Sexual Transmitted Diseases
Genital Ulcers

Specific tests for the evaluation of genital ulcers include the following:

• Darkfield examination or direct immunofluorescence test for Treponema pallidum,
• Culture or antigen test for HSV, and
• Culture for Haemophilus ducreyi.
• Polymerase chain reaction (PCR) tests for these organisms might become available commercially.

A health-care provider often must treat a patient before test results are available. In such a circumstance, the clinician should treat for the diagnosis considered most likely. If the diagnosis is unclear, many experts recommend treatment for syphilis, or for both syphilis and chancroid if the patient resides in a community in which H. ducreyi is a significant cause of genital ulcers, especially when diagnostic capabilities for chancroid or syphilis are not ideal. However, even after complete diagnostic evaluation, at least 25% of patients who have genital ulcers have no laboratory-confirmed diagnosis.

Chancroid
A definitive diagnosis of chancroid requires identification of H. ducreyi on special culture media that are not widely available from commercial sources; even using these media, sensitivity is less than or equal to 80%.
A probable diagnosis, for both clinical and surveillance purposes, may be made if the following criteria are met:

• the patient has one or more painful genital ulcers;
• the patient has no evidence of T. pallidum infection by darkfield examination of ulcer exudate or by a serologic test for syphilis performed at least 7 days after onset of ulcers; and
• the clinical presentation, appearance of genital ulcers, and regional lymphadenopathy, if present, are typical for chancroid and a test for HSV is negative. The combination of a painful ulcer and tender inguinal adenopathy, which occurs among one third of patients, suggests a diagnosis of chancroid; when accompanied by suppurative inguinal adenopathy, these signs are almost pathognomonic. PCR testing for H. ducreyi might become available soon.
  

Treatment of Chancroid

• Azithromycin 1 g orally in a single dose,  or
• Ceftriaxone 250 mg intramuscularly (IM) in a single dose, or
• Ciprofloxacin 500 mg orally twice a day for 3 days, or
• Erythromycin base 500 mg orally four times a day for 7 days.

NOTE: Ciprofloxacin is contraindicated for pregnant and lactating women and for persons aged less than 18 years.
All four regimens are effective for treatment of chancroid in HIV-infected patients.
Azithromycin and ceftriaxone offer the advantage of single-dose therapy.

Follow-Up
Patients should be reexamined 3-7 days after initiation of therapy. If treatment is successful, ulcers improve symptomatically within 3 days and objectively within 7 days after therapy. If no clinical improvement is evident, the clinician must consider whether

• a) the diagnosis is correct,
• b) the patient is coinfected with
• another STD,
• c) the patient is infected with HIV, d) the treatment was not taken as instructed, or e) the H. ducreyi strain causing the infection is resistant to the prescribed antimicrobial. The time required for complete healing depends on the size of the ulcer; large ulcers may require greater than 2 weeks. In addition, healing is slower for some uncircumcised men who have ulcers under the foreskin. Clinical resolution of fluctuant lymphadenopathy is slower than that of ulcers and may require drainage, even during otherwise successful therapy. Although needle aspiration of buboes is a simpler procedure, incision and drainage of buboes may be preferred because of less need for subsequent drainage procedures.
  

Management of Sex Partners
Sex partners of patients who have chancroid should be examined and treated, regardless of whether symptoms of the disease are present, if they had sexual contact with the patient during the 10 days preceding onset of symptoms in the patient.

HIV-infected patients who have chancroid should be monitored closely. Such patients may require longer courses of therapy than those recommended for HIV-negative patients. Healing may be slower among HIV-infected patients, and treatment failures occur with any regimen.

Genital Herpes Simplex Virus (HSV-2) Infection
First Clinical Episode of Genital Herpes
Management of patients with first clinical episode of genital herpes includes antiviral therapy and counseling regarding the natural history of genital herpes, sexual and perinatal transmission, and methods to reduce such transmission. Five percent to 30% of first-episode cases of genital herpes are caused by HSV-1, but clinical recurrences are much less frequent for HSV-1 than HSV-2 genital infection. Therefore, identification of the type of the infecting strain has prognostic importance and may be useful for counseling purposes.

Recommended Regimens

• Acyclovir 400 mg orally three times a day for 7-10 days,  or
• Acyclovir 200 mg orally five times a day for 7-10 days,  or
• Famciclovir 250 mg orally three times a day for 7-10 days,  or
• Valacyclovir 1 g orally twice a day for 7-10 days.
  
  NOTE: Treatment may be extended if healing is incomplete after 10 days of therapy.
  

Higher dosages of acyclovir (i.e., 400 mg orally five times a day) were used in treatment studies of first-episode herpes proctitis and first-episode oral infection, including stomatitis or pharyngitis. It is unclear whether these forms of mucosal infection require higher doses of acyclovir than used for genital herpes. Valacyclovir and famciclovir probably are also effective for acute HSV proctitis or oral infection, but clinical experience is lacking.

Patients should be advised to abstain from sexual activity when lesions or prodromal symptoms are present and encouraged to inform their sex partners that they have genital herpes. The use of condoms during all sexual exposures with new or uninfected sex partners should be encouraged.

Sexual transmission of HSV can occur during asymptomatic periods. Asymptomatic viral shedding occurs more frequently in patients who have genital HSV-2 infection than HSV-1 infection and in patients who have had genital herpes for less than 12 months. Such patients should be counseled to prevent spread of the infection.

The risk for neonatal infection should be explained to all patients, including men. Childbearing-aged women who have genital herpes should be advised to inform health-care providers who care for them during pregnancy about the HSV infection.

Patients having a first episode of genital herpes should be advised that a) episodic antiviral therapy during recurrent episodes might shorten the duration of lesions and b) suppressive antiviral therapy can ameliorate or prevent recurrent outbreaks.

Recurrent Episodes of HSV Disease

Most patients with first-episode genital HSV-2 infection will have recurrent episodes of genital lesions. Episodic or suppressive antiviral therapy might shorten the duration of lesions or ameliorate recurrences. Because many patients benefit from antiviral therapy, options for treatment should be discussed with all patients.

When treatment is started during the prodrome or within 1 day after onset of lesions, many patients who have recurrent disease benefit from episodic therapy.

If episodic treatment of recurrences is chosen, the patient should be provided with antiviral therapy, or a prescription for the medication, so that treatment can be initiated at the first sign of prodrome or genital lesions.

Daily suppressive therapy reduces the frequency of genital herpes recurrences by greater than or equal to 75% among patients who have frequent recurrences (i.e., six or more recurrences per year). Safety and efficacy have been documented among patients receiving daily therapy with acyclovir for as long as 6 years, and with valacyclovir and famciclovir for 1 year. Suppressive therapy has not been associated with emergence of clinically significant acyclovir resistance among immunocompetent patients. After 1 year of continuous suppressive therapy, discontinuation of therapy should be discussed with the patient to assess the patient's psychological adjustment to genital herpes and rate of recurrent episodes, as the frequency of recurrences decreases over time in many patients. Insufficient experience with famciclovir and valacyclovir prevents recommendation of these drugs for greater than 1 year.

Suppressive treatment with acyclovir reduces but does not eliminate asymptomatic viral shedding. Therefore, the extent to which suppressive therapy may prevent HSV transmission is unknown.

Recommended Regimens for Episodic Recurrent Infection

• Acyclovir 400 mg orally three times a day for 5 days, or
• Acyclovir 200 mg orally five times a day for 5 days,  or
• Acyclovir 800 mg orally twice a day for 5 days,  or
• Famciclovir 125 mg orally twice a day for 5 days,  or
• Valacyclovir 500 mg orally twice a day for 5 days.
  

Recommended Regimens for Daily Suppressive Therapy

• Acyclovir 400 mg orally twice a day, or
• Famciclovir 250 mg orally twice a day, or
• Valacyclovir 250 mg orally twice a day,  or
• Valacyclovir 500 mg orally once a day,  or
• Valacyclovir 1,000 mg orally once a day.
  
  Valacyclovir 500 mg once a day appears less effective than other valacyclovir dosing regimens in patients who have very frequent recurrences (i.e., greater than or equal to 10 episodes per year). Few comparative studies of valacyclovir and famciclovir with acyclovir have been conducted. The results of these studies suggest that valacyclovir and famciclovir are comparable to acyclovir in clinical outcome. However, valacyclovir and famciclovir may provide increased ease in administration, which is an important consideration for prolonged treatment.
  

Rx of Severe Disease
IV therapy should be provided for patients who have severe disease or complications necessitating hospitalization, such as disseminated infection, pneumonitis, hepatitis, or complications of the central nervous system (e.g., meningitis or encephalitis).
Recommended Regimens
Acyclovir 5-10 mg/kg body weight IV every 8 hours for 5-7 days or until clinical resolution is attained.

Management of Sex Partners
The sex partners of patients who have genital herpes are likely to benefit from evaluation and counseling. Symptomatic sex partners should be evaluated and treated in the same manner as patients who have genital lesions. However, most persons who have genital HSV infection do not have a history of typical genital lesions. These persons and their future sex partners may benefit from evaluation and counseling. Thus, even asymptomatic sex partners of patients who have newly diagnosed genital herpes should be questioned concerning histories of typical and atypical genital lesions, and they should be encouraged to examine themselves for lesions in the future and seek medical attention promptly if lesions appear.

Most of the available HSV antibody tests do not accurately discriminate between HSV-1 and HSV-2 antibodies, and their use is not currently recommended.

Sensitive and type-specific serum antibody assays may become commercially available and contribute to future intervention strategies.

Special Considerations

Herpes Simplex Infection in HIV Infection patients:
Immunocompromised patients might have prolonged and/or severe episodes of genital or perianal herpes. Lesions caused by HSV are relatively common among HIV-infected patients and may be severe, painful, and atypical. Intermittent or suppressive therapy with oral antiviral agents is often beneficial.

The dosage of antiviral drugs for HIV-infected patients is controversial, but clinical experience strongly suggests that immunocompromised patients benefit from increased doses of antiviral drugs. Regimens such as acyclovir 400 mg orally three to five times a day, as used for other immunocompromised patients, have been useful. Therapy should be continued until clinical resolution is attained. Famciclovir 500 mg twice a day has been effective in decreasing both the rate of recurrences and the rate of subclinical shedding among HIV-infected patients. In immunocompromised patients, valacyclovir in doses of 8 g per day has been associated with a syndrome resembling either hemolytic uremic syndrome or thrombotic thrombocytopenic purpura. However, in the doses recommended for treatment of genital herpes, valacyclovir, acyclovir, and famciclovir probably are safe for use in  immunocompromised patients.

For severe cases, acyclovir 5 mg/kg IV every 8 hours may be required.

If lesions persist in a patient receiving acyclovir treatment, resistance of the HSV strain to acyclovir should be suspected. Such patients should be managed in

consultation with an expert. For severe cases caused by proven or suspected acyclovir-resistant strains, alternate therapy should be administered. All

acyclovir-resistant strains are resistant to valacyclovir, and most are resistant to famciclovir. Foscarnet, 40 mg/kg body weight IV every 8 hours until clinical

resolution is attained, is often effective for treatment of acyclovir-resistant genital herpes. Topical cidofovir gel 1% applied to the lesions once daily for 5

consecutive days also might be effective.

Pregnancy

The safety of systemic acyclovir and valacyclovir therapy in pregnant women has not been established. Glaxo-Wellcome, Inc., in cooperation with CDC,

maintains a registry to assess the use and effects of acyclovir and valacyclovir during pregnancy. Women who receive acyclovir or valacyclovir during

pregnancy should be reported to this registry; telephone (800) 722-9292, extension 38465.

Current registry findings do not indicate an increased risk for major birth defects after acyclovir treatment (i.e., in comparison with the general population).

These findings provide some assurance in counseling women who have had prenatal exposure to acyclovir. The accumulated case histories represent an

insufficient sample for reaching reliable and definitive conclusions regarding the risks associated with acyclovir treatment during pregnancy. Prenatal exposure

to valacyclovir and famciclovir is too limited to provide useful information on pregnancy outcomes.

The first clinical episode of genital herpes during pregnancy may be treated with oral acyclovir. In the presence of life-threatening maternal HSV infection (e.g.,

disseminated infection, encephalitis, pneumonitis, or hepatitis), acyclovir administered IV is indicated. Investigations of acyclovir use among pregnant women

suggest that acyclovir treatment near term might reduce the rate of abdominal deliveries among women who have frequently recurring or newly acquired genital

herpes by decreasing the incidence of active lesions. However, routine administration of acyclovir to pregnant women who have a history of recurrent genital

herpes is not recommended at this time.

Perinatal Infection

Most mothers of infants who acquire neonatal herpes lack histories of clinically evident genital herpes. The risk for transmission to the neonate from an infected

mother is high among women who acquire genital herpes near the time of delivery (30%-50%) and is low among women who have a history of recurrent

herpes at term and women who acquire genital HSV during the first half of pregnancy (3%). Therefore, prevention of neonatal herpes should emphasize

prevention of acquisition of genital HSV infection during late pregnancy. Susceptible women whose partners have oral or genital HSV infection, or those

whose sex partners' infection status is unknown, should be counseled to avoid unprotected genital and oral sexual contact during late pregnancy. The results of

viral cultures during pregnancy do not predict viral shedding at the time of delivery, and such cultures are not indicated routinely.

At the onset of labor, all women should be examined and carefully questioned regarding whether they have symptoms of genital herpes. Infants of women who

do not have symptoms or signs of genital herpes infection or its prodrome may be delivered vaginally. Abdominal delivery does not completely eliminate the

risk for HSV infection in the neonate.

Infants exposed to HSV during birth, as proven by virus isolation or presumed by observation of lesions, should be followed carefully. Some authorities

recommend that such infants undergo surveillance cultures of mucosal surfaces to detect HSV infection before development of clinical signs. Available data do

not support the routine use of acyclovir for asymptomatic infants exposed during birth through an infected birth canal, because the risk for infection in most

infants is low. However, infants born to women who acquired genital herpes near term are at high risk for neonatal herpes, and some experts recommend

acyclovir therapy for these infants. Such pregnancies and newborns should be managed in consultation with an expert. All infants who have evidence of

neonatal herpes should be promptly evaluated and treated with systemic acyclovir (19). Acyclovir 30-60 mg/

Granuloma Inguinale (Donovanosis)
Granuloma inguinale, a rare disease in the United States, is caused by the intracellular Gram-negative bacterium Calymmatobacterium granulomatis. The disease is endemic in certain tropical and developing areas, including India, Papua New Guinea, central Australia, and southern Africa. The disease presents clinically as painless, progressive, ulcerative lesions without regional lymphadenopathy. The lesions are highly vascular (i.e., a beefy red appearance) and bleed easily on contact. The causative organism cannot be cultured on standard microbiologic media, and diagnosis requires visualization of dark-staining Donovan bodies on tissue crush preparation or biopsy. A secondary bacterial infection might develop in the lesions, or the lesions might be coinfected with another sexually transmitted pathogen.

Treatment

Treatment appears to halt progressive destruction of tissue, although prolonged duration of therapy often is required to enable granulation and re-epithelialization of the ulcers. Relapse can occur 6-18 months later despite effective initial therapy.

Recommended Regimens
Trimethoprim-sulfamethoxazole one double-strength tablet orally twice a day for a minimum of 3 weeks,
OR
Doxycycline 100 mg orally twice a day for a minimum of 3 weeks.
Therapy should be continued until all lesions have healed completely.

Alternative Regimens
Ciprofloxacin 750 mg orally twice a day for a minimum of 3 weeks, OR
Erythromycin base 500 mg orally four times a day for a minimum of 3 weeks.

For any of the above regimens, the addition of an aminoglycoside (gentamicin 1 mg/kg IV every 8 hours) should be considered if lesions do not respond within the first few days of therapy.

Follow-Up
Patients should be followed clinically until signs and symptoms have resolved.
Management of Sex Partners

Sex partners of patients who have granuloma inguinale should be examined and treated if they a) had sexual contact with the patient during the 60 days preceding the onset of symptoms in the patient and b) have clinical signs and symptoms of the disease.

Special Considerations
Pregnancy
Pregnancy is a relative contraindication to the use of sulfonamides. Both pregnant and lactating women should be treated with the erythromycin regimen. The addition of a parenteral aminoglycoside (e.g., gentamicin) should be strongly considered.

HIV Infection
HIV-infected persons who have granuloma inguinale should be treated following the regimens cited previously. The addition of a parenteral aminoglycoside (e.g., gentamicin) should be strongly considered.

Lymphogranuloma Venereum
Lymphogranuloma venereum (LGV), a rare disease in the United States, is caused by the invasive serovars L1, L2, or L3 of C. trachomatis. The most frequent clinical manifestation of LGV among heterosexual men is tender inguinal and/or femoral lymphadenopathy that is usually unilateral. Women and homosexually active men might have proctocolitis or inflammatory involvement of perirectal or perianal lymphatic tissues that can result in fistulas and strictures.

When most patients seek medical care, they no longer have the self-limited genital ulcer that sometimes occurs at the inoculation site. The diagnosis usually is made serologically and by exclusion of other causes of inguinal lymphadenopathy or genital ulcers.

Treatment
Treatment cures infection and prevents ongoing tissue damage, although tissue reaction can result in scarring. Buboes may require aspiration through intact skin or incision and drainage to prevent the formation of inguinal/femoral ulcerations. Doxycycline is the preferred treatment.

Recommended Regimens
Doxycycline 100 mg orally twice a day for 21 days.

Alternative Regimens
Erythromycin base 500 mg orally four times a day for 21 days.

The activity of azithromycin against C. trachomatis suggests that it may be effective in multiple doses over 2-3 weeks, but clinical data regarding its use are lacking.

Follow-Up
Patients should be followed clinically until signs and symptoms have resolved.

Management of Sex Partners
Sex partners of patients who have LGV should be examined, tested for urethral or cervical chlamydial infection, and treated if they had sexual contact with the patient during the 30 days preceding onset of symptoms in the patient.

Special Considerations
Pregnancy
Pregnant women should be treated with the erythromycin regimen.

HIV Infection
HIV-infected persons who have LGV should be treated according to the regimens cited previously. Anecdotal evidence suggests that LGV infection in HIV-positive patients may require prolonged therapy and that resolution might be delayed.

Syphilis
General Principles
Background
Syphilis is a systemic disease caused by T. pallidum. Patients who have syphilis may seek treatment for signs or symptoms of primary infection (i.e., ulcer or chancre at the infection site), secondary infection (i.e., manifestations that include rash, mucocutaneous lesions, and adenopathy), or tertiary infection (i.e., cardiac, neurologic, ophthalmic, auditory, or gummatous lesions). Infections also may be detected by serologic testing during the latent stage. Latent syphilis acquired within the preceding year is referred to as early latent syphilis; all other cases of latent syphilis are either late latent syphilis or syphilis of unknown duration. Treatment for late latent syphilis, as well as tertiary syphilis, theoretically may require a longer duration of therapy because organisms are dividing more slowly; however, the validity and importance of this concept have not been determined.

Diagnostic Considerations and Use of Serologic Tests
Darkfield examinations and direct fluorescent antibody tests of lesion exudate or tissue are the definitive methods for diagnosing early syphilis. A presumptive diagnosis is possible with the use of two types of serologic tests for syphilis: a) nontreponemal (e.g., Venereal Disease Research Laboratory {VDRL} and RPR) and b) treponemal (e.g., fluorescent treponemal antibody absorbed {FTA-ABS} and microhemagglutination assay for antibody to T. pallidum {MHA-TP}). The use of only one type of test is insufficient for diagnosis because false-positive nontreponemal test results occasionally occur secondary to various medical conditions. Nontreponemal test antibody titers usually correlate with disease activity, and results should be reported quantitatively. A fourfold change in titer, equivalent to a change of two dilutions (e.g., from 1:16 to 1:4 or from 1:8 to 1:32), usually is considered necessary to demonstrate a clinically significant difference between two nontreponemal test results that were obtained by using the same serologic test. It is expected that the nontreponemal test will eventually become nonreactive after treatment; however, in some patients, nontreponemal antibodies can persist at a low titer for a long period, sometimes for the remainder of their lives. This response is referred to as the serofast reaction. Most patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of treatment or disease activity. However, 15%-25% of patients treated during the primary stage might revert to being serologically nonreactive after 2-3 years. Treponemal test antibody titers correlate poorly with disease activity and should not be used to assess treatment response.

Sequential serologic tests should be performed by using the same testing method (e.g., VDRL or RPR), preferably by the same laboratory. The VDRL and RPR are equally valid, but quantitative results from the two tests cannot be compared directly because RPR titers often are slightly higher than VDRL titers.

HIV-infected patients can have abnormal serologic test results (i.e., unusually high, unusually low, and fluctuating titers). For such patients with clinical syndromes suggestive of early syphilis, use of other tests (e.g., biopsy and direct microscopy) should be considered. However, for most HIV-infected patients, serologic tests appear to be accurate and reliable for the diagnosis of syphilis and for evaluation of treatment response.

No single test can be used to diagnose all cases of neurosyphilis. The diagnosis of neurosyphilis can be made based on various combinations of reactive serologic test results, abnormalities of cerebrospinal fluid (CSF) cell count or protein, or a reactive VDRL-CSF with or without clinical manifestations. The CSF leukocyte count usually is elevated (greater than 5 WBCs/mm3) when neurosyphilis is present, and it also is a sensitive measure of the effectiveness of

therapy. The VDRL-CSF is the standard serologic test for CSF; when reactive in the absence of substantial contamination of CSF with blood, it is considered diagnostic of neurosyphilis. However, the VDRL-CSF may be nonreactive when neurosyphilis is present. Some experts recommend performing an FTA-ABS test on CSF. The CSF FTA-ABS is less specific (i.e., yields more false-positive results) for neurosyphilis than the VDRL-CSF. However, the test is believed to be highly sensitive, and some experts believe that a negative CSF FTA-ABS test excludes neurosyphilis.

Treatment
Parenteral penicillin G is the preferred drug for treatment of all stages of syphilis. The preparation(s) used (i.e., benzathine, aqueous procaine, or aqueous crystalline), the dosage, and the length of treatment depend on the stage and clinical manifestations of disease.

The efficacy of penicillin for the treatment of syphilis was well established through clinical experience before the value of randomized controlled clinical trials was recognized. Therefore, almost all the recommendations for the treatment of syphilis are based on expert opinion reinforced by case series, clinical trials, and 50 years of clinical experience.

Parenteral penicillin G is the only therapy with documented efficacy for neurosyphilis or for syphilis during pregnancy. Patients who report a penicillin allergy, including pregnant women with syphilis in any stage and patients with neurosyphilis, should be desensitized and treated with penicillin. Skin testing for penicillin allergy may be useful in some settings (see Management of Patients Who Have a History of Penicillin Allergy), because the minor determinants needed for penicillin skin testing are unavailable commercially.

The Jarisch-Herxheimer reaction is an acute febrile reaction -- often accompanied by headache, myalgia, and other symptoms -- that might occur within the first 24 hours after any therapy for syphilis; patients should be advised of this possible adverse reaction. The Jarisch-Herxheimer reaction often occurs among patients who have early syphilis. Antipyretics may be recommended, but no proven methods prevent this reaction. The Jarisch-Herxheimer reaction may induce early labor or cause fetal distress among pregnant women. This concern should not prevent or delay therapy (see Syphilis During Pregnancy).

Management of Sex Partners
Sexual transmission of T. pallidum occurs only when mucocutaneous syphilitic lesions are present; such manifestations are uncommon after the first year of infection. However, persons exposed sexually to a patient who has syphilis in any stage should be evaluated clinically and serologically according to the following recommendations:

Persons who were exposed within the 90 days preceding the diagnosis of primary, secondary, or early latent syphilis in a sex partner might be infected even if seronegative; therefore, such persons should be treated presumptively.

Persons who were exposed greater than 90 days before the diagnosis of primary, secondary, or early latent syphilis in a sex partner should be treated presumptively if serologic test results are not available immediately and the opportunity for follow-up is uncertain.  

For purposes of partner notification and presumptive treatment of exposed sex partners, patients with syphilis of unknown duration who have high nontreponemal serologic test titers (i.e., greater than or equal to 1:32) may be considered as having early syphilis. However, serologic titers should not be used to differentiate early from late latent syphilis for the purpose of determining treatment (see section regarding treatment of latent syphilis).

Long-term sex partners of patients who have late syphilis should be evaluated clinically and serologically for syphilis and treated on the basis of the findings of the evaluation.

The time periods before treatment used for identifying at-risk sex partners are a) 3 months plus duration of symptoms for primary syphilis, b) 6 months plus duration of symptoms for secondary syphilis, and c) 1 year for early latent syphilis.

Primary and Secondary Syphilis
Treatment
Parenteral penicillin G has been used effectively for four decades to achieve a local cure (i.e., healing of lesions and prevention of sexual transmission) and to prevent late sequelae. However, no adequately conducted comparative trials have been performed to guide the selection of an optimal penicillin regimen (i.e., the dose, duration, and preparation). Substantially fewer data are available concerning nonpenicillin regimens.

Recommended Regimen for Adults
Patients who have primary or secondary syphilis should be treated with the following regimen:
Benzathine penicillin G 2.4 million units IM in a single dose.
NOTE: Recommendations for treating pregnant women and HIV-infected patients for syphilis are discussed in separate sections.

Recommended Regimen for Children
After the newborn period, children in whom syphilis is diagnosed should have a CSF examination to detect symptomatic neurosyphilis, and birth and maternal medical records should be reviewed to assess whether the child has congenital or acquired syphilis (see Congenital Syphilis). Children with acquired primary or secondary syphilis should be evaluated (including consultation with child-protection services) and treated by using the following pediatric regimen (see Sexual Assault or Abuse of Children).

Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose.

Other Management Considerations
All patients who have syphilis should be tested for HIV infection. In geographic areas in which the prevalence of HIV is high, patients who have primary syphilis should be retested for HIV after 3 months if the first HIV test result was negative. This recommendation will become particularly important if it can be demonstrated that intensive antiviral therapy administered soon after HIV seroconversion is beneficial.

Patients who have syphilis and who also have symptoms or signs suggesting neurologic disease (e.g., meningitis) or ophthalmic disease (e.g., uveitis) should be evaluated fully for neurosyphilis and syphilitic eye disease; this evaluation should include CSF analysis and ocular slit-lamp examination. Such patients should be treated appropriately according to the results of this evaluation.

Invasion of CSF by T. pallidum accompanied by CSF abnormalities is common among adults who have primary or secondary syphilis. However, neurosyphilis develops in only a few patients after treatment with the regimens described in this report. Therefore, unless clinical signs or symptoms of neurologic or ophthalmic involvement are present, lumbar puncture is not recommended for routine evaluation of patients who have primary or secondary syphilis.

Follow-Up
Treatment failures can occur with any regimen. However, assessing response to treatment often is difficult, and no definitive criteria for cure or failure have been established. Serologic test titers may decline more slowly for patients who previously had syphilis. Patients should be reexamined clinically and serologically at both 6 months and 12 months; more frequent evaluation may be prudent if follow-up is uncertain.

Patients who have signs or symptoms that persist or recur or who have a sustained fourfold increase in nontreponemal test titer (i.e., in comparison with either the baseline titer or a subsequent result) probably failed treatment or were reinfected. These patients should be re-treated after reevaluation for HIV infection.

Unless reinfection with T. pallidum is certain, a lumbar puncture also should be performed.

Failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis identifies persons at risk for treatment failure. Such persons should be reevaluated for HIV infection. Optimal management of such patients is unclear. At a minimum, these patients should have additional clinical and serologic follow-up. HIV-infected patients should be evaluated more frequently (i.e., at 3-month intervals instead of 6-month intervals).

If additional follow-up cannot be ensured, re-treatment is recommended. Some experts recommend CSF examination in such situations.

When patients are re-treated, most experts recommend re-treatment with three weekly injections of benzathine penicillin G 2.4 million units IM, unless CSF examination indicates that neurosyphilis is present.

Management of Sex Partners
Refer to General Principles, Management of Sex Partners.

Special Considerations
Penicillin Allergy
Nonpregnant penicillin-allergic patients who have primary or secondary syphilis should be treated with one of the following regimens. Close follow-up of such patients is essential.

Recommended Regimens
Doxycycline 100 mg orally twice a day for 2 weeks,  OR
Tetracycline 500 mg orally four times a day for 2 weeks.
There is less clinical experience with doxycycline than with tetracycline, but compliance is likely to be better with doxycycline. Therapy for a patient who cannot tolerate either doxycycline or tetracycline should depend on whether the patient's compliance with the therapy regimen and with follow-up examinations can be ensured.

Pharmacologic and bacteriologic considerations suggest that ceftriaxone should be effective, but data concerning ceftriaxone are limited and clinical experience is insufficient to enable identification of late failures. The optimal dose and duration have not been established for ceftriaxone, but a suggested daily regimen of 1 g may be considered if treponemacidal levels in the blood can be maintained for 8-10 days. Single-dose ceftriaxone therapy is not effective for treating syphilis.

For nonpregnant patients whose compliance with therapy and follow-up can be ensured, an alternative regimen is erythromycin 500 mg orally four times a day for 2 weeks. However, erythromycin is less effective than the other recommended regimens.

Patients whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with penicillin. Skin testing for penicillin allergy

may be useful in some circumstances in which the reagents and expertise to perform the test adequately are available (see Management of Patients Who Have a History of Penicillin Allergy).

Pregnancy
Pregnant patients who are allergic to penicillin should be desensitized, if necessary, and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy and Syphilis During Pregnancy).

HIV Infection
Refer to Syphilis in HIV-Infected Persons.

Latent Syphilis
Latent syphilis is defined as those periods after infection with T. pallidum when patients are seroreactive, but demonstrate no other evidence of disease.

Patients who have latent syphilis and who acquired syphilis within the preceding year are classified as having early latent syphilis. Patients can be demonstrated as having early latent syphilis if, within the year preceding the evaluation, they had a) a documented seroconversion, b) unequivocal symptoms of primary or secondary syphilis, or c) a sex partner who had primary, secondary, or early latent syphilis. Almost all other patients have latent syphilis of unknown duration and should be managed as if they had late latent syphilis. Nontreponemal serologic titers usually are higher during early latent syphilis than late latent syphilis.

However, early latent syphilis cannot be reliably distinguished from late latent syphilis solely on the basis of nontreponemal titers. Regardless of the level of the nontreponemal titers, patients in whom the illness does not meet the definition of early syphilis should be treated as if they have late latent infection. All sexually active women with reactive nontreponemal serologic tests should have a pelvic examination before syphilis staging is completed to evaluate for internal mucosal lesions. All patients who have syphilis should be tested for HIV infection.

Treatment
Treatment of latent syphilis is intended to prevent occurrence or progression of late complications. Although clinical experience supports the effectiveness of penicillin in achieving these goals, limited evidence is available for guidance in choosing specific regimens. There is minimal evidence to support the use of nonpenicillin regimens.

Recommended Regimens for Adults
The following regimens are recommended for nonallergic patients who have normal CSF examinations (if performed):

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 three doses of 2.4 million units IM each at 1-week intervals.

Recommended Regimens for Children
After the newborn period, children in whom syphilis is diagnosed should have a CSF examination to exclude neurosyphilis, and birth and maternal medical

records should be reviewed to assess whether the child has congenital or acquired syphilis (see Congenital Syphilis). Older children with acquired latent syphilis should be evaluated as described for adults and treated using the following pediatric regimens (see Sexual Assault or Abuse of Children). These regimens are for non-allergic children who have acquired syphilis and whose results of the CSF examination were normal.

Early Latent Syphilis:  
Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose.

Late Latent Syphilis or Latent Syphilis of Unknown Duration:
Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units, administered as three doses at 1-week intervals (total 150,000 units/kg up to the adult total dose of 7.2 million units).

Other Management Considerations
All patients who have latent syphilis should be evaluated clinically for evidence of tertiary disease (e.g., aortitis, neurosyphilis, gumma, and iritis). Patients who have syphilis and who demonstrate any of the following criteria should have a prompt CSF examination:
Neurologic or ophthalmic signs or symptoms;
Evidence of active tertiary syphilis (e.g., aortitis, gumma, and iritis);
Treatment failure; and  HIV infection with late latent syphilis or syphilis of unknown duration.

If dictated by circumstances and patient preferences, a CSF examination may be performed for patients who do not meet these criteria. If a CSF examination is performed and the results indicate abnormalities consistent with neurosyphilis, the patient should be treated for neurosyphilis (see Neurosyphilis).

Follow-Up
Quantitative nontreponemal serologic tests should be repeated at 6, 12, and 24 months. Limited data are available to guide evaluation of the treatment response for patients who have latent syphilis. Patients should be evaluated for neurosyphilis and re-treated appropriately if a) titers increase fourfold, b) an initially high titer (greater than or equal to 1:32) fails to decline at least fourfold (i.e., two dilutions) within 12-24 months, or c) signs or symptoms attributable to syphilis develop in the patient.

Management of Sex Partners
Refer to General Principles, Management of Sex Partners.

Special Considerations
Penicillin Allergy
Nonpregnant patients who have latent syphilis and who are allergic to penicillin should be treated with one of the following regimens.

Recommended Regimens
Doxycycline 100 mg orally twice a day,  OR
Tetracycline 500 mg orally four times a day.
Both drugs should be administered for 2 weeks if the duration of infection is known to have been less than 1 year; otherwise, they should be administered for 4 weeks.

Pregnancy
Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy and Syphilis During Pregnancy).

HIV Infection
Refer to Syphilis in HIV-Infected Persons.

Tertiary Syphilis
Tertiary syphilis refers to gumma and cardiovascular syphilis, but not to neurosyphilis. Nonallergic patients without evidence of neurosyphilis should be treated with the following regimen.

Recommended Regimens
Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at 1-week intervals.

Other Management Considerations
Patients who have symptomatic late syphilis should have a CSF examination before therapy is initiated. Some experts treat all patients who have cardiovascular syphilis with a neurosyphilis regimen. The complete management of patients who have cardiovascular or gummatous syphilis is beyond the scope of these guidelines. These patients should be managed in consultation with an expert.

Follow-Up
Information is lacking with regard to follow-up of patients who have late syphilis. The clinical response depends partially on the nature of the lesions.

Management of Sex Partners
Refer to General Principles, Management of Sex Partners.

Special Considerations
Penicillin Allergy
Patients allergic to penicillin should be treated according to the recommended regimens for late latent syphilis.

Pregnancy
Pregnant patients who are allergic to penicillin should be desensitized, if necessary, and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy and Syphilis During Pregnancy).

HIV Infection
Refer to Syphilis in HIV-Infected Persons.

Neurosyphilis
Treatment
Central nervous system disease can occur during any stage of syphilis. A patient who has clinical evidence of neurologic involvement with syphilis (e.g., ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis) should have a CSF examination.

Syphilitic uveitis or other ocular manifestations frequently are associated with neurosyphilis; patients with these symptoms should be treated according to the recommendations for neurosyphilis. A CSF examination should be performed for all such patients to identify those with abnormalities who should have follow-up CSF examinations to assess treatment response.

Patients who have neurosyphilis or syphilitic eye disease (e.g., uveitis, neuroretinitis, or optic neuritis) and who are not allergic to penicillin should be treated with the following regimen:

Recommended Regimens
Aqueous crystalline penicillin G 18-24 million units a day, administered as 3-4 million units IV every 4 hours for 10-14 days.

If compliance with therapy can be ensured, patients may be treated with the following alternative regimen:

Alternative Regimen
Procaine penicillin 2.4 million units IM a day, PLUS Probenecid 500 mg orally four times a day, both for 10-14 days.

The durations of the recommended and alternative regimens for neurosyphilis are shorter than that of the regimen used for late syphilis in the absence of neurosyphilis. Therefore, some experts administer benzathine penicillin, 2.4 million units IM, after completion of these neurosyphilis treatment regimens to provide a comparable total duration of therapy.

Other Management Considerations
Other considerations in the management of patients who have neurosyphilis are as follows:
All patients who have syphilis should be tested for HIV.
Many experts recommend treating patients who have evidence of auditory disease caused by syphilis in the same manner as for neurosyphilis, regardless of the findings on CSF examination. Although systemic steroids are used frequently as adjunctive therapy for otologic syphilis, such drugs have not been proven beneficial.

Follow-Up
If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. Follow-up CSF examinations also can be used to evaluate changes in the VDRL-CSF or CSF protein after therapy; however, changes in these two parameters are slower, and persistent abnormalities are of less importance. If the cell count has not decreased after 6 months, or if the CSF is not entirely normal after 2 years, re-treatment should be considered.

Management of Sex Partners
Refer to General Principles, Management of Sex Partners.

Special Considerations
Penicillin Allergy

Data have not been collected systematically for evaluation of therapeutic alternatives to penicillin for treatment of neurosyphilis. Patients who report being allergic to penicillin should either be densensitized to penicillin or be managed in consultation with an expert. In some situations, skin testing to confirm penicillin allergy may be useful (see Management of Patients Who Have a History of Penicillin Allergy).

Pregnancy
Pregnant patients who are allergic to penicillin should be desensitized, if necessary, and treated with penicillin (see Syphilis During Pregnancy).

HIV Infection
Refer to Syphilis in HIV-Infected Persons.

Syphilis in HIV-Infected Persons
Diagnostic Considerations
Unusual serologic responses have been observed among HIV-infected persons who have syphilis. Most reports involved serologic titers that were higher than expected, but false-negative serologic test results or delayed appearance of seroreactivity also have been reported. Nevertheless, both treponemal and nontreponemal serologic tests for syphilis can be interpreted in the usual manner for most patients who are coinfected with T. pallidum and HIV.

When clinical findings suggest that syphilis is present, but serologic tests are nonreactive or unclear, alternative tests (e.g., biopsy of a lesion, darkfield examination, or direct fluorescent antibody staining of lesion material) may be useful.

Neurosyphilis should be considered in the differential diagnosis of neurologic disease in HIV-infected persons.

Treatment
In comparison with HIV-negative patients, HIV-infected patients who have early syphilis may be at increased risk for neurologic complications and may have higher rates of treatment failure with currently recommended regimens. The magnitude of these risks, although not defined precisely, is probably minimal. No treatment regimens for syphilis are demonstrably more effective in preventing neurosyphilis in HIV-infected patients than the syphilis regimens  recommended

for HIV-negative patients. Careful follow-up after therapy is essential.

Primary and Secondary Syphilis in HIV-Infected Persons
Treatment
Treatment with benzathine penicillin G, 2.4 million units IM, as for HIV-negative patients, is recommended. Some  experts recommend additional treatments (e.g., three weekly doses of benzathine penicillin G as suggested for late syphilis) or other supplemental antibiotics in addition to benzathine penicillin G 2.4 million units IM.

Other Management Considerations
CSF abnormalities often occur among both asymptomatic HIV-infected patients in the absence of syphilis and HIV-negative patients who have primary or secondary syphilis. Such abnormalities in HIV-infected patients who have primary or secondary syphilis are of unknown prognostic significance. Most HIV-infected patients respond appropriately to the currently recommended penicillin therapy; however, some experts recommend CSF examination before therapy and modification of treatment accordingly.

Follow-Up
It is important that HIV-infected patients be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy. Although of unproven benefit, some experts recommend a CSF examination after therapy (i.e., at 6 months).

HIV-infected patients who meet the criteria for treatment failure should be managed the same as HIV-negative patients (i.e., a CSF examination and re-treatment). CSF examination and re-treatment also should be strongly considered for patients whose nontreponemal test titer does not decrease fourfold within 6-12 months. Most experts would re-treat patients with 7.2 million units of benzathine penicillin G (administered as three weekly doses of 2.4 million units each) if CSF examinations are normal.

Special Considerations
Penicillin Allergy

Penicillin-allergic patients who have primary or secondary syphilis and HIV infection should be managed according to the recommendations for penicillin-allergic HIV-negative patients.

Latent Syphilis in HIV-Infected Persons
Diagnostic Considerations
HIV-infected patients who have early latent syphilis should be managed and treated according to the recommendations for HIV-negative patients who have primary and secondary syphilis.

HIV-infected patients who have either late latent syphilis or syphilis of unknown duration should have a CSF examination before treatment.

Treatment
A patient with late latent syphilis or syphilis of unknown duration and a normal CSF examination can be treated with 7.2 million units of benzathine penicillin G (as three weekly doses of 2.4 million units each). Patients who have CSF consistent with neurosyphilis should be treated and managed as described for neurosyphilis (see Neurosyphilis).

Follow-Up
Patients should be evaluated clinically and serologically at 6, 12, 18, and 24 months after therapy. If, at any time, clinical symptoms develop or nontreponemal titers rise fourfold, a repeat CSF examination should be performed and treatment administered accordingly. If between 12 and 24 months the nontreponemal titer fails to decline fourfold, the CSF examination should be repeated, and treatment administered accordingly.

Special Considerations
Penicillin Allergy

Penicillin regimens should be used to treat all stages of syphilis in HIV-infected patients. Skin testing to confirm penicillin allergy may be used (see Management of Patients Who Have a History of Penicillin Allergy). Patients may be desensitized, then treated with penicillin.

Syphilis During Pregnancy
All women should be screened serologically for syphilis during the early stages of pregnancy. In populations in which utilization of prenatal care is not optimal, RPR-card test screening and treatment (i.e., if the RPR-card test is reactive) should be performed at the time a pregnancy is diagnosed. For communities and populations in which the prevalence of syphilis is high or for patients at high risk, serologic testing should be performed twice during the third trimester, at 28 weeks of gestation and at delivery. (Some states mandate screening at delivery for all women.) Any woman who delivers a stillborn infant after 20 weeks of gestation should be tested for syphilis. No infant should leave the hospital without the maternal serologic status having been determined at least once during pregnancy.

Diagnostic Considerations
Seropositive pregnant women should be considered infected unless an adequate treatment history is documented clearly in the medical records and sequential serologic antibody titers have declined.

Treatment
Penicillin is effective for preventing maternal transmission to the fetus and for treating fetal-established infection. Evidence is insufficient to determine whether the specific, recommended penicillin regimens are optimal.

Recommended Regimens
Treatment during pregnancy should be the penicillin regimen appropriate for the stage of syphilis.

Other Management Considerations
Some experts recommend additional therapy in some settings. A second dose of benzathine penicillin 2.4 million units IM may be administered 1 week after the initial dose for women who have primary, secondary, or early latent syphilis. Ultrasonographic signs of fetal syphilis (i.e., hepatomegaly and hydrops) indicate a greater risk for fetal treatment failure; such cases should be managed in consultation with obstetric specialists.

Women treated for syphilis during the second half of pregnancy are at risk for premature labor and/or fetal distress if the treatment precipitates the Jarisch-Herxheimer reaction. These women should be advised to seek obstetric attention after treatment if they notice any contractions or decrease in fetal movements. Stillbirth is a rare complication of treatment, but concern for this complication should not delay necessary treatment. All patients who have syphilis should be offered testing for HIV infection.

Follow-Up
Coordinated prenatal care and treatment follow-up are important, and syphilis case management may help facilitate prenatal enrollment. Serologic titers should be repeated in the third trimester and at delivery. Serologic titers may be checked monthly in women at high risk for reinfection or in geographic areas in which the prevalence of syphilis is high. The clinical and antibody response should be appropriate for the stage of disease. Most women will deliver before their serologic response to treatment can be assessed definitively.

Management of Sex Partners
Refer to General Principles, Management of Sex Partners.

Special Considerations
Penicillin Allergy

There are no proven alternatives to penicillin for treatment of syphilis during pregnancy. Pregnant women who have a  history of penicillin allergy should be desensitized and treated with penicillin. Skin testing may be helpful (see Management of Patients Who Have a History of Penicillin Allergy).

Tetracycline and doxycycline usually are not used during pregnancy. Erythromycin should not be used, because it does not reliably cure an infected fetus. Data are insufficient to recommend azithromycin or ceftriaxone.

HIV Infection
Refer to Syphilis in HIV-Infected Persons.