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STDs Affecting the Reproductive System

Our courses fulfill continuing nursing education requirements in all 50 states. For more accreditation information, click here. Nurse practitioners may apply these contact hours to pharmacy continuing education and prescriptive authorization.

This course is recommended for advanced practitioners and others who treat or counsel clients about STDs.

Wild Iris Medical Education has adapted the material for this course from guidelines published by the Centers for Disease Control and Prevention (CDC). The original material was published by the National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Division of STD Prevention. The post test and learning objectives were prepared by Sharon A. Sanders, RN.

Sexually Transmitted Diseases Treatment Guidelines, 2006 was prepared for the CDC by Kimberly A. Workowski, MD, and Stuart M. Berman, MD.
References may be viewed at http://www.cdc.gov/std/treatment/2006/rr5511.pdf.

These guidelines for the treatment of people who have sexually transmitted diseases (STDs) were developed by Centers for Disease Control and Prevention (CDC) after consultation with professionals knowledgeable in the field who met in Atlanta April 19–21, 2005. The information in this report updates the 2002 Sexually Transmitted Diseases Treatment Guidelines (CDC, 2002).

Included in these updated guidelines are:

• An expanded diagnostic evaluation for cervicitis and trichomoniasis
• New antimicrobial recommendations for trichomoniasis
• Additional data on the clinical efficacy of azithromycin for chlamydial infections in pregnancy
• Discussion of the role of Mycoplasma genitalium and trichomoniasis in urethritis/cervicitis with treatment-related implications
• Emergence of lymphogranuloma venereum proctocolitis among men who have sex with men (MSM)
• Expanded discussion of the criteria for spinal fluid examination to evaluate for neurosyphilis
• The emergence of azithromycin-resistant Treponema pallidum
• Increasing prevalence of quinolone-resistant Neisseria gonorrhoeae in MSM
• Revised discussion about the sexual transmission of hepatitis C
• Postexposure prophylaxis after sexual assault
• An expanded discussion of STD prevention approaches

Wild Iris Medical Education has divided this material into four courses: (1) STDs: detection, referral, and counseling; (2) STDs affecting the reproductive system; (3) STDs: hepatitis, proctitis, and ectoparasitic infections; and (4) STDs related to sexual assault.

DISEASES CHARACTERIZED BY GENITAL ULCERS

In the United States, the majority of young, sexually active patients who have genital ulcers have either genital herpes, syphilis, or chancroid. Frequency of each condition differs by geographic area and patient population; however, genital herpes is the most prevalent of these diseases. More than one of these diseases can be present in a patient who has genital ulcers. All three of these diseases has been associated with an increased risk for HIV-infection. Not all genital ulcers are caused by sexually transmitted infections.

A diagnosis based only on the patient's medical history and physical examination is frequently inaccurate. Therefore, all patients who have genital ulcers should be evaluated with a serologic test for syphilis and a diagnostic evaluation for genital herpes; in settings where chancroid is prevalent, a test for Haemophilus ducreyi should also be performed. Specific tests for evaluation of genital ulcers include (1) syphilis serology and either darkfield examination or direct immunofluorescence test for T. pallidum; (2) culture or antigen test for herpes simplex virus (HSV); and (3) culture for H. ducreyi.

No FDA-cleared polymerase chain reaction (PCR) test for these organisms is available in the United States; however, such testing can be performed by clinical laboratories that have developed their own tests and conducted a clinical laboratory improvement amendment (CLIA) verification study. Type-specific serology for HSV-2 may be helpful in identifying individuals with genital herpes.

Biopsy of genital ulcers could be helpful in identifying the cause of ulcers that are unusual or that do not respond to initial therapy. HIV testing should be performed on all patients who have genital ulcers caused by T. pallidum or H. ducreyi, and should be strongly considered for those who have genital ulcers caused by HSV. Healthcare providers often need to treat patients before test results are available because early treatment decreases the possibility of ongoing transmission and because successful treatment of genital herpes depends on prompt initiation of therapy.

The clinician should treat for the diagnosis considered most likely, on the basis of clinical presentation and epidemiologic circumstances. In some instances, treatment must be initiated for additional conditions because of diagnostic uncertainty. Even after complete diagnostic evaluation, at least 25% of patients who have genital ulcers have no laboratory-confirmed diagnosis.

Chancroid

In the United States, chancroid usually occurs in discrete outbreaks, although the disease is endemic in some areas. Chancroid is a co-factor for HIV transmission, as are genital herpes and syphilis; high rates of HIV-infection among patients who have chancroid occur in the United States and other countries. Approximately 10% of individuals who have chancroid that was acquired in the United States are coinfected with T. pallidum or HSV; this percentage is higher in individuals who have acquired chancroid outside the United States.

A definitive diagnosis of chancroid requires the identification of H. ducreyi on special culture media that is not widely available from commercial sources; even when these media are used, sensitivity is less than 80%. No FDA-cleared PCR test for H. ducreyi is available in the United States, but such testing can be performed by clinical laboratories that have developed their own PCR test and conducted a Clinical Laboratory Improvement Amendments (CLIA) verification study.

The combination of a painful genital ulcer and tender suppurative inguinal adenopathy suggests the diagnosis of chancroid. A probable diagnosis of chancroid, for both clinical and surveillance purposes, can be made if all of the following criteria are met:

• Patient has one or more painful genital ulcers
• 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
• Clinical presentation, appearance of genital ulcers, and (if present) regional lymphadenopathy are typical for chancroid
• Test for HSV performed on the ulcer exudate is negative

TREATMENT

Successful treatment for chancroid cures the infection, resolves the clinical symptoms, and prevents transmission to others. In advanced cases, scarring can result despite successful therapy.

OTHER MANAGEMENT CONSIDERATIONS

Male patients who are uncircumcised and patients with HIV-infection do not respond as well to treatment as those who are circumcised or HIV-negative. Patients should be tested for HIV-infection at the time chancroid is diagnosed. Patients should be retested for syphilis and HIV 3 months after the diagnosis of chancroid, if the initial test results were negative.

Followup

Patients should be reexamined 3 to 7 days after initiation of therapy. If treatment is successful, ulcers usually improve symptomatically within 3 days and objectively within 7 days after therapy. If no clinical improvement is evident, the clinician must consider whether (1) the diagnosis is correct, (2) the patient is co-infected with another STD, (3) the patient is infected with HIV, (4) the treatment was not used as instructed, or (5) the H. ducreyi strain causing the infection is resistant to the prescribed antimicrobial.

Time required for complete healing depends on the size of the ulcer; large ulcers may require more 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 resolution for ulcers and might require needle aspiration or incision and drainage. Although needle aspiration of chancroid buboes is a simple procedure, incision and drainage might be preferred because of a reduced need for repeat drainage procedures.

Management of Sex Partners

Sex partners of patients who have chancroid should be examined and treated, whether or not symptoms of the disease are present, if they had sexual contact with the patient during the 10 days preceding the patient's onset of symptoms.

Pregnancy

The safety and efficacy of azithromycin for pregnant and lactating women have not been established. Ciprofloxacin is contraindicated during pregnancy and lactation. No adverse effects of chancroid on pregnancy outcome have been reported.

HIV-Infection

HIV-infected patients who have chancroid should be monitored closely because, as a group, these patients are more likely to experience treatment failure and to have ulcers that heal slowly. HIV-infected patients might require longer courses of therapy than those recommended for HIV-negative patients, and treatment failures can occur with any regimen.

Because evidence is limited about the therapeutic efficacy of the recommended ceftriaxone and azithromycin regimens in HIV-infected patients, these regimens should be used for such patients only if followup can be ensured. Some specialists prefer the erythromycin 7-day regimen for treating HIV-infected individuals.

Genital Herpes (HSV)

Genital herpes is a chronic, lifelong viral infection. Two types of HSV have been identified: HSV-1 and HSV-2. The majority of cases of recurrent genital herpes are caused by HSV-2, although HSV-1 might become more common as a cause of first-episode genital herpes. At least 50 million people in the United States have genital HSV infection.

The majority of those infected with HSV-2 have not been diagnosed with genital herpes. Many such individuals have mild or unrecognized infections but shed virus intermittently in the genital tract. Most genital herpes is transmitted by individuals unaware that they have the infection or who are asymptomatic when transmission occurs.

The clinical diagnosis of genital herpes is both insensitive and nonspecific. The classical painful multiple vesicular or ulcerative lesions are absent in many infected individuals. Up to 50% of first-episode cases of genital herpes are caused by HSV-1, but recurrences and subclinical shedding are much less frequent for genital HSV-1 infection than genital HSV-2 infection. Therefore, whether genital herpes is caused by HSV-1 or HSV-2 influences prognosis and counseling.

Therefore, the clinical diagnosis of genital herpes should be confirmed by laboratory testing. Both virologic and type-specific serologic tests for HSV should be available in clinical settings that provide care for patients with STDs or those at risk for STDs.

VIROLOGIC TESTS

Isolation of HSV in cell culture is the preferred virologic test for patients who seek medical treatment for genital ulcers or other mucocutaneous lesions. However, the sensitivity of culture is low, especially for recurrent lesions, and declines rapidly as lesions begin to heal. PCR assays for HSV DNA are more sensitive and have been used instead of viral culture; however, PCR tests are not FDA-cleared for testing of genital specimens. PCR is the test of choice for detecting HSV in spinal fluid for diagnosis of HSV-infection of the central nervous system (CNS). Viral culture isolates should be typed to determine if HSV-1 or HSV-2 is the cause of the infection. Lack of HSV detection (culture or PCR) does not indicate a lack of HSV-infection, as viral shedding is intermittent.

The use of cytologic detection of cellular changes of HSV-infection is an insensitive and nonspecific method of diagnosis, both for genital lesions (Tzanck preparation) and for cervical Pap smears, and should not be relied upon.

TYPE-SPECIFIC SEROLOGIC TESTS

Both type-specific and nontype-specific antibodies to HSV develop during the first several weeks after infection and persist indefinitely. Accurate type-specific HSV serologic assays are based on the HSV-specific glycoprotein G2 (HSV-2) and glycoprotein G1 (HSV-1). Such assays first became commercially available in 1999, but older assays that do not accurately distinguish HSV-1 from HSV-2 antibody (despite claims to the contrary) remain on the market. Therefore, the serologic type-specific glycoprotein G (gG)-based assays should be specifically requested when serology is performed.

The FDA-cleared glycoprotein G-based type-specific assays include the laboratory-based:

• HerpeSelect-1 enzyme-linked immunosorbent assay (ELISA) immunoglobulin G (IgG) (Focus Technology, Inc., Herndon , Virginia) or
• HerpeSelect-2 ELISA IgG and
• HerpeSelect 1 and 2 Immunoblot IgG (Focus Technology, Inc., Herndon , Virginia), and
• HSV-2 ELISA (Trinity Biotech USA, Berkeley Heights, New Jersey)

Two other assays, are point-of-care tests that provide results for HSV-2 antibodies from capillary blood or serum during a clinic visit:

• Biokit HSV-2 (Biokit USA, Lexington, Massachusetts) and
• SureVue HSV-2 (Fisher Scientific, Pittsburgh, Pennsylvania)

The sensitivities of these glycoprotein G type-specific tests for the detection of HSV-2 antibody vary from 80% to 98%, and false-negative results might be more frequent at early stages of infection. The specificities of these assays are greater than 96%. False-positive results can occur, especially in patients with a low likelihood of HSV infection. Repeat or confirmatory testing might be indicated, especially if recent acquisition of genital herpes is suspected.

Because nearly all HSV-2 infections are sexually acquired, the presence of type-specific HSV-2 antibody implies anogenital infection, and education and counseling appropriate for individuals with genital herpes should be provided. The presence of HSV-1 antibody alone is more difficult to interpret.

The majority of those with HSV-1 antibody have oral HSV infection acquired during childhood, which might be asymptomatic. However, acquisition of genital HSV-1 appears to be increasing, and genital HSV-1 also might be asymptomatic.

Lack of symptoms in an HSV-1 seropositive patient does not distinguish anogenital from orolabial or cutaneous infection. Patients with HSV-1 infection, regardless of site of infection, remain at risk for HSV-2 acquisition.

Type-specific HSV serologic assays might be useful in the following scenarios: (1) recurrent genital symptoms or atypical symptoms with negative HSV cultures; (2) a clinical diagnosis of genital herpes without laboratory confirmation; and (3) a partner with genital herpes. Some specialists believe that HSV serologic testing should be included in a comprehensive evaluation for STDs among individuals with multiple sex partners, with HIV-infection, and among MSM at increased risk for HIV acquisition. Screening for HSV-1 or HSV-2 in the general population is not indicated.

MANAGEMENT OF GENITAL HERPES

Antiviral chemotherapy offers clinical benefits to the majority of symptomatic patients and is the mainstay of management. Counseling regarding the natural history of genital herpes, sexual and perinatal transmission, and methods to reduce transmission is integral to clinical management.

Systemic antiviral drugs can partially control the signs and symptoms of herpes episodes when used to treat first clinical and recurrent episodes, or when used as daily suppressive therapy. However, these drugs neither eradicate latent virus nor affect the risk, frequency, or severity of recurrences after the drug is discontinued. Randomized trials have indicated that three antiviral medications provide clinical benefit for genital herpes: acyclovir, valacyclovir, and famciclovir. Valacyclovir is the valine ester of acyclovir and has enhanced absorption after oral administration. Famciclovir also has high oral bioavailability. Topical therapy with antiviral drugs offers minimal clinical benefit, and its use is discouraged.

First Clinical Episode

Many individuals with first-episode herpes have mild clinical manifestations but later develop severe or prolonged symptoms. Therefore, patients with initial genital herpes should receive antiviral therapy.

Established HSV-2 Infection

The majority of patients with symptomatic, first-episode, genital HSV-2 infection subsequently experience recurrent episodes of genital lesions; recurrences are less frequent after initial genital HSV-1 infection. Intermittent asymptomatic shedding occurs in individuals with genital HSV-2 infection, even in those with longstanding or clinically silent infection.

Antiviral therapy for recurrent genital herpes can be administered either episodically to ameliorate or shorten the duration of lesions or continuously as suppressive therapy to reduce the frequency of recurrences. Many individuals, including those with mild or infrequent recurrent outbreaks, benefit from antiviral therapy; therefore, options for treatment should be discussed. Some individuals might prefer suppressive therapy, which has the additional advantage of decreasing the risk of genital HSV-2 transmission to susceptible partners.

Suppressive Therapy for Recurrent Genital Herpes

Suppressive therapy reduces the frequency of genital herpes recurrences by 70% to 80% in patients who have frequent recurrences (>6 recurrences per year), and many patients report no symptomatic outbreaks. Treatment also is effective in patients with less frequent recurrences. Safety and efficacy have been documented among patients receiving daily therapy with acyclovir for as long as 6 years and with valacyclovir or famciclovir for 1 year. Quality of life frequently is improved in patients with frequent recurrences who receive suppressive therapy, compared with episodic treatment.

The frequency of recurrent genital herpes outbreaks diminishes over time in many patients, and the patient's psychological adjustment to the disease might change. Therefore, periodically during suppressive treatment (eg, once a year), providers should discuss the need to continue therapy with the patient.

Daily treatment with valacyclovir 500 mg decreases the rate of HSV-2 transmission in discordant heterosexual couples in which the source partner has a history of genital HSV-2 infection. Such couples should be encouraged to consider suppressive antiviral therapy as part of a strategy to prevent transmission, in addition to consistent condom use and avoidance of sexual activity during recurrences. Suppressive antiviral therapy probably reduces transmission when used by individuals who have multiple partners (including MSM) and by those who are HSV-2 seropositive without a history of genital herpes.

Valacyclovir 500 mg once a day might be less effective than other valacyclovir or acyclovir dosing regimens in patients who have very frequent recurrences (>10 episodes per year).

Several studies have compared valacyclovir or famciclovir with acyclovir. The results of these studies suggest that valacyclovir and famciclovir are comparable to acyclovir in clinical outcome. Ease of administration and cost are important considerations for prolonged treatment.

Episodic Therapy for Recurrent Genital Herpes

Effective episodic treatment of recurrent herpes requires initiation of therapy within 1 day of lesion onset or during the prodrome that precedes some outbreaks. The patient should be provided with a supply of drug or a prescription for the medication with instructions to initiate treatment immediately when symptoms begin.

Severe Disease

Intravenous (IV) acyclovir therapy should be provided for patients who have severe HSV disease or complications that necessitate hospitalization (disseminated infection, pneumonitis, hepatitis) or CNS complications (meningitis, encephalitis). The recommended regimen is acyclovir 5 to 10 mg/kg body weight IV every 8 hours for 2 to 7 days or until clinical improvement is observed, followed by oral antiviral therapy to complete at least 10 days of total therapy.

COUNSELING

Counseling of infected individuals and their sex partners is critical to the management of genital herpes. The goals of counseling are to (1) help patients cope with the infection, and (2) prevent sexual and perinatal transmission. Although initial counseling may be provided at the first visit, many patients benefit from learning about the chronic aspects of the disease after the acute illness subsides. Multiple resources, including websites (http://www.ashastd.org and http://www.ihmf.org) and printed materials, are available to assist patients, their partners, and clinicians in counseling.

HSV-infected individuals might express anxiety about genital herpes that does not reflect the actual clinical severity of their disease; the psychological effect of HSV infection frequently is substantial. Common concerns regarding genital herpes include the severity of initial clinical manifestations, recurrent episodes, sexual relationships and transmission to sex partners, and ability to bear healthy children. The misconception that HSV causes cancer should be dispelled. The psychological effect of a serologic diagnosis of HSV-2 infection in a person with asymptomatic or unrecognized genital herpes appears small and transient.

The following recommendations apply to counseling of patients with HSV infection.

Individuals who have genital herpes should be educated about the natural history of the disease, with emphasis on the potential for recurrent episodes, asymptomatic viral shedding, and the attendant risks of sexual transmission.

Individuals experiencing a first episode of genital herpes should be advised that suppressive therapy is available and is effective in preventing symptomatic recurrent episodes, and that episodic therapy sometimes is useful in shortening the duration of recurrent episodes.

All individuals with genital HSV infection should be encouraged to inform their current sex partners that they have genital herpes and to inform future partners before initiating a sexual relationship.

Sexual transmission of HSV can occur during asymptomatic periods. Asymptomatic viral shedding is more frequent in genital HSV-2 infection than genital HSV-1 infection and is most frequent during the first 12 months after acquiring HSV-2.

All individuals with genital herpes should remain abstinent from sexual activity with uninfected partners when lesions or prodromal symptoms are present.

The risk of HSV-2 sexual transmission can be decreased by the daily use of valacyclovir by the infected person.

Recent studies indicate that latex condoms, when used consistently and correctly, might reduce the risk for genital herpes transmission.

Sex partners of infected individuals should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of asymptomatic partners of individuals with genital herpes is recommended to determine whether risk for HSV acquisition exists.

The risk for neonatal HSV infection should be explained to all individuals, including men. Pregnant women and women of childbearing age who have genital herpes should inform providers who care for them during pregnancy and those who will care for their newborn infant. Pregnant women who are not infected with HSV-2 should be advised to avoid intercourse during the third trimester with men who have genital herpes. Similarly, pregnant women who are not infected with HSV-1 should be counseled to avoid genital exposure to HSV-1 during the third trimester (oral sex with a partner with oral herpes and vaginal intercourse with a partner with genital HSV-1 infection).

Asymptomatic individuals diagnosed with HSV-2 infection by type-specific serologic testing should receive the same counseling messages as individuals with symptomatic infection. In addition, such individuals should be taught about the clinical manifestations of genital herpes.

OTHER CONSIDERATIONS

Management of Sex Partners

The sex partners of patients who have genital herpes can benefit from evaluation and counseling. Symptomatic sex partners should be evaluated and treated in the same manner as patients who have genital lesions. Asymptomatic sex partners of patients who have genital herpes should be questioned about histories of genital lesions and offered type-specific serologic testing for HSV infection.

Allergy, Intolerance, and Adverse Reactions

Allergic and other adverse reactions to acyclovir, valacyclovir, and famciclovir are rare. Desensitization to acyclovir has been described.

HIV-Infection

Immunocompromised patients might have prolonged or severe episodes of genital, perianal, or oral herpes. Lesions caused by HSV are common among HIV-infected patients and might be severe, painful, and atypical. HSV shedding is increased in HIV-infected individuals. Whereas antiretroviral therapy reduces the severity and frequency of symptomatic genital herpes, frequent subclinical shedding still occurs.

Suppressive or episodic therapy with oral antiviral agents is effective in decreasing the clinical manifestations of HSV among HIV-positive individuals. HIV-infected individuals are likely to be more contagious for HSV; the extent to which suppressive antiviral therapy will decrease HSV transmission from this population is unknown. Some specialists suggest that HSV type-specific serologies be offered to HIV-positive individuals during their initial evaluation, and that suppressive antiviral therapy be considered in those who have HSV-2 infection.

Acyclovir, valacyclovir, and famciclovir are safe for use in immunocompromised patients in the doses recommended for treatment of genital herpes. For severe HSV disease, initiating therapy with acyclovir 5 to 10 mg/kg body weight IV every 8 hours might be necessary.

If lesions persist or recur in a patient receiving antiviral treatment, HSV resistance should be suspected and a viral isolate should be obtained for sensitivity testing. Such patients should be managed in consultation with an HIV specialist, and alternate therapy should be administered.

All acyclovir-resistant strains are resistant to valacyclovir, and the majority are resistant to famciclovir. Foscarnet (40 mg/kg body weight IV every 8 hours until clinical resolution is attained) is frequently 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. This preparation is not commercially available and must be compounded at a pharmacy.

Pregnancy

Mothers of infants who acquire neonatal herpes generally lack histories of clinically evident genital herpes. The risk for transmission to the neonate from an infected mother is high (30%–50%) among women who acquire genital herpes near the time of delivery and is low (<1%) among women with histories of recurrent herpes at term or who acquire genital HSV during the first half of pregnancy. However, because recurrent genital herpes is much more common than initial HSV infection during pregnancy, the proportion of neonatal HSV infections acquired from mothers with recurrent herpes is substantial.

Prevention of neonatal herpes depends both on preventing acquisition of genital HSV infection during late pregnancy and avoiding exposure of the infant to herpetic lesions during delivery.

Women without known genital herpes should be counseled to avoid intercourse during the third trimester with partners known or suspected of having genital herpes. In addition, pregnant women without known orolabial herpes should be advised to avoid receptive oral sex during the third trimester with partners known or suspected to have orolabial herpes.

Some specialists believe that type-specific serologic tests are useful to identify pregnant women at risk for HSV infection and to guide counseling regarding the risk for acquiring genital herpes during pregnancy. Such testing should be offered to women without genital herpes whose sex partner has HSV infection. The effectiveness of antiviral therapy to decrease the risk for HSV transmission to pregnant women has not been studied.

All pregnant women should be asked whether they have a history of genital herpes. At the onset of labor, all women should be questioned carefully about symptoms of genital herpes, including prodromal symptoms, and all women should be examined carefully for herpetic lesions. Women without symptoms or signs of genital herpes or its prodrome can deliver vaginally.

The majority of specialists recommend that women with recurrent genital herpetic lesions at the onset of labor deliver by cesarean section to prevent neonatal herpes. However, cesarean section does not completely eliminate the risk for HSV transmission to the infant.

The safety of systemic acyclovir, valacyclovir, and famciclovir therapy in pregnant women has not been definitively established.

Available data do not indicate an increased risk for major birth defects compared with the general population in women treated with acyclovir during the first trimester. These findings provide some assurance to women who have had prenatal exposure to acyclovir. The experience with prenatal exposure to valacyclovir and famciclovir is too limited to provide useful information on pregnancy outcomes.

Acyclovir may be administered orally to pregnant women with first-episode genital herpes or severe recurrent herpes and should be administered IV to pregnant women with severe HSV infection. Acyclovir treatment late in pregnancy reduces the frequency of cesarean sections among women who have recurrent genital herpes by diminishing the frequency of recurrences at term, and many specialists recommend such treatment.

No data support the use of antiviral therapy among HSV seropositive women without a history of genital herpes. The risk for herpes is high in infants of women who acquire genital HSV during late pregnancy; such women should be managed in consultation with an infectious diseases specialist. Some specialists recommend acyclovir therapy in this circumstance, some recommend routine cesarean section to reduce the risk for neonatal herpes, and others recommend both.

Neonatal Herpes

Infants exposed to HSV during birth, as documented by maternal virologic testing or presumed by observation of maternal lesions, should be followed carefully in consultation with a specialist. Some specialists recommend that such infants undergo surveillance cultures of mucosal surfaces to detect HSV infection before development of clinical signs of neonatal herpes. In addition, some specialists recommend the use of acyclovir for infants born to women who acquired HSV near term because the risk for neonatal herpes is high for these infants.

All infants who have neonatal herpes should be promptly evaluated and treated with systemic acyclovir. The recommended regimen for infants treated for known or suspected neonatal herpes is acyclovir 20 mg/kg body weight IV every 8 hours for 21 days for disseminated and CNS disease or for 14 days for disease limited to the skin and mucous membranes.

Granuloma Inguinale (Donovanosis)

Granuloma inguinale is a genital ulcerative disease caused by the intracellular gram-negative bacterium Klebsiella granulomatis (formerly known as Calymmatobacterium granulomatis). The disease occurs rarely in the United States, although it is endemic in some tropical and developing areas, including India; Papua, New Guinea; central Australia; and southern Africa. Clinically, the disease is commonly characterized as painless, progressive ulcerative lesions without regional lymphadenopathy.

The lesions are highly vascular (beefy red appearance) and bleed easily on contact. However, the clinical presentation also can include hypertrophic, necrotic, or sclerotic variants. The causative organism is difficult to culture, and diagnosis requires visualization of dark-staining Donovan bodies on tissue crush preparation or biopsy. No FDA-cleared PCR tests for the detection of K. granulomatis DNA exist, but such an assay might be useful if a CLIA verification study has been conducted. The lesions might develop secondary bacterial infection or can coexist with other sexually transmitted pathogens.

TREATMENT

A limited number of studies on Donovanosis treatment have been published. Treatment halts progression of lesions, although prolonged therapy is usually required to permit granulation and re-epithelialization of the ulcers. Healing typically proceeds inward from the ulcer margins. Relapse can occur 6 to 18 months after apparently effective therapy. Several antimicrobial regimens have been effective, but a limited number of controlled trials have been published.

Therapy should be continued for at least 3 weeks and until all lesions have completely healed. Some specialists recommend the addition of an aminoglycoside (eg, gentamicin 1 mg/kg IV every 8 hours) to these regimens if improvement is not evident within the first few days of therapy.

Followup

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

Management of Sex Partners

Individuals who have had sexual contact with a patient who has granuloma inguinale within the 60 days before onset of the patient's symptoms should be examined and offered therapy. However, the value of empiric therapy in the absence of clinical signs and symptoms has not been established.

Pregnancy

Pregnancy is a relative contraindication to the use of sulfonamides. Pregnant and lactating women should be treated with the erythromycin regimen, and consideration should be given to the addition of a parenteral aminoglycoside (eg, gentamicin). Azithromycin might prove useful for treating granuloma inguinale during pregnancy, but published data are lacking. Doxycycline and ciprofloxacin are contraindicated in pregnant women.

HIV-Infection

Individuals with both granuloma inguinale and HIV-infection should receive the same regimens as those who are HIV-negative. Consider adding a parenteral aminoglycoside (eg, gentamicin).

Lymphogranuloma Venereum

Lymphogranuloma venereum (LGV) is caused by C. trachomatis serovars L1, L2, or L3. The most common clinical manifestation of LGV among heterosexuals is tender inguinal and/or femoral lymphadenopathy that is typically unilateral. A self-limited genital ulcer or papule sometimes occurs at the site of inoculation. However, by the time patients seek care, the lesions might have disappeared. Rectal exposure in women or MSM might result in proctocolitis (including mucoid and/or hemorrhagic rectal discharge, anal pain, constipation, fever, and/or tenesmus).

Lymphogranuloma venereum is an invasive, systemic infection, and if it is not treated early, LGV proctocolitis might lead to chronic, colorectal fistulas and strictures. Genital and colorectal LGV lesions might also develop secondary bacterial infection or might be co-infected with other sexually and nonsexually transmitted pathogens.

Diagnosis is based on clinical suspicion, epidemiologic information, and the exclusion of other etiologies (of proctocolitis, inguinal lymphadenopathy, or genital or rectal ulcers), along with C. trachomatis testing, if available.

Genital and lymph node specimens (lesion swab, bubo aspirate) may be tested for C. trachomatisby culture, direct immunofluorescence, or nucleic acid detection. Nucleic acid amplification tests (NAAT) for C. trachomatis are not FDA-cleared for testing rectal specimens. Additional procedures (eg, genotyping) are required for differentiating LGV from non-LGV C. trachomatis but are not widely available. Chlamydia serology (complement fixation titers >1:64) can support the diagnosis in the appropriate clinical context.

Comparative data between types of serologic tests are lacking, and the diagnostic utility of serologic methods other than complement fixation and some micro-immunofluorescence procedures has not been established. Serologic test interpretation for LGV is not standardized, tests have not been validated for clinical proctitis presentations, and C. trachomatis serovar-specific serologic tests are not widely available.

In the absence of specific LGV diagnostic testing, patients with a clinical syndrome consistent with LGV, including proctocolitis or genital ulcer disease with lymphadenopathy, should be treated for LGV as described in this report.

TREATMENT

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

Followup

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

Management of Sex Partners

Individuals who have had sexual contact with a patient who has LGV within the 60 days before onset of the patient's symptoms should be examined, tested for urethral or cervical chlamydial infection, and treated with a standard chlamydia regimen (azithromycin 1 gm orally once a day or doxycycline 100 mg orally twice a day for 7 days). The optimum contact interval is unknown; some specialists use longer contact intervals.

Pregnancy

Pregnant and lactating women should be treated with erythromycin. Azithromycin might prove useful for treatment of LGV in pregnancy, but no published data are available regarding its safety and efficacy. Doxycycline is contraindicated in pregnant women.

HIV-Infection

Individuals with both LGV and HIV-infection should receive the same regimens as those who are HIV-negative. Prolonged therapy might be required, and delay in resolution of symptoms might occur.

Syphilis

Syphilis is a systemic disease caused by T. pallidum. Patients who have syphilis might seek treatment for signs or symptoms of primary infection (ulcer or chancre at the infection site), secondary infection (including, but not limited to, skin rash, mucocutaneous lesions, and lymphadenopathy), or tertiary infection (cardiac or ophthalmic manifestations, auditory abnormalities, or gummatous lesions).

Latent infections (those lacking clinical manifestations) are detected by serologic testing. 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 latent syphilis of unknown duration. Treatment for both late latent syphilis and tertiary syphilis theoretically might require a longer duration of therapy because organisms are dividing more slowly; however, the validity of this concept has not been assessed.

DIAGNOSIS AND SEROLOGIC TESTS

Darkfield examinations and direct fluorescent antibody (DFA) 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:

• Nontreponemal tests (eg, venereal disease research laboratory [VDRL] and rapid plasma reagins [RPR])
• Treponemal tests (eg, fluorescent treponemal antibody absorbed [FTA-ABS] and T. pallidum particle agglutination [TP-PA])

The use of only one type of serologic test is insufficient for diagnosis because false-positive nontreponemal test results are sometimes associated with medical conditions unrelated to syphilis.

Nontreponemal 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 (eg, from 1:16–1:4 or from 1:8–1:32), is considered necessary to demonstrate a clinically significant difference between two nontreponemal test results that were obtained using the same serologic test.

Sequential serologic tests in individual patients should be performed by using the same testing method (VDRL or RPR), preferably by the same laboratory. The VDRL and RPR are equally valid assays, but quantitative results from the two tests cannot be compared directly because RPR titers are frequently slightly higher than VDRL titers. Nontreponemal tests usually become nonreactive with time after treatment; however, in some patients, nontreponemal antibodies can persist at a low titer for a long period of time, sometimes for the life of the patient. This response is referred to as the serofast reaction.

The majority of patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of treatment or disease activity. However, 15% to 25% of patients treated during the primary stage revert to being serologically nonreactive after 2 to 3 years. Treponemal antibody titers do not correlate with disease activity and should not be used to assess treatment response.

Some clinical laboratories and blood banks have begun to screen samples using treponemal EIA tests. This strategy will identify both individuals with previous treatment and individuals with untreated or incompletely treated syphilis. False-positive results can occur, particularly among populations with a low prevalence of syphilis.

Individuals with a positive treponemal screening test should have a standard nontreponemal test with titer to guide patient management decisions. If the nontreponemal test is negative, then a different treponemal test should be performed to confirm the results of the initial test. If a second treponemal test is positive, treatment decisions should be discussed in consultation with a specialist.

Some HIV-infected patients can have atypical serologic test results (unusually high, unusually low, or fluctuating). For such patients, when serologic tests do not correspond with clinical syndromes suggestive of early syphilis, use of other tests (biopsy, direct microscopy) should be considered. However, for the majority of HIV-infected patients, serologic tests are accurate and reliable for the diagnosis of syphilis and for following the response to treatment.

No single test can be used to diagnose neurosyphilis. The VDRL-cerebrospinal fluid (CSF) is highly specific, but it is insensitive. The majority of other tests are both insensitive and nonspecific and must be interpreted in relation to other test results and the clinical assessment. Therefore, the diagnosis of neurosyphilis usually depends on various combinations of reactive serologic test results, CSF cell count or protein, or a reactive VDRL-CSF with or without clinical manifestations. The CSF leukocyte count usually is elevated (>5 white blood cell count [WBC]/mm³) in patients with neurosyphilis; this count is also a sensitive measure of the effectiveness of therapy.

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

TREATMENT

Penicillin G, administered parenterally, is the preferred drug for treatment of all stages of syphilis. The preparation(s) used (benzathine, aqueous procaine, or aqueous crystalline), the dosage, and the length of treatment depend on the stage and clinical manifestations of the disease. However, neither combinations of benzathine penicillin and procaine penicillin nor oral penicillin preparations are considered appropriate for the treatment of syphilis.

Reports have indicated that inappropriate use of combination benzathine-procaine penicillin (Bicillin C-R) instead of the standard benzathine penicillin product widely used in the United States (Bicillin L-A) has occurred. Practitioners, pharmacists, and purchasing agents should be aware of the similar names of these two products and avoid use of the inappropriate combination therapy agent for treating syphilis.

The efficacy of penicillin for the treatment of syphilis was well established through clinical experience even before the value of randomized controlled clinical trials was recognized. Therefore, nearly all the recommendations for the treatment of syphilis are based on the opinions of individuals knowledgeable about STDs and are reinforced by case series, clinical trials, and fifty years of clinical experience.

Parenteral penicillin G is the only therapy with documented efficacy for syphilis during pregnancy. Pregnant women with syphilis in any stage who report penicillin allergy should be desensitized and treated with penicillin. Skin testing for penicillin allergy might be useful in pregnant women; such testing may also be useful in other patients.

The Jarisch-Herxheimer reaction is an acute febrile reaction frequently accompanied by headache, myalgia, and other symptoms that usually occur within the first 24 hours after any therapy for syphilis. Patients should be informed about this possible adverse reaction. The Jarisch-Herxheimer reaction occurs most frequently among patients who have early syphilis. Antipyretics may be used, but they have not been proven to prevent this reaction. The Jarisch-Herxheimer reaction might induce early labor or cause fetal distress in pregnant women, but this possibly should not prevent or delay therapy.

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, individuals exposed sexually to a patient who has syphilis in any stage should be evaluated clinically and serologically and treated with a recommended regimen, according to the following recommendations:

• Individuals 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 individuals should be treated presumptively.
• Individuals who were exposed >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 followup 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 (>1:32) can be assumed to have early syphilis. However, serologic titers should not be used to differentiate early from late latent syphilis for the purpose of determining treatment.
• Long-term sex partners of patients who have latent syphilis should be evaluated clinically and serologically for syphilis and treated on the basis of the evaluation findings.

For identification of at-risk sexual partners, the periods before treatment 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.

TREATMENT OF PRIMARY AND SECONDARY SYPHILIS

Parenteral penicillin G has been used effectively for more than fifty years to achieve clinical resolution (healing of lesions and prevention of sexual transmission) and to prevent late sequelae. However, no comparative trials have been adequately conducted to guide the selection of an optimal penicillin regimen (dose, duration, preparation). Substantially fewer data are available for nonpenicillin regimens.

After the newborn period (aged >1 month), clinicians should do a CSF examination on children with syphilis to detect asymptomatic neurosyphilis, and review birth and maternal medical records to assess whether such children have congenital or acquired syphilis (see Congenital Syphilis). Children with acquired primary or secondary syphilis should be evaluated (in consultation with child protection services) and treated as follows.

OTHER 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.

Patients who have syphilis and symptoms or signs suggesting neurologic disease (eg, meningitis) or ophthalmic disease (eg, uveitis, iritis, neuroretinitis, or optic neuritis) should have an evaluation that includes CSF analysis and ocular slit-lamp examination. Treatment should be guided by 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 limited number of patients after treatment with the penicillin regimens recommended for primary and secondary syphilis.

Therefore, unless clinical signs or symptoms of neurologic or ophthalmic involvement are present, CSF analysis is not recommended for routine evaluation of patients who have primary or secondary syphilis.

Followup

Treatment failure can occur with any regimen. However, assessing response to treatment is frequently difficult, and definitive criteria for cure or failure have not been established.

Nontreponemal test titers might decline more slowly for individuals who previously had syphilis. Patients should be re-examined clinically and serologically 6 months and 12 months after treatment; more frequent evaluation might be prudent if followup is uncertain.

Patients who have signs or symptoms that persist or recur or who have a sustained fourfold increase in nontreponemal test titer (compared with the maximum or baseline titer at the time of treatment) probably failed treatment or were re-infected. These patients should be retreated and re-evaluated for HIV-infection. Because treatment failure usually cannot be reliably distinguished from re-infection with T. pallidum, a CSF analysis also should be performed. Clinical trial data have demonstrated that 15% of patients with early syphilis treated with the recommended therapy will not achieve a two-dilution decline in nontreponemal titer used to define response at 1 year after treatment.

Failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis probably indicates treatment failure. Individuals for whom titers remain serofast should be re-evaluated for HIV-infection. Optimal management of such patients is unclear.

At a minimum, these patients should receive additional clinical and serologic followup. HIV-infected patients should be evaluated more frequently (at 3-month intervals instead of 6-month intervals). If additional followup cannot be ensured, re-treatment is recommended. Because treatment failure might be the result of unrecognized CNS infection, many specialists recommend CSF examination in such situations.

For retreatment, the majority of STD specialists recommend administering weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks, unless CSF examination indicates that neurosyphilis is present. In rare instances, serologic titers do not decline despite a negative CSF examination and a repeated course of therapy. Additional therapy or repeated CSF examinations are not warranted in these circumstances.

Management of Sex Partners

Management of sex partners follows the general principles set forth earlier.

Penicillin Allergy

Data to support the use of alternatives to penicillin in the treatment of early syphilis are limited. However, several therapies might be effective in nonpregnant, penicillin-allergic patients who have primary or secondary syphilis. Doxycycline (100 mg orally twice daily for 14 days) and tetracycline (500 mg four times daily for 14 days) are regimens that have been used for many years.

Compliance is likely to be better with doxycycline than tetracycline because tetracycline can cause gastrointestinal side effects. Although limited clinical studies, along with biologic and pharmacologic evidence, suggest that ceftriaxone is effective for treating early syphilis, the optimal dose and duration of ceftriaxone therapy have not been defined.

Some specialists recommend 1 g daily either IM or IV for 8 to 10 days. Some patients who are allergic to penicillin also might be allergic to ceftriaxone; in these circumstances, use of an alternative agent might be required. Preliminary data suggest that azithromycin might be effective as a single oral dose of 2 g. However, several cases of azithromycin treatment failure have been reported, and resistance to azithromycin has been documented in several geographic areas.

Close followup of individuals receiving alternative therapies is essential. The use of any of these therapies in HIV-infected individuals has not been well studied; therefore, the use of doxycycline, ceftriaxone, and azithromycin in such individuals must be undertaken with caution.

Patients with penicillin allergy whose compliance with therapy or followup cannot be ensured should be desensitized and treated with benzathine penicillin. Skin testing for penicillin allergy might be useful in some circumstances in which the reagents and expertise are available to perform the test adequately.

Pregnancy

Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin.

TREATMENT OF LATENT SYPHILIS

Latent syphilis is defined as syphilis characterized by seroreactivity without 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' conditions can be diagnosed as early latent syphilis if, within the year preceding the evaluation, they had:

• A documented seroconversion, or fourfold or greater increase in titer of a nontreponemal test
• Unequivocal symptoms of primary or secondary syphilis
• A sex partner documented to have primary, secondary, or early latent syphilis
• Reactive nontreponemal and treponemal tests from a person whose only possible exposure occurred within the previous 12 months.

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. All patients with latent syphilis should have careful examination of all accessible mucosal surfaces (the oral cavity, the perineum in women, the perianal area, and beneath the foreskin in uncircumcised men) to evaluate for internal mucosal lesions. All patients who have syphilis should be tested for HIV-infection.

Treatment of latent syphilis usually does not affect transmission and is intended to prevent late complications. Although clinical experience supports the effectiveness of penicillin in achieving this goal, limited evidence is available for guidance in choosing specific regimens.

The following regimens are recommended for penicillin nonallergic patients who have normal CSF examinations (if performed).

After the newborn period, children with syphilis should have a CSF examination to exclude neurosyphilis. In addition, birth and maternal medical records should be reviewed to assess whether children have 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 penicillin non-allergic children who have acquired syphilis and who have normal CSF examination results.

OTHER CONSIDERATIONS

All individuals who have latent syphilis should be evaluated clinically for evidence of tertiary disease (aortitis, gumma) and syphilitic ocular disease (iritis, uveitis).

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 and gumma)
• Treatment failure
• 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. Some specialists recommend performing a CSF examination on all patients who have latent syphilis and a nontreponemal serologic test of >1:32 or if the patient is HIV-infected with a serum CD4 count <350. However, the likelihood of neurosyphilis in this circumstance is unknown.

If a CSF examination is performed and the results indicate abnormalities consistent with neurosyphilis, the patient should be treated for neurosyphilis (see Neurosyphilis). If a patient misses a dose of penicillin in a course of weekly therapy for late syphilis, the appropriate course of action is unclear. Pharmacologic considerations suggest that an interval of 10 to 14 days between doses of benzathine penicillin for late syphilis or latent syphilis of unknown duration might be acceptable before restarting the sequence of injections.

Missed doses are not acceptable for pregnant patients receiving therapy for late latent syphilis; pregnant women who miss any dose of therapy must repeat the full course of therapy.

Followup

Quantitative nontreponemal serologic tests should be repeated at 6, 12, and 24 months. Patients with a normal CSF examination should be re-treated for latent syphilis if (a) titers increase fourfold, (b) an initially high titer, >1:32, fails to decline at least fourfold (two dilutions) within 12 to 24 months of therapy, or (c) signs or symptoms attributable to syphilis develop. In rare instances, despite a negative CSF examination and a repeated course of therapy, serologic titers still might not decline. In these circumstances, the need for additional therapy or repeated CSF examinations is unclear.

Management of Sex Partners

Management of sex partners follows the general principles set forth earlier.

Penicillin Allergy

The effectiveness of alternatives to penicillin in the treatment of latent syphilis has not been well documented.

Nonpregnant patients allergic to penicillin who have clearly defined early latent syphilis should respond to therapies recommended as alternatives to penicillin for the treatment of primary and secondary syphilis (see Treatment of Primary and Secondary Syphilis). The only acceptable alternatives for the treatment of late latent syphilis or latent syphilis of unknown duration are doxycycline (100 mg orally twice daily) or tetracycline (500 mg orally four times daily), both for 28 days. These therapies should be used only in conjunction with close serologic and clinical followup.

Limited clinical studies, along with biologic and pharmacologic evidence, suggest that ceftriaxone might be effective for treating late latent syphilis or syphilis of unknown duration. However, the optimal dose and duration of ceftriaxone therapy have not been defined, and treatment decisions should be discussed in consultation with a specialist. Some patients who are allergic to penicillin also might be allergic to ceftriaxone; in these circumstances, use of an alternative agent might be required. The efficacy of these alternative regimens in HIV-infected individuals has not been well studied and must be considered with caution.

Pregnancy

Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin.

TREATMENT OF TERTIARY SYPHILIS

Tertiary syphilis refers to gumma and cardiovascular syphilis but not to all neurosyphilis. Patients who are not allergic to penicillin and have no evidence of neurosyphilis should be treated with the following regimen.

OTHER CONSIDERATIONS

Patients who have symptomatic late syphilis should be given a CSF examination before therapy is initiated. Some providers 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 the 2006 guidelines. These patients should be managed in consultation with an infectious diseases specialist.

Followup

Limited information is available about clinical response and followup of patients who have tertiary syphilis.

Penicillin Allergy

Patients allergic to penicillin should be treated according to treatment regimens recommended for late latent syphilis.

Pregnancy

Pregnant patients who are allergic to penicillin should be desensitized, if necessary, and treated with penicillin.

TREATMENT OF NEUROSYPHILIS

Central nervous system involvement can occur during any stage of syphilis. A patient who has clinical evidence of neurologic involvement with syphilis (cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, 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 patients with neurosyphilis. A CSF examination should be performed for all such patients to identify those with abnormalities that require followup CSF examinations to assess treatment response.

Patients who have neurosyphilis or syphilitic eye disease (uveitis, neuroretinitis, optic neuritis) should be treated with the following regimen.

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

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 specialists administer benzathine penicillin, 2.4 million units IM once a week for up to 3 weeks 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 specialists recommend treating patients who have evidence of auditory disease caused by syphilis in the same manner as patients who have neurosyphilis, regardless of CSF examination results. Although systemic steroids are used frequently as adjunctive therapy for otologic syphilis, such drugs have not been proven beneficial.

Followup

If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. Followup CSF examinations can also be used to evaluate changes in the VDRL-CSF or CSF protein after therapy; however, changes in these two parameters occur more slowly than cell counts, and persistent abnormalities may be less important. If the cell count has not decreased after 6 months or if the CSF is not normal after 2 years, re-treatment should be considered.

Recent data on HIV-infected individuals with neurosyphilis suggest that CSF abnormalities might persist for extended periods in these individuals, and close clinical followup is warranted.

Management of Sex Partners

Management of sex partners follows the general principles set forth earlier.

Penicillin Allergy

Ceftriaxone can be used as an alternative treatment for patients with neurosyphilis, although the possibility of cross-reactivity between this agent and penicillin exists. Some specialists recommend ceftriaxone 2 g daily either IM or IV for 10 to 14 days. Other regimens have not been adequately evaluated for treatment of neurosyphilis.

If concern exists regarding the safety of ceftriaxone for a patient with neurosyphilis, the patient should obtain skin testing to confirm penicillin allergy and, if necessary, be desensitized and managed in consultation with a specialist.

Pregnancy

Pregnant patients who are allergic to penicillin should be desensitized, if necessary, and treated with penicillin.

HIV-Infection

Unusual serologic responses have been observed among HIV-infected individuals who have syphilis. The majority of reports have involved serologic titers that were higher than expected, but false-negative serologic test results and delayed appearance of seroreactivity also have been reported. However, unusual serologic responses are uncommon, and the majority of specialists believe that both treponemal and nontreponemal serologic tests for syphilis can be interpreted in the usual manner for the majority of patients who are co-infected with T. pallidum and HIV.

When clinical findings are suggestive of syphilis but serologic tests are nonreactive or their interpretation is unclear, alternative tests (biopsy of a lesion, darkfield examination, DFA staining of lesion material) might be useful for diagnosis. Neurosyphilis should be considered in the differential diagnosis of neurologic disease in HIV-infected individuals.

HIV-positive patients who have early syphilis might be at increased risk for neurologic complications and might have higher rates of treatment failure with currently recommended regimens. Though the magnitude of these risks is not defined it is likely minimal. No treatment regimens for syphilis have been demonstrated to be more effective in preventing neurosyphilis in HIV-infected patients than the syphilis regimens recommended for HIV-negative patients. Careful followup after therapy is essential.

Primary and Secondary Syphilis Among HIV-Infected Individuals

Treatment with benzathine penicillin G, 2.4 million units IM in a single dose, is recommended. Some specialists recommend additional treatments (eg, benzathine penicillin G administered at 1-week intervals for 3 weeks, as recommended for late syphilis) in addition to benzathine penicillin G 2.4 million units IM.

Because CSF abnormalities (mononuclear pleocytosis, elevated protein levels) are common in patients with early syphilis and in individuals with HIV-infection, the clinical and prognostic significance of such CSF abnormalities in HIV-infected individuals with primary or secondary syphilis is unknown.

Although the majority of HIV-infected individuals respond appropriately to standard benzathine penicillin therapy, some specialists recommend intensified therapy when CNS syphilis is suspected in these individuals. They recommend CSF examination before treatment of HIV-infected individuals with early syphilis, with followup CSF examination conducted after treatment in individuals with initial abnormalities.

HIV-infected individuals should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy. Although of unproven benefit, some specialists recommend a CSF examination 6 months after therapy.

HIV-infected individuals who meet the criteria for treatment failure (signs or symptoms that persist or recur, or individuals who have fourfold increase in nontreponemal test titer) should be managed in the same manner as HIV-negative patients (CSF examination and re-treatment). CSF examination and re-treatment also should be strongly considered for individuals whose nontreponemal test titers do not decrease fourfold within 6 to 12 months of therapy. The majority of specialists would re-treat patients with benzathine penicillin G administered as 3 doses of 2.4 million units IM each at weekly intervals, if CSF examinations are normal.

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. The use of alternatives to penicillin has not been well studied in HIV-infected patients.

Latent Syphilis Among HIV-Infected Individuals

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.

Patients with late latent syphilis or syphilis of unknown duration and a normal CSF examination can be treated with benzathine penicillin G, at weekly doses of 2.4 million units for 3 weeks. Patients who have CSF consistent with neurosyphilis should be treated and managed as patients who have neurosyphilis.

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 is performed and treatment administered accordingly. If over 12 to 24 months the nontreponemal titer does not decline fourfold, the CSF examination should be repeated and treatment administered accordingly.

The efficacy of alternative nonpenicillin regimens in HIV-infected individuals has not been well studied. Patients with penicillin allergy whose compliance with therapy or followup cannot be ensured should be desensitized and treated with penicillin. These therapies should be used only in conjunction with close serologic and clinical followup. Limited clinical studies, along with biologic and pharmacologic evidence, suggest that ceftriaxone might be effective. However, optimal dose and duration of ceftriaxone therapy have not been defined.

All pregnant women should be screened serologically for syphilis during the early stages of pregnancy. Most states mandate screening at the first prenatal visit for all women.

Antepartum screening by nontreponemal antibody testing is typical, but in some settings treponemal antibody testing is being used. Pregnant women with reactive treponemal screening tests should have confirmatory testing with nontreponemal tests with titers. In populations in which use of prenatal care is not optimal, RPR-card test screening and treatment (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 to 32 weeks' gestation and at delivery.

Any woman who delivers a stillborn infant after 20 weeks' 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.

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. Serofast low antibody titers may not require treatment; however, persistent higher titer antibody tests might indicate reinfection and require treatment.

Penicillin is effective for preventing maternal transmission to the fetus and for treating fetal infection. Evidence is insufficient to determine specific, recommended penicillin regimens that are optimal. Treatment during pregnancy should be the penicillin regimen appropriate for the stage of syphilis.

Some specialists recommend additional therapy for pregnant women in some settings (eg, a second dose of benzathine penicillin 2.4 million units IM administered 1 week after the initial dose for women who have primary, secondary, or early latent syphilis). During the second half of pregnancy, syphilis management may be facilitated by a sonographic fetal evaluation for congenital syphilis, but this evaluation should not delay therapy. Sonographic signs of fetal or placental syphilis (hepatomegaly, ascites, hydrops, thickened placenta) indicate a greater risk for fetal treatment failure; such cases should be managed in consultation with obstetric specialists. Evidence is insufficient to recommend specific regimens for these situations.

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.

Coordinated prenatal care and treatment followup are vital. Serologic titers should be repeated at 28 to 32 weeks' gestation, at delivery, and following the recommendations for the stage of disease. Serologic titers can be checked monthly in women at high risk for re-infection 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.

The majority of women deliver before their serologic response to treatment can be assessed definitively. Inadequate maternal treatment is likely if delivery occurs within 30 days of therapy, if clinical signs of infection are present at delivery, or if the maternal antibody titer is fourfold higher than the pretreatment titer.

Management of sex partners follows the general principles set forth earlier.

For treatment of syphilis during pregnancy, no proven alternatives to penicillin exist. Pregnant women who have a history of penicillin allergy should be desensitized and treated with penicillin. Skin testing may be helpful.

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 for treatment of maternal infection and prevention of congenital syphilis.

Placental inflammation from congenital infection might increase the risk for perinatal transmission of HIV. All HIV-infected women should be evaluated for infectious syphilis and treated. Data are insufficient to recommend a specific regimen.

CONGENITAL SYPHILIS

Effective prevention and detection of congenital syphilis depends on the identification of syphilis in pregnant women and, therefore, on the routine serologic screening of pregnant women during the first prenatal visit. In communities and populations in which the risk for congenital syphilis is high, serologic testing and a sexual history also should be obtained at 28 weeks' gestation and at delivery. Moreover, as part of the management of pregnant women who have syphilis, information about treatment of sex partners should be obtained to assess the risk for re-infection.

All pregnant women who have syphilis should be tested for HIV-infection. Routine screening of newborn sera or umbilical cord blood is not recommended. Serologic testing of the mother's serum is preferred rather than testing of the infant's serum because the serologic tests performed on infant serum can be nonreactive if the mother's serologic test result is of low titer or was infected late in pregnancy.

No infant or mother should leave the hospital unless the maternal serologic status has been documented at least once during pregnancy, and at delivery in communities and populations in which the risk for congenital syphilis is high.

The First Month of Life

The diagnosis of congenital syphilis is complicated by the transplacental transfer of maternal nontreponemal and treponemal IgG antibodies to the fetus. This transfer of antibodies makes difficult the interpretation of reactive serologic tests for syphilis in infants. Treatment decisions frequently must be made on the basis of (1) identification of syphilis in the mother; (2) adequacy of maternal treatment; (3) presence of clinical, laboratory, or radiographic evidence of syphilis in the infant; and (4) comparison of maternal (at delivery) and infant nontreponemal serologic titers by using the same test and preferably the same laboratory.

All infants born to mothers who have reactive nontreponemal and treponemal test results should be evaluated with a quantitative nontreponemal serologic test (RPR or VDRL) performed on infant serum because umbilical cord blood can become contaminated with maternal blood and could yield a false-positive result. Conducting a treponemal test (TP-PA or FTA-ABS) on a newborn's serum is not necessary. No commercially available immunoglobulin (IgM) test can be recommended.

All infants born to women who have reactive serologic tests for syphilis should be examined thoroughly for evidence of congenital syphilis (nonimmune hydrops, jaundice, hepatosplenomegaly, rhinitis, skin rash, and/or pseudoparalysis of an extremity). Pathologic examination of the placenta or umbilical cord by using specific fluorescent antitreponemal antibody staining is suggested. Darkfield microscopic examination or DFA staining of suspicious lesions or body fluids (eg, nasal discharge) should also be performed.

TREATMENT

The following scenarios describe the evaluation and treatment of infants for congenital syphilis.

Scenario 1.Infants with proven or highly probable disease and

1. an abnormal physical examination that is consistent with congenital syphilis,
2. a serum quantitative nontreponemal serologic titer that is fourfold higher than the mother's titer (the absence of a fourfold or greater titer for an infant does not exclude congenital syphilis) or
3. a positive darkfield or fluorescent antibody test of body fluid(s).

Recommended evaluation:

• CSF analysis for VDRL, cell count, and protein*
• Complete blood count (CBC) and differential and platelet count
• Other tests as clinically indicated (long-bone radiographs, chest radiograph, liver-function tests, cranial ultrasound, ophthalmologic examination, auditory brainstem response)

* CSF test results obtained during the neonatal period can be difficult to interpret; normal values differ by gestational age and are higher in preterm infants. Values as high as 25 white blood cells (WBCs)/mm3 and/or protein of 150 mg/dL might occur among normal neonates; some specialists, however, recommend that lower values (i.e., 5 WBCs/mm3 and protein of 40 mg/dL) be considered the upper limits of normal. Other causes of elevated values should be considered when an infant is being evaluated for congenital syphilis.

If more than 1 day of therapy is missed, the entire course should be restarted. Data are insufficient regarding the use of other antimicrobial agents (eg, ampicillin). When possible, a full 10-day course of penicillin is preferred, even if ampicillin was initially provided for possible sepsis.

The use of agents other than penicillin requires close serologic followup to assess adequacy of therapy. In all other situations, the maternal history of infection with T. pallidum and treatment for syphilis must be considered when evaluating and treating the infant.

Scenario 2.Infants who have a normal physical examination and a serum quantitive nontreponemal serologic titer the same or less than fourfold the maternal titer and the

1. mother was not treated, inadequately treated, or has no documentation of having received treatment;
2. mother was treated with erythromycin or other nonpenicillin regimen (a woman treated with a regimen other than those recommended in these guidelines for treatment should be considered untreated) or
3. mother received treatment <4 weeks before delivery.

Recommended evaluation:

• CSF analysis for VDRL, cell count, and protein
• CBC and differential and platelet count
• Long-bone radiographs

A complete evaluation is not necessary if 10 days of parenteral therapy is administered. However, such evaluations might be useful; a lumbar puncture might document CSF abnormalities that would prompt close followup. Other tests (CBC, platelet count, bone radiographs) may be performed to further support a diagnosis of congenital syphilis.

If a single dose of benzathine penicillin G is used, then the infant must be fully evaluated (through CSF examination, long-bone radiographs, and CBC with platelets), the full evaluation must be normal, and followup must be certain.

If any part of the infant's evaluation is abnormal or not performed or if the CSF analysis is rendered un-interpretable because of contamination with blood, then a 10-day course of penicillin is required. (If the infant's nontreponemal test is nonreactive and the likelihood of the infant being infected is low, certain specialists recommend no evaluation but treatment of the infant with a single IM dose of benzathine penicillin G 50,000 units/kg for possible incubating syphilis, after which the infant should receive close serologic followup.)

Some specialists prefer the 10 days of parenteral therapy if the mother has untreated early syphilis at delivery.

Scenario 3.Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the

1. mother was treated during pregnancy, treatment was appropriate for the stage of infection, and treatment was administered >4 weeks before delivery; and
2. mother has no evidence of reinfection or relapse.

Recommended evaluation:

No evaluation is required.

Scenario 4.Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the

1. mother's treatment was adequate before pregnancy, and
2. mother's nontreponemal serologic titer remained low and stable before and during pregnancy and at delivery (VDRL <1:2; RPR <1:4).

Recommended evaluation:

No evaluation is required.

Older Infants and Children

Children who are identified as having reactive serologic tests for syphilis after the neonatal period (aged >1 month) should have maternal serology and records reviewed to assess whether the child has congenital or acquired syphilis. Any child at risk for congenital syphilis should receive a full evaluation and testing for HIV-infection.

Recommended evaluation:

1. CSF analysis for VDRL, cell count, and protein
2. CBC, differential, and platelet count
3. Other tests as clinically indicated (long-bone radiographs, chest radiograph, liver function tests, abdominal ultrasound, ophthalmologic examination, auditory brain stem response)

If the child has no clinical manifestations of disease, the CSF examination is normal, and the CSF VDRL test result is negative, some specialists would treat with up to 3 weekly doses of benzathine penicillin G, 50,000 U/kg IM.

Any child who is suspected of having congenital syphilis or who has neurologic involvement should be treated with aqueous penicillin G. Some specialists also suggest giving these patients a single dose of benzathine penicillin G, 50,000 units/kg IM after the 10-day course of IV aqueous penicillin. This treatment would also be adequate for children who might have other treponemal infections.

Followup

All seroreactive infants (or infants whose mothers were seroreactive at delivery) should receive careful followup examinations and serologic testing (nontreponemal test) every 2 to 3 months until the test becomes nonreactive or the titer has decreased fourfold. Nontreponemal antibody titers should decline by age 3 months and should be nonreactive by age 6 months if the infant was not infected (ie, if the reactive test result was caused by passive transfer of maternal IgG antibody) or was infected but adequately treated.

The serologic response after therapy might be slower for infants treated after the neonatal period. If these titers are stable or increase after age 6 to 12 months, the child should be given a CSF examination and treated with a 10-day course of parenteral penicillin G.

Treponemal tests should not be used to evaluate treatment response because the results for an infected child can remain positive despite effective therapy. Passively transferred maternal treponemal antibodies can be present in an infant until age 15 months. A reactive treponemal test after age 18 months is diagnostic of congenital syphilis. If the nontreponemal test is nonreactive at this time, no further evaluation or treatment is necessary. If the nontreponemal test is reactive at age 18 months, the infant should be fully (re)evaluated and treated for congenital syphilis.

Infants whose initial CSF evaluations are abnormal should undergo a repeat lumbar puncture approximately every 6 months until the results are normal. A reactive CSF VDRL test or abnormal CSF indices that cannot be attributed to other ongoing illness requires re-treatment for possible neurosyphilis.

Followup of children treated for congenital syphilis after the newborn period should be conducted as is recommended for neonates.

Penicillin Allergy

Infants and children who require treatment for syphilis but who have a history of penicillin allergy or develop an allergic reaction presumed secondary to penicillin should be desensitized and then treated with penicillin. Data are insufficient regarding the use of other antimicrobial agents (eg, ceftriaxone); if a nonpenicillin agent is used, close serologic and CSF followup are indicated.

HIV-Infection

Evidence is insufficient to determine whether infants who have congenital syphilis and whose mothers are co-infected with HIV require different evaluation, therapy, or followup for syphilis than is recommended for all infants.

Penicillin Shortage

During periods when the availability of penicillin is compromised, the following is recommended:

1. For infants with clinical evidence of congenital syphilis (Scenario 1), check local sources for aqueous crystalline penicillin G (potassium or sodium). If IV penicillin G is limited, substitute some or all daily doses with procaine penicillin G (50,000 U/kg/dose IM a day in a single daily dose for 10 days).
   
   If aqueous or procaine penicillin G is not available, ceftriaxone (in doses according to age and weight) may be considered with careful clinical and serologic followup. Ceftriaxone must be used with caution in infants with jaundice.
   
   For infants aged >30 days, use 75 mg/kg IV/IM a day in a single daily dose for 10 to 14 days; however, dose adjustment might be necessary based on birthweight. For older infants, the dose should be 100 mg/kg a day in a single daily dose.
   
   Studies that strongly support ceftriaxone for the treatment of congenital syphilis have not been conducted. Therefore, ceftriaxone should be used in consultation with a specialist in the treatment of infants with congenital syphilis. Management may include a repeat CSF examination at age 6 months if the initial examination was abnormal.
    
2. For infants at risk for congenital syphilis without any clinical evidence of infection (Scenarios 2 and 3), use
   1. procaine penicillin G, 50,000 U/kg/dose IM a day in a single dose for 10 days;
      or
   2. benzathine penicillin G, 50,000 U/kg IM as a single dose.
   
   If any part of the evaluation for congenital syphilis is abnormal, CSF examination is not interpretable, CSF examination was not performed, or followup is uncertain, procaine penicillin G is recommended. A single dose of ceftriaxone is inadequate therapy.
    
3. For premature infants at risk for congenital syphilis but who have no other clinical evidence of infection (Scenarios 2 and 3) and who might not tolerate IM injections because of decreased muscle mass, IV ceftriaxone may be considered with careful clinical and serologic followup (see Penicillin Shortage, number 1). Ceftriaxone dosing must be adjusted to age and birthweight.

MANAGEMENT OF PENICILLIN ALLERGY

No proven alternatives to penicillin are available for treating neurosyphilis, congenital syphilis, or syphilis in pregnant women. Penicillin is also recommended for use, whenever possible, in HIV-infected patients. Of the adult U.S. population, 3% to 10% have experienced an immunoglobulin E (IgE) mediated allergic response to penicillin such as urticaria, angioedema, or anaphylaxis (upper airway obstruction, bronchospasm, or hypotension).

Re-administration of penicillin to these patients can cause severe, immediate reactions. Because anaphylactic reactions to penicillin can be fatal, every effort should be made to avoid administering penicillin to penicillin-allergic patients, unless they undergo acute desensitization to eliminate anaphylactic sensitivity.

An estimated 10% of individuals who report a history of severe allergic reactions to penicillin remain allergic. With the passage of time, the majority of individuals who have had a severe reaction to penicillin stop expressing penicillin-specific IgE. These individuals can be treated safely with penicillin. The results of many investigations indicate that skin testing with the major and minor determinants of penicillin can reliably identify individuals at high risk for penicillin reactions.

Although these reagents are easily generated and have been available for >30 years, only benzylpenicilloyl poly-L-lysine (Pre-Pen [the major determinant]) and penicillin G have been available commercially. Testing with only the major determinant and penicillin G identifies an estimated 90% to 97% of the currently allergic patients. However, because skin testing without the minor determinants would still miss 3% to 10% of allergic patients, and because serious or fatal reactions can occur among these minor-determinant–positive patients, specialists suggest exercising caution when the full battery of skin-test reagents is not available (see box below). An additional challenge has occurred with the recent unavailability of Pre-Pen; however, there are plans for future availability of this product, as well as a companion minor determinant mixture.

Recommendations

If the full battery of skin-test reagents is available, including the major and minor determinants, patients who report a history of penicillin reaction and who are skin-test negative can receive conventional penicillin therapy. Skin-test–positive patients should be desensitized.

If the full battery of skin-test reagents, including the minor determinants, is not available, the patient should be skin tested using benzylpenicilloyl poly-L-lysine (the major determinant) and penicillin G. Patients who have positive test results should be desensitized. Some specialists suggest that individuals who have negative test results should be regarded as probably allergic and should be desensitized. Others suggest that those with negative skin-test results can be test-dosed gradually with oral penicillin in a monitored setting in which treatment for anaphylactic reaction can be provided.

If the major determinant (Pre-Pen) is not available for skin testing, all patients with a history suggesting IgE mediated reactions (anaphylaxis, angioedema, bronchospasm, urticaria) to penicillin should be desensitized in a hospital setting. In patients with reactions not likely to be IgE mediated, outpatient oral desensitization or monitored test doses may be considered.

Penicillin Allergy Skin Testing

Patients at high risk for anaphylaxis, including those who (1) have a history of penicillin-related anaphylaxis, asthma, or other diseases that would make anaphylaxis more dangerous, or (2) are being treated with beta-adrenergic blocking agents, should be tested with 100-fold dilutions of the full-strength skin-test reagents before being tested with full-strength reagents.

In these situations, patients should be tested in a monitored setting in which treatment for an anaphylactic reaction is available. If possible, the patient should not have taken antihistamines recently (chlorpheniramine maleate or terfenadine during the preceding 24 hours, diphenhydramine HCl or hydroxyzine during the preceding 4 days, or astemizole during the preceding 3 weeks).

PROCEDURES

Dilute the antigens either (1) 100-fold for preliminary testing if the patient has had a life-threatening reaction to penicillin, or (2) 10-fold if the patient has had another type of immediate, generalized reaction to penicillin within the preceding year.

Epicutaneous (Prick) Tests

Duplicate drops of skin-test reagent are placed on the volar surface of the forearm. The underlying epidermis is pierced with a 26-gauge needle without drawing blood.

An epicutaneous test is positive if the average wheal diameter after 15 minutes is 4 mm larger than that of negative controls; otherwise, the test is negative. The histamine controls should be positive to ensure that results are not falsely negative because of the effect of antihistaminic drugs.

Intradermal Test

If epicutaneous tests are negative, duplicate 0.02-mL intradermal injections of negative control and antigen solutions are made into the volar surface of the forearm by using a 26- or 27-gauge needle on a syringe. The diameters of the wheals induced by the injections should be recorded.

The following table provides the protocols for desensitization following a positive skin test. Observe an observation period of 30 minutes before parenteral administration of penicillin.

ORAL DESENSITIZATION PROTOCOL FOR POSITIVE SKIN TEST

Penicillin V suspension dose*	Amount** (units/mL)	mL	Units	Cumulative dose (units)
1	1,000	0.1	100	100
2	1,000	0.2	200	300
3	1,000	0.4	400	700
4	1,000	0.8	800	1,500
5	1,000	1.6	1,600	3,100
6	1,000	3.2	3,200	6,300
7	1,000	6.4	6,400	12,700
8	10,000	1.2	12,000	24,700
9	10,000	2.4	24,000	48,700
10	10,000	4.8	48,000	96,700
11	80,000	1.0	80,000	176,700
12	80,000	2.0	160,000	336,700
13	80,000	4.0	320,000	656,700
14	80,000	8.0	640,000	1,296,700
*Interval between doses: 15 minutes; elapsed time: 3 hours and 45 minutes; and cumulative dose: 1.3 million units. **The specific amount of drug was diluted in approximately 30 mL of water and then administered orally. Source: Wendel et al., 1985. Reprinted with permission from New England Journal of Medicine.

DISEASES CHARACTERIZED BY URETHRITIS AND CERVICITIS

Management of Male Patients Who Have Urethritis

Urethritis, as characterized by urethral inflammation, can result from infectious and noninfectious conditions. Symptoms, if present, include discharge of mucopurulent or purulent material, dysuria, or urethral pruritus. Asymptomatic infections are common. N. gonorrhoeae and C. trachomatis are clinically important infectious causes of urethritis. If clinic-based diagnostic tools (Gram stain microscopy) are not available, patients should be treated for both gonorrhea and chlamydia.

Further testing to determine the specific etiology is recommended because both chlamydia and gonorrhea are reportable to state health departments, and a specific diagnosis might enhance partner notification and improve compliance with treatment, especially in exposed partners. Culture, nucleic acid hybridization tests, and nucleic acid amplification tests are available for the detection of both N. gonorrhoeae and C. trachomatis.

Culture and hybridization tests require urethral swab specimens, whereas amplification tests can be performed on urine specimens. Because of their higher sensitivity, amplification tests are preferred for the detection of C. trachomatis.

ETIOLOGY

Several organisms can cause infectious urethritis. The presence of Gram-negative intracellular diplococci (GNID) on urethral smear is indicative of gonorrhea infection, which is frequently accompanied by chlamydial infection.

Nongonococcal urethritis (NGU) is diagnosed when microscopy indicates inflammation without GNID. C. trachomatis is a frequent cause of NGU (15%–55% of cases); however, the prevalence varies by age group, with lower prevalence among older men. The proportion of NGU cases caused by chlamydia has been declining gradually. Complications of NGU among men infected with C. trachomatis include epididymitis, prostatitis, and Reiter's syndrome. Documentation of chlamydia infection is essential because of the need for partner referral for evaluation and treatment.

The etiology of the majority of cases of nonchlamydial NGU is unknown. Ureaplasma urealyticum and Mycoplasma genitalium have been implicated as etiologic agents of NGU in some studies; however, detection of these organisms is frequently difficult. T. vaginalis, HSV, and adenovirus might also cause NGU.

Diagnostic and treatment procedures for these organisms are reserved for situations in which these infections are suspected (contact with trichomoniasis and genital lesions or severe dysuria and meatitis, which might suggest genital herpes) or when NGU is not responsive to therapy. Enteric bacteria have been identified as an uncommon cause of NGU and might be associated with insertive anal sex.

CONFIRMED URETHRITIS

Clinicians should document that urethritis is present. Urethritis can be documented on the basis of any of the following signs or laboratory tests:

• Mucopurulent or purulent discharge.
• Gram stain of urethral secretions demonstrating >5 white blood cells (WBC) per oil-immersion field. (The Gram stain is the preferred rapid diagnostic test for evaluating urethritis. It is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection.) Gonococcal infection is established by documenting the presence of WBC containing GNID, or
• Positive leukocyte esterase test on first-void urine or microscopic examination of first-void urine sediment demonstrating >10 WBC per high-power field.

If none of these criteria are present, treatment should be deferred and the patient tested for N. gonorrhoeae and C. trachomatis and followed closely if test results are negative. If the results demonstrate infection with either N. gonorrhoeae or C. trachomatis, the appropriate treatment should be given and sex partners referred for evaluation and treatment.

Empiric treatment of symptoms without documentation of urethritis is recommended only for patients at high risk for infection who are unlikely to return for a followup evaluation. Such patients should be treated for gonorrhea and chlamydia. Partners of patients treated empirically should be evaluated and treated.

Management of Patients Who Have Nongonococcal Urethritis

DIAGNOSIS

All patients who have confirmed or suspected urethritis should be tested for gonorrhea and chlamydia. Testing for chlamydia is strongly recommended because of the increased utility and availability of highly sensitive and specific testing methods and because a specific diagnosis might enhance partner notification and improve compliance with treatment, especially in the exposed partner.

TREATMENT

Treatment should be initiated as soon as possible after diagnosis. Azithromycin and doxycycline are highly effective for chlamydial urethritis; however, infections with M. genitalium may respond better to azithromycin.

Single-dose regimens have the advantage of improved compliance and directly observed treatment. To improve compliance, ideally the medication should be provided in the clinic or healthcare provider's office.

Followup

Patients should be instructed to return for evaluation if symptoms persist or recur after completion of therapy. Symptoms alone, without documentation of signs or laboratory evidence of urethral inflammation, are not a sufficient basis for retreatment.

Patients should be instructed to abstain from sexual intercourse until 7 days after therapy is initiated, provided their symptoms have resolved and their sex partners have been adequately treated. Persistence of pain, discomfort, and irritative voiding symptoms beyond 3 months should alert the clinician to the possibility of chronic prostatitis/chronic pelvic pain syndrome in men. Individuals whose conditions have been diagnosed as a new STD should receive testing for other STDs, including syphilis and HIV.

Management of Sex Partners

Individuals with NGU should refer for evaluation and treatment all sex partners within the preceding 60 days. Because a specific diagnosis might facilitate partner referral, testing for gonorrhea and chlamydia is encouraged.

Recurrent and Persistent Urethritis

Objective signs of urethritis should be present before initiation of antimicrobial therapy. In individuals who have persistent symptoms after treatment without objective signs of urethritis, the value of extending the duration of antimicrobials has not been demonstrated. Individuals who have persistent or recurrent urethritis can be re-treated with the initial regimen if they did not comply with the treatment regimen or if they were re-exposed to an untreated sex partner. Otherwise, a T. vaginalis culture should be performed using an intraurethral swab or a first-void urine specimen.

Some cases of recurrent urethritis after doxycycline treatment might be caused by tetracycline-resistant U. urealyticum. Urologic examinations usually do not reveal a specific etiology. Approximately 50% of men with chronic nonbacterial prostatitis/chronic pelvic pain syndrome have evidence of urethral inflammation without any identifiable microbial pathogens. If the patient was compliant with the initial regimen and re-exposure can be excluded, the following regimen is recommended.

HIV-Infection

Gonococcal urethritis, chlamydial urethritis, and nongonococcal, nonchlamydial urethritis might facilitate HIV transmission. Patients who have NGU and also are infected with HIV should receive the same treatment regimen as those who are HIV-negative.

Management of Patients Who Have Cervicitis

Two major diagnostic signs characterize cervicitis: (1) a purulent or mucopurulent endocervical exudate visible in the endocervical canal or on an endocervical swab specimen, and (2) sustained endocervical bleeding easily induced by gentle passage of a cotton swab through the cervical os. Either or both signs might be present. Cervicitis frequently is asymptomatic, but some women complain of an abnormal vaginal discharge and intermenstrual vaginal bleeding (eg, after sexual intercourse). A finding of leukorrhea (>10 WBC per high-power field on microscopic examination of vaginal fluid) has been associated with chlamydial and gonococcal infection of the cervix.

In the absence of inflammatory vaginitis, leukorrhea might be a sensitive indicator of cervical inflammation with a high negative predictive value. Although some specialists consider an increased number of polymorphonuclear leukocytes on endocervical Gram stain as being useful in the diagnosis of cervicitis, this criterion has not been standardized. In addition, it has a low positive-predictive value (PPV) for infection with C. trachomatis and N. gonorrhoeae and is not available in the majority of clinical settings.

Finally, although the presence of Gram-negative intracellular diplococci (GNID) on Gram stain of endocervical fluid is specific for the diagnosis of gonococcal cervical infection, it is insensitive because it is observed in only 50% of women with this infection.

ETIOLOGY

When an etiologic organism is isolated in the setting of cervicitis, it is typically C. trachomatis or N. gonorrhoeae. Cervicitis can also accompany trichomoniasis and genital herpes (especially primary HSV-2 infection). However, in the majority of cases of cervicitis, no organism is isolated, especially in women at relatively low risk for recent acquisition of these STDs (eg, women aged >30 years). Limited data indicate that infection with M. genitalium and BV as well as frequent douching might cause cervicitis.

For reasons that are unclear, cervicitis can persist despite repeated courses of antimicrobial therapy. Because the majority of persistent cases of cervicitis are not caused by relapse or reinfection with C. trachomatis or N. gonorrhoeae, other determinants (persistent abnormality of vaginal flora, dou