since most of the studies evaluating ceftriaxone have used the 2 g dose.
Although there is much less experience with ceftriaxone compared with penicillin, observational data support the use of ceftriaxone for treatment of ocular, otic, or early neurosyphilis [47,48]. In one report of 365 patients with neurosyphilis (42 in the ceftriaxone group and 166 in the penicillin group), patients who received ceftriaxone were more likely to have a clinical response to treatment (98 versus 76 percent, respectively; crude odds ratio 13.02, 95% CI 1.73-97.66) . In this trial, a similar number of patients in each group achieved an appropriate serological response at six months (88 versus 82 percent for ceftriaxone and penicillin, respectively).
On rare occasions a patient may not be able to be desensitized to penicillin or take a cephalosporin (eg, patients with Stevens-Johnson syndrome). In this setting, doxycycline (200 mg orally twice daily) for 21 to 28 days can be used. However, this regimen should be reserved for these exceptional circumstances since this regimen has very limited supporting data .
●Alternative to IV therapy – There are no well-established alternatives to IV therapy for treatment of neurosyphilis. Previously, penicillin G procaine (2.4 million units IM once daily) plus probenecid (500 mg orally four times a day) was an option , but penicillin G procaine has been discontinued worldwide.
When the diagnosis of neurosyphilis is unclear — In certain settings the diagnosis of neurosyphilis cannot be confirmed. When this occurs, the approach to treatment must be individualized and depends upon the clinical suspicion for neurosyphilis.
As an example, we would treat a patient for neurosyphilis with IV penicillin G if they had a compatible clinical syndrome, risk factors for syphilis, reactive blood serology for syphilis, and a CSF pleocytosis, even if the CSF-Venereal Disease Research Laboratory (VDRL) was not reactive. The CSF-VDRL test may be falsely negative in as many as 70 percent of patients with neurosyphilis. (See "Neurosyphilis", section on 'Diagnosis'.)
By contrast, if there is a low suspicion for neurosyphilis, we may treat for late latent syphilis (ie, three weekly doses of penicillin G benzathine 2.4 million units IM), rather than administer IV treatment. This situation typically occurs in older patients with mild cognitive deficits consistent with early dementia for whom 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.
MANAGEMENT OF PREGNANT PERSONS — Pregnant persons with syphilis should be treated with penicillin. The formulation and dose depend upon the disease manifestation. Those who are allergic to penicillin should be managed in conjunction with an allergist so they can be desensitized or rechallenged and treated with penicillin G. Syphilis in pregnancy is discussed in detail elsewhere. (See "Syphilis in pregnancy".)
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 [24,51]. 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 . 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 [51,53,54].
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, nonsteroidal 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.
Serologic testing — Nontreponemal (rapid plasma reagin [RPR] or Venereal Disease Research Laboratory [VDRL]) titers should be monitored after treatment. 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 (CDC) has suggested definitions to assess the patient's response to treatment . 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'.)
Assessing response — A fourfold decline in the nontreponemal titer, equivalent to a change of two dilutions (eg, from 1:32 to 1:8 or from 1:16 to 1:4), is considered an adequate serologic response. Over time, most patients successfully treated for syphilis experience seroreversion; however, some do not.
●Seroreversion – The loss of nontreponemal 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. Once the nontreponemal titer has become nonreactive, additional testing is not needed unless it is being done because of concerns for a new infection. (See 'Patient monitoring' above.)
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) [55,56].
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.
●Fourfold or greater decline in titer – 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 an adequate response to syphilis therapy. The duration of time it takes to achieve this is depends on the stage of disease, as discussed above. (See 'How often to monitor' below.)
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 .
Some patients may have nontreponemal titers that decline ≥4-fold but do not serorevert or continue to fall after 12 to 24 months of monitoring; this had previously been referred to as being serofast. As long as the titers do not start to increase, retreatment is usually not needed. The frequency with which we repeat testing depends on the ongoing risk for infection. As an example, if the person is at risk for reinfection, we would check titers every three months at first, and then at increasing intervals (eg, every six months and then annually) to assess for possible late failure or reinfection.
In one study, fewer than half of patients who were treated for syphilis became seronegative within five years . Nontreponemal titers often stabilize at a low level (eg, a titer of <1:8) after an initial fourfold or greater decline. However, higher titers are occasionally seen, particularly in persons with HIV due to immunodysregulation of antibody production . Individuals with persistently high titers should be tested for HIV infection if testing has not been recently performed. (See "Screening and diagnostic testing for HIV infection".)
●Less than fourfold decline in titer – Most patients who have less than a fourfold decline in titers are considered to have treatment failure or reinfection, as discussed below. However, some patients (eg, those with antibody titers <1:8) may be less likely to have a fourfold decline than those with higher titers. The evaluation of patients with possible treatment failure is discussed below. (See 'Persons with an inadequate response to treatment' below.)
How often to monitor — Whenever possible, a nontreponemal titer should be obtained just before initiating therapy (ideally, on the first day of treatment) since titers can change significantly in the time between diagnosis of syphilis and treatment initiation. In a study of 766 persons treated for syphilis in Australia, in which the median time between diagnosis and treatment was six days, 113 patients (14.8 percent) had a >4-fold change in RPR titer during the interval between diagnosis and treatment .
Follow-up testing depends upon the stage of infection:
●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 'Assessing 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 patients infected with HIV with syphilis is discussed elsewhere. (See "Syphilis in patients with HIV".)
Antibody titers decline at varying rates following treatment, depending upon the stage of infection and the magnitude of the pretreatment 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 . 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 [39,55,60].
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 (CSF) abnormalities may also be warranted. A discussion of monitoring after treatment for neurosyphilis is found elsewhere. (See "Neurosyphilis".)
PERSONS WITH AN INADEQUATE RESPONSE TO TREATMENT — If a patient has not had an adequate response to treatment (eg, persistent signs or symptoms, a documented fourfold increase in nontreponemal titers for >2 weeks after an initial decline, <4-fold decrease in nontreponemal titer), 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.
Patients without HIV
Evaluation and management — Our approach to patients without HIV who have had an inadequate response to therapy 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 those who present with any of the following signs or symptoms:
-Neurologic symptoms (eg, cranial nerve dysfunction).
-Signs or symptoms of syphilis that persist or recur.
-A fourfold or greater increase in nontreponemal test titers persisting for >2 weeks in patients with no sexual exposure during the previous year.
-Persons treated for late latent syphilis with an initially high titer (≥1:32) that fails to decline at least four-fold within 24 months of treatment. If the cerebrospinal fluid (CSF) is abnormal, then the patient needs a treatment course for neurosyphilis. (See 'Treatment of neuro/ocular/otic syphilis' 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.
●If there is no evidence of new infection and an LP is not indicated, patients can be treated with weekly injections of benzathine penicillin G 2.4 million units intramuscularly (IM) for three weeks. However, for some patients (eg, those with a baseline titer <1:8), clinical assessment and serologic testing every six months is a reasonable option for those who are considered likely to be adherent with follow up visits. If the titer remains stable, the time interval between assessments can be increased over time.
If 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.
Additional considerations — 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 (IV) penicillin G. There is no evidence that longer courses of treatment or use of different antibiotics change the outcome.
Patients with HIV — The approach to patients with HIV and possible treatment failure is similar to those without HIV. However, if there is no evidence for new infection, an LP is indicated for most patients. This is discussed in greater detail in a separate topic review. (See "Syphilis in patients with HIV".)
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 2) and described in more detail above. (See 'Treatment of early syphilis' above and 'Treatment of neuro/ocular/otic syphilis' 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".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
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
●Natural history – Syphilis is caused by the bacterium Treponema pallidum. If untreated, syphilis can have a number of significant late manifestations including cardiovascular, gummatous, and neurologic complications. (See 'Introduction' above.)
•Stage and classification of disease – Recommended treatments are specific to stage and location of disease. These are defined in the table (table 2).
•Serology – A nontreponemal titer (eg, rapid plasma reagin [RPR], Venereal Disease Research Laboratory [VDRL]) should be obtained just before initiating therapy (ideally, on the first day of treatment). Titers can increase between diagnosis and treatment initiation, even in a few days. (See 'Pretreatment evaluation' above.)
Nontreponemal titers are used to monitor response to treatment. Although treponemal titers are more specific, they are not used for monitoring since they are reported as qualitative rather than quantitative and may remain positive for life. (See "Syphilis: Screening and diagnostic testing".)
●Treatment of early syphilis – For adults with early syphilis (primary, secondary, and early latent syphilis) without neurosyphilis, we suggest a single dose of penicillin G benzathine (2.4 million units intramuscularly [IM]) rather than an extended course of penicillin therapy (Grade 2B). Clinical cure rates are high (>90 percent) with this single-dose regimen.
●Late syphilis – For patients with late latent syphilis or tertiary syphilis (gummatous or cardiovascular disease) without evidence of neurosyphilis, we suggest IM penicillin G benzathine 2.4 million units once weekly for three weeks (Grade 2C). This longer duration of treatment is advised for late syphilis since organisms might be dividing more slowly.
If a patient misses a dose, and if more than 14 days have elapsed since the prior dose, the three dose series should be reinitiated. (See 'Treatment of late syphilis' above.)
Alternative regimens for nonpregnant patients are summarized in the table (table 2).
●Treatment of neurologic, ocular, or otic syphilis
•Neurosyphilis – For patients with neurosyphilis, we recommend treatment with IV penicillin G (Grade 1B). IV therapy is required to achieve adequate levels in the cerebrospinal fluid (CSF). (See 'Preferred regimens' above.)
For patients with clinical manifestations of late disease (eg, general paresis or tabes dorsalis), we suggest an additional single dose of IM penicillin G benzathine after the IV course (Grade 2C). Without this IM dose, the duration of treatment for neurosyphilis is shorter than the regimens used for other forms of late syphilis and may be insufficient. However, data supporting this approach are lacking, and it is reasonable for a patient or provider to defer this additional dose.
•Ocular or otic syphilis – We also suggest IV penicillin for those with ocular or otic disease, even if CSF testing is normal (Grade 2C). IM penicillin G benzathine may not penetrate these "protected sites" that sequester T. pallidum. (See 'Preferred regimens' above.)
●Treatment of patients allergic to penicillin – For selected patients with a reported penicillin allergy, we suggest allergy testing followed by desensitization or rechallenge with penicillin (Grade 2C). This includes pregnant patients; those with ocular, otic, or neurosyphilis; those with cardiovascular manifestations of late syphilis; and/or those with treatment failure. (See 'Patients who are allergic to penicillin' above.)
●Assessing treatment response – For patients without HIV the frequency of serologic testing depends upon the stage of disease (see 'Serologic testing' above):
•Early syphilis – Six and 12 months following treatment; an adequate response is expected by 12 months.
•Late syphilis – Six, 12, and 24 months following treatment; it may take up to two years to achieve an adequate response in patients with late syphilis.
Patients with HIV are typically monitored more frequently. (See "Syphilis in patients with HIV".)
Patients with neurosyphilis and persistent symptoms may also warrant CSF monitoring. (See 'Patients with neurosyphilis' above.)
A fourfold decline in the nontreponemal titer, equivalent to a change of two dilutions (eg, from 1:32 to 1:8 or from 1:16 to 1:4), is considered an adequate serologic response. Over time, most but not all patients successfully treated for syphilis serorevert (nonreactive nontreponemal test). In contrast, treponemal titers may remain positive for life even after successful treatment. (See 'Clinical assessment' above and 'Serologic testing' above.)
If a patient has not had an adequate response to therapy, this may indicate treatment failure, reinfection, or a slow response. Such patients require further evaluation, and possibly additional treatment. 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 'Persons with an inadequate response to treatment' above.)
●Management of other STIs and sexual partners – We evaluate all patients with syphilis for other sexually transmitted infections (STIs) (table 1).
Sexual partners should be evaluated clinically and serologically for evidence of infection. The need for empiric treatment depends upon when the exposure occurred and the stage of their partner's infection. (See 'Treatment after an exposure' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges P Frederick Sparling, MD, who contributed to an earlier version of this topic review.
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