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STDs Affecting the Reproductive System

Sharon A. Sanders, RN

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The material in this course was adapted 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. 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, douching or exposure to chemical irritants, or idiopathic inflammation in the zone of ectopy) might be involved.

DIAGNOSIS

Because cervicitis might be a sign of upper genital tract infection (endometritis), women who seek medical treatment for a new episode of cervicitis should be assessed for signs of PID and should be tested for C. trachomatis and for N. gonorrhoeae with the most sensitive and specific test available, NAAT. Women with cervicitis should also be evaluated for the presence of BV and trichomoniasis, and these conditions treated, if present. Because the sensitivity of microscopy to detect T. vaginalis is relatively low (approximately 50%), symptomatic women with cervicitis and negative microscopy for trichomonads should receive further testing (using culture or antigen-based detection). Although HSV-2 infection has been associated with cervicitis, the utility of specific testing (culture or serologic testing) for HSV-2 in this setting is unclear. Standardized diagnostic tests for M. genitalium are not commercially available.

Nucleic acid amplification tests for C. trachomatis and N. gonorrhoeae are preferred for the diagnostic evaluation of cervicitis and can be performed on either cervical or urine samples. A finding of >10 WBC in vaginal fluid, in the absence of trichomoniasis, might indicate endocervical inflammation caused specifically by C. trachomatis or N. gonorrhoeae.

TREATMENT

Several factors should affect the decision to provide presumptive therapy for cervicitis or to await the results of diagnostic tests. Treatment with antibiotics for C. trachomatis should be provided in women at increased risk for this common STD (age <25 years, new or multiple sex partners, and unprotected sex), especially if followup cannot be ensured and if a relatively insensitive diagnostic test (not a NAAT) is used. Concurrent therapy for N. gonorrhoeae is indicated if the prevalence of this infection is high (>5%) in the patient population (young age and facility prevalence).

Concomitant trichomoniasis or symptomatic BV should also be treated if detected. For women in whom any component of (or all) presumptive therapy is deferred, the results of sensitive tests for C. trachomatis and N. gonorrhoeae (NAAT) should determine the need for treatment subsequent to the initial evaluation.

Recurrent and Persistent Cervicitis

Women with persistent cervicitis should be re-evaluated for possible re-exposure to an STD, and the vaginal flora re-assessed. If relapse and/or re-infection with a specific STD has been excluded, BV is not present, and sex partners have been evaluated and treated, management options for persistent cervicitis are undefined.

For such women, the value of repeated or prolonged administration of antibiotic therapy for persistent symptomatic cervicitis is unknown. Women who receive such a course should return after treatment so that a determination can be made regarding whether cervicitis has resolved. In women with persistent symptoms that are clearly attributable to cervicitis, ablative therapy may be considered by a gynecologic specialist.

Followup

Followup should be conducted as recommended for the infections for which a woman is treated. If symptoms persist, women should be instructed to return for re-evaluation.

Management of Sex Partners

Management of sex partners of women treated for cervicitis should be appropriate for the identified or suspected STD. Partners should be notified and examined if chlamydia, gonorrhea, or trichomoniasis was identified or suspected in the initial (index) patient and treated for the STDs for which the index patient received treatment. To avoid re-infection, patients and their sex partners should abstain from sexual intercourse until therapy is completed (7 days after a single-dose regimen, or after completion of a 7-day regimen).

HIV-Infection

Patients who have cervicitis and are also infected with HIV should receive the same treatment regimen as those who are HIV-negative. Treatment of cervicitis in HIV-infected women is vital because cervicitis increases cervical HIV shedding. Treatment of cervicitis in HIV-infected women reduces HIV shedding from the cervix and might reduce HIV transmission to susceptible sex partners.

Chlamydial Infections: Adolescents and Adults

In the United States, chlamydial genital infection is the most frequently reported infectious disease, and the prevalence is highest in individuals aged <25 years. Several important sequelae can result from C. trachomatis infection in women; the most serious of these include PID, ectopic pregnancy, and infertility. Some women who have uncomplicated cervical infection already have subclinical upper reproductive tract infection.

Asymptomatic infection is common among both men and women, and to detect chlamydial infections healthcare providers frequently rely on screening tests. Annual screening of all sexually active women aged <25 years is recommended, as is screening of older women with risk factors (those who have a new sex partner or multiple sex partners). The benefits of C. trachomatis screening in women have been demonstrated in areas where screening programs have reduced both the prevalence of infection and rates of PID.

Evidence is insufficient to recommend routine screening for C. trachomatis in sexually active young men, based on feasibility, efficacy, and cost-effectiveness. However, screening of sexually active young men should be considered in clinical settings with a high prevalence of chlamydia (adolescent clinics, correctional facilities, STD clinics). An appropriate sexual risk assessment should be conducted for all individuals and might indicate more frequent screening for some women or certain men.

DIAGNOSIS

C. trachomatis urogenital infection in women can be diagnosed by testing urine or swab specimens collected from the endocervix or vagina. Diagnosis of C. trachomatis urethral infection in men can be made by testing a urethral swab or urine specimen. Rectal C. trachomatisinfections in individuals that engage in receptive anal intercourse can be diagnosed by testing a rectal swab specimen. Culture, direct immunofluorescence, EIA, nucleic acid hybridization tests, and NAATs are available for the detection of C. trachomatis on endocervical and male urethral swab specimens. Nucleic acid amplification tests are the most sensitive for these specimens and are FDA-cleared for use with urine, and some tests are cleared for use with vaginal swab specimens.

The majority of tests, including NAAT and nucleic acid hybridization tests, are not FDA-cleared for use with rectal swab specimens, and chlamydia culture is not widely available for this purpose. Some noncommercial laboratories have initiated NAAT of rectal swab specimens after establishing the performance of the test to meet CLIA requirements. Patients whose condition has been diagnosed as chlamydia also should be tested for other STDs.

TREATMENT

Treating infected patients prevents transmission to sex partners. In addition, treating pregnant women usually prevents transmission of C. trachomatis to infants during birth. Treatment of sex partners helps to prevent re-infection of the index patient and infection of other partners.

Coinfection with C. trachomatis frequently occurs among patients who have gonococcal infection; therefore, presumptive treatment of such patients for chlamydia is appropriate. The following recommended treatment regimens and alternative regimens cure infection and usually relieve symptoms.

A recent meta-analysis of twelve randomized clinical trials of azithromycin versus doxycycline for the treatment of genital chlamydial infection demonstrated that the treatments were equally efficacious, with microbial cure rates of 97% and 98%, respectively. These studies were conducted primarily in populations in which followup was encouraged, adherence to a 7-day regimen was effective, and culture or EIA (rather than the more sensitive NAAT) was used for determining microbiological outcome. Azithromycin should always be available to treat patients for whom compliance with multi-day dosing is in question.

In populations that have erratic healthcare-seeking behavior, poor treatment compliance, or unpredictable followup, azithromycin might be more cost effective because it enables the provision of a single-dose of directly observed therapy.

However, doxycycline costs less than azithromycin and has no higher risk for adverse events. Erythromycin might be less efficacious than either azithromycin or doxycycline, mainly because of the frequent occurrence of gastrointestinal side effects that discourage compliance. Ofloxacin and levofloxacin are effective treatment alternatives but are more expensive and offer no advantage in the dosage regimen. Other quinolones either are not reliably effective against chlamydial infection or have not been evaluated adequately.

To maximize compliance with recommended therapies, medications for chlamydial infections are dispensed on site, so that the first dose can be directly observed. To minimize transmission, individuals treated for chlamydia should be instructed to abstain from sexual intercourse for 7 days after single-dose therapy or until completion of a 7-day regimen.

To minimize the risk for re-infection, patients also should be instructed to abstain from sexual intercourse until all of their sex partners are treated.

Followup

Except in pregnant women, test of cure (repeat testing 3–4 weeks after completing therapy) is not recommended for individuals treated with the recommended or alterative regimens, unless therapeutic compliance is in question, symptoms persist, or re-infection is suspected. Moreover, the validity of chlamydial diagnostic testing at <3 weeks after completion of therapy (to identify patients who did not respond to therapy) has not been established.

False-negative results might occur because of persistent infections involving limited numbers of chlamydial organisms. In addition, NAAT conducted at <3 weeks after completion of therapy in individuals who were treated successfully could yield false-positive results because of the continued presence of dead organisms.

A high prevalence of C. trachomatis infection is observed in women who were treated for chlamydial infection in the preceding several months. The majority of posttreatment infections result from re-infection, frequently occurring because the patient's sex partners were not treated or because the patient resumed sex with a new partner infected with C. trachomatis. Repeat infections confer an elevated risk for PID and other complications when compared with the initial infection. Therefore, recently infected women are a major priority for repeat testing for C. trachomatis.

Clinicians and healthcare agencies should consider advising all women with chlamydial infection to be retested approximately 3 months after treatment. Providers also are strongly encouraged to retest all women treated for chlamydial infection whenever they next seek medical care within the following 3 to 12 months, regardless of whether the patient believes that her sex partners were treated.

Recognizing that retesting is distinct from a test of cure is vital. Limited evidence is available on the benefit of retesting for chlamydia in men previously infected; however, some specialists suggest retesting men approximately 3 months after treatment.

Management of Sex Partners

Patients should be instructed to refer their sex partners for evaluation, testing, and treatment. The following recommendations on exposure intervals are based on limited evaluation.

Sex partners should be evaluated, tested, and treated if they had sexual contact with the patient during the 60 days preceding onset of symptoms in the patient or diagnosis of chlamydia. The most recent sex partner should be evaluated and treated, even if the time of the last sexual contact was >60 days before symptom onset or diagnosis.

If concerns exist that sex partners will not seek evaluation and treatment, or if other management strategies are impractical or unsuccessful, then delivery of antibiotic therapy (either a prescription or medication) by heterosexual male or female patients to their partners might be an option. Limited studies to date have demonstrated a trend toward a decrease in rates of persistent or recurrent chlamydia with this approach compared with standard partner referral.

Male patients must inform female partners of their infection and be given accompanying written materials about the importance of seeking evaluation for PID (especially if symptomatic). Patient-delivered partner therapy is not routinely recommended for MSM because of a high risk for coexisting infections, especially undiagnosed HIV-infection, in their partners.

Patients should be instructed to abstain from sexual intercourse until they and their sex partners have completed treatment. Abstinence should be continued until 7 days after a single-dose regimen or after completion of a 7-day regimen. Timely treatment of sex partners is essential for decreasing the risk for reinfecting the index patient.

Pregnancy

Doxycycline, ofloxacin, and levofloxacin are contraindicated in pregnant women. However, clinical experience and studies suggest that azithromycin is safe and effective. Repeat testing (preferably by NAAT) 3 weeks after completion of therapy with the following regimens is recommended for all pregnant women to ensure therapeutic cure, considering the sequelae that might occur in the mother and neonate if the infection persists. The frequent gastrointestinal side effects associated with erythromycin might discourage patient compliance with the alternative regimens.

Erythromycin estolate is contraindicated during pregnancy because of drug-related hepatotoxicity. The lower dose 14-day erythromycin regimens may be considered if gastrointestinal tolerance is a concern.

HIV-Infection

Patients who have chlamydial infection and also are infected with HIV should receive the same treatment regimen as those who are HIV negative.

Chlamydial Infections: Infants

Prenatal screening of pregnant women can prevent chlamydial infection among neonates. Pregnant women aged <25 years are at high risk for infection. Local or regional prevalence surveys of chlamydial infection can be conducted to confirm the utility of using these recommendations in particular settings.

C. trachomatis infection of neonates results from perinatal exposure to the mother's infected cervix. Neonatal ocular prophylaxis with silver nitrate solution or antibiotic ointments does not prevent perinatal transmission of C. trachomatis from mother to infant. However, ocular prophylaxis with those agents does prevent gonococcal ophthalmia and, therefore, should be continued.

Initial C. trachomatis perinatal infection involves the mucous membranes of the eye, oropharynx, urogenital tract, and rectum, and might be asymptomatic in these locations. C. trachomatis infection in neonates is most frequently recognized by conjunctivitis that develops 5 to 12 days after birth.

C. trachomatis also can cause a subacute, afebrile pneumonia with onset at ages 1 to 3 months. C. trachomatis has been the most frequent identifiable infectious cause of ophthalmia neonatorum, but perinatal chlamydial infections, including ophthalmia and pneumonia, are detected less frequently because of the institution of widespread prenatal screening and treatment of pregnant women.

Ophthalmia Neonatorum Caused by C. Trachomatis

A chlamydial etiology should be considered for all infants aged <30 days who have conjunctivitis, especially if the mother has a history of untreated chlamydia infection.

DIAGNOSIS

Sensitive and specific methods used to diagnose chlamydial ophthalmia in the neonate include both tissue culture and nonculture tests (DFA, EIA, and NAAT). The majority of nonculture tests are not FDA-cleared for the detection of chlamydia from conjunctival swabs, and clinical laboratories must verify the procedure according to CLIA regulations.

Specimens must contain conjunctival cells, not exudate alone. Specimens for culture isolation and nonculture tests should be obtained from the everted eyelid using a Dacron-tipped swab or the swab specified by the manufacturer's test kit. A specific diagnosis of C. trachomatis infection confirms the need for treatment not only for the neonate but also for the mother and her sex partner(s). Ocular exudate from infants being evaluated for chlamydial conjunctivitis should also be tested for N. gonorrhoeae.

Topical antibiotic therapy alone is inadequate for treatment of chlamydial infection and is unnecessary when systemic treatment is administered.

Followup

The efficacy of erythromycin treatment is approximately 80%; a second course of therapy might be required and therefore followup of infants is recommended to determine whether initial treatment was effective. The possibility of concomitant chlamydial pneumonia should be considered.

Management of Mothers and Their Sex Partners

The mothers of infants who have chlamydial infection and the sex partners of these women should be evaluated and treated.

Infant Pneumonia Caused by C. trachomatis

Characteristic signs of chlamydial pneumonia in infants include (1) a repetitive staccato cough with tachypnea, and (2) hyperinflation and bilateral diffuse infiltrates on a chest radiograph.

Wheezing is rare, and infants are typically afebrile. Peripheral eosinophilia (>400 cells/mm³) occurs frequently. Because clinical presentations differ, initial treatment and diagnostic tests should include C. trachomatis for all infants aged 1 to 3 months who possibly have pneumonia (especially with untreated maternal chlamydial infection).

DIAGNOSIS

Specimens for chlamydial testing should be collected from the nasopharynx. Tissue culture is the definitive standard for chlamydial pneumonia. Nonculture tests (EIA, DFA, and NAAT) can be used, although nonculture tests of nasopharyngeal specimens have a lower sensitivity and specificity than nonculture tests of ocular specimens. DFA is the only FDA-cleared test for the detection of C. trachomatis from nasopharyngeal specimens. Tracheal aspirates and lung biopsy specimens, if collected, should be tested for C. trachomatis.

Because of the delay in obtaining test results for chlamydia, the decision to provide treatment for C. trachomatis pneumonia must frequently be based on clinical and radiologic findings. The results of tests for chlamydial infection assist in the management of an infant's illness and determine the need for treating the mother and her sex partner(s).

Followup

The effectiveness of erythromycin in treating pneumonia caused by C. trachomatis is approximately 80%; a second course of therapy might be required. Followup of infants is recommended to determine whether the pneumonia has resolved.

Some infants with chlamydial pneumonia have abnormal pulmonary function tests later in childhood.

Management of Mothers and Their Sex Partners

Mothers of infants who have chlamydia pneumonia and the sex partners of these women should be evaluated and treated according to the recommended treatment of adults for chlamydial infections.

Infants Born to Mothers Who Have Chlamydial Infection

Infants born to mothers who have untreated chlamydia are at high risk for infection; however, prophylactic antibiotic treatment is not indicated, and the efficacy of such treatment is unknown. Infants should be monitored to ensure appropriate treatment if symptoms develop.

Chlamydial Infections Among Children

Sexual abuse must be considered a cause of chlamydial infection in pre-adolescent children, although perinatally transmitted C. trachomatis infection of the nasopharynx, urogenital tract, and rectum might persist for >1 year (see Wild Iris course on STDs and Sexual Assault).

DIAGNOSIS

Nonculture, nonamplified probe tests for chlamydia (EIA, direct fluorescent antibody [DFA]) should not be used because of the possibility of false-positive test results. With respiratory tract specimens, false-positive results can occur because of cross-reaction of test reagents with C. pneumoniae; with genital and anal specimens, false-positive results might occur because of cross-reaction with fecal flora.

OTHER MANAGEMENT CONSIDERATIONS

See Wild Iris course on STDs and Sexual Assault.

Followup

Followup cultures are necessary to ensure that treatment has been effective.

Gonococcal Infections: Adolescents and Adults

In the United States, an estimated 600,000 new N. gonorrhoeae infections occur each year. Gonorrhea is the second most commonly reported bacterial STD. The majority of urethral infections caused by N. gonorrhoeae among men produce symptoms that cause them to seek curative treatment soon enough to prevent serious sequelae, but treatment might not be soon enough to prevent transmission to others.

Among women, several infections do not produce recognizable symptoms until complications (eg, PID) have occurred. Both symptomatic and asymptomatic cases of PID can result in tubal scarring that can lead to infertility or ectopic pregnancy.

Because gonococcal infections among women frequently are asymptomatic, an essential component of gonorrhea control in the United States continues to be the screening of women at high risk for STDs. The U.S. Preventive Services Task Force (USPSTF) recommends that clinicians screen all sexually active women, including those who are pregnant, for gonorrhea infection if they are at increased risk. Women aged <25 years are at highest risk for gonorrhea infection.

Other risk factors for gonorrhea include a previous gonorrhea infection, other sexually transmitted infections, new or multiple sex partners, inconsistent condom use, commercial sex work, and drug use. The prevalence of gonorrhea infection varies widely among communities and patient populations. The USPSTF does not recommend screening for gonorrhea in men and women who are at low risk for infection.

DIAGNOSIS

Because of high specificity (>99%) and sensitivity (>95%), a Gram stain of a male urethral specimen that demonstrates polymorphonuclear leukocytes with intracellular Gram-negative diplococci can be considered diagnostic for infection with N. gonorrhoeae in symptomatic men. However, because of lower sensitivity, a negative Gram stain should not be considered sufficient for ruling out infection in asymptomatic men.

In addition, Gram stain of endocervical, pharyngeal, or rectal specimens are not sufficient to detect infection and therefore are not recommended. Specific testing for N. gonorrhoeae is recommended because of the increased utility and availability of highly sensitive and specific testing methods and because a specific diagnosis might enhance partner notification.

Specific diagnosis of infection with N. gonorrhoeae may be performed by testing endocervical, vaginal, male urethral, or urine specimens. Culture, nucleic acid hybridization tests, and NAAT are available for the detection of genitourinary infection with N. gonorrhoeae. Culture and nucleic acid hybridization tests require female endocervical or male urethral swab specimens.

NAAT offer the widest range of testing specimen types because they are FDA-cleared for use with endocervical swabs, vaginal swabs, male urethral swabs, and female and male urine. However, product inserts for each NAAT vendor must be carefully examined to assess current indications because FDA-cleared specimen types might vary.

In general, culture is the most widely available option for the diagnosis of infection with N. gonorrhoeae in nongenital sites (rectum, pharynx). Nonculture tests are not FDA-cleared for use in the rectum and pharynx. Some NAATs have the potential to cross-react with nongonococcal Neisseria and related organisms that are commonly found in the throat.

Some noncommercial laboratories have initiated NAAT of rectal and pharyngeal swab specimens after establishing the performance of the test to meet CLIA requirements.

Because nonculture tests cannot provide antimicrobial susceptibility results, in cases of persistent gonococcal infection after treatment, clinicians should perform both culture and antimicrobial susceptibility testing.

All patients tested for gonorrhea should be tested for other STDs, including chlamydia, syphilis, and HIV.

DUAL THERAPY FOR GONORRHEA AND CLAMYDIA

Patients infected with N. gonorrhoeae frequently are co-infected with C. trachomatis; this finding has led to the recommendation that patients treated for gonococcal infection also be treated routinely with a regimen that is effective against uncomplicated genital C. trachomatisinfection. Because the majority of gonococci in the United States are susceptible to doxycycline and azithromycin, routine co-treatment might also hinder the development of antimicrobial-resistant N. gonorrhoeae.

Because of the high sensitivity of NAATs for chlamydial infection, patients with a negative chlamydial NAAT result at the time of treatment for gonorrhea do not need to be treated for chlamydia as well. However, if chlamydial test results are not available or if a non-NAAT was negative for chlamydia, patients should be treated for both gonorrhea and chlamydia.

QUINOLONE-RESISTANT N. GONORRHOEAE (QRNG)

Quinolone-resistant N. gonorrhoeae (QRNG) continues to spread, making the treatment of gonorrhea with quinolones such as ciprofloxacin inadvisable in many areas and populations. Resistance to ciprofloxacin usually indicates resistance to other quinolones as well. Quinolone-resistant N. gonorrhoeae is common in parts of Europe, the Middle East, Asia, and the Pacific; in the United States, QRNG is becoming increasingly common. Previously, CDC had advised that quinolones not be used in California and Hawaii because of the high prevalence of QRNG in these areas. The prevalence of QRNG has increased in other areas of the United States, which has resulted in changes in recommended treatment regimens by other states and local areas. QRNG prevalence will continue to increase, and quinolones will eventually not be advisable for the treatment of gonorrhea.

The CDC website (http://www.cdc.gov/std/gisp) or state health departments can provide the most current information. In 2004, of 6,322 isolates collected by CDC's Gonococcal Isolate Surveillance Project (GISP), 6.8% were resistant to ciprofloxacin (minimum inhibitory concentrations >1.0 μg/mL). Excluding isolates from California and Hawaii, 3.6% of isolates were QRNG. Quinolone-resistant N. gonorrhoeae was more common among MSM than among heterosexual men (23.9% vs 2.9%). In 2004, the incidence of QRNG among heterosexual men outside of California and Hawaii was 1.4%.

Quinolones should not be used for the treatment of gonorrhea among MSM or in areas with increased QRNG prevalence in the United States (eg, California, Hawaii) or for infections acquired while traveling abroad. Because oral alternatives to quinolones are limited, quinolones may continue to be used for heterosexual men and women in areas and populations not known to have elevated levels of resistance.

Clinicians should obtain information on the sexual behavior and recent travel history (including histories from sex partners) of individuals to be treated for gonorrhea to ensure appropriate antibiotic therapy.

Resistance of N. gonorrhoeae to fluoroquinolones and other antimicrobials is expected to continue to spread; therefore, state and local surveillance for antimicrobial resistance is crucial for guiding local therapy recommendations. GISP, which samples approximately 3% of all U.S. men who have gonococcal infections, is a mainstay of surveillance.

However, surveillance by clinicians also is critical. Clinicians who have diagnosed N. gonorrhoeae infection in an individual who was previously treated with a recommended regimen and who probably has not been re-exposed should perform culture and susceptibility testing of relevant clinical specimens and report the case to the local health department.

OTHER CONSIDERATIONS

Uncomplicated Gonococcal Infections of the Cervix, Urethra, and Rectum

MSM or Heterosexuals with a History of Recent Travel*

To maximize compliance with recommended therapies, medications for gonococcal infections should be dispensed on site. Ceftriaxone in a single injection of 125 mg provides sustained, high bactericidal levels in the blood. Extensive clinical experience indicates that ceftriaxone is safe and effective for the treatment of uncomplicated gonorrhea at all anatomic sites, curing 98.9% of uncomplicated urogenital and anorectal infections in published clinical trials.

Cefixime has an antimicrobial spectrum similar to that of ceftriaxone, but the 400 mg oral dose does not provide as high, nor as sustained, a bactericidal level as that provided by the 125 mg dose of ceftriaxone. In published clinical trials, the 400 mg dose cured 97.4% of uncomplicated urogenital and anorectal gonococcal infections. The advantage of cefixime is that it can be administered orally. Updates on the availability of cefixime are available from CDC or state health departments.

Ciprofloxacin is no longer universally effective against N. gonorrhoeae in the United States. However, ciprofloxacin is safe, inexpensive, and can be administered orally. In published clinical trials of uncomplicated urogenital and anorectal infections in the absence of QRNG, a dose of 500 mg of ciprofloxacin provides sustained bactericidal levels with cure rates of 99.8%. If QRNG is suspected, ceftriaxone IM or cefixime PO (by mouth) should be used. If neither of these regimens are feasible options, then one of the alternative nonquinolone regimens in this report should be considered.

Like ciprofloxacin, ofloxacin is no longer universally effective against N. gonorrhoeae in the United States. The 400 mg oral dose of ofloxacin has been effective for treatment of uncomplicated urogenital and anorectal infections; in clinical trials, 98.6% of infections were cured. Levofloxacin, the active l-isomer of ofloxacin, can be used in place of ofloxacin as a single dose of 250 mg.

Several other antimicrobials are active against N. gonorrhoeae, but none have substantial advantages over the recommended regimens. Spectinomycin is expensive and must be injected; however, it has been effective in published clinical trials, curing 98.2% of uncomplicated urogenital and anorectal gonococcal infections. Spectinomycin is useful for the treatment of patients who cannot tolerate cephalosporins and quinolones.

Single-dose cephalosporin regimens (other than ceftriaxone 125 mg IM and cefixime 400 mg orally) that are safe and highly effective against uncomplicated urogenital and anorectal gonococcal infections include ceftizoxime (500 mg, administered IM), cefoxitin (2 g, administered IM with probenecid 1 g orally), and cefotaxime (500 mg, administered IM). None of the injectable cephalosporins offer any advantage over ceftriaxone.

Single-dose quinolone regimens include gatifloxacin 400 mg orally, norfloxacin 800 mg orally, and lomefloxacin 400 mg orally. These regimens appear to be safe and effective for the treatment of uncomplicated gonorrhea, but data regarding their use are limited. None of the regimens appear to offer any advantage over ciprofloxacin, ofloxacin, or levofloxacin, and they are not effective against QRNG.

Some evidence suggests that cefpodoxime and cefuroxime axetil 1 g orally might be additional oral alternatives in the treatment of uncomplicated urogenital gonorrhea; additional information on alternative oral regimens are available at http://www.cdc.gov/std.

Cefpodoxime proxetil 200 mg PO is less active against N. gonorrhoeae than cefixime and also does not quite meet the minimum efficacy criteria (demonstrated efficacy with lower 95% confidence interval [CI] of >95% in summed clinical trials) with cure rates, 96.5% (CI = 94.8%−98.9%) for urogenital and rectal infection. Efficacy in treating pharyngeal infection is unsatisfactory at 78.9% (CI = 54.5%−94%). Clinical studies are being conducted to assess whether cefpodoxime 400 mg PO is an acceptable oral alternative.

Treatment with cefuroxime axetil 1 g PO does not quite meet the minimum efficacy criteria for urogenital and rectal infection (95.9%; CI = 94.5%−97.3%) and, its efficacy in treating pharyngeal infection is unacceptable (56.9%; CI = 42.2%−70.7%).

Azithromycin 2 g orally is effective against uncomplicated gonococcal infection but is expensive and causes gastrointestinal distress and is not recommended for treatment of gonorrhea.

Although azithromycin 1 g theoretically meets alternative regimen criteria, it is not recommended because of concerns regarding the possible rapid emergence of antimicrobial resistance. N. gonorrhoeae in the United States is not adequately susceptible to penicillins, tetracyclines, and macrolides (eg, erythromycin) for these antimicrobials to be recommended.

Uncomplicated Gonococcal Infections of the Pharynx

Gonococcal infections of the pharynx are more difficult to eradicate than infections at urogenital and anorectal sites. Few antimicrobial regimens can reliably cure >90% of gonococcal pharyngeal infections. Although chlamydial coinfection of the pharynx is unusual, co-infection at genital sites sometimes occurs. Therefore, treatment for both gonorrhea and chlamydia is recommended.

Followup

Patients who have uncomplicated gonorrhea and who are treated with any of the recommended or alternative regimens do not need a test of cure. Patients who have symptoms that persist after treatment should be evaluated by culture for N. gonorrhoeae, and any gonococci isolated should be tested for antimicrobial susceptibility. Persistent urethritis, cervicitis, or proctitis also might be caused by C. trachomatis or other organisms.

A high prevalence of N. gonorrhoeae infection is observed in patients who have had gonorrhea in the preceding several months. The majority of infections identified after treatment with one of the recommended regimens result from re-infection rather than treatment failure, indicating a need for improved patient education and referral of sex partners.

Repeat infection might confer an elevated risk for PID and other complications, when compared with initial infection.

Clinicians should consider advising all patients with gonorrhea to be retested 3 months after treatment. If patients do not seek medical care for retesting in 3 months, providers are encouraged to test these patients whenever they next seek medical care within the following 12 months, whether or not the patient believes sex partners were treated.

Retesting is distinct from test of cure to detect therapeutic failure, which is not recommended.

Management of Sex Partners

Effective clinical management of patients with treatable STDs requires treatment of the patients' recent sex partners to prevent re-infection and curtail further transmission. Patients should be instructed to refer their sex partners for evaluation and treatment. Sex partners of patients with N. gonorrhoeae infection whose last sexual contact with the patient was within 60 days before onset of symptoms or diagnosis of infection in the patient should be evaluated and treated for N. gonorrhoeae and C. trachomatis infections.

If a patient's last sexual intercourse was >60 days before onset of symptoms or diagnosis, the patient's most recent sex partner should be treated. Patients should be instructed to avoid sexual intercourse until therapy is completed and until they and their sex partners no longer have symptoms.

For patients with gonorrhea whose partners' treatment cannot be ensured or is unlikely, delivery of antibiotic therapy (either a prescription or medication) by heterosexual male or female patients to their partners is an option. Use of this approach should always be accompanied by efforts to educate partners about symptoms and to encourage partners to seek clinical evaluation. Male patients must inform female partners of their infection and be given accompanying materials about the importance of seeking medical evaluation for PID (especially if symptomatic).

Possible undertreatment of PID in female partners and possible missed opportunities to diagnose other STDs are of concern and have not been evaluated in comparisons with patient-delivered therapy and partner referral. Patient-delivered therapy for patients with gonorrhea should routinely include treatment for chlamydia. This approach should not be considered a routine partner management strategy in MSM because of the high risk of coexisting undiagnosed STDs or HIV-infection.

Allergy, Intolerance, and Adverse Reactions

Individuals who cannot tolerate cephalosporins or quinolones should be treated with spectinomycin. Because spectinomycin is unreliable (52% effective) against pharyngeal infections, patients who have suspected or known pharyngeal infection should have a pharyngeal culture 3 to 5 days after treatment to verify eradication of infection.

Pregnancy

Pregnant women should not be treated with quinolones or tetracyclines. Those infected with N. gonorrhoeae should be treated with a recommended or alternate cephalosporin.

Women who cannot tolerate a cephalosporin should be administered a single 2 g dose of spectinomycin IM. Either azithromycin or amoxicillin is recommended for treatment of presumptive or diagnosed C. trachomatis infection during pregnancy (see Chlamydial Infections).

Administration of Quinolones to Adolescents

Fluoroquinolones have not been recommended for individuals aged <18 years because studies have indicated that they can damage articular cartilage in some young animals. However, no joint damage attributable to quinolone therapy has been observed in children treated with prolonged ciprofloxacin regimens. Therefore, children who weigh >45 kg can be treated with any regimen recommended for adults (See Gonococcal Infections).

HIV-Infection

Patients who have gonococcal infection and also are infected with HIV should receive the same treatment regimen as those who are HIV-negative.

Gonococcal Conjunctivitis

In the only published study of the treatment of gonococcal conjunctivitis among U.S. adults, all 12 study participants responded to a single 1 g IM injection of ceftriaxone. The following recommendation reflects the opinions of consultants knowledgeable in the field of STDs.

Management of Sex Partners

Patients should be instructed to refer their sex partners for evaluation and treatment.

Disseminated Gonococcal Infection (DGI)

Disseminated gonococcal infection (DGI) results from gonococcal bacteremia. It frequently results in petechial or pustular acral skin lesions, asymmetrical arthralgia, tenosynovitis, or septic arthritis. The infection is complicated occasionally by perihepatitis and rarely by endocarditis or meningitis. Some strains of N. gonorrhoeae that cause DGI may cause minimal genital inflammation. No studies on the treatment of DGI among adults have been published since publication of the 2002 CDC STD guidelines. DGI treatment recommendations reflect the opinions of consultants. No treatment failures have been reported with the recommended regimens.

Hospitalization is recommended for initial therapy, especially for patients who might not comply with treatment, for those in whom diagnosis is uncertain, and for those who have purulent synovial effusions or other complications. Patients should be examined for clinical evidence of endocarditis and meningitis. Patients treated for DGI should be treated presumptively for concurrent C. trachomatis infection, unless appropriate testing excludes this infection.

All of the preceding regimens should be continued for 24 to 48 hours after improvement begins, at which time therapy may be switched to one of the following regimens to complete at least 1 week of antimicrobial therapy.

Management of Sex Partners

Gonococcal infection frequently is asymptomatic in sex partners of patients who have DGI. As with uncomplicated gonococcal infections, patients should be instructed to refer their sex partners for evaluation and treatment.

Gonococcal Meningitis and Endocarditis

Therapy for meningitis should be continued for 10 to 14 days; therapy for endocarditis should be continued for at least 4 weeks. Treatment of complicated DGI should be undertaken in consultation with a specialist.

Management of Sex Partners

Patients should be instructed to refer their sex partners for evaluation and treatment.

Gonococcal Infections Among Infants

Gonococcal infection among infants usually results from exposure to infected cervical exudate at birth. It is usually an acute illness that manifests 2 to 5 days after birth. The prevalence of infection among infants depends on the prevalence of infection among pregnant women, whether pregnant women are screened for gonorrhea, and whether newborns receive ophthalmia prophylaxis. The most severe manifestations of N. gonorrhoeae infection in newborns are ophthalmia neonatorum and sepsis, which can include arthritis and meningitis. Less severe manifestations include rhinitis, vaginitis, urethritis, and re-infection at sites of fetal monitoring.

OPHTHALMIA NEONATORUM CAUSED BY N. GONORRHOEAE

In the United States, although N. gonorrhoeae causes ophthalmia neonatorum less frequently than C. trachomatis and nonsexually transmitted agents, identifying and treating this infection is especially important because ophthalmia neonatorum can result in perforation of the globe of the eye that results in blindness.

DIAGNOSIS

Infants at increased risk for gonococcal ophthalmia are those who do not receive ophthalmia prophylaxis and those whose mothers have had no prenatal care or whose mothers have a history of STDs or substance abuse. Gonococcal ophthalmia is strongly suspected when intracellular Gram-negative diplococci are identified in conjunctival exudate, justifying presumptive treatment for gonorrhea after appropriate cultures for N. gonorrhoeae are obtained. Appropriate chlamydial testing should be done simultaneously. Presumptive treatment for N. gonorrhoeae might be indicated for newborns who are at increased risk for gonococcal ophthalmia and who have conjunctivitis but do not have gonococci in a Gram-stained smear of conjunctival exudate.

In all cases of neonatal conjunctivitis, conjunctival exudates should be cultured for N. gonorrhoeae and tested for antibiotic susceptibility before a definitive diagnosis is made. A definitive diagnosis is vital because of the public health and social consequences of a diagnosis of gonorrhea.

Nongonococcal causes of neonatal ophthalmia include Moraxella catarrhalis and other Neisseria species that are indistinguishable from N. gonorrhoeae on Gram-stained smear but can be differentiated in the microbiology laboratory.

Topical antibiotic therapy alone is inadequate and is unnecessary if systemic treatment is administered.

OTHER CONSIDERATIONS

Simultaneous infection with C. trachomatis should be considered when a patient does not improve after treatment. Both mother and infant should be tested for chlamydial infection at the same time that gonorrhea testing is conducted. Ceftriaxone should be administered cautiously to hyperbilirubinemic infants, especially those born prematurely.

Followup

Infants who have gonococcal ophthalmia should be hospitalized and evaluated for signs of disseminated infection (sepsis, arthritis, meningitis). One dose of ceftriaxone is adequate therapy for gonococcal conjunctivitis.

Management of Mothers and Their Sex Partners

The mothers of infants who have gonococcal infection and the mothers' sex partners should be evaluated and treated according to the recommendations for treating gonococcal infections in adults.

DGI and Gonococcal Scalp Abscesses in Newborns

Sepsis, arthritis, and meningitis (or any combination thereof) are rare complications of neonatal gonococcal infection. Localized gonococcal infection of the scalp can result from fetal monitoring through scalp electrodes. Detection of gonococcal infection in neonates who have sepsis, arthritis, meningitis, or scalp abscesses requires cultures of blood, CSF, and joint aspirate on chocolate agar. Specimens obtained from the conjunctiva, vagina, oropharynx, and rectum that are cultured on gonococcal-selective medium are useful for identifying the primary site(s) of infection, especially if inflammation is present. Positive Gram-stained smears of exudate, CSF, or joint aspirate provide a presumptive basis for initiating treatment for N. gonorrhoeae. Diagnoses based on Gram-stained smears or presumptive identification of cultures should be confirmed with definitive tests on culture isolates.

Infants Whose Mothers Have Gonococcal Infection

Infants born to mothers who have untreated gonorrhea are at high risk for infection.

Both mother and infant should be tested for chlamydial infection.

Followup

Followup examination is not required.

Management of Mothers and Their Sex Partners

The mothers of infants who have gonococcal infection and the mothers' sex partners should be evaluated and treated according to the recommendations for treatment of gonococcal infections in adults.

Gonococcal Infections Among Children

Sexual abuse is the most frequent cause of gonococcal infection in pre-adolescent children. Vaginitis is the most common manifestation of gonococcal infection in pre-adolescent girls. Pelvic inflammatory disease following vaginal infection is probably less common in children than among adults. Among sexually abused children, anorectal and pharyngeal infections with N. gonorrhoeae are common and frequently asymptomatic.

DIAGNOSIS

Because of the legal implications of a diagnosis of N. gonorrhoeae infection in a child, only standard culture procedures for the isolation of N. gonorrhoeae should be used for children. Nonculture gonococcal tests for gonococci (Gram-stained smear, nucleic acid hybridization tests, EIA, and NAAT) should not be used without standard culture; none of these tests have been approved by FDA for use with specimens obtained from the oropharynx, rectum, or genital tract of children. Specimens from the vagina, urethra, pharynx, or rectum should be streaked onto selective media for isolation of N. gonorrhoeae, and all presumptive isolates of N. gonorrhoeae should be identified definitively by at least two tests that involve different principles (biochemical, enzyme substrate, serologic). Isolates should be preserved to enable additional or repeated testing.

Fluoroquinolones have not been recommended for individuals aged <18 years because they have damaged articular cartilage in young animals. However, no such joint damage clearly attributable to quinolone therapy has been observed in children, even in those receiving multiple-dose regimens.

Followup

Followup cultures are unnecessary if ceftriaxone is used. If spectinomycin is used to treat pharyngitis, a followup culture is necessary to ensure that treatment was effective.

OTHER CONSIDERATIONS

Only parenteral cephalosporins are recommended for use in children. Ceftriaxone is approved for all gonococcal infections in children; cefotaxime is approved for gonococcal ophthalmia only. Oral cephalosporins used for treatment of gonococcal infections in children have not been adequately evaluated.

All children who have gonococcal infections should be evaluated for co-infection with syphilis and C. trachomatis. (For a discussion of concerns regarding sexual assault, refer to the Wild Iris course, STDs Related to Sexual Assault).

Ophthalmia Neonatorum Prophylaxis

To prevent gonococcal ophthalmia neonatorum, a prophylactic agent should be instilled into the eyes of all newborn infants; this procedure is required by law in the majority of states. All of the recommended prophylactic regimens in this section prevent gonococcal ophthalmia. However, the efficacy of these preparations in preventing chlamydial ophthalmia is less clear, and they do not eliminate nasopharyngeal colonization by C. trachomatis. The diagnosis and treatment of gonococcal and chlamydial infections in pregnant women is the best method for preventing neonatal gonococcal and chlamydial disease. Not all women, however, receive prenatal care. Ocular prophylaxis is warranted because it can prevent sight-threatening gonococcal ophthalmia and because it is safe, easy to administer, and inexpensive.

One of the recommended preparations should be instilled into both eyes of every neonate as soon as possible after delivery.

If prophylaxis is delayed (not administered in the delivery room), a monitoring system should be established to ensure that all infants receive prophylaxis. All infants should be administered ocular prophylaxis, whether they are delivered vaginally or by cesarean section. Single-use tubes or ampules are preferable to multiple-use tubes. Bacitracin is not effective. Use of povidone iodine has not been studied adequately.

DISEASES CHARACTERIZED BY VAGINAL DISCHARGE

Management of Patients Who Have Vaginal Infections

Vaginitis is usually characterized by a vaginal discharge and/or vulvar itching and irritation, and a vaginal odor might be present. The three diseases most frequently associated with vaginal discharge are BV (replacement of the normal vaginal flora by an overgrowth of anaerobic microorganisms, mycoplasmas, and Gardnerella vaginalis), trichomoniasis (T. vaginalis), and candidiasis (usually caused by Candida albicans). Cervicitis can sometimes cause a vaginal discharge.

Although vulvovaginal candidiasis (VVC) usually is not transmitted sexually, it is included in this section because it is frequently diagnosed in women being evaluated for STDs. Various diagnostic methods are available to identify the etiology of an abnormal vaginal discharge. Laboratory testing fails to identify the cause of vaginitis in a minority of women.

The cause of vaginal symptoms usually can be determined by pH and microscopic examination of fresh samples of the discharge. The pH of the vaginal secretions can be determined by narrow-range pH paper; an elevated pH (>4.5) is common with BV or trichomoniasis but might not be highly specific.

Discharge can be further examined by diluting one sample in 1 to 2 drops of 0.9% normal saline solution on one slide and a second sample in 10% potassium hydroxide (KOH) solution. An amine odor detected immediately after applying KOH suggests BV. Cover slips are placed on the slides, and they are examined under a microscope at low and high dry power. Motile T. vaginalis or clue cells (epithelial cells with borders obscured by small bacteria), which are characteristic of BV, usually are identified easily in the saline specimen.

While blood cells without evidence of trichomonads or yeast are usually suggestive of cervicitis (see Cervicitis). The yeast or pseudohyphae of Candida species are more easily identified in the KOH specimen. However, the absence of trichomonads or pseudohyphae does not rule out these infections because several studies have demonstrated the presence of these pathogens by culture or PCR after a negative microscopic examination.

The presence of objective signs of vulvar inflammation in the absence of vaginal pathogens, along with a minimal amount of discharge, suggests the possibility of mechanical, chemical, allergic, or other noninfectious irritation of the vulva. Culture for T. vaginalis is more sensitive than microscopic examination. In settings where microscopy is not available, alternative point-of-care tests may be used to diagnose vaginitis.

Bacterial Vaginosis

Bacterial vaginosis (BV) is a polymicrobial clinical syndrome resulting from replacement of the normal H₂O₂–producing Lactobacillus sp. in the vagina with high concentrations of anaerobic bacteria (Prevotella sp. and Mobiluncus sp.), G. vaginalis, and Mycoplasma hominis. Bacterial vaginosis is the most prevalent cause of vaginal discharge or malodor; however, more than 50% of women with BV are asymptomatic.

The cause of the microbial alteration is not fully understood. BV is associated with having multiple sex partners, a new sex partner, douching, and lack of vaginal lactobacilli; whether BV results from acquisition of a sexually transmitted pathogen is unclear. Women who have never been sexually active are rarely affected. Treatment of male sex partners has not been beneficial in preventing the recurrence of BV.

DIAGNOSIS

Bacterial vaginosis can be diagnosed by the use of clinical criteria or Gram stain. Clinical criteria require three of the following symptoms or signs:

• Homogeneous, thin, white discharge that smoothly coats the vaginal walls
• presence of clue cells on microscopic examination
• pH of vaginal fluid >4.5 and
• a fishy odor of vaginal discharge before or after addition of 10% KOH (the whiff test).

When a Gram stain is used, determining the relative concentration of lactobacilli (long Gram-positive rods), Gram-negative and Gram-variable rods and cocci (G. vaginalis, Prevotella, Porphyromonas, and Peptostreptococci), and curved Gram-negative rods (Mobiluncus) characteristic of BV is considered the gold standard laboratory method for diagnosing BV. Culture of G. vaginalis is not recommended as a diagnostic tool because it is not specific. However, a DNA probe-based test for high concentrations of G. vaginalis (Affirm VP III, Becton Dickinson, Sparks, Maryland) might have clinical utility.

Cervical Pap tests have no clinical utility for the diagnosis of BV because of low sensitivity. Other commercially available tests that might be useful for the diagnosis of BV include a card test for the detection of elevated pH and trimethylamine (QuickVue Advance Quidel, San Diego, California) and proline aminopeptidase (Pip Activity TestCard, Quidel, San Diego, California).

TREATMENT

The established benefits of therapy for BV in nonpregnant women are to (1) relieve vaginal symptoms and signs of infection, and (2) reduce the risk for infectious complications after abortion or hysterectomy. Other potential benefits might include a reduction in risk for other infections (HIV, other STDs). All women who have symptomatic disease require treatment.

Bacterial vaginosis during pregnancy is associated with adverse pregnancy outcomes, including premature rupture of the membranes, preterm labor, preterm birth, intra-amniotic infection, and postpartum endometritis. The established benefit of therapy for BV in pregnant women is to relieve vaginal symptoms and signs of infection. Additional potential benefits of therapy include (1) reducing the risk for infectious complications associated with BV during pregnancy, and (2) reducing the risk for other infections.

The results of several investigations indicate that treatment of pregnant women with BV who are at high risk for preterm delivery (those who previously delivered a premature infant) might reduce the risk for prematurity. Therefore, clinicians should consider evaluation and treatment of high-risk pregnant women with asymptomatic BV.

The bacterial flora that characterizes BV have been recovered from the endometria and salpinges of women who have PID. BV has been associated with endometritis, PID, and vaginal cuff cellulitis after invasive procedures, including endometrial biopsy, hysterectomy, hysterosalpingography, placement of an IUD, cesarean section, and uterine curettage.

The results of two randomized controlled trials have indicated that treatment of BV with metronidazole substantially reduced postabortion PID. Three trials that evaluated the use of anaerobic antimicrobial coverage (metronidazole) for routine operative prophylaxis before abortion and seven trials that evaluated this additional coverage for women undergoing hysterectomy demonstrated a substantial reduction in postoperative infectious complications.

Because of the increased risk for postoperative infection associated with BV, some specialists recommend that, before performing surgical abortion or hysterectomy, providers should screen and treat women with BV in addition to providing routine prophylaxis. However, more information is needed before recommending treatment of asymptomatic BV before other invasive procedures.

Patients should be advised to avoid consuming alcohol during treatment with metronidazole and for 24 hours thereafter. Clindamycin cream is oil-based and might weaken latex condoms and diaphragms for 5 days after use. Refer to clindamycin product labeling for additional information. Topical clindamycin preparations should not be used in the second half of pregnancy.

The recommended metronidazole regimens are equally effective. The recommended intravaginal clindamycin regimen might be less efficacious than the metronidazole regimens. One randomized trial evaluated the clinical equivalency of intravaginal metronidazole gel 0.75% once daily versus twice daily and demonstrated similar cure rates 1 month after therapy.

Metronidazole 2 g single-dose therapy has the lowest efficacy for BV and is no longer a recommended or alternative regimen. The FDA has cleared metronidazole 750 mg extended-release tablets once daily for 7 days and a single dose of clindamycin intravaginal cream. No data have been published that compares the clinical or microbiologic equivalencies of these regimens with other regimens. Cure rates do not differ between intravaginal clindamycin cream and ovules.

Several studies have evaluated the clinical and microbiologic effectiveness of using lactobacillus intravaginal suppositories to restore normal flora and treat BV. However, no currently available lactobacillus suppository was determined to be better than placebo 1 month after therapy for either clinical or microbiologic cure. No data support the use of douching for treatment or relief of symptoms.

Followup

Followup visits are unnecessary if symptoms resolve. Because recurrence of BV is not unusual, women should be advised to return for additional therapy if symptoms recur. A treatment regimen different from the original regimen may be used to treat recurrent disease. However, women with multiple recurrences should be managed in consultation with a specialist. One randomized trial for persistent BV indicated that metronidazole gel 0.75% twice per week for 6 months after completion of a recommended regimen was effective in maintaining a clinical cure for 6 months.

Management of Sex Partners

The results of clinical trials indicate that a woman's response to therapy and the likelihood of relapse or recurrence are not affected by treatment of her sex partner(s). Therefore, routine treatment of sex partners is not recommended.

Allergy or Intolerance to the Recommended Therapy

Intravaginal clindamycin cream is preferred in case of allergy or intolerance to metronidazole. Intravaginal metronidazole gel can be considered for patients who do not tolerate systemic metronidazole, but patients allergic to oral metronidazole should not be administered intravaginal metronidazole.

Pregnancy

All pregnant women who have symptomatic disease require treatment. Bacterial vaginosis has been associated with adverse pregnancy outcomes (premature rupture of membranes, chorioamnionitis, preterm labor, preterm birth, intra-amniotic infection, postpartum endometritis, postcesarean wound infection). Some specialists prefer using systemic therapy to treat possible subclinical upper genital tract infections.

Treatment of BV in asymptomatic pregnant women at high risk for preterm delivery (those who have previously delivered a premature infant) with a recommended oral regimen has reduced preterm delivery in 3 of 4 randomized controlled trials; some specialists recommend screening and oral treatment of these women. However, the optimal treatment regimens have not been established. Screening (if conducted) and treatment should be performed during the first prenatal visit.

Two trials that evaluated the efficacy of metronidazole during pregnancy used the 250 mg regimen. However, some specialists suggest using a regimen of 500 mg twice daily in pregnant women. One small trial demonstrated that treatment with oral metronidazole 500 mg twice daily was equally effective as metronidazole gel, with cure rates of 70%. These regimens were not effective in reducing preterm birth in any group of women. Multiple studies and meta-analyses have not demonstrated an association between metronidazole use during pregnancy and teratogenic or mutagenic effects in newborns.

Whether treatment of asymptomatic pregnant women with BV who are at low risk for preterm delivery reduces adverse outcomes of pregnancy is unclear. One trial in which oral clindamycin was used demonstrated a reduction in spontaneous preterm birth. Several trials have evaluated the use of intravaginal clindamycin during pregnancy to reduce preterm birth and treat asymptomatic BV.

One trial in which women were treated before 20 weeks' gestation demonstrated a reduction in preterm birth. In three other trials, intravaginal clindamycin cream was administered at 16 to 32 weeks' gestation, and an increase in adverse events (low birthweight, neonatal infections) was observed in newborns. Therefore, intravaginal clindamycin cream should only be used during the first half of pregnancy.

Followup of Pregnant Women

Treatment of BV in asymptomatic pregnant women who are at high risk for preterm delivery might prevent adverse pregnancy outcomes. Therefore, a followup evaluation 1 month after completion of treatment should be considered to evaluate whether therapy was effective.

HIV-Infection

Patients who have BV and also are infected with HIV should receive the same treatment regimen as those who are HIV-negative. BV appears to be more persistent in HIV-positive women.

Trichomoniasis

Trichomoniasis is caused by the protozoan T. vaginalis. Some men who are infected with T. vaginalis might not have symptoms; others have nongonococcal urethritis (NGU). Many infected women have symptoms characterized by a diffuse, malodorous, yellow-green vaginal discharge with vulvar irritation. However, some women have minimal or no symptoms.

Diagnosis of vaginal trichomoniasis is usually performed by microscopy of vaginal secretions, but this method has a sensitivity of only approximately 60% to 70% and requires immediate evaluation of wet preparation slide for optimal results. Other FDA-cleared tests for trichomoniasis in women include OSOM Trichomonas Rapid Test (Genzyme Diagnostics, Cambridge, Massachusetts), an immunochromatographic capillary flow dipstick technology, and the Affirm VP III (Becton Dickenson, San Jose, California), a nucleic acid probe test that evaluates for T. vaginalis, G. vaginalis, and C. albicans.

These tests are both performed on vaginal secretions and have a sensitivity >83% and a specificity >97%. Both tests are point-of-care diagnostics. The results of the OSOM Trichomonas Rapid Test are available in approximately 10 minutes, and results of the Affirm VP III are available within 45 minutes.

Although these tests tend to be more sensitive than vaginal wet preparation, false positives might occur, especially in low-prevalence populations. Culture is the most sensitive and specific commercially available method of diagnosis. In women in whom trichomoniasis is suspected but not confirmed by microscopy, vaginal secretions should be cultured for T. vaginalis.

In men, wet preparation is insensitive, and culture testing of urethral swab, urine, and semen is required for optimal sensitivity. No FDA-cleared PCR test for T. vaginalis is available in the United States, but such testing might be available from commercial laboratories that have developed their own PCR tests.

Patients should be advised to avoid consuming alcohol during treatment with metronidazole or tinidazole. Abstinence from alcohol use should continue for 24 hours after completion of metronidazole or 72 hours after completion of tinidazole.

The nitroimidazoles comprise the only class of drugs useful for the oral or parenteral therapy of trichomoniasis. Of these drugs, metronidazole and tinidazole are available in the United States and are cleared by the FDA for the treatment of trichomoniasis.

In randomized clinical trials, the recommended metronidazole regimens have resulted in cure rates of approximately 90% to 95%, and the recommended tinidazole regimen has resulted in cure rates of approximately 86% to 100%.

The appropriate treatment of sex partners might increase these reported rates. Randomized controlled trials comparing single 2 g doses of metronidazole and tinidazole suggest that tinidazole is equivalent to, or superior to, metronidazole in achieving parasitologic cure and resolution of symptoms. Treatment of patients and sex partners results in relief of symptoms, microbiologic cure, and reduction of transmission.

Metronidazole gel is considerably less effective for the treatment of trichomoniasis (<50%) than oral preparations of metronidazole. Topically applied antimicrobials (metronidazole gel) are unlikely to achieve therapeutic levels in the urethra or perivaginal glands; therefore, use of the gel is not recommended. Several other topically applied antimicrobials occasionally have been used for treatment of trichomoniasis; however, these preparations probably do not have greater efficacy than metronidazole gel.

Followup

Followup is unnecessary for men and women who become asymptomatic after treatment or who are initially asymptomatic. Some strains of T. vaginalis can have diminished susceptibility to metronidazole; however, infections caused by the majority of these organisms respond to tinidazole or higher doses of metronidazole. Low-level metronidazole resistance has been identified in 2% to 5% of cases of vaginal trichomoniasis. High-level resistance is rare. Tinidazole has a longer serum half-life and reaches higher levels in genitourinary tissues than metronidazole. In addition, many T. vaginalis isolates have lower minimum inhibitory concentrations (MICs) to tinidazole than metronidazole.

If treatment failure occurs with metronidazole 2 g single dose and re-infection is excluded, the patient can be treated with metronidazole 500 mg orally twice daily for 7 days or tinidazole 2 g single dose. For patients failing either of these regimens, clinicians should consider treatment with tinidazole or metronidazole at 2 g orally for 5 days. If these therapies are not effective, further management should be discussed with a specialist. Ideally the consultant should include determination of the susceptibility of T. vaginalis to metronidazole and tinidazole. Consultation and T. vaginalis susceptibility testing is available from CDC (phone 770-488-4115; website http://www.cdc.gov/std).

Management of Sex Partners

Sex partners of patients with T. vaginalis should be treated. Patients should be instructed to avoid sex until they and their sex partners are cured (when therapy has been completed and patient and partners are asymptomatic).

Allergy, Intolerance, and Adverse Reactions

Metronidazole and tinidazole are both nitroimidazoles. Patients with an immediate-type allergy to a nitroimidazole can be managed by metronidazole desensitization in consultation with a specialist. Topical therapy with drugs other than nitroimidazoles can be attempted, but cure rates are low (<50%).

Pregnancy

Vaginal trichomoniasis has been associated with adverse pregnancy outcomes, particularly premature rupture of membranes, preterm delivery, and low birthweight. However, data do not suggest that metronidazole treatment results in a reduction in perinatal morbidity. Although some trials suggest the possibility of increased prematurity or low birthweight after metronidazole treatment, limitations of the studies prevent definitive conclusions regarding risks of treatment.

Treatment of T. vaginalis may relieve symptoms of vaginal discharge in pregnant women and might prevent respiratory or genital infection of the newborn as well as further sexual transmission. Clinicians should counsel patients regarding the potential risks and benefits of treatment. Some specialists would defer therapy in asymptomatic pregnant women until after 37 weeks' gestation. In addition, these pregnant women should be provided careful counseling regarding condom use and the continued risk of sexual transmission.

Women may be treated with 2 g of metronidazole in a single dose. Metronidazole is pregnancy category B (animal studies have revealed no evidence of harm to the fetus, but no adequate, well-controlled studies among pregnant women have been conducted). Multiple studies and meta-analyses have not demonstrated a consistent association between metronidazole use during pregnancy and teratogenic or mutagenic effects in infants. Tinidazole is pregnancy category C (animal studies have demonstrated an adverse event, and no adequate, well-controlled studies in pregnant women have been conducted), and its safety in pregnant women has not been well evaluated.

In lactating women who are administered metronidazole, withholding breastfeeding during treatment and for 12 to 24 hours after the last dose will reduce the exposure of metronidazole to the infant. While using tinidazole, interruption of breastfeeding is recommended during treatment and for 3 days after the last dose.

HIV-Infection

Patients who have trichomoniasis and also are infected with HIV should receive the same treatment regimen as those who are HIV-negative. The incidence, persistence, and recurrence of trichomoniasis in HIV-infected women are not correlated with immune status.

Vulvovaginal Candidiasis

Vulvovaginal candidiasis (VVC) usually is caused by C. albicans but occasionally is caused by other Candida sp. or yeasts. Typical symptoms of VVC include pruritus, vaginal soreness, dyspareunia, external dysuria, and abnormal vaginal discharge. None of these symptoms is specific for VVC. An estimated 75% of women will have at least one episode of VVC, and 40% to 45% will have two or more episodes. On the basis of clinical presentation, microbiology, host factors, and response to therapy, VVC can be classified as either uncomplicated or complicated (see table below). Approximately 10% to 20% of women will have complicated VVC, suggesting diagnostic and therapeutic considerations.

CLASSIFICATION OF VULVOVAGINAL CANDIDIASIS (VVC)

Uncomplicated VVC	Complicated VVC
Sporadic or infrequent VVC and Mild-to-moderate VVC and Likely to be Candida albicans and Non-immunocompromised women	Recurrent VVC or Severe VVC or Non-albicans candidiasis or Women with uncontrolled diabetes, debilitation, or immunosuppression, or those who are pregnant

UNCOMPLICATED VVC

A diagnosis of Candida vaginitis is suggested clinically by the presence of external dysuria and vulvar pruritus, pain, swelling, and redness. Signs include vulvar edema, fissures, excoriations, or thick curdy vaginal discharge. The diagnosis can be made in a woman who has signs and symptoms of vaginitis when either (1) a wet preparation (saline, 10% KOH) or Gram stain of vaginal discharge demonstrates yeasts or pseudohyphae, or (2) a culture or other test yields a positive result for a yeast species.

Candida vaginitis is associated with a normal vaginal pH (<4.5). Use of 10% KOH in wet preparations improves the visualization of yeast and mycelia by disrupting cellular material that might obscure the yeast or pseudohyphae. Examination of a wet mount with KOH preparation should be performed for all women with symptoms or signs of VVC, and women with a positive result should receive treatment. For those with negative wet mounts, vaginal cultures for Candida should be considered for those with any sign or multiple symptoms.

If Candida cultures cannot be done, empiric treatment can be considered for symptomatic women with any sign of VVC on examination when the wet mount is negative. Identifying Candida by culture in the absence of symptoms or signs is not an indication for treatment because approximately 10% to 20% of women harbor Candida sp. and other yeasts in the vagina. Vulvovaginal candidiasis can occur concomitantly with STDs. The majority of healthy women with uncomplicated VVC have no identifiable precipitating factors.

TREATMENT

Short-course topical formulations (single dose and regimens of 1–3 days) effectively treat uncomplicated VVC. The topically applied azole drugs are more effective than nystatin. Treatment with azoles results in relief of symptoms and negative cultures in 80% to 90% of patients who complete therapy.

The creams and suppositories in this regimen are oil-based and might weaken latex condoms and diaphragms. Refer to condom product labeling for further information.

Intravaginal preparations of butoconazole, clotrimazole, miconazole, and tioconazole are available over-the-counter (OTC).

Women whose condition has previously been diagnosed with VVC are not necessarily more likely to be able to diagnose themselves; therefore, any woman whose symptoms persist after using an OTC preparation, or who has a recurrence of symptoms within 2 months, should be evaluated with office-based testing. Unnecessary or inappropriate use of OTC preparations is common and can lead to a delay in the treatment of other vulvovaginitis etiologies, which can result in adverse clinical outcomes.

Followup

Patients should be instructed to return for followup visits only if symptoms persist or recur within 2 months of onset of initial symptoms.

Management of Sex Partners

Vulvovaginal candidiasis is not usually acquired through sexual intercourse; treatment of sex partners is not recommended but may be considered in women who have recurrent infection. A minority of male sex partners might have balanitis, which is characterized by erythematous areas on the glans of the penis in conjunction with pruritus or irritation. These men benefit from treatment with topical antifungal agents to relieve symptoms.

Allergy, Intolerance, and Adverse Reactions

Topical agents usually cause no systemic side effects, although local burning or irritation might occur. Oral agents occasionally cause nausea, abdominal pain, and headache. Therapy with the oral azoles has been associated rarely with abnormal elevations of liver enzymes. Clinically important interactions can occur when these oral agents are administered with other drugs, including astemizole, calcium channel antagonists, cisapride, coumadin, cyclosporin A, oral hypoglycemic agents, phenytoin, protease inhibitors, tacrolimus, terfenadine, theophylline, trimetrexate, and rifampin.

COMPLICATED VVC: RECURRENT

Recurrent vulvovaginal candidiasis (RVVC), usually defined as four or more episodes of symptomatic VVC in 1 year, affects a small percentage of women (<5%). The pathogenesis of RVVC is poorly understood, and the majority of women with RVVC have no apparent predisposing or underlying conditions. Vaginal cultures should be obtained from patients with RVVC to confirm the clinical diagnosis and to identify unusual species, including non-albicans species, particularly Candida glabrata (C. glabrata does not form pseudohyphae or hyphae and is not easily recognized on microscopy). Candida glabrata and other non-albicans Candida species are observed in 10% to 20% of patients with RVVC. Conventional antimycotic therapies are not as effective against these species as against C. albicans.

TREATMENT

Each individual episode of RVVC caused by C. albicans responds well to short duration oral or topical azole therapy. However, to maintain clinical and mycologic control, some specialists recommend a longer duration of initial therapy (7–14 days of topical therapy or a 100 mg, 150 mg, or 200 mg oral dose of fluconazole every third day for a total of 3 doses (day 1, 4, and 7) to attempt mycologic remission before initiating a maintenance antifungal regimen.

If this regimen is not feasible, some specialists recommend topical clotrimazole 200 mg twice a week, clotrimazole (500 mg dose vaginal suppositories once weekly), or other topical treatments used intermittently.

Suppressive maintenance antifungal therapies are effective in reducing RVVC. However, 30% to 50% of women will have recurrent disease after maintenance therapy is discontinued. Routine treatment of sex partners is controversial. Candida albicans azole resistance is rare in vaginal isolates, and susceptibility testing is usually not warranted for individual treatment guidance.

SEVERE VVC

Severe vulvovaginitis (extensive vulvar erythema, edema, excoriation, fissure formation) is associated with lower clinical response rates in patients treated with short courses of topical or oral therapy. Either 7 to 14 days of topical azole or 150 mg of fluconazole in two sequential doses (second dose 72 hours after initial dose) is recommended.

NON-ALBICANS VVC

The optimal treatment of non-albicans VVC remains unknown. Options include longer duration of therapy (7–14 days) with a nonfluconazole azole drug (oral or topical) as first-line therapy. If recurrence occurs, 600 mg of boric acid in a gelatin capsule is recommended, administered vaginally once daily for 2 weeks. This regimen has clinical and mycologic eradication rates of approximately 70%. If symptoms recur, referral to a specialist is advised.

Compromised Host

Women with underlying debilitating medical conditions (those with uncontrolled diabetes or those receiving corticosteroid treatment) do not respond as well to short-term therapies. Efforts to correct modifiable conditions should be made, and more prolonged (7–14 days) conventional antimycotic treatment is necessary.

Pregnancy

Vulvovaginalis candidiasis frequently occurs during pregnancy. Only topical azole therapies, applied for 7 days, are recommended for use among pregnant women.

HIV-Infection

The incidence of VVC in HIV-infected women is unknown. Vaginal Candida colonization rates among HIV-infected women are higher than among those for seronegative women with similar demographic characteristics and high-risk behaviors, and the colonization rates correlate with increasing severity of immunosuppression.

Symptomatic VVC is more frequent in seropositive women and similarly correlates with severity of immunodeficiency. In addition, among HIV-infected women, systemic azole exposure is associated with the isolation of non-albicans Candida species from the vagina. Based on available data, therapy for VVC in HIV-infected women should not differ from that for seronegative women.

Although longterm prophylactic therapy with fluconazole at a dose of 200 mg weekly has been effective in reducing C. albicans colonization and symptomatic VVC, this regimen is not recommended for routine primary prophylaxis in HIV-infected women in the absence of recurrent VVC. Given the frequency at which RVVC occurs in the immunocompetent healthy population, the occurrence of RVVC should not be considered an indication for HIV testing.

PELVIC INFLAMMATORY DISEASE

Pelvic inflammatory disease (PID) comprises a spectrum of inflammatory disorders of the upper female genital tract, including any combination of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis. Sexually transmitted organisms, especially N. gonorrhoeae and C. trachomatis, are implicated in many cases; however, microorganisms that comprise the vaginal flora (anaerobes, G. vaginalis, Haemophilus influenzae, enteric Gram-negative rods, and Streptococcus agalactiae) also have been associated with PID. In addition, cytomegalovirus (CMV), M. hominis, U. urealyticum, and M. genitalium might be associated with some cases of PID. All women who are diagnosed with acute PID should be tested for N. gonorrhoeae C. trachomatis and should be screened for HIV-infection.

DIAGNOSIS

Acute PID is difficult to diagnose because of the wide variation in the symptoms and signs. Many women with PID have subtle or mild symptoms. Delay in diagnosis and treatment probably contributes to inflammatory sequelae in the upper reproductive tract. Laparoscopy can be used to obtain a more accurate diagnosis of salpingitis and a more complete bacteriologic diagnosis. However, this diagnostic tool is not readily available, and its use is not easy to justify when symptoms are mild or vague. Moreover, laparoscopy will not detect endometritis and might not detect subtle inflammation of the fallopian tubes. Consequently, a diagnosis of PID usually is based on clinical findings.

The clinical diagnosis of acute PID is imprecise. Data indicate that a clinical diagnosis of symptomatic PID has a positive predictive value (PPV) for salpingitis of 65% to 90% compared with laparoscopy. The PPV of a clinical diagnosis of acute PID depends on the epidemiologic characteristics of the population, with higher PPVs among sexually active young women (particularly adolescents), among patients attending STD clinics, or in other settings where the rates of gonorrhea or chlamydia are high.

In all settings, however, no single historical, physical, or laboratory finding is both sensitive and specific for the diagnosis of acute PID (can be used both to detect all cases of PID and to exclude all women without PID). Combinations of diagnostic findings that improve either sensitivity (detect more women who have PID) or specificity (exclude more women who do not have PID) do so only at the expense of the other. For example, requiring two or more findings excludes more women who do not have PID but also reduces the number of women with PID who are identified.

Many episodes of PID go unrecognized. Although some cases are asymptomatic, others are not diagnosed because the patient or the healthcare provider fails to recognize the implications of mild or nonspecific symptoms or signs (abnormal bleeding, dyspareunia, vaginal discharge). Because of the difficulty of diagnosis and the potential for damage to the reproductive health of women, even by apparently mild or subclinical PID, healthcare providers should maintain a low threshold for the diagnosis of PID.

The optimal treatment regimen and long-term outcome of early treatment of women with asymptomatic or subclinical PID are unknown. The following recommendations for diagnosing PID are intended to help healthcare providers recognize when PID should be suspected and when they need to obtain additional information to increase diagnostic certainty. Diagnosis and management of other common causes of lower abdominal pain (ectopic pregnancy, acute appendicitis, functional pain) are unlikely to be impaired by initiating empiric antimicrobial therapy for PID.

Empiric treatment of PID should be initiated in sexually active young women and other women at risk for STDs if they are experiencing pelvic or lower abdominal pain, if no cause for the illness other than PID can be identified, and if one or more of the following minimum criteria are present on pelvic examination:

• Cervical motion tenderness
  or
• Uterine tenderness
  or
• Adnexal tenderness

The requirement that all three minimum criteria be present before the initiation of empiric treatment could result in insufficient sensitivity for the diagnosis of PID. The presence of signs of lower genital tract inflammation, in addition to one of the three minimum criteria, increases the specificity of diagnosis. In deciding upon the initiation of empiric treatment, clinicians should also consider the risk profile of the patient for STDs.

More elaborate diagnostic evaluation frequently is needed because incorrect diagnosis and management might cause unnecessary morbidity. These additional criteria may be used to enhance the specificity of the minimum criteria. The following additional criteria can be used to enhance the specificity of the minimum criteria and support a diagnosis of PID:

• Oral temperature >101°F (>38.3°C)
• Abnormal cervical or vaginal mucopurulent discharge
• Presence of abundant numbers of WBC on saline microscopy of vaginal secretions
• Elevated erythrocyte sedimentation rate
• Elevated C-reactive protein and
• Laboratory documentation of cervical infection with N. gonorrhoeae or C. trachomatis.

The majority of women with PID have either mucopurulent cervical discharge or evidence of WBC on a microscopic evaluation of a saline preparation of vaginal fluid. If the cervical discharge appears normal and no WBCs are observed on the wet prep of vaginal fluid, the diagnosis of PID is unlikely, and alternative causes of pain should be investigated. A wet prep of vaginal fluid offers the ability to detect the presence of concomitant infections (bacterial vaginosis, trichomoniasis).

The most specific criteria for diagnosing PID include the following:

• Endometrial biopsy with histopathologic evidence of endometritis
• Transvaginal sonography or magnetic resonance imaging techniques showing thickened, fluid-filled tubes with or without free pelvic fluid or tubo-ovarian complex, or Doppler studies suggesting pelvic infection (e.g., tubal hyperemia) and
• Laparoscopic abnormalities consistent with PID

A diagnostic evaluation that includes some of these more extensive studies might be warranted in some cases. Endometrial biopsy is warranted in women undergoing laparoscopy who do not have visual evidence of salpingitis, as some women with PID have endometritis alone.

TREATMENT

Treatment regimens for PID must provide empiric, broad-spectrum coverage of likely pathogens. Several antimicrobial regimens have been effective in achieving clinical and microbiologic cure in randomized clinical trials with shortterm followup. However, only a limited number of investigations have assessed and compared these regimens as to elimination of infection in the endometrium and fallopian tubes or determined the incidence of long-term complications (tubal infertility, ectopic pregnancy) after antimicrobial regimens.

All treatment regimens should be effective against N. gonorrhoeae and C. trachomatis because negative endocervical screening for these organisms does not rule out upper reproductive tract infection. The need to eradicate anaerobes from women who have PID has not been determined definitively.

Anaerobic bacteria have been isolated from the upper reproductive tract of women who have PID, and data from in vitro studies have revealed that some anaerobes (Bacteroides fragilis) can cause tubal and epithelial destruction. In addition, BV also is present in many women who have PID. Until treatment regimens that do not adequately cover these microbes have been demonstrated to prevent longterm sequelae (infertility and ectopic pregnancy) as successfully as the regimens that are effective against these microbes, the use of regimens with anaerobic activity should be considered.

Treatment should be initiated as soon as the presumptive diagnosis has been made because prevention of long-term sequelae is dependent on immediate administration of appropriate antibiotics. When selecting a treatment regimen, healthcare providers should consider availability, cost, patient acceptance, and antimicrobial susceptibility.

Some specialists have recommended that all patients with PID be hospitalized so that bed rest and supervised treatment with parenteral antibiotics can be initiated. However, in women with PID of mild or moderate clinical severity, outpatient therapy can provide short- and long-term clinical outcomes similar to inpatient therapy. Limited data support the use of outpatient therapy in women with more severe clinical presentations. The decision whether hospitalization is necessary should be based on the discretion of the healthcare provider.

We suggest the following criteria for hospitalization:

• Surgical emergencies (eg, appendicitis) cannot be excluded
• The patient is pregnant
• The patient does not respond clinically to oral antimicrobial therapy
• The patient is unable to follow or tolerate an outpatient oral regimen
• The patient has severe illness, nausea and vomiting, or high fever
• The patient has a tubo-ovarian abscess

Many practitioners have preferred to hospitalize adolescent women whose condition is diagnosed as acute PID. No evidence is available suggesting that adolescents benefit from hospitalization for treatment of PID. Younger women with mild-to-moderate acute PID have similar outcomes with either outpatient therapy or inpatient therapy. Further, clinical response to outpatient treatment is similar among younger and older women. The decision to hospitalize adolescents with acute PID should be based on the same criteria used for older women. Whether women in their later reproductive years benefit from hospitalization for treatment of PID also is unclear, although women aged >35 years who are hospitalized with PID are more likely than younger women to have a complicated clinical course.

PARENTERAL TREATMENT

For women with PID of mild or moderate severity, parenteral and oral therapy appears to have similar clinical efficacy. Many randomized trials have demonstrated the efficacy of both parenteral and oral regimens. In the majority of clinical trials, parenteral treatment for at least 48 hours has been used after the patient has demonstrated substantial clinical improvement. Clinical experience should guide decisions regarding transition to oral therapy, which usually can be initiated within 24 hours of clinical improvement. The majority of clinicians recommend at least 24 hours of direct inpatient observation for patients who have tubo-ovarian abscesses.

Because of the pain associated with infusion, doxycycline should be administered orally when possible, even when the patient is hospitalized. Oral and IV administration of doxycycline provide similar bioavailability.

Parenteral therapy may be discontinued 24 hours after a patient improves clinically, and oral therapy with doxycycline (100 mg twice a day) should continue to complete 14 days of therapy. When tubo-ovarian abscess is present, many healthcare providers use clindamycin or metronidazole with doxycycline for continued therapy, rather than doxycycline alone, because it provides more effective anaerobic coverage.

Clinical data are limited regarding the use of other second- or third-generation cephalosporins (ceftizoxime, cefotaxime, ceftriaxone), which also might be effective therapy for PID and may replace cefotetan or cefoxitin. However, these cephalosporins are less active than cefotetan or cefoxitin against anaerobic bacteria.

Although use of a single daily dose of gentamicin has not been evaluated for the treatment of PID, it is efficacious in analogous situations. Parenteral therapy can be discontinued 24 hours after a patient improves clinically; continuing oral therapy should consist of doxycycline 100 mg orally twice a day or clindamycin 450 mg orally four times a day to complete a total of 14 days of therapy. When tubo-ovarian abscess is present, many healthcare providers use clindamycin for continued therapy, rather than doxycycline, because clindamycin provides more effective anaerobic coverage.

Limited data support the use of other parenteral regimens, but the following three regimens have been investigated in at least one clinical trial, and they have broad spectrum coverage.

Intravenous ofloxacin has been investigated as a single agent; however, because of concerns regarding its spectrum, metronidazole may be included in the regimen. Levofloxacin is as effective as ofloxacin and may be substituted; its single daily dosing makes it advantageous from a compliance perspective.

One trial demonstrated high shortterm clinical cure rates with azithromycin, either alone for 1 week (at least one IV dose followed by oral therapy) or with a 12-day course of metronidazole. Ampicillin/sulbactam plus doxycycline is effective coverage against C. trachomatis, N. gonorrhoeae, and anaerobes and for patients who have tubo-ovarian abscess.

ORAL TREATMENT

Oral therapy may be considered for women with mild to moderately severe acute PID, as the clinical outcomes among women treated with oral therapy are similar to those treated with parenteral therapy. The following regimens provide coverage against the frequent etiologic agents of PID. Patients who do not respond to oral therapy within 72 hours should be re-evaluated to confirm the diagnosis and should be administered parenteral therapy on either an outpatient or inpatient basis.

Levofloxacin is as effective as ofloxacin and may be substituted. Azithromycin has been demonstrated in one randomized trial to be an effective regimen for acute PID. The addition of metronidazole should be considered, as anaerobic organisms are suspected in the etiology of the majority of PID cases. Metronidazole will also treat BV, which frequently is associated with PID.

The optimal choice of a cephalosporin for Regimen B is unclear; although cefoxitin has better anaerobic coverage, ceftriaxone has better coverage against N. gonorrhoeae. Clinical trials have demonstrated that a single dose of cefoxitin is effective in obtaining shortterm clinical response in women who have PID. However, the theoretical limitations in cefoxitin's coverage of anaerobes might require the addition of metronidazole to the treatment regimen. Metronidazole will also effectively treat BV, which is frequently associated with PID.

No data have been published regarding the use of oral cephalosporins for the treatment of PID. Limited data suggest that the combination of oral metronidazole and doxycycline after primary parenteral therapy is safe and effective.

Followup

Patients should demonstrate substantial clinical improvement (defervescence; reduction in direct or rebound abdominal tenderness; and reduction in uterine, adnexal, and cervical motion tenderness) within 3 days after initiation of therapy. Patients who do not improve within this period usually require hospitalization, additional diagnostic tests, and surgical intervention.

If no clinical improvement has occurred within 72 hours after outpatient oral or parenteral therapy (using the above criteria), the clinician should perform an examination. Subsequent hospitalization, parenteral therapy, and diagnostic evaluation, including the consideration of diagnostic laparoscopy for alternative diagnoses, are recommended in women without clinical improvement.

Some specialists also recommend rescreening for C. trachomatis and N. gonorrhoeae 4 to 6 weeks after therapy is completed in women with documented infection with these pathogens. All women diagnosed with acute PID should be offered HIV testing.

Management of Sex Partners

Male sex partners of women with PID should be examined and treated if they had sexual contact with the patient during the 60 days preceding the patient's onset of symptoms. Evaluation and treatment are imperative because of the risk for re-infection of the patient and the strong likelihood of urethral gonococcal or chlamydial infection in the sex partner. Male partners of women who have PID caused by C. trachomatis and/or N. gonorrhoeae frequently are asymptomatic. Sex partners should be treated empirically with regimens effective against both of these infections, regardless of the etiology of PID or pathogens isolated from the infected woman.

Even in clinical settings in which only women are treated, arrange to provide care for male sex partners of women who have PID. When providing care for male sex partners is not feasible, healthcare providers should ensure that sex partners are referred for appropriate treatment.

Prevention

Prevention of chlamydial infection by screening and treating high-risk women reduces the incidence of PID. Theoretically, the majority of cases of PID can be prevented by screening all women—or those determined to be at high risk (based on age or other factors)—by using DNA amplification on cervical specimens (in women receiving pelvic examinations) and on urine specimens (in women not undergoing examinations). Although BV is associated with PID, whether the incidence of PID can be reduced by identifying and treating women with BV is unclear.

Pregnancy

Because of the high risk for maternal morbidity and preterm delivery, pregnant women who have suspected PID should be hospitalized and treated with parenteral antibiotics.

HIV-Infection

Differences in the clinical manifestations of PID between HIV-infected women and HIV-negative women have not been well-delineated. In previous observational studies, HIV-infected women with PID were more likely to require surgical intervention. More comprehensive observational and controlled studies (published since the 2002 STD guidelines) have demonstrated that HIV-infected women with PID had similar symptoms when compared with uninfected controls. They were more likely to have a tubo-ovarian abscess but responded equally well to standard parenteral and oral antibiotic regimens when compared with HIV-negative women.

The microbiologic findings for HIV-positive and HIV-negative women were similar, except HIV-infected women had higher rates of concomitant M. hominis, Candida, streptococcal, and HPV infections and HPV-related cytologic abnormalities. Whether the management of immunodeficient HIV-infected women with PID requires more aggressive interventions (hospitalization, parenteral antimicrobial regimens) has not been determined.

Intrauterine Devices (IUDs)

Intrauterine contraceptive devices are becoming a popular contraceptive choice for women. Both levonorgestrel and copper-containing devices are marketed in the United States. The risk of PID associated with IUD use is primarily confined to the first 3 weeks after insertion and is uncommon thereafter. Given the popularity of IUDs, practitioners might encounter PID in IUD users.

No evidence suggests that IUDs should be removed in women diagnosed with acute PID. However, caution should be exercised if the IUD remains in place, and close clinical followup is mandatory. The rate of treatment failure and recurrent PID in women continuing to use an IUD is unknown. No data exist on antibiotic selection and treatment outcomes according to type of IUD (e.g., copper or levonorgestrel).

EPIDIDYMITIS

Acute epididymitis is a clinical syndrome consisting of pain, swelling, and inflammation of the epididymis of <6 weeks. Chronic epididymitis is characterized by a 3-month or longer history of symptoms of discomfort and/or pain in the scrotum, testicle, or epididymis that is localized on clinical examination. Chronic epididymitis has been subcategorized into inflammatory chronic epididymitis, obstructive chronic epididymitis, and chronic epididymalgia.

Among sexually active men aged <35 years, acute epididymitis is most frequently caused by C. trachomatis or N. gonorrhoeae. Acute epididymitis caused by sexually transmitted enteric organisms (e.g., Escherichia coli) also occurs among men who are the insertive partner during anal intercourse. Sexually transmitted acute epididymitis usually is accompanied by urethritis, which frequently is asymptomatic and is generally not accompanied by bacteriuria.

In men aged >35 years, sexually transmitted epididymitis is uncommon. However, bacteriuria secondary to obstructive urinary disease is relatively common. In this group, nonsexually transmitted epididymitis is associated with urinary tract instrumentation or surgery, systemic disease, or immunosuppression.

Although the majority of patients can be treated on an outpatient basis, hospitalization should be considered when severe pain suggests other diagnoses (torsion, testicular infarction, abscess) or when patients are febrile or might be noncompliant with an antimicrobial regimen.

DIAGNOSIS

Men who have acute epididymitis typically have unilateral testicular pain and tenderness; hydrocele and palpable swelling of the epididymis usually are present. Although the inflammation and swelling usually begin in the tail of the epididymis, they can spread to involve the rest of the epididymis and testicle. The spermatic cord is usually tender and swollen.

Testicular torsion, a surgical emergency, should be considered in all cases, but it occurs more frequently among adolescents and in men without evidence of inflammation or infection. Emergency testing for torsion might be indicated when the onset of pain is sudden, pain is severe, or the test results available during the initial examination do not support a diagnosis of urethritis or urinary-tract infection. If the diagnosis is questionable, a specialist should be consulted immediately because testicular viability might be compromised.

Radionuclide scanning of the scrotum is the most accurate radiologic method of diagnosis, although it is not routinely available. Color duplex Doppler ultrasonography has a sensitivity of 70% and a specificity of 88% in diagnosing acute epididymitis.

The evaluation of men for epididymitis should include one of the following:

• Gram stain of urethral secretions demonstrating >5 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 intracellular Gram-negative diplococci on urethral Gram stain.
• Positive leukocyte esterase test on first-void urine or microscopic examination of first-void urine sediment demonstrating >10 WBC per high-power field.

Culture, nucleic acid hybridization tests, and NAAT are available for the detection of both N. gonorrhoeaeand C. trachomatis. Culture and nucleic acid 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. Depending on the risk, patients whose conditions have been diagnosed as a new STD should receive testing for other STDs.

TREATMENT

Empiric therapy is indicated before laboratory test results are available. The goals of treatment of acute epididymitis caused by C. trachomatis or N. gonorrhoeae are (1) microbiologic cure of infection, (2) improvement of signs and symptoms, (3) prevention of transmission to others, and (4) a decrease in potential complications (infertility, chronic pain). As an adjunct to therapy, bed rest, scrotal elevation, and analgesics are recommended until fever and local inflammation have subsided.

Followup

Failure to improve within 3 days of the initiation of treatment requires re-evaluation of both the diagnosis and therapy. Swelling and tenderness that persist after completion of antimicrobial therapy should be evaluated comprehensively. The differential diagnosis includes tumor, abscess, infarction, testicular cancer, TB, and fungal epididymitis.

Management of Sex Partners

Patients who have acute epididymitis, confirmed or suspected to be caused by N. gonorrhoeae or C. trachomatis, should be instructed to refer sex partners for evaluation and treatment if their contact with the index patient was within the 60 days preceding onset of the patient's symptoms. Patients should be instructed to avoid sexual intercourse until they and their sex partners are cured (until therapy is completed and patient and partners no longer have symptoms).

HIV-Infection

Patients who have uncomplicated acute epididymitis and also are infected with HIV should receive the same treatment regimen as those who are HIV-negative. Fungi and mycobacteria, however, are more likely to cause acute epididymitis in immunosuppressed patients than in immunocompetent patients.

HUMAN PAPILLOMAVIRUS (HPV) INFECTION

More than one hundred types of HPV exist; more than thirty types can infect the genital area. The majority of HPV infections are asymptomatic, unrecognized, or subclinical. Genital HPV infection is common and usually self-limited. Genital HPV infection occurs more frequently than visible genital warts among both men and women and cervical cell changes among women.

Genital HPV infection can cause genital warts, usually associated with HPV types 6 or 11. Other HPV types that infect the anogenital region (high-risk HPV types 16, 18, 31, 33, and 35) are strongly associated with cervical neoplasia. Persistent infection with high-risk types of HPV is the most important risk factor for cervical neoplasia.

Pre-Exposure Vaccine

A quadrivalent vaccine against human papillomavirus (HPV types 6, 11, 16, 18) is now available and licensed for females aged 9 to 26 years.

HPV Tests

A definitive diagnosis of HPV infection is based on detection of viral nucleic acid (DNA or RNA) or capsid protein. Tests that detect several types of HPV DNA in cells scraped from the cervix are available and might be useful in the triage of women with atypical squamous cells of undetermined significance (ASC-US) or in screening women aged >30 years in conjunction with the Pap test.

Women determined to have HPV infection on such testing should be counseled that HPV infection is common, infection is frequently transmitted between partners, and infection usually goes away on its own. If any Pap test or biopsy abnormalities have been observed, further evaluation is recommended. Screening women or men with the HPV test, outside of the above recommendations for use of the test with cervical cancer screening, is not recommended.

TREATMENT

In the absence of genital warts or cervical squamous intraepithelial lesion (SIL), treatment is not recommended for subclinical genital HPV infection, whether it is diagnosed by colposcopy, biopsy, acetic acid application, or through the detection of HPV by laboratory tests. Genital HPV infection frequently goes away on its own, and no therapy has been identified that can eradicate infection. In the presence of coexistent SIL, management should be based on histopathologic findings.

GENITAL WARTS

Human papillomavirus types 6 or 11 are commonly found before, or at the time of, detection of genital warts; however, the use of HPV testing for genital wart diagnosis is not recommended.

Genital warts are usually flat, papular, or pedunculated growths on the genital mucosa. Diagnosis of genital warts is made by visual inspection and may be confirmed by biopsy, although biopsy is needed only under certain circumstances (if the diagnosis is uncertain; the lesions do not respond to standard therapy; the disease worsens during therapy; the patient is immunocompromised; or warts are pigmented, indurated, fixed, bleeding, or ulcerated). No data support the use of HPV nucleic acid tests in the routine diagnosis or management of visible genital warts.

The application of 3% to 5% acetic acid usually turns HPV-infected genital mucosal tissue to a whitish color. However, acetic acid application is not a specific test for HPV infection, and the specificity and sensitivity of this procedure for screening have not been defined. Therefore, the routine use of this procedure for screening to detect HPV infection is not recommended. However, some clinicians, who are experienced in the management of genital warts, have determined that this test is useful for identifying flat genital warts.

In addition to the external genitalia (penis, vulva, scrotum, perineum, and perianal skin), genital warts can occur on the uterine cervix and in the vagina, urethra, anus, and mouth. Intra-anal warts are observed predominantly in patients who have had receptive anal intercourse; these warts are distinct from perianal warts, which can occur in men and women who do not have a history of anal sex. In addition to the genital area, HPV types 6 and 11 have been associated with conjunctival, nasal, oral, and laryngeal warts. Genital warts are usually asymptomatic, but depending on the size and anatomic location, genital warts can be painful, friable, or pruritic.

Human papillomavirus types 16, 18, 31, 33, and 35 are found occasionally in visible genital warts and have been associated with external genital (vulvar, penile, and anal) squamous intraepithelial neoplasia (squamous cell carcinoma in situ, bowenoid papulosis, Erythroplasia of Queyrat, or Bowen disease of the genitalia). These HPV types also have been associated with vaginal, anal, and cervical intraepithelial neoplasia (CIN) and anogenital and some head and neck squamous cell carcinomas. Patients who have visible genital warts are frequently infected simultaneously with multiple HPV types.

TREATMENT

The primary goal of treating visible genital warts is the removal of the warts. In the majority of patients, treatment can induce wart-free periods. If left untreated, visible genital warts might resolve on their own, remain unchanged, or increase in size or number. Treatment possibly reduces, but does not eliminate, HPV infection. Existing data indicate that currently available therapies for genital warts might reduce, but probably do not eradicate, HPV infectivity. Whether the reduction in HPV viral DNA, resulting from treatment, impacts future transmission remains unclear. No evidence indicates that the presence of genital warts or their treatment is associated with the development of cervical cancer.

Treatment of genital warts should be guided by the preference of the patient, the available resources, and the experience of the healthcare provider. No definitive evidence suggests that any of the available treatments are superior to any other and no single treatment is ideal for all patients or all warts. The use of locally developed and monitored treatment algorithms has been associated with improved clinical outcomes and should be encouraged. Because of uncertainty regarding the effect of treatment on future transmission of HPV and the possibility of spontaneous resolution, an acceptable alternative for some individuals is to forego treatment and wait for spontaneous resolution.

The majority of patients have <10 genital warts, with a total wart area of 0.5 to 1.0 cm². These warts respond to various treatment modalities. Factors that might influence selection of treatment include wart size, wart number, anatomic site of wart, wart morphology, patient preference, cost of treatment, convenience, adverse effects, and provider experience.

Factors that might affect response to therapy include the presence of immunosuppression and compliance with therapy. The majority of patients require a course of therapy rather than a single treatment. In general, warts located on moist surfaces or in intertriginous areas respond better to topical treatment than do warts on drier surfaces.

The treatment modality should be changed if a patient has not improved substantially. The majority of genital warts respond within 3 months of therapy. The response to treatment and its side effects should be evaluated throughout the course of therapy.

Complications rarely occur if treatments for warts are employed properly. Patients should be warned that persistent hypopigmentation or hyperpigmentation occurs commonly with ablative modalities. Depressed or hypertrophic scars are uncommon but can occur, especially if the patient has had insufficient time to heal between treatments. Rarely, treatment can result in disabling chronic pain syndromes (vulvodynia or analdynia, and hyperesthesia of the treatment site) or, in the case of rectal warts, painful defecation or fistulas. A limited number of case reports of severe systemic effects from podophyllin resin and interferon have been documented.

Treatment regimens are classified into patient-applied and provider-applied modalities. Patient-applied modalities are preferred by some patients because they can be administered in the privacy of the patient's home. To use patient-applied modalities effectively, compliance is important, along with the ability to identify and reach all genital warts.

Podofilox 0.5% solution or gel, an antimitotic drug that destroys warts, is relatively inexpensive, easy to use, safe, and self-applied by patients. The majority of patients experience mild-to-moderate pain or local irritation after treatment. Imiquimod is a topically active immune enhancer that stimulates production of interferon and other cytokines. Local inflammatory reactions are common with the use of imiquimod; these reactions include redness and irritation and are usually mild to moderate.

Traditionally, followup visits are not required for patients using self-administered therapy. However, followup might be useful several weeks into therapy to determine the appropriateness of medication use and the response to treatment.

Cryotherapy destroys warts by thermal-induced cytolysis. Healthcare providers must be trained in the proper use of this therapy because over- and under-treatment may result in complications or low efficacy. Pain after application of the liquid nitrogen, followed by necrosis and sometimes blistering, is common. Local anesthesia (topical or injected) might facilitate therapy if warts are present in many areas or if the area of warts is large.

Podophyllin resin, which contains several compounds, including antimitotic podophyllin lignans, is another treatment option. The resin is most frequently compounded at 10% to 25% in a tincture of Benzoin. However, podophyllin resin preparations differ in the concentration of active components and contaminants. The shelf life and stability of podophyllin preparations are unknown. A thin layer of podophyllin resin must be applied to the warts and allowed to air dry before the treated area comes into contact with clothing; over-application or failure to air dry can result in local irritation caused by spread of the compound to adjacent areas.

Both trichloroacetic acid (TCA) and bichloroacetic acid (BCA) are caustic agents that destroy warts by chemical coagulation of proteins. Although these preparations are widely used, they have not been investigated thoroughly. TCA solutions have a low viscosity comparable with that of water and can spread rapidly if applied excessively; therefore, they can damage adjacent tissues. Both TCA and BCA should be applied sparingly and allowed to dry before the patient sits or stands. If pain is intense, the acid can be neutralized with soap or sodium bicarbonate.

Surgical therapy has the advantage of usually eliminating warts at a single visit. However, such therapy requires substantial clinical training, additional equipment, and a longer office visit. After local anesthesia is applied, the visible genital warts can be physically destroyed by electrocautery, in which case no additional hemostasis is required. Care must be taken to control the depth of electrocautery to prevent scarring.

Alternatively, the warts can be removed either by tangential excision with a pair of fine scissors or a scalpel or by curettage. Because the majority of warts are exophytic, this procedure can be accomplished with a resulting wound that only extends into the upper dermis. Hemostasis can be achieved with an electrocautery unit or a chemical styptic (eg, an aluminum chloride solution).

Suturing is neither required nor indicated in the majority of cases if surgical removal is performed properly. Surgical therapy is most beneficial for patients who have a large number or area of genital warts. Carbon dioxide laser and surgery might be useful in the management of extensive warts or intraurethral warts, particularly for those patients who have not responded to other treatments.

Interferons, both natural or recombinant, have been used for the treatment of genital warts. They have been administered systemically (subcutaneously at a distant site, or IM) and intralesionally (injected into the warts). Systemic interferon is not effective. The efficacy and recurrence rates of intralesional interferon are comparable to other treatment modalities. Administration of intralesional interferon is associated with stinging, burning, and pain at the injection site. Interferon is probably effective because of its antiviral and/or immunostimulating effects. Interferon therapy is not recommended as a primary modality because of inconvenient routes of administration, frequent office visits, and the association between its use and a high frequency of systemic adverse effects.

Because of the shortcomings associated with all available treatments, some clinics employ combination therapy (simultaneous use of two or more modalities on the same wart at the same time). No data support the use of more than one therapy at a time to improve efficacy of treatment, and some specialists believe that combining modalities might increase complications.

COUNSELING

Genital HPV Infection

Education and counseling are vital aspects of managing patients with genital warts. Patients can be educated through patient education materials, including pamphlets, hotlines, and websites (http://www.ashastd.org or http://www.cdc.gov/std/hpv).

The clinician should convey the following key messages:

• Genital HPV infection is common among sexually active adults. The majority of sexually active adults will have it at some point in their lives, although the majority of them will never know because the infection usually has no symptoms and clears on its own.
• Genital HPV infection is usually sexually transmitted. The incubation period (the interval between initial exposure and established infection or disease) is variable, and determining the timing and source of infection is frequently difficult. Within ongoing sexual relationships, sex partners usually are infected by the time of the patient's diagnosis, although they might have no symptoms or signs of infection.
• No recommended uses of the HPV test to diagnose HPV infection in sex partners have been established. HPV infection is commonly transmitted to partners but usually goes away on its own.

Genital Warts

Genital warts are caused by specific types of HPV infection. The types that cause genital warts are different from the types that cause cervical and other anogenital cancers.

Individuals may have infection with the types of HPV that cause genital warts but never develop symptoms. Why some individuals with genital HPV infection develop warts and others do not is unclear. Immunity probably plays a key role.

The natural history of genital warts is usually benign, but recurrence of genital warts within the first several months after treatment is common. Treatment for genital warts can reduce HPV infection, but whether the treatment results in a reduction in risk for transmission of HPV to sex partners is unclear. The duration of infectivity after wart treatment is unknown.

Condoms might reduce the risk for HPV-associated diseases (genital warts and cervical cancer). Consistent condom use also may reduce the risk for genital HPV. Human papillomavirus infection can occur in areas that are not covered or protected by a condom (scrotum, vulva, perianus).

The presence of genital warts is not an indication for HPV testing, a change in the frequency of Pap tests, or cervical colposcopy. HPV testing is not indicated for partners of individuals with genital warts.

OTHER CONSIDERATIONS

Followup

After visible genital warts have cleared, a followup evaluation might be helpful. Patients should be cautioned to watch for recurrences, which occur most frequently during the first 3 months. External genital warts can be difficult to identify, so it may be useful for patients to have a followup evaluation 3 months after treatment. Earlier followup visits might be useful for some patients to document the absence of warts, to monitor for or treat complications of therapy, and to provide an additional opportunity for patient education and counseling. Women should be counseled to undergo regular Pap screening as recommended for women without genital warts.

Management of Sex Partners

Examination of sex partners is not necessary for the management of genital warts because no data indicate that re-infection plays a role in recurrences. In addition, providing treatment for genital warts solely for the purpose of preventing future transmission cannot be recommended because the value of treatment in reducing infectivity is unknown. However, sex partners of patients who have genital warts might benefit from counseling and examination to assess the presence of genital warts and other STDs.

The counseling of sex partners provides an opportunity for these partners to (1) learn that HPV infection is common and probably shared between partners and (2) receive STD evaluation and screening and Pap screening if they are female. Female sex partners of patients who have genital warts should be reminded that cytologic screening for cervical cancer is recommended for all sexually active women.

Pregnancy

Imiquimod, podophyllin, and podofilox should not be used during pregnancy. However, because genital warts can proliferate and become friable during pregnancy, many specialists advocate their removal during pregnancy. HPV types 6 and 11 can cause respiratory papillomatosis in infants and children.

The route of transmission—transplacental, perinatal, or postnatal—is not completely understood. Whether cesarean section prevents respiratory papillomatosis in infants and children is unclear; therefore, cesarean delivery should not be performed solely to prevent transmission of HPV infection to the newborn.

Cesarean delivery might be indicated for women with genital warts if the pelvic outlet is obstructed or if vaginal delivery would result in excessive bleeding. Pregnant women with genital warts should be counseled about the risk (though low) for warts on the larynx (recurrent respiratory papillomatosis) in their infants or children. No controlled studies have suggested that cesarean section prevents this condition.

HIV-Infection

No data suggest that treatment modalities for external genital warts should be different in relation to HIV-infection. However, individuals who are immunosuppressed because of HIV or for other reasons may have larger or more numerous warts, might not respond as well as immunocompetent individuals to therapy for genital warts, and might have more frequent recurrences after treatment. Squamous cell carcinomas arising in or resembling genital warts might occur more frequently among immunosuppressed individuals, requiring biopsy for confirmation of diagnosis.

Because of the increased incidence of anal cancer in HIV-infected homosexual men, screening for anal SIL by cytology in this population is recommended by some specialists. However, evidence is limited about the natural history of anal intraepithelial neoplasias, the reliability of screening methods, the safety and response to treatments, and the programmatic considerations that would support this screening approach. Until additional data are generated on screening for anal SIL, this screening approach cannot be recommended.

Squamous Cell Carcinoma in Situ

Patients in whom squamous cell carcinoma in situ of the genitalia is diagnosed should be referred to a specialist for treatment. Ablative modalities usually are effective, but careful followup is essential. The risk for these lesions leading to invasive squamous cell carcinoma of the external genitalia in immunocompetent patients is unknown but is probably low. Female partners of male patients who have squamous cell carcinoma in situ are at high risk for cervical abnormalities.

CERVICAL CANCER SCREENING

Women with a history of STDs might be at increased risk for cervical cancer, and women attending STD clinics might have other risk factors that place them at even greater risk. Prevalence studies indicate that precursor lesions for cervical cancer occur approximately 5 times more frequently among women attending STD clinics than among women attending family planning clinics. Cervical cancer screening using the Pap test is an effective, low-cost screening test for preventing invasive cervical cancer.

Recommendations

Recommendations for cervical cancer screening intervals vary in the United States, but guidelines of the American Cancer Society and American College of Obstetricians and Gynecologists recommend annual screening for women aged 21 to 30 years and then every 2 to 3 years for women aged >30 years if three consecutive annual Pap tests are negative.

During the appointment in which a pelvic examination for STD screening is performed, the healthcare provider should inquire about the result of the patient's most recent Pap test and discuss the following information with the patient:

• Purpose and importance of a Pap test
• Need for regularly scheduled Pap tests from age 21 to 65 years
• Whether a Pap test will be obtained during this clinic visit and
• If a Pap test will not be obtained during this examination, the names of local providers or referral clinics that can perform Pap tests and adequately followup results if indicated

If a woman has not had a Pap test during the previous 12 months, a Pap test may be obtained as part of the routine pelvic examination. Healthcare providers should be aware that women frequently equate having a pelvic examination with having a Pap test; they believe that a Pap test was taken when they actually received only a pelvic examination. Thus they might over-report having had a recent Pap test. Therefore, STD clinics should have a protocol to encourage cervical cancer screening and a Pap test during the routine clinical evaluation of women who do not have documentation of a normal Pap test within the preceding 12 months.

A woman might benefit from receiving printed information about Pap tests and a report containing a statement that a Pap test was obtained during her clinic visit. If possible, a copy of the Pap test result should be provided to the patient for her records when it becomes available.

Followup

STD clinics offering cervical cancer screening are encouraged to use cytopathology laboratories that report results by using the Bethesda System of classification.* If the results of the Pap test are abnormal, followup care should be provided according to the ASCCP Consensus Guidelines for Management of Abnormal Cervical Cytology, or information regarding followup care is available at http//www.asccp.org. If resources in STD clinics do not allow followup of abnormal results, protocols for referral of women needing followup and case management should be in place.

* The Bethesda System for Reporting Cervical/Vaginal Cytologic Results uses the terms "low-grade SIL" and "high-grade SIL" for abnormal results. Low-grade SIL encompasses cytological changes associated with HPV and mild dysplasia. High-grade SIL includes cytological changes associated with moderate dysplasia, severe dysplasia, and carcinoma in situ. Cytological results should be distinguished from histological results obtained from biopsy specimens.

Pap tests indicating low- or high-grade SIL should always include referral to a clinician who can perform a colposcopic examination of the lower genital tract and, if indicated, colposcopically directed biopsy. For patients with an equivocal Pap test report indicating ASC-US, three options are available for followup management: (1) immediate colposcopy, (2) repeat Pap tests at 6-month intervals for 3 intervals, or (3) an HPV DNA test.

Women with ASC-US may be considered for immediate colposcopy if concerns for patient adherence with recommended followup or for other clinical indications are a factor. The presence of high-grade histologic changes after ASC-US Pap test reports is usually <10%.

If repeat Pap tests are used to follow ASC-US results, a test should be performed every 6 months until 3 negative results are noted before the women returns to cervical cancer screening at a normal interval for age. If subsequent Pap tests demonstrate progression to SIL, followup should be conducted according to ASCCP guidelines (frequent colposcopy and directed cervical biopsy).

If specific infections other than HPV are identified, the patient might need to have a repeat Pap test after appropriate treatment for those infections. In the majority of instances, even in the presence of some severe infections, Pap tests will be reported as satisfactory for evaluation, so they may be read and final reports produced without the necessity to treat and repeat the Pap test.

When repeating the Pap test is necessary because of an unsatisfactory for interpretation report, the repeat test must be interpreted by the laboratory as satisfactory and also be negative before returning the woman to Pap tests at regularly scheduled intervals.

A third strategy for managing patients with ASC-US Pap test results involves testing for HPV DNA. Whereas conducting HPV testing in some STD clinics might not be possible or appropriate because of inadequate resources, such testing may be appropriate in other public health clinic settings. Only one FDA-cleared test exists, the Digene Hybrid Capture II. The HPV DNA test may be performed by (1) co-collecting a specimen; (2) using a supplied swab at the time of the Pap test, if conventional cytology is used; (3) reflex testing, if liquid-based cytology is used and enough residual material is available in the cytology test vial; or (4) scheduling a separate followup appointment when the Pap test report results are known.

If the high-risk HPV DNA test is positive, women are referred immediately for colposcopy, and if indicated, directed cervical biopsy. Because many public health clinics, including the majority of STD clinics, cannot provide clinical followup of abnormal Pap tests, women with Pap tests demonstrating low- or high-grade SIL or ASC-US usually need a referral to other local healthcare providers or clinics for colposcopy and biopsy.

Clinics and healthcare providers who offer Pap test screening services but cannot provide appropriate colposcopic followup of abnormal Pap tests should arrange referral to healthcare facilities in which (1) a patient will be promptly evaluated and treated, and (2) the results of the evaluation will be reported to the referring clinic or healthcare provider.

Clinics and healthcare providers should develop protocols that identify women who miss followup appointments so that these women can be located and scheduled for needed studies and management, and they should re-evaluate such protocols routinely. Pap test results, type and location of followup appointments, and results of followup appointments should be clearly documented in the clinic record. The establishment of colposcopy and biopsy services in local health departments, especially in circumstances in which referrals are difficult and followup is unlikely, should be considered if resources are available.

OTHER CONSIDERATIONS

Other considerations in performing Pap tests include the following:

• The Pap test should not be considered a screening test for STDs.
• All women, regardless of sexual orientation (heterosexual women and those who identify themselves as lesbian or bisexual), should be considered for cervical cancer screening in an STD clinic setting.
• If a woman is menstruating, a Pap test should be postponed, and the woman should be advised to have a Pap test at the earliest opportunity.
• The presence of a mucopurulent discharge should not delay the Pap test. The test can be performed after careful removal of the discharge with a saline-soaked cotton swab.
• Women who have external genital warts do not need Pap tests more frequently than women who do not have warts, unless otherwise indicated.
• The sequence of Pap testing in relation to collection of other cervicovaginal specimens does not appear to influence Pap test results or their interpretation. Therefore, when other cultures or specimens are collected for STD diagnoses, the Pap test can be obtained last.
• Women who have had a total hysterectomy do not require a routine Pap test unless the hysterectomy was performed because of cervical cancer or its precursor lesions. In these situations, women should be advised to continue followup with the physician(s) who provided healthcare at the time of the hysterectomy, if possible. If the cervix remains after a hysterectomy, a woman should receive regularly scheduled Pap tests.
• Healthcare providers who receive basic retraining on Pap test collection and clinics that use simple quality assurance measures obtain fewer unsatisfactory tests. The use of cytobrushes and brooms also improves the number of satisfactory Pap tests.
• Whereas evidence supports the option of HPV testing for the triage of women with ASC-US Pap test reports, this option might not be appropriate in an STD clinic because of limited resources. Studies to define the cost-effectiveness of HPV testing for the triage of women with ASC-US Pap tests are ongoing. The HPV test strategy that might be most cost-effective is the collection of a cervical swab placed in liquid media (i.e., liquid-based cytology or collection of a separate swab stored in HPV DNA transport media) during the initial visit when a Pap test is collected. When the Pap test report is available, an HPV DNA test can be performed on the residual material, if indicated, without the patient needing another clinic visit.
• Liquid-based cytology is an alternative to conventional Pap tests; it has a higher sensitivity for detection of SIL and can facilitate HPV testing in women with ASC-US. However, liquid-based cytology has a lower specificity, resulting in more false-positive tests and, therefore, more administrative and patient-related costs, which could reduce the cost-effectiveness of cervical cancer screening and increase the risk of patient harm because of unnecessary followup tests.

Pregnancy

Pregnant women should have a Pap test as part of routine prenatal care. A cytobrush and an Ayers spatula might be used for obtaining Pap tests in pregnant women.

HIV-Infection

Several studies have documented an increased prevalence of SIL in HIV-infected women. The following recommendations for Pap test screening among HIV-infected women are consistent with other guidelines published by the U.S. Department of Health and Human Services and are based partly on the opinions of professionals knowledgeable about the care and management of cervical cancer and HIV-infection in women.

After obtaining a complete history of previous cervical disease, HIV-infected women should be provided a comprehensive gynecologic examination, including a pelvic examination and Pap test, as part of their initial evaluation. A Pap test should be obtained twice in the first year after diagnosis of HIV-infection and, if the results are normal, annually thereafter.

If the results of the Pap test are abnormal, care should be provided according to the ASCCP Consensus Guidelines for Management of Abnormal Cervical Cytology. Women with cytological reports of ASC-US, low- or high-grade SIL or squamous cell carcinoma, regardless of CD4+ count or antiretroviral treatment status, should undergo colposcopy and directed biopsy. Colposcopy and biopsy are not indicated in HIV-positive women with negative Pap test reports.

ILLITERACY AND HEALTH

Illiteracy is often silent, yet it is a potentially deadly problem in healthcare. In a field where vocabulary is unfamiliar to many and information is often presented at the college level (despite the fact that the average American reads at the eighth-grade level!) a client who has difficulty reading or calculating numbers is at a terrible disadvantage when it comes to understanding what they need to be healthy (Marcus, 2006).

A client's language difficulties, which may range from poor skills to no skills, may be the result of:

• Never having acquired reading and calculating skills
• Having had them but lost them due to an illness or accident
• Possessing them only in another language

The problem is frequently made worse by the shame and embarrassment that research has shown often accompanies illiteracy. It is a situation requiring tact and understanding on the part of healthcare staff (Marcus, 2006).

All clients benefit when healthcare providers:

• Develop an awareness of signs that may indicate a patient cannot read
• Learn simple tests to quietly confirm that suspicion
• Work out alternative methods to convey medical information

The lack of reading or calculating skills should be considered in when a client is noncompliant, and staff should be alert when clients repeatedly say they cannot fill out a form because they "forgot their reading glasses" or "have a headache." Once aware of a possible problem, diagnostic techniques can be as simple as handing a client an instruction sheet upside down and asking them to read it out loud, watching to see if they turn it right side up before they begin (Ratnayake, 2006).

Alternative methods for delivering information requires adapting the information to the needs of clients. Be aware that even simple pictures do not always have shared meanings. Healthcare providers need to familiarize themselves with the literature on the subject and the resources that are currently available. For example, Medlineplus, an online medical information provider, includes over 160 strictly audio/video presentations on common illnesses, tests, and procedures (Doyle, 2003).

Remember too that office staff are often in a position to notice any problems clients may have with forms (Marcus, 2006). Be sure to share your knowledge!

Posted November 10, 2006

Expires August 1, 2009

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