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Published: August 2010

Sexually Transmitted Diseases

Rabin K. Shrestha

Kristin Englund

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The term sexually transmitted diseases (STDs) refers to many diseases and the number keeps expanding with the discovery of newer pathogens (e.g., HIV) or a new route of acquisition of a known pathogen (e.g., hepatitis C). The terminology can be confusing as well. Historically, the term venereal disease was used for the class of diseases known to be transmitted by sexual intercourse. Other terminology includes sexually transmitted infections, because some infections may be asymptomatic and not cause disease, sexually transmissible diseases and infections, because some diseases such as hepatitis C may be transmitted predominantly by a nonsexual route, and reproductive tract infections, because the sexual transmission of some diseases such as bacterial vaginosis are still debated. In this chapter, STD is used to encompass all these diseases. Although there is a vast number of STDs, only a few important ones that are classically associated with sexual transmission will be discussed. HIV infection is not discussed in this chapter.

STDs have complex social, political, and public health implications, in addition to their medical significance. Even with the introduction of effective treatments such as penicillin for syphilis more than 60 years ago, syphilis continues to remain an important disease. In fact, the rate of syphilis in men who have sex with men (MSM) is on the rise in some areas in the United States. STDs remain among the most common infectious diseases in developed and developing countries. The fact that diseases for which there are effective therapies that can be prevented by changing behavior are still rampant illustrates the complex nature of these diseases and the enormous challenges faced by the medical and public health communities in dealing with them.

The STDs discussed in this chapter can be categorized into two main categories: diseases characterized by genital ulcers and those characterized by genital discharge.

Sexually transmitted diseases with ulcers

Herpes simplex virus (HSV) infections, syphilis, and chancroid account for almost all the STDs characterized by genital ulcers in the United States. More than one may be present in a patient who presents with genital ulcers and each of these diseases has been associated with an increased risk of HIV infection. A diagnosis based only on the patient's medical history and examination is often inaccurate and laboratory confirmation should be sought. Often, the clinician must treat the patient before laboratory results are available. In this case, the clinician should treat based on the clinical presentation or epidemiologic circumstances. Even after a complete diagnostic evaluation, at least 25% of patients who have genital ulcers have no laboratory-confirmed diagnosis. Noninfectious causes of genital ulcers, including Crohn's disease, Behçet's disease, and traumatic ulcers, should be considered.

Herpes Simplex Virus Infections

Genital HSV infection prevalence has markedly increased over the past two decades. About 50 million persons in the United States have genital HSV infection based on seroprevalence studies and most of them remain undiagnosed. Most infections are transmitted by those who are asymptomatic. Two serotypes, HSV-1 and HSV-2 have been identified, and both have been implicated as the pathogen in genital HSV infection. Although genital HSV infections are usually caused by HSV-2, up to 50% of first episodes of genital herpes are caused by HSV-1. However, recurrences are much less frequent for HSV-1; thus, distinction of the serotypes influences prognosis and counseling. HSV-2 infections are almost always sexually acquired, whereas HSV-1 infections may be caused by anogenital or orolabial infections.

Laboratory diagnosis of HSV infections consists of virologic and serologic tests. Viral culture is the preferred test for patients with mucocutaneous lesions. However, the sensitivity is low and declines rapidly as lesions begin to heal. Antigen detection by direct fluorescent antibody (DFA) and polymerase chain reaction (PCR) assays to detect viral DNA are other methods. The PCR assay is not widely available and has not been well studied for genital lesions but is the preferred method of diagnosis in spinal fluid specimens. Type-specific serologic tests are useful for the diagnosis of patients who are asymptomatic or for whom virologic test results are negative. Cytologic detection of cellular changes from lesions (using the Tzanck test) is insensitive and nonspecific and should not be relied on for diagnosis.

The clinical manifestations of first-episode genital HSV infections differ greatly from recurrent episodes and will be discussed separately.

First-Episode Genital Herpes Infection

Primary genital HSV infection is one in which the patient has not had prior infection by any HSV serotype. Patients with primary infection are more likely to have a symptomatic and more severe infection.

First-episode infections often are associated with prolonged systemic and local symptoms. Systemic symptoms include fever, headache, malaise, and myalgias. These appear in the first 3 to 4 days after the onset of lesions and gradually recede over the next 3 to 4 days. Local symptoms are characterized by papules or vesicular lesions that coalesce to form painful ulcers and can also include itching, urethral discharge, dysuria, vaginal discharge, and painful inguinal adenopathy. Cervicitis manifesting with ulcerative lesions in the exocervix and purulent or bloody vaginal discharge may be present. Local symptoms often last 3 weeks and peak at about the end of the first week. Pharyngitis and proctitis can also occur, depending on the site of inoculation of the virus. Complications of first-episode genital HSV infection include aseptic meningitis (usually with HSV-2), urinary retention (because of autonomic dysfunction), transverse myelitis, and extragenital lesions, usually on the buttocks and caused by autoinoculation, disseminated infection with both cutaneous or visceral involvement and pelvic inflammatory disease. Women may also be superinfected by yeast vaginitis during the course of the illness.

Most patients with primary genital herpes should receive antiviral therapy because they may have mild symptoms early but could develop severe disease later. The recommended therapy is acyclovir, 200 mg five times daily or 400 mg three times daily, or famciclovir, 250 mg three times daily, or valacyclovir, 1 g twice daily. The recommended duration of therapy is 7 to 10 days.

Recurrent Genital Herpes

Almost all persons infected with HSV-2 have the infection reactivated in the genital region. About 60% of episodes are preceded by prodromal symptoms, such as a mild tingling sensation or shooting pains in the buttocks or hips. The lesions tend to be more severe in women. As with the primary episode, the lesions are classically described as painful vesicles that ulcerate and later crust, without leaving a scar. However, compared with the primary episode, the lesions are less painful, heal faster, and are not associated with systemic symptoms. Also, the lesions may not be typical, and all genital ulcers should be evaluated for HSV. The frequency of recurrences decreases over time.

The strategy for managing recurrent episodes consists of episodic treatment to ameliorate or shorten the duration of illness or suppressive treatment to reduce the frequency of recurrences. Recommended regimens for episodic treatment include acyclovir, 400 mg three times daily or 800 mg twice daily, famciclovir, 125 mg twice daily, or valacyclovir, 500 mg twice daily or 1 g daily. The recommended duration of therapy is 5 days, except for valacyclovir, 500 mg twice daily, which has been shown to be as effective with 3-day therapy as 5-day therapy. Treatment should be started within 1 day of onset of lesions; hence, the patient should be provided with a prescription for of the relevant drug(s) so that therapy can be self-initiated when symptoms arise.

Suppressive treatment has been shown to reduce the frequency of genital herpes by 70% to 80% in patients who have more than six recurrent episodes per year. Recommendations for suppressive therapy include acyclovir, 400 mg twice daily, famciclovir, 250 mg twice daily, or valacyclovir, 1 g daily. Because the frequency of recurrences decreases over time, continuation of suppressive therapy should be reassessed periodically.

Other Considerations

Severe Disease. 

In patients with severe disease or with disseminated infection such as meningitis, IV acyclovir should be given. The recommended regimen is acyclovir, 5 to 10 mg/kg body weight every 8 hours for 2 to 7 days, or until clinical improvement is observed, followed by oral therapy for a total of 10 days.

Herpes Simplex Virus in Pregnancy. 

The risk of neonatal herpes in an infant born to a mother who has primary HSV infection is 30% to 50% and is less than 1% in mothers with a history of recurrent herpes or those who acquire herpes in the first half of pregnancy. Prevention of neonatal herpes depends both on preventing the acquisition of HSV during late pregnancy and avoiding exposure of the infant to herpetic lesions during delivery. It is recommended that mothers with a history of recurrent genital HSV infection who have prodromal symptoms or herpetic lesions on examination undergo cesarean section to lessen the chance of neonatal herpes infection.

Herpes Simplex Virus in HIV infection. 

HSV infection increases the risk of HIV infection. In addition, HIV patients may have more severe and prolonged episodes of recurrent herpes. The recommendations for episodic and suppressive therapy differ from those for immunocompetent patients. Recommended therapy for episodic treatment is oral therapy for 5 to 10 days with acyclovir, 400 mg three times daily or 200 mg five times daily, famciclovir, 500 mg twice daily, or valacyclovir, 1 g twice daily. Recommended therapy for suppressive therapy is oral therapy as follows: acyclovir, 400 to 800 mg two or three times daily, famciclovir, 500 mg twice daily, or valacyclovir, 500 mg twice daily.

Counseling Discordant Couples. 

Transmission of HSV from the patient to a seronegative partner can occur during asymptomatic shedding. Hence, discordant couples should be advised to abstain from sexual activity when active lesions are present and encouraged to use condoms consistently at other times. However, condoms do not fully prevent transmission because there can be asymptomatic shedding from areas such as the perineum, which are not protected by condoms.

Syphilis

Syphilis is a systemic disease caused by the spirochete Treponema pallidum. The natural history of syphilis consists of different stages with distinctive clinical stages: primary, secondary, latent, and tertiary syphilis. Neurosyphilis, often considered part of tertiary syphilis, can occur with any of the different stages and requires special attention because of its therapeutic implications. Syphilis and its complications were common in medical practice in the earlier part of the 20th century. After the introduction of penicillin and public health efforts to control the disease, its prevalence has declined. Advanced stages of syphilis are now rare and clinicians are often unfamiliar with its various manifestations. However, outbreaks have occurred in several groups and, in the presence of HIV infection, may manifest different signs and symptoms. Thus, there is renewed interest in this disease.

Because it has not been possible to grow the organisms in vitro, definitive diagnosis depends on visualizing the organisms by dark field microscopy or DFA tests of lesion exudates or tissue. A presumptive diagnosis can be made based on two types of serologic tests: nontreponemal tests (e.g., Venereal Diseases Research Laboratory [VDRL]) and rapid plasma reagin [RPR]); and treponemal tests, such as fluorescent treponemal antibody adsorption (FTA-ABS) and T. pallidum particle agglutination (TP-PA) assays. Nontreponemal test titers correlate with disease activity and therefore should be quantitative. Treatment can be considered effective if follow-up titers at 6 months have fallen at least fourfold. They usually become negative after treatment. If the titer has dropped at least fourfold, but remains positive, the patient is considered serofast (usually in the 1 : 2 to 1 : 4 range). Sequential tests in individual patients should be performed using the same test because the two tests (VDRL and RPR) cannot be compared. Patients who have positive treponemal test results generally remain positive for the rest of their lives.

The incubation period of syphilis is 10 to 90 days (average, 2 weeks). Clinical manifestations depend on the stage of the disease, which are discussed here.

Primary Syphilis

The lesion of primary syphilis starts as a painless papule at the site of inoculation, which subsequently develops into an ulcer (chancre). The chancre is a painless, slightly elongated ulcer 1 to 2 cm across, with a clean base and an indurated margin. Moderate painless, bilateral, inguinal lymphadenopathy is usually present. Lesions are usually solitary and can be missed if they are not in visible regions because of their painless nature. Untreated, they spontaneously heal in 3 to 6 weeks. Treatment is with benzathine penicillin, 2.4 million units IM, in a single dose.

Secondary Syphilis

Secondary syphilis develops 4 to 10 weeks after the initial appearance of primary lesions. It starts as an evanescent macular rash followed in a few days by a symmetrical papular eruption involving the entire trunk and extremities. Characteristically, it involves the palms and soles. The papules are reddish brown and generally scaly, and may be mistaken for psoriasis. Other manifestations could be a patchy alopecia (moth-eaten alopecia), mucosal lesions (painless aphthous ulcers or gray plaques), condyloma latum (raised, moist whitish lesions in warm moist areas such as the axilla or groin region), and lymphadenopathy. It is a systemic disease with possible symptoms of low-grade fever, sore throat, headache, malaise, and weight loss. The lesions of primary and secondary syphilis are highly infectious. Treatment, as for primary syphilis, is benzathine penicillin, 2.4 million units IM in a single dose.

Latent Syphilis

If secondary syphilis is untreated, there is a spontaneous resolution of symptoms in 3 to 12 weeks. The patient then enters into the latent phase, during which the patient is asymptomatic but has serologic evidence of ongoing infection. During the first year of latent syphilis, the patient may have relapses of secondary syphilis. This phase is early latent syphilis. After the first year, during the late latent phase, it is highly unlikely that the patient will have any recurrences of secondary syphilis. Often, the duration of infection cannot be determined to classify the infection as early or late.

These patients, with latent syphilis of unknown duration, should be treated as if they had late latent syphilis. Recommended treatment for early latent syphilis is benzathine penicillin, 2.4 million units IM in a single dose. The recommended treatment for late latent syphilis is benzathine penicillin, 2.4 million units IM given weekly for 3 weeks consecutively.

Tertiary Syphilis

About one third of patients with late latent disease go on to develop tertiary syphilis if left untreated. This includes gummatous disease (benign late syphilis), cardiovascular syphilis, and neurosyphilis.

Gummatous disease, now uncommon, can manifest as recurrent nodular lesions in the skin that ulcerate and heal leaving an atrophic scar. In addition to the skin, skeletal and upper respiratory tract areas are the more common sites involved.

Cardiovascular syphilis consists mainly of an aortitis of the ascending aorta. The aortic valve and coronary ostia may also be involved. Gummatous disease and cardiovascular syphilis are treated with benzathine penicillin, 2.4 million units IM given weekly for 3 weeks consecutively.

Neurosyphilis is classically described as a part of tertiary syphilis. There may be several forms with overlap, among them; these forms include asymptomatic, meningeal, meningovascular, parenchymatous (general paresis and tabes dorsalis), and gummatous disease. Asymptomatic syphilis is manifest by cerebrospinal fluid (CSF) findings suggestive of meningitis. Usually, there is a CSF pleocytosis, predominantly lymphocytic, with more than 5 cells/mm3. The protein level is elevated and there may be decreased glucose levels. The VDRL test result is positive in most cases; this is specific but not very sensitive. The FTA-ABS test result on the CSF is sensitive but not specific and may be used to exclude a diagnosis of central nervous system (CNS) syphilis when the CSF VDRL test result is negative. Syphilitic meningitis manifests as cranial nerve palsies and hearing loss caused by basilar meningitis. There may also be signs of uveitis. Meningovascular syphilis can result in cerebrovascular accidents.

The recommended treatment regimen for neurosyphilis is aqueous penicillin G, 18 to 24 million units daily, given as 3 to 4 million units IV every 4 hours or as a continuous infusion for 10 to 14 days. Alternatively, procaine penicillin, 2.4 million units IM once daily, plus probenecid, 500 mg PO four times daily, may be given, both for 10 to 14 days. A CSF examination should be repeated every 6 months until the cell count is normal. If the cell count has not decreased after 6 months or the CSF is not normal after 2 years, re-treatment should be considered.

Other Considerations
Jarisch-Herxheimer Reaction. 

After treatment for primary or secondary syphilis patients may have a febrile reaction because of the release of treponemal constituents. It starts 4 to 6 hours after treatment, subsides in 24 hours, and is characterized by fever, chills, headache, arthralgias, and a transient increase in prominence of the lesions. Patients should be managed with an anti-inflammatory agent such as ibuprofen.

Penicillin Allergy. 

For patients with primary or secondary syphilis or early latent syphilis, other options include doxycycline, 100 mg PO twice daily for 14 days, or tetracycline, 500 mg PO four times daily for 14 days. Ceftriaxone, 1 g IM or IV daily for 8 to 10 days, is another option. Some reports have suggested that azithromycin, 2 g PO as a single dose is effective. However, other reports have suggested that there may be substantial resistance to azithromycin, based on molecular studies, so caution should be used with this approach. For patients with late latent syphilis, doxycycline or tetracycline may be used for 28 days. For patients with neurosyphilis, ceftriaxone, 2 g IV or IM for 10 to 14 days, may be used. Pregnant women who are allergic to penicillin should be desensitized and treated with penicillin.

Follow-up. 

Because any therapy could fail, follow-up is extremely important. In patients without HIV, 6-month and 1- and 2-year follow-ups are recommended. Patients who have continued signs and symptoms or a fourfold increase in titer during follow-up are considered to be therapeutic failures. Also, if patients do not achieve a fourfold decrease in nontreponemal titers in 6 months, they are considered therapeutic failures. In this case, the patient should be checked for HIV and neurosyphilis. For therapeutic failures, the patient should receive three weekly doses of benzathine penicillin.

Syphilis in HIV-Infected Persons. 

Patients with HIV infection have an increased risk of developing neurosyphilis, even if they are not severely immunocompromised, and the disease may progress more rapidly. In addition, they may have higher rates of treatment failure. Some specialists have recommended treatment for primary syphilis, secondary syphilis, and early latent syphilis in HIV-infected patients with 2.4 million units of benzathine penicillin every week for 3 weeks. In addition, many specialists would do a CSF examination to rule out neurosyphilis before starting treatment. Follow-up is recommended at 3-month intervals in HIV-infected patients for the first year of follow-up.

Syphilis in Pregnancy. 

Infants born to mothers at any stage of syphilis are at risk of becoming infected with congenital syphilis. The mode of transmission is transplacental. The risk, however, decreases with later stages of disease. Syphilis during pregnancy is associated with increased risk of miscarriage. All pregnant women should be screened serologically for syphilis at their first prenatal visit. Treatment should consist of the penicillin regimen appropriate for the stage of syphilis. Penicillin-allergic patients should be desensitized and treated with penicillin.

Chancroid

Chancroid is an ulcerative disease caused by Haemophilus ducreyi. The U.S. incidence of chancroid has declined since 1987, with less than 100 cases per year reported to the Centers for Disease Control and Prevention (CDC). It usually occurs in discrete outbreaks, although it is endemic in some U.S. regions. About 10% of persons in the United States who acquire chancroid are coinfected with T. pallidum or HSV.

Clinically, it manifests as a tender erythematous papule that may develop at the site of inoculation after 4 to 7 days. This then progresses to form a pustule that may rupture after 2 to 3 more days to form painful shallow ulcers. These ulcers typically have a granulomatous base, with purulent exudates and overhanging margins. Painful tender lymphadenopathy is seen in up to 50% of cases and is usually unilateral; this may become fluctuant and drain spontaneously unless aspirated or drained by incision.

Chancroid ulcers take several weeks or months to resolve in the absence of effective therapy. As with other ulcerative diseases, chancroid is a cofactor in the transmission of HIV.

The definitive microbiologic diagnosis of chancroid is challenging, so chancroid is usually diagnosed clinically. A special medium is required to isolate H. ducreyi in culture, and is not widely available. Even using this medium, the sensitivity is less than 80%. Several commercial laboratories offer DNA amplification assays for H. ducreyi but these are not widely available. For treatment purposes, a probable diagnosis can be made if the following criteria are met: the patient has one or more painful genital ulcers; the patient has no evidence of T. pallidum infection by dark field examination of ulcer exudates or by serologic testing for syphilis performed at least 7 days after the onset of ulcers; the clinical presentation, appearance of genital ulcers and, if present, regional lymphadenopathy are typical of chancroid; and a test for HSV performed on the ulcer exudates is negative. It must be remembered that such a definition excludes coinfections.

Treatment

Recommended regimens are as follows:

  • Azithromycin, 1 g PO single dose, or
  • Ceftriaxone, 250 mg IM single dose, or
  • Ciprofloxacin, 500 mg PO twice daily for 3 days, or
  • Erythromycin base, 500 mg PO three times daily for 7 days

Patients with HIV and uncircumcised men do not respond well to therapy, compared to those who are HIV negative and circumcised. These patients should be carefully followed. Some specialists recommend using the erythromycin 7-day regimen for HIV-positive patients. Patients should be tested for HIV when chancroid is diagnosed. Patients who test negative for HIV and syphilis when chancroid is diagnosed should be retested again for these diseases after 3 months.

Patients should be re-examined within 3 to 7 days; they should have symptomatic improvement within 3 days and objective improvement within 7 days after therapy is initiated. If no clinical improvement is apparent, consideration should be given to the possibility of an incorrect diagnosis, coinfection with another STD such as HSV or syphilis, HIV coinfection, noncompliance, or resistance of the organism. Complete healing of the ulcer may take longer than 2 weeks. Resolution of fluctuant lymphadenopathy is slower than ulcers. These buboes should be drained to provide symptomatic relief to the patient and avoid spontaneous rupture. Sexual partners of patients with chancroid should be treated regardless of symptoms if they have had sexual contact with the patient within 10 days preceding the patient's onset of symptoms.

Lymphogranuloma Venereum

Lymphogranuloma venereum (LGV) is caused by the L1, L2, and L3 serovars of Chlamydia trachomatis. These serovars are more invasive than other C. trachomatis serovars. The disease is rare in the United States and other industrialized nations but is endemic in Africa, southeast Asia, Central and South America, and the Caribbean islands.

The clinical manifestations of LGV can be divided into three stages. After an incubation period of 3 to 30 days at the site of inoculation, the patient may develop a painless papule that may ulcerate (primary stage). The lesion is self limited and often may go unnoticed. After several weeks of the primary lesion, the patients may have involvement of the inguinal lymph nodes or the anus and rectum (secondary stage). Inguinal lymph nodes are usually involved in men. The lymphadenopathy is typically unilateral, tender, and firm. It may manifest on both sides of the inguinal ligament, which forms a groove, called the groove sign. Stellate abscesses that are present in the lymph nodes coalesce and form discharging sinuses. Many patients present with systemic complaints such as fever, myalgias, and headache.

Anorectal involvement manifests as an acute hemorrhagic proctitis. Patients present with rectal pain and bleeding and often with pronounced systemic complains. A recent outbreak in the Netherlands in MSM highlights the importance of awareness of this manifestation of LGV.

In untreated LGV, fibrosis caused by chronic inflammation is present (tertiary stage). Fibrosis can lead to lymphatic obstruction and elephantiasis of the genitalia in either gender. Rectal involvement may cause strictures and fistulas. These conditions are more common in women and can lead to widespread destruction of the genitalia, a condition known as esthiomene (from the Greek, “eating away”).

Diagnosis may be made by serologic testing or detection of the organism. Because the disease is invasive, antibody titers to Chlamydia are high. Laboratory criteria consistent with a diagnosis of LGV include a complement fixation titer for Chlamydia of 1 : 64 or higher, or a microimmunofluorescence test for C. trachomatis titer of 1 : 128 or higher. C. trachomatis may also be identified in buboes by tissue culture or by DFA staining on a bubo or ulcer smear. A PCR diagnostic assay has been described.

Treatment

Treatment cures infection and prevents ongoing tissue scarring. The recommended regimen is doxycycline, 100 mg PO twice daily for 21 days. An alternative regimen is erythromycin base, 500 mg PO four times daily for 21 days. Some specialists believe that azithromycin, 1 g PO once weekly for 3 weeks is effective, but clinical data are lacking.

Patients should be followed until signs and symptoms have resolved. Sexual partners of the patient within the last 60 days should be evaluated. In the absence of symptoms, sexual partners should be treated with azithromycin, 1 g PO as a single dose, or doxycycline, 100 mg PO twice daily for 7 days.

Granuloma Inguinale (Donovanosis)

Granuloma inguinale is caused by the bacterium Calymmatobacterium granulomatis, which has been seldom isolated on culture. The disease is rare in the United States but endemic in Papua, New Guinea, parts of South Africa and India, Brazil, and among aborigines in Australia. In addition to sexual transmission, the disease may also be transmitted during birth and to children, probably when sitting on the laps of infected persons.

The incubation period is uncertain, with estimates ranging from 1 to 360 days. Experimental lesions in humans appear after 50 days of inoculation. The lesions of donovanosis start as a firm papule that ulcerates. Lymphadenopathy is typically absent. Classically, four types of lesions are described: ulcerogranulomatous (nontender beefy red lesions that bleed easily on touch); hypertrophic or verrucous ulcer, with irregular margins; necrotic, foul-smelling deep ulcers causing tissue destruction; and sclerotic or cicatricial lesions, with fibrous or scar tissue. Lesions generally occur in the genital areas or inguinal region. Lesions may also occur in the cervix or upper genital tract of women. Occasionally, lesions may appear in the oral cavity or pharynx. Rarely, disseminated infection is present, which may involve the bone and liver, and is usually associated with pregnancy and cervical infection.

Diagnosis requires visualization of dark-staining Donovan bodies on tissue crush section or biopsy. Other methods of preparation of the specimen have been described. One technique is to firmly roll a cotton-tipped swab across the surface of the lesion after removing debris from the surface of the wound. The swab is then rolled over a glass slide and stained by a rapid Giemsa method. If multiple samples for different tests are taken at the same time, the sample for Donovan bodies should be taken first so that enough cells are obtained.

The treatment regimen recommended by the CDC is as follows:

  • Doxycycline, 100 mg PO twice daily for at least 3 weeks, or
  • Alternative regimens include the following:
  • Ciprofloxacin, 750 mg twice daily for at least 3 weeks, or
  • Erythromycin, base 500 mg PO twice daily for at least 3 weeks, or
  • Azithromycin, 1 g PO once/week for at least 3 weeks
  • Trimethoprim-sulfamethoxazole, one double-strength tablet PO twice daily for at least 3 weeks

Three weeks of the above-recommended therapy is generally sufficient, although the addition of an aminoglycoside such as gentamicin, 1 mg/kg IV every 8 hours, to these regimens may be considered if improvement is not evident in the first few days of therapy.

Despite optimal therapy, relapse can occur after 6 to 18 months. Persons who have had sexual contact with the patient within 60 days before onset of the patient's symptoms should be examined and offered therapy, although the value of treating asymptomatic contacts has not been established.

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Sexually transmitted diseases with genital discharge

Pelvic Inflammatory Disease

Pelvic inflammatory disease (PID) is the term used to describe any single infection or combination of infections of the upper female genital tract such as endometritis, salpingitis, tubo-ovarian abscess and pelvic peritonitis. In the United States alone, approximately 1,200,000 women and girls acquire PID annually; of these, 100,000 are likely to become infertile as a result of the infection, and more than 150 will die as a result of PID or its complications. Even mild to moderate or asymptomatic disease could result in long-term morbidity, such as infertility, ectopic pregnancy, and chronic pelvic pain.

PID is caused by various organisms. The sexually transmitted organisms C. trachomatis and Neisseria gonorrhoeae are believed to be important in the pathogenesis. Gonococcus infection generally causes a more acute illness, whereas that caused by Chlamydia tends to be mild or subtle. Other organisms generally found in the vaginal flora have also been implicated: namely anaerobes, facultative gram-negative organisms, and streptococci. In addition, cytomegalovirus, Mycoplasma hominis, and Ureaplasma urealyticum may be causative agents. Immunologic mechanisms seem to be important, especially in Chlamydia infection, in which recurrent episodes tend to be more severe than the first. Risk factors for PID include younger age (teenagers), STDs (Chlamydia, gonococcus, and bacterial vaginosis), intrauterine contraceptive devices, and douching. Oral contraceptives have been associated with a decreased severity of PID caused by Chlamydia, probably by modifying the immune response of the body.

The diagnosis of PID is difficult and a combination of signs, symptoms, and tests may be used. The clinical diagnosis of PID has a positive predictive value of 65% to 90% compared with that for laparoscopy. Some cases are asymptomatic and many cases go undiagnosed because of mild or nonspecific symptoms. In addition, a delay in initiating treatment has been shown to increase the risk of long-term gynecologic complications. It is therefore recommended that health care providers have a low threshold for the diagnosis of PID and that empirical therapy be initiated promptly. The minimum criteria in women at risk of STDs for the diagnosis of PID, when no other cause of illness can be identified, include uterine or adnexal tenderness and cervical motion tenderness.

Additional criteria used to increase diagnostic specificity, especially in low-risk women, include the following:

  • Oral temperature higher than 101° F (38.3° C)
  • Abnormal vaginal or uterine mucopurulent discharge
  • Presence of white blood cells on saline microscopy of vaginal secretions
  • Elevated erythrocyte sedimentation rate
  • Elevated C-reactive protein level
  • Laboratory documentation of cervical infection with N. gonorrhoeae or C. trachomatis

If the cervical discharge appears normal and no white cells are seen on a vaginal wet preparation, the diagnosis of PID is unlikely and alternative causes of pain should be considered. More specific criteria for the diagnosis of PID include an endometrial biopsy showing endometritis, transvaginal ultrasound or magnetic resonance imaging showing a fluid-filled salpinx (or salpinges), or laparoscopic findings consistent with PID.

PID may occasionally manifest more acutely with peritonitis and frank vaginal discharge. Acute complications of PID include periappendicitis and perihepatitis (Fitz-Hugh–Curtis syndrome).

Treatment

In the past, many specialists recommended that all patients with PID be hospitalized so that bed rest and parenteral antibiotics could be initiated. However, outpatient therapy is being increasingly used, based on the important PEACH trial data. This randomized clinical trial (PID evaluation and clinical health [PEACH]) compared short- and long-term outcomes of parenteral (cefoxitin-doxycycline) with oral (cefoxitin-probenecid or ceftriaxone plus doxycycline) for mild to moderate symptomatic PID in several U.S. centers showed no difference in short-term and long-term outcomes.

The treatment regimen generally consists of antibiotics that will be effective against N. gonorrhoeae, C. trachomatis, anaerobes, facultative gram-negative bacilli, and streptococci.

Recommended Parenteral Treatment. 

Parenteral treatment regimens include the following:

  • Cefoxitin, 2 g IV every 6 hours (or cefotetan, 2 g IV every 12 hours) plus doxycycline, 100 mg PO or IV every 12 hours. IV therapy is continued for 24 hours after clinical improvement. The patient can then take oral doxycycline to complete 14 days of therapy. If the patient has a tubo-ovarian abscess, metronidazole or clindamycin may be added for better anaerobic coverage.
  • Clindamycin, 900 mg IV every 8 hours, plus gentamicin, 2-mg/kg IV loading dose followed by 1.5 mg/kg every 8 hours (single daily dosing may be substituted). Parenteral therapy can be discontinued after 24 hours of clinical improvement and the patient can be switched to oral therapy with clindamycin, 450 mg PO four times daily, or doxycycline, 100 mg PO twice daily, to complete 14 days of therapy.

Alternative, less-preferred regimens include the following:

  • Ofloxacin, 400 mg IV every 12 hours (or levofloxacin, 500 mg IV every 24 hours), with or without metronidazole
  • Ampicillin-sulbactam, 3 g IV every 6 hours, plus doxycycline, 100 mg PO or IV every 12 hours

These regimens can be switched to oral therapy when clinical improvement is apparent.

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Oral and intramuscular treatments

Oral or intramuscular treatments can be given to patients who do not appear very ill, are not pregnant, do not have a tubo-ovarian abscess, can tolerate oral therapy, and for whom surgical emergencies such as appendicitis is unlikely. Patients who do not improve despite 72 hours of oral therapy should be admitted for parenteral therapy.

The recommended oral and IM regimens are as follows:

  • Ofloxacin, 400 mg PO once daily (or levofloxacin, 500 mg PO once daily), with or without metronidazole, 500 mg PO twice daily, administered for 14 days
  • Ceftriaxone, 250 mg IM single dose, or cefoxitin, 2 g IM single dose, and probenecid, 1 g PO administered concurrently or another third-generation cephalosporin administered parenterally, plus doxycycline, 100 mg PO twice daily (with or without metronidazole, 500 mg PO twice daily), administered for 14 days.

Follow-up is necessary, especially for oral therapy. Clinical improvement should be apparent in 72 hours. Some specialists have recommend rescreening for N. gonorrhoeae and C. trachomatis 4 to 6 weeks after completion of therapy. Male sexual partners of women with PID should be treated empirically, even if they are asymptomatic, with a regimen that covers both N. gonorrhoeae and C. trachomatis to prevent reinfection.

Bacterial Vaginosis

Bacterial vaginosis (BV) is a clinical syndrome resulting from the replacement of normal hydrogen peroxide–producing Lactobacillus in the vagina with high concentrations of anaerobic bacteria, Gardnerella vaginalis, and Mycoplasma hominis. It does not appear to be a sexually transmitted disease, although it has been associated with having multiple sex partners. However, it is the most common cause of vaginal discharge or malodor and is commonly encountered in the context of STDs. This syndrome will be summarized here.

The clinical diagnosis of BV requires three of the following four symptoms or signs: a homogeneous, white, noninflammatory discharge that smoothly coats the vaginal walls; the presence of clue cells on microscopic examination (clue cells are squamous epithelial cells covered with many vaginal bacteria, giving the cells a stippled appearance); a vaginal fluid pH higher than 4.5; and a fishy odor of vaginal discharge before or after the addition of 10% KOH (positive whiff test).

A diagnosis can also be made based on Gram staining criteria. Scoring for the absence of large gram-positive rods (Lactobacillus), and the presence of small gram-negative or variable rods (Gardnerella) and curved gram-negative rods (Mobiluncus) provides evidence for BV. Commercially available tests such as Affirm VP III (Becton-Dickinson, Sparks, Md), FemExam test card (Cooper Surgical, Shelton, Conn), and QuickVue Advance (Quidel, San Diego, Calif) can also be used.

Treatment

BV has been associated with endometritis, PID, and vaginal cuff cellulitis after invasive procedures. It has also been associated with postabortion PID. Thus, treatment of BV is aimed at relieving symptoms as well as preventing complications after invasive procedures.

Recommended regimens are as follows:

  • Metronidazole, 500 mg PO twice daily for 7 days, or
  • Metronidazole 0.75% cream, one full applicator (5 g) intravaginally once daily for 5 days, or
  • Clindamycin 2% cream, one full applicator (5 g) intravaginally at bedtime for 7 days

Alternative regimens are less efficacious and include the following:

  • Clindamycin, 300 mg PO twice daily for 7 days, or
  • Clindamycin ovules, 100 g intravaginally, once at bedtime for 3 days

BV occurring during pregnancy has been associated with adverse pregnancy outcomes, including preterm labor, premature rupture of membranes, chorioamnionitis, preterm birth, postpartum endometritis, and postcesarean wound infection. All symptomatic pregnant women should be tested and treated for BV. It is also recommended that all asymptomatic pregnant women at high risk for preterm delivery (i.e., those who have previously delivered a preterm infant) be screened for BV during their first antenatal visit and be treated if positive. Currently, there is no recommendation to do the same for mothers at low risk. Intravaginal therapy is not recommended for pregnant patients.

The regimens recommended for pregnant women are the following:

  • Metronidazole, 500 mg PO twice daily for 7 days, or
  • Metronidazole, 250 mg PO three times daily for 7 days, or
  • Clindamycin, 300 mg PO twice daily for 7 days

No teratogenic of mutagenic effects of metronidazole have been demonstrated despite concerns about this possibility.

Follow-up visits are unnecessary if symptoms resolve, except in pregnant women who have been treated for asymptomatic BV, for whom a 1-month follow-up is recommended. There has been no benefit shown in treating sexual partners of patients with BV.

Trichomoniasis

Trichomoniasis is caused by the protozoan Trichomonas vaginalis. An estimated 3 million American women contract trichomoniasis each year. They usually have a diffuse, malodorous, sometimes frothy, yellow-green discharge with vulvar pruritis, but some women may have no symptoms. On colposcopy, a strawberry cervix may be seen. In men, trichomoniasis may be asymptomatic or may manifest as a nongonococcal urethritis.

Diagnosis of vaginal trichomoniasis is by microscopic examination of a wet mount, which is 60% to 70% sensitive. It is important to obtain a fresh specimen because the organism is identified by its motility and hence must be viable when it arrives in the laboratory. Culture is a more sensitive method.

Recommended treatment for trichomoniasis is metronidazole, 2 g PO in a single dose. Alternatively, metronidazole, 500 mg twice daily for 7 days, is recommended.

Certain strains of Trichomonas have diminished susceptibility to metronidazole and respond to higher doses of metronidazole. In case of treatment failure with either regimen, patients should be re-treated with metronidazole, 500 mg twice daily for 7 days. If this fails, patients should be treated with 2 g daily for 3 to 5 days. Tinidazole in a single dose of 2 g has recently been approved for treatment of trichomoniasis.

Sexual partners of patients should be treated to avoid reinfection. Pregnant patients with trichomoniasis should be treated if symptomatic with metronidazole, 2 g PO. Although trichomoniasis has been associated with adverse pregnancy outcomes such as premature rupture of membranes, preterm delivery, and low neonatal birth weight, data have not indicated that treating asymptomatic patients reduces this risk.

Gonococcal Infections

In the United States, nearly 340,000 new cases of gonococcal were reported to the CDC in 2005. Although gonococcal infection is a notifiable disease in the United States, it is estimated that about 50% of these infections go unreported. N. gonorrhoeae, the causative agent of gonorrhea, is a gram-negative diplococcus. In clinical specimens, a smear is considered positive for gonorrhea when gram-negative diplococci with typical morphology are identified in or closely associated with polymorphonuclear leukocytes. A smear is considered equivocal if the organisms are not cell-associated or intracellular organisms do not have the typical morphology.

Gonococcal infections have a wide variety of clinical manifestations and can manifest as asymptomatic or symptomatic local infections in men and women. It may also manifest as a complicated local infection with systemic dissemination.

Local infections may manifest as urethritis, proctitis, pharyngitis, or cervicitis. Acute anterior urethritis is the most common manifestation in men. Most men are symptomatic after infection. It manifest after an incubation period of 1 to 14 days, usually 2 to 5 days, with purulent discharge and dysuria. Varying degrees of meatal erythema and edema accompany the infection. Untreated, the infection tends to resolve in most patients. Local complications include epididymitis, prostatitis, and seminal vesiculitis. Periurethral abscess, urethral stricture, and fistulas are rare in the era of antibiotic therapy.

Urogenital infection in women has a nonspecific presentation and includes increased vaginal discharge, dysuria, intermenstrual bleeding, and menorrhagia. Many patients have purulent to mucopurulent cervicitis on examination. Purulent exudates may occasionally be expressed from the urethra, periurethral glands, or Bartholin's gland (duct).

Rectal infection is common in women with gonococcal cervicitis and infection is probably from perineal contamination of infected cervical secretions. It is usually asymptomatic. Rectal infection in MSM is caused by direct inoculation. Symptoms range from minimal anal pruritis, mucopurulent discharge, or scant rectal bleeding to overt proctitis, with severe rectal pain and tenesmus.

Orogenital sexual contact can result in pharyngeal infection. Most of these cases are asymptomatic but may occasionally cause acute pharyngitis or tonsillitis associated with cervical lymphadenopathy. Pharyngeal infection may also be a source of gonococcal urethritis in MSM. Rarely, adults may present with conjunctivitis from autoinoculation.

Systemic Complications

Disseminated gonococcal infection (DGI) is the most common systemic complication of acute gonorrhea. DGI manifests with fever accompanied by joint pain and skin lesions: arthritis-dermatitis syndrome. Joint pain is polyarticular in more than 50% of cases, but monoarticular arthritis in a young, sexually active person should have gonococcus (GC) in the differential. Joint pain may be caused by arthralgias or tenosynovitis or possible by frank arthritis with effusion. Joints involved are usually the wrists, metacarpophalangeal joints, ankles, or knees but any joint may be involved. The classic skin lesion is a necrotic pustule on an erythematous base. The skin lesions, however, may manifest as macules, papules, pustules, petechiae, bullae, or ecchymoses. They generally occur in the distal extremities and are sparse. Diagnosis is made by demonstrating the presence of the organism from clinical specimens. The likelihood of recovery of the organism is best from mucosal surfaces (e.g., urethra, pharynx, rectum) when this syndrome is suspected. Other systemic complications are rare and include endocarditis and meningitis.

Diagnosis

Culture and Gram staining of urethral, rectal, or pharyngeal swabs have been the methods traditionally used for diagnosis. A Gram stain showing intracellular diplococci resembling gonococci is highly specific and sensitive in the presence of urethral discharge. However, Gram staining is not sensitive for screening asymptomatic patients. Newer tests include nonamplification tests such as DNA probes or amplification tests such as PCR assay and transcription-mediated amplification. These tests are highly sensitive and specific and can also be used to screen patients for N. gonorrhoeae and Chlamydia from urine samples. However, they should not be used to test for N. gonorrhoeae in pharyngeal or rectal specimens because of the presence of commensal Neisseria, which can yield a false-positive result.

Treatment

N. gonorrhoeae was initially sensitive to penicillin, but the 1970s saw the emergence of plasmid-mediated resistance to penicillin (penicillinase-producing N. gonorrhoeae [PPNG]). Also, the emergence of chromosomally mediated resistant N. gonorrhoeae (CMRNG), resistant to penicillin as well as tetracycline, emerged in the 1970s. In 2003, 16.4% of isolates were penicillin resistant, tetracycline resistant, or both. Quinolones have been increasingly used for oral therapy, but recently there have been reports of strains of increasing quinolone-resistant N. gonorrhoeae (QRNG) from different states, especially in MSM. It was recommended that patients who acquired gonorrhea in Asia, the Pacific Islands, Hawaii, or California not be treated with a quinolone because of a high prevalence of resistance in these areas. With the emergence of resistance in MSM, it is now recommended that quinolones not be used for the treatment of MSM with gonorrhea.

Patients infected with N. gonorrhoeae are frequently coinfected with C. trachomatis. This has led to the recommendation that patients with gonococcal infection be routinely treated with a regimen effective for Chlamydia as well. Routine dual therapy without testing for Chlamydia is cost-effective for patients in whom coinfection occurs more than 10% to 30% of the time.

Recommended treatment regimens for uncomplicated gonococcal infections of the cervix, urethra, and rectum are as follows:

  • Ceftriaxone, 125 mg IM single dose, or
  • Cefixime, 400 mg PO single dose, or
  • Ciprofloxacin, 500 mg PO single dose, or
  • Ofloxacin, 400 mg PO single dose, or
  • Levofloxacin, 250 mg PO single dose

In addition, treatment for C. trachomatis with azithromycin 1 g PO in a single dose, or doxycycline 100 mg PO twice daily for 7 days, may be initiated. Note that cefixime is currently not available in the United States after its manufacturer discontinued making the medication.

Alternative regimens include the following:

  • Spectinomycin, 2 g IM single dose, or
  • Other single-dose third-generation cephalosporins: ceftizoxime, 500 mg IM, cefoxitin, 2 g IM plus 1 g probenecid, cefotaxime, 500 mg IM
  • Other single-dose quinolones: gatifloxacin, 400 mg PO, norfloxacin, 800 mg PO, or lomefloxacin, 400 mg PO
  • Azithromycin, 2 g PO single dose, has been shown to be effective but may have high rates of gastrointestinal intolerance.

Uncomplicated gonococcal infections of the pharynx are more difficult to eradicate. The following is recommended:

  • Ceftriaxone, 125 mg IM single dose, or
  • Ciprofloxacin, 500 mg PO single dose

In addition, treatment for C. trachomatis with azithromycin, 1 g PO in a single dose, or doxycycline, 100 mg PO twice daily for 7 days, may be initiated.

Other Considerations

Persons who have persistent symptoms should be evaluated by culture and for antimicrobial susceptibility. Persistent symptoms may be caused by untreated coinfection with Chlamydia or other infections, such as trichomoniasis.

Patient should abstain from sexual activity for 7 days after therapy is started. All sex partners within 60 days before onset of symptoms or diagnosis should be treated. If the last sexual encounter was more than 60 days before the onset of symptoms or diagnosis, the patient's most recent sex partner should be treated. Pregnant women should be treated with a cephalosporin or spectinomycin; avoid quinolone.

For complicated infections, higher doses of antibiotics are recommended:

  • Gonococcal conjunctivitis: ceftriaxone, 1 g IM, single dose
  • Disseminated gonococcal infection: ceftriaxone, 1 g IV or IM every 24 hours. Alternative treatment regimens for DGI include the following:
    • Equivalent third-generation cephalosporin, or
    • Ciprofloxacin, 400 mg IV every 12 hours (or equivalent quinolone), or
    • Spectinomycin, 2 g IM every 12 hours, until 24 to 48 hours of clinical improvement

Therapy can then be completed with oral cefixime, 400 mg twice daily, ciprofloxacin 500 mg twice daily, levofloxacin 500 mg daily, or ofloxacin, 400 mg twice daily, to complete at least 1 week of antimicrobial therapy.

  • Gonococcal meningitis or endocarditis, ceftriaxone, 1 to 2 g IV every 12 hours. Therapy is continued for 10 to 14 days for meningitis and at least 4 weeks for endocarditis.

Chlamydia Infection

C. trachomatis infection of the genital tract, a reportable disease in the United States, has been increasing in prevalence probably to the result of an actual increase in prevalence and also increased screening and more sensitive tests. In 2004, there were approximately 930,000 cases reported to the CDC. Underreporting is a major problem because most patients are asymptomatic.

An estimated 2,800,000 Americans are infected each year. Genital infections caused by Chlamydia are similar to those of N. gonorrhoeae in that similar syndromes develop: urethritis, epididymitis, cervicitis, PID, and proctitis. However, the symptoms tend to be less abrupt in onset and tend to be milder or asymptomatic. The incubation period for chlamydial infection is 1 to 3 weeks, longer than that of gonococcus. Some syndromes are discussed here.

Symptoms of urethritis include dysuria and a mild to moderate whitish to clear urethral discharge. Because coinfection with gonococcus is common, patients may present after being treated for gonococcal urethritis with a persistent discharge, although milder. Urethritis may be asymptomatic, although even these patients will exhibit signs of ongoing inflammation manifested by the presence of urethral leukocytes.

In male patients, chlamydial infection has also been implicated as a common pathogen in epididymitis in sexually active young men. Non-LGV serotypes of Chlamydia may cause proctitis. This organism has also been associated with nonbacterial prostatitis and Reiter's syndrome: urethritis, conjunctivitis, arthritis, and skin lesions.

In female patients, chlamydia is frequently isolated from the cervix. Infection is often silent and symptoms such as discharge, if present, are nonspecific. Findings on examination suggestive of chlamydial infection include easily induced endocervical bleeding, mucopurulent endocervical discharge, and edema within an area of ectopy. Mucopurulent discharge from the cervix may have other causes, such as gonococcal cervicitis, endometritis, or PID.

In addition to cervicitis, female patients may also have an acute urethritis, bartholinitis, and PID caused by Chlamydia. Fitz-Hugh–Curtis syndrome, perihepatitis as a result of PID, although once considered to be a complication of only gonococcal infection, has been shown to be more often associated with Chlamydia.

Diagnosis

The preferred methods of diagnostic testing are molecular. Both DNA probes and amplification assays are available, with the latter being more sensitive. Amplification assays include PCR assay and transcription-mediated amplification. Using these assays may be inhibited in clinical specimens, sometimes yielding a false-negative result. The ligase chain reaction, another amplification assay that was once widely used, is no longer available. Other diagnostic methods include culture, antigen tests (e.g., DFA), enzyme immunoassay (EIA), and serologic assays. Culture needs special precautions during collection and cell culture systems may not be available in many centers. Antigen assays are not very sensitive and serologic assays are difficult to interpret because of the high prevalence of infection in the population and largely asymptomatic infection in women.

Empirical therapy is started in symptomatic patients and often in contacts. However, where possible, a confirmatory test should be done because it helps in tracing contacts and controlling the epidemic.

Treatment

Recommended regimens include the following:

  • Azithromycin, 1 g PO single dose, or
  • Doxycycline, 100 mg PO twice daily for 7 days

Alternative regimens include the following:

  • Erythromycin base, 500 mg PO four times daily for 7 days, or
  • Erythromycin ethylsuccinate, 800 mg four times daily for 7 days, or
  • Ofloxacin 300, mg twice daily for 7 days, or
  • Levofloxacin, 500 mg PO daily for 7 days

It is recommended that a test for cure be done at 3 weeks for pregnant women when amplification tests are used. This is not recommended in others unless there is a suspicion of noncompliance. However, because of a high rate of reinfection caused by C. trachomatis in patients who have received therapy, and because a second infection confers a higher risk for PID, health care providers should consider rescreening all female patients who have received treatment 3 to 4 months after completion of therapy.

Patients should abstain from sexual activity for 7 days after therapy is started. All sex partners within 60 days before the onset of symptoms or diagnosis should be treated. If the last sexual encounter was more than 60 days before the onset of symptoms or diagnosis, the patient's most recent sex partner should be treated.

In pregnancy, doxycycline and quinolones are contraindicated. Thus, the recommended regimens are as follows:

  • Azithromycin, 1 g PO in a single dose, or
  • Amoxicillin, 500 mg three times daily for 7 days

Alternative regimens during pregnancy are erythromycin base or erythromycin ethylsuccinate for 7 days or 14 days, depending on the dose.

Chlamydial infections and gonococcal infections are frequent in women but often asymptomatic. Even asymptomatic infections can have serious long-term consequences, mainly infertility and ectopic pregnancy. Hence, it is recommended that all sexually active adolescent women and women aged 20 to 25 years be screened for chlamydial infection annually, even if they are asymptomatic. Older women with risk factors (e.g., new sexual partner and those with multiple sexual partners) should also be screened annually.

Urethritis

Urethritis is a syndrome characterized by urethral discharge of mucopurulent or purulent material and sometimes by dysuria or urethral pruritis. Infected patients may also be asymptomatic. It is a syndrome mainly found in men. The principal bacterial pathogens implicated are N. gonorrhoeae and C. trachomatis. Gonococcal urethritis is diagnosed if intracellular gram-negative diplococci with characteristic morphology are identified on urethral smears. Otherwise, it is classified as nongonococcal urethritis (NGU). C. trachomatis is a frequent cause (15%-55%) of NGU. The cause of most cases of nonchlamydial NGU is unknown. Ureaplasma urealyticum and Mycoplasma hominis have been implicated in some studies. However, detection of these organisms is often difficult and specific diagnostic tests for these organisms are not indicated. T. vaginalis and HSV sometimes cause NGU, and diagnosis should be pursued if these infections are suspected (e.g., nonresponse to therapy or history of exposure).

Diagnosis

A diagnosis of urethritis is made if any of the following are present:

  • Mucopurulent or purulent discharge
  • Gram staining of urethral discharge demonstrating more than 5 white blood cells (WBCs)/oil immersion field

This is the preferred method for rapid diagnostic testing because it is highly sensitive and specific for documenting urethritis as well as the presence or absence of gonococcal infection.

  • Positive leukocyte esterase test on first-void urine or microscopic examination of first-void urine demonstrating 10 WBCs or more per high-power field

If none of these conditions is met, treatment should be deferred and the patient should be tested for N. gonorrhoeae and C. trachomatis and followed closely if results are negative. Empirical treatment of symptoms without documentation is recommended only for patients at high risk for infection and who are unlikely to return for follow-up. Such patients should be treated for both gonorrhea and chlamydia. Their partners should be also evaluated and treated.

Treatment

Treatment for gonococcal urethritis has been discussed earlier (see “Gonococcal Infections”). For NGU, treatment should begin as soon as possible after diagnosis. Recommended regimens, aimed at treating mainly C. trachomatis (but also effective against Mycoplasma and Ureaplasma), include the following:

  • Azithromycin, 1 g PO in a single dose (this regimen has the advantage of compliance and directly observed therapy), or
  • Doxycycline, 100 mg PO twice daily for 7 days

Alternative regimens include the following:

  • Erythromycin base, 500 mg PO four times daily for 7 days, or
  • Erythromycin ethylsuccinate, 800 mg PO four times daily for 7 days, or
  • Ofloxacin, 300 mg PO twice daily for 7 days, or
  • Levofloxacin, 500 mg PO once daily for 7 days

Patients should be instructed to abstain from sexual intercourse for 7 days after therapy is initiated. They should be retested if symptoms persist or recur after completion of therapy. All sex partners within the last 60 days should be evaluated.

For patients with objective signs of recurrent or persistent urethritis, patients should be evaluated for noncompliance or re-exposure to an untreated sex partner. After this has been excluded, patients should have a culture of an intraurethral swab as well as a first-void urine specimen tested for T. vaginalis. Also, some cases of recurrent urethritis may be caused by tetracycline-resistant U. urealyticum. Thus, the recommended regimen for these patients is metronidazole, 2 g PO in a single dose, plus erythromycin base, 500 mg PO four times daily, or erythromycin ethylsuccinate, 800 mg PO four times daily for 7 days.

Mucopurulent Cervicitis

Mucopurulent cervicitis (MPC) is characterized by purulent or mucopurulent endocervical exudate visible in the endocervical canal or in an endocervical swab specimen. It is often asymptomatic, but some patients may have an abnormal vaginal discharge or vaginal bleeding after intercourse. MPC can be caused by N. gonorrhoeae or C. trachomatis, but in most cases neither organism is isolated. This may be the result of nonmicrobiologic causes (e.g., inflammation of the zone of ectopy).

Patients with MPC should be tested for N. gonorrhoeae and C. trachomatis using sensitive and specific tests and therapy should be based on these results. Empirical therapy may be given for patients in whom the likelihood of infection is high and who are unlikely to return for follow-up. In patients with MPC, signs of PID should be sought because this may manifest as MPC.

Human Papilloma Virus

Human papilloma virus (HPV) infections of the genital tract can be asymptomatic or can manifest as genital warts or as intraepithelial neoplasia or carcinoma of the vulva, cervix, penis, or anus. About 1% of the sexually active population in the United States has genital warts. There are more than 100 different types of HPV. Types 6 and 11 are the most common types associated with genital warts. Intraepithelial neoplasia is most commonly associated with types 16, 18, 31, 32, and 34 (also called high-risk types). Types 6 and 11 also cause respiratory papillomatosis in infants and children and it is believed that transmission occurs perinatally.

Genital Warts

These commonly manifest as flesh-colored, painless, cauliflower-like lesions (condyloma acuminata), but may also manifest as smooth, dome-shaped papules (papular warts), flat crusty papules resembling seborrheic keratosis (keratotic warts), or macular or slightly raised flat-topped papules. They occur on the penis, scrotum, perianal area, vulva, or perineum. Less often, they may appear on the crural folds, thighs, or pubic area. They may also appear on the vaginal wall, on the cervix, or in the anus. Occasionally, patients report itching, burning, pain, or bleeding. Perianal warts may appear, even in the absence of anal intercourse. Application of 5% acetic acid to genital warts turns the lesion a whitish color, a property sometimes used to differentiate a wart from other lesions.

Genital warts may resolve spontaneously, grow in size or number, or remain the same. Warts that have been present for less than 1 year respond better to therapy. Treatment of genital warts reduces viral DNA and probably reduces infectivity. Response to therapy is variable and recurrences can occur, usually in the first 3 months after therapy. Therapy is usually undertaken to remove aesthetically unpleasant lesions.

Treatment for External Genital Warts. 

Therapy can be divided into patient-applied or provider-administered therapy. The choice of therapy depends on the patient and provider. Generally, if there is no significant improvement after three provider-administered therapies, or if warts have not completely cleared after six treatments, the treatment modality should be changed. Hypo- or hyperpigmentation or scars can occur at sites of treatment.

Patient-Applied Treatment. 

Podofilox, 0.5% solution, should be applied with a cotton swab, and podofilox gel should be applied with a finger to visible warts twice daily for 3 days, followed by 4 days of no therapy. This cycle should be repeated for up to four cycles as necessary. No more than 0.5 mL/day should be applied and the total wart area treated should not exceed 10 cm2.

The patient should apply imiquimod 5% cream once daily at bedtime three times a week for up to 16 weeks. The treatment area should be washed with soap and water 6 to 10 hours after the application.

Provider-Administered Treatment. 

A small amount of podophyllin resin, 10% to 25%, in a compounded tincture of benzoin, should be applied to each wart and allowed to dry. Because systemic absorption can lead to complications such as bone marrow suppression and neuropathy, less than 0.5 mL of the resin should be applied to a wart area smaller than 10 cm2 per session. Some experts recommend washing off the area 1 to 4 hours after application to reduce local irritation. The treatment can be repeated weekly if necessary.

A small amount of trichloroacetic acid (TCA) or bicholoroacetic acid (BCA), 80% to 90%, should be applied only to the warts and allowed to dry so that a white frosting develops. Excess acid can be removed by applying powdered talc, sodium bicarbonate (baking soda), or liquid soap to the area. The treatment may be repeated weekly if necessary. Some centers apply a repellent such as petroleum jelly (Vaseline) to the skin area surrounding the warts before applying podophyllin or TCA to prevent application to unaffected areas.

Cryotherapy using liquid nitrogen or cryoprobe and surgical removal by excision, curettage, or electrosurgery are other recommended modalities. Alternative modalities include intralesional interferon and laser surgery.

Treatment for Other Genital Warts. 

For vaginal warts, recommended treatment includes cryotherapy or TCA or BCA. Urethral meatus warts can be treated with cryotherapy or podophyllin resin. Anal warts can be treated with cryotherapy, TCA or BCA, or surgical excision. For cervical warts, squamous intraepithelial lesions should be excluded from treatment.

Cervical Cancer Screening

It is believed that cervical intraepithelial neoplasia is an early lesion in the continuum of changes leading to cervical cancer after HPV infection. This concept has remained the principle behind cervical cancer screening using the Papanicolaou (Pap) test, which has helped reduce the incidence of cervical cancer in developed countries. Cervical cancer can occur in young, sexually active women as well as in older women, and it is important to ensure that all women presenting with STDs be screened for cervical cancer using the Pap test. It is recommended that women who are sexually active be screened every year for cervical cancer, but can be screened less frequently if three consecutive Pap tests show no abnormality. A thin-preparation medium is widely available in developed countries that allows for Pap smear and HPV testing to be performed on the same sample.

Results are reported as the presence or absence of a low- or high-risk HPV type. High-risk HPV types (16, 18, 31, 32, 34) predict those women who are at greater risk of progressing to high-grade SIL or cervical cancer. Patients with atypical squamous cells of undetermined significance (ASCUS) or low-grade SIL who also have high-risk HPV types as determined by the Pap smear should be referred for colposcopy.

Other Considerations

No evidence exists to suggest that the presence of genital warts (low-risk HPV types) or their treatment is associated with the development of cervical cancer. Thus, HPV typing of patients with genital warts is not recommended, nor is colposcopy or increased frequency of Pap smear recommended.

Genital warts can proliferate and become friable during pregnancy and many experts advocate their removal during pregnancy. Imiquimod, podofilox, or podophyllin should not be used during pregnancy. Although HPV types 6 and 11, which can also cause genital warts, cause respiratory papillomatosis, their transmission is not well understood. Cesarean section is not recommended as a preventive measure in patients with genital warts. A Pap smear is recommended during pregnancy.

The use of latex condoms has been associated with a lower rate of cervical cancer, an HPV-associated disease. However, they are not effective in preventing the transmission of genital warts, because condoms cannot cover all the affected skin.

In June 2006, the U.S. Food and Drug Administration approved a quadrivalent vaccine for HPV. Two low-risk types that cause most genital warts, HPV 6 and 8, are targeted, as well as the two high-risk types that cause 70% of U.S. cervical cancer cases, HPV types 16 and 18. The vaccine is most effective when given before the initiation of sexual intercourse, so recommendations are for girls and young women between the ages of 9 and 26. Approval will eventually be sought for boys and young men because they can develop genital warts and penile or anal cancer from HPV as well. The vaccine is generally well tolerated and is given as a series of three vaccines at 0, 1, and 6 months. Several states have already recommended making HPV vaccination mandatory for middle school–aged girls.

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Summary

  • STDs are still a major cause of morbidity in the United States and worldwide.
  • Pelvic inflammatory disease can lead to devastating long-term sequelae, even when symptoms are mild. If PID is suspected, it should be treated.
  • Neisseria gonorrhoeae is becoming more quinolone resistant. Thus, quinolone should not be used as first-line treatment for the MSM population, and all other populations should be carefully monitored, because recommendations may change.
  • HPV vaccine is available for use in girls and young women aged 9 to 26 years. It is highly effective in preventing genital warts and, most importantly, in preventing cervical cancer.

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Suggested Readings

  • Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006. MMWR Morb Mortal Weekly Rep. 2006, 55: (RR-11): 1-94.
  • Centers for Disease Control and Prevention. Quadrivalent human papillomavirus vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Weekly Rep. 2007, 56: (RR-2): 1-24.
  • Holmes KK, Mardh PA, Sparling PF (eds): Sexually Transmitted Diseases. 3rd ed San Francisco: McGraw-Hill, 1999.
  • Ness RB, Soper DE, Holley RL, et al: Effectiveness of inpatient and outpatient treatment strategies for women with pelvic inflammatory disease: Results from the Pelvic Inflammatory Disease Evaluation and Clinical Health (PEACH) Randomized Trial. Am J Obstet Gynecol. 2002, 186: 929-937.