Karen A. Wendel
Jonathan M. Zenilman
Sexually transmitted diseases (STDs) are common in the primary care setting. Their associated morbidity ranges from mild genitourinary pain or irritation to infertility, adverse pregnancy outcomes, facilitation of human immunodeficiency virus (HIV) transmission, and genital tract epithelial cancers. STDs are often asymptomatic. Therefore, clinicians should regularly obtain a sexual history, inquire about genitourinary symptoms, provide counseling regarding safe sexual practices, and screen persons at risk. This chapter will review the presentation of common STDs, their differential diagnosis, and treatment. The STDs are delineated by syndrome. Chapter 102 discussesvaginitis and pelvic inflammatory disease.
Genital Ulcer Disease
In the United States, genital herpes is the major cause of infectious genital ulcer disease, followed by syphilis. The prevalence of each is dependent on the patient population and geographic area, especially for syphilis, which is largely confined to urban areas and the Southeast and is the object of a national elimination campaign. Chancroid and granuloma inguinale are rare and are usually associated with travel to endemic areas outside the United States. Recently, lymphogranuloma venereum has been identified in Europe, the United Kingdom, Canada, and the United States in men who have sex with men (MSM) (1). More than 25% of patients with genital ulceration will not have a definitive diagnosis even after full microbiologic evaluation (2). The evaluation and treatment of genital ulcers is important for control of the primary infection and is also important in preventing the transmission and acquisition of HIV (3, 4, 5, 6, 7). Patients with genital ulcer disease should be tested for HIV infection at the time of diagnosis and 3 months after their initial presentation.
Since “classical” presentations are uncommon, pathogen specific testing should be performed (8, 9, 10). Genital ulcers are generally attributable to sexually transmitted
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infections but can also be caused by other medical conditions such as Behcet disease, Crohn disease, lichen planus, carcinoma, leishmania, fixed drug eruptions, and other drug toxicities.
Treatment should be based on clinical assessment and geographic prevalence of disease (Fig. 37.1). Treatment protocols are published periodically by the Centers for Disease Control and Prevention (CDC). Often clinicians provide empiric treatment of several possible etiologies simultaneously (2).
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FIGURE 37.1. Evaluation and treatment of genital ulcer disease. a In homosexual men lymphogranuloma venereum (LGV) should be considered in the differential diagnosis; testing for chlamydia (see Lympogranuloma Venereum) should be performed simultaneously with syphilis and herpes tests. Empiric therapy for LGV should be considered while awaiting test results. b In outbreak settings of syphilis or chancroid, empiric treatment of these diseases should take priority. |
Herpes
Recurrent genital herpes is most often caused by sexually transmitted herpes simplex virus 2 (HSV-2), but HSV-1 now accounts for 32% to 78% of first-episode cases in the United States presumably related to increased oro-genital transmission (11,12). HSV-2 is almost always sexually acquired. Genital herpes simplex is a chronic infection and the incidence can be assessed only indirectly. Data collected from the U.S. population-based National Health and Nutritional Examination Surveys (NHANES) III (1988–1994) and NHANES IV (1999–2000) have shown that the seroprevalence of HSV-2 infection in 14-year-olds to 49-year-olds has decreased by 17%. In the latter period, HSV-2 prevalence was 18%. Less than 10% of seropositive persons report a history of genital lesions, and up to 60% of patients with newly acquired HSV-2 are asymptomatic (13,14). With education about the manifestations of genital herpes, up to 50% of patients who previously denied symptomatic disease will be able to correctly identify HSV-2 out-breaks (15).
After infection the incubation period ranges from 2 to 20 days with a mean of 7 to 10 days (16, 17, 18). The classic presentation of primary infection is of grouped vesicular lesions 1 mm to 3 mm in size on an erythematous base. Without treatment, the vesicles persist for 10 to 12 days and then erode to form superficial ulcers that heal over 10 to 14 days. When symptomatic, the primary infection may have extragenital and constitutional symptoms including lymphadenopathy, fever, malaise, headache, dysuria, and hemorrhagic cervicitis.
HSV latency is established in the dorsal root ganglia of the sensory nerves innervating the infection site. The chronic phase of HSV infection is characterized by clinical recurrences and asymptomatic shedding (19,20).
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HSV-2 is associated with more frequent recurrences of genital lesions than is HSV-1. Higher recurrence rates are also associated with male sex and with a prolonged primary episode (younger age of acquisition) (19). Compared to the primary episode, recurrences tend to be less severe and shorter. They are often preceded by a prodome, which can include burning, itching, or genital pain. Recurrence rates of HSV-2 vary but in a study of over 400 people with HSV-2, 38% had ≥6 recurrences in 1 year and 20% had ≥10 recurrences (19). The highest risk of transmission occurs via viral shedding when active HSV lesions are present. Patients also shed virus (27% of days) when they are asymptomatic (21), and patients are often unaware that asymptomatic shedding can transmit infection. On a population basis, the majority of HSV transmission occurs during asymptomatic shedding or in patients who are unaware of their infection.
Except for a classical presentation, clinical diagnosis of genital herpes is neither sensitive nor specific, and laboratory diagnostics should be used. Viral culture of lesion exudates is the most commonly used diagnostic test and can also distinguish HSV-1 from HSV-2 infection with its concomitant prognostic implications. HSV culture sensitivity is highest in early disease, especially when vesicles are present. Antigen detection assays from swabs taken at the base of genital ulcers are more rapid than HSV culture and have higher sensitivity for HSV diagnosis in late-stage lesions (22). HSV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) of genital lesions is a promising new diagnostic tool that appears to have high sensitivity. But this has not been standardized and is not yet available commercially (23). Papanicolaou smear and Tzanck preparation have low sensitivity.
Accurate Food and Drug Administration (FDA)-approved type-specific serologic assays for HSV have been available since 1999. Point-of-care tests for HSV-2 antibodies are available and can provide accurate results during a clinic visit (Biokit HSV-2 by Biokit USA and SureVue HSV-2 by Fisher Scientific) (24). HerpesSelect HSV-1 and HSV-2 enzyme-linked immunoabsorbent assay (ELISA) (Focus Technologies) and Trinity Biotech HSV-2 ELISA are also available as send-out tests from major referral laboratories, and are increasingly available at large hospitals. HSV-1 and HSV-2 immunoblots (Focus Technologies) can be used to confirm positive results in low risk patients. Type-specific ELISA has a sensitivity from 80% to 90% and specificity ≥95% (25, 26, 27). Patients seroconvert between 4 to 6 weeks following primary infection.
Use of HSV-2 type-specific serology allows the clinician to manage difficult diagnoses of genital lesions and challenging counseling, such as assessing patients with a past history of genital lesions or with prior nondiagnostic genital ulcer evaluations. Type-specific serology can provide information regarding a patient's HSV-2 status and thereby allow for proper counseling. Because many persons are unaware of their HSV-2 infection, its is often difficult to determine by history if a patient is still at risk of acquiring HSV-2 when their sexual partner has a known history or new diagnosis of HSV-2. In couples who are thought to be discordant for HSV-2 infection, type-specific serologies can clarify the true risk of acquiring new infection and assist in counseling about sexual practices, suppressive therapy, and risk of HSV-2 transmission. Some authorities have recommended offering HSV-2 serological screening routinely to all individuals with HIV-infection, multiple sex partners, or individuals being evaluated for STDs. However, the practicality of this approach, especially the counseling issues, present large logistic and operational challenges. The consequences of new HSV infection are most severe in neonates born to mothers who either have active ulcers during delivery, or who develop primary HSV infection during pregnancy. Knowing the serologic status of pregnant women and their partners would assist in counseling patients about the risks of HSV exposure in late pregnancy.
Treatment of primary, symptomatic HSV can reduce fever and other constitutional symptoms within 48 hours (28). Skin lesions take longer to respond. Acute antiviral therapy will not cure the disease or change the subsequent natural history of recurrent disease. Treatment of recurrences can be given as episodic treatment or suppressive therapy. In patients who elect episodic treatment, education regarding the symptoms of recurrences is an important part of management. These patients should have HSV antiviral medication on hand or a prescription they can readily fill when prodromal symptoms occur or lesions develop. Effective therapy of HSV recurrences requires that patients initiate treatment as early as possible—preferably within 1 day of lesion onset.
Suppressive therapy can decrease the number of recurrences patients develop by 70% to 80% while on therapy (2). In patients with six or more HSV recurrences a year suppressive antiviral treatment is effective and has also been shown to significantly improve quality of life (29). The dose of antiretroviral medication needed to suppress HSV recurrences may be patient-dependent, and individual titration may be necessary. Suppressive antiviral treatment also decreases asymptomatic shedding. Recently, a multicenter double-blind, randomized, controlled trial of suppressive valacyclovir 500 mg versus placebo daily for 8 months in HSV-2 discordant couples demonstrated a 48% decrease in HSV-2 transmission (30). In many patients the frequency of HSV recurrences decreases over time. Clinicians should re-evaluate the patient's requirements for treatment on a yearly basis and discuss the risks and benefits of discontinuing suppressive therapy.
Antiviral therapy for HSV includes the nucleoside analogs acyclovir, famciclovir, and valacyclovir (Table 37.1). All of these agents interfere with the action of viral thymidine kinase. Famciclovir, a prodrug of penciclovir,
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and valacyclovir, a valine ester of acyclovir, have better absorption after oral dosing than acyclovir. As a result, they can be taken less frequently, but are more expensive. These drugs have little toxicity. Acyclovir has been safe in patients using it daily for greater than 10 years (2). Topical acyclovir is not recommended for treatment of genital herpes.
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TABLE 37.1 Oral Therapy of Genital Herpes |
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In patients with HIV infection, HSV outbreaks may be more prolonged and severe, and they often require higher doses and prolonged courses of treatment for HSV. Severe episodes of HSV in immunocompromised patients, especially when HSV becomes disseminated, may necessitate hospital admission. Acyclovir-resistant HSV is unusual and has been reported almost exclusively in immunosuppressed patients who have had prolonged exposure to the drug. In these patients, valacyclovir will be ineffective, and the virus is often also resistant to famciclovir. These patients usually require therapy with intravenous foscarnet. Patients with refractory HSV infection should have viral cultures and acyclovir drug-sensitivity testing performed at a reference center. Patients with acyclovir-resistant HSV should be managed in consultation with an expert.
Along with antiviral therapy, counseling plays a central role in the care of patients with newly diagnosed HSV. Patients must be educated about the potential for recurrences and the availability of episodic and suppressive therapy. They should be aware that viral shedding occurs not only during the times of active lesions but can also occur during asymptomatic periods. With this in mind, they should be instructed to inform their sexual partners about their HSV status prior to sexual activity, and abstain from sex with uninfected partners when prodromal sym-ptoms or active lesions are present. Patients should be informed that the use of condoms might decrease the risk of transmission of HSV during asymptomatic periods and given the option of suppressive therapy to attempt to decrease transmission to a seronegative partner (31). Men and women should be informed about the risks of neonatal herpes infection. Type-specific serologies for HSV may prove helpful in determining if sexual partners are truly discordant for HSV-2 infection. Patients may obtain more HSV information by accessing informational Internet sites including the CDC site (http://www.cdc.gov/std/Herpes/STDFact-Herpes.htm) and the Planned Parenthood site (http://www.plannedparenthood.org/pp2/portal/files/portal/medicalinfo/sti/pub-sti-herpes.xml). A free patient pamphlet, “Genital Herpes: A Patient Guide to Treatment,” can be ordered from the American Medical Association by calling 312-464-2588.
Syphilis (Chancre)
See section on “Syphilis—Primary Syphilis.”
Chancroid
Chancroid is caused by the organism Haemophilus ducreyi. It is relatively common in Africa, the Caribbean, and Southwest Asia, but is seen infrequently in the United States. Chancroid has been seen in episodic outbreaks especially associated with prostitution and drug use and is endemic in several large cities in the United States (32, 33, 34). Its incidence is likely underreported secondary to difficulties in diagnosis. In 1987, almost 5,000 cases were reported to the CDC but in 1996 only 386 were reported (35). Chancroid should be suspected in individuals with a genital ulcer who have recently had sexual exposure in a developing country.
The incubation period for chancroid is 4 to 7 days. Initially a papule forms and over several days erodes into a deep ulcer with irregular undermined borders. The ulcers are generally multiple but can be solitary and are extremely painful. Chancroid ulcers are friable and often have a purulent base. The ulcers are usually found on the coronal sulcus in circumcised men or on the prepuce of uncircumcised men and in women on the labia or perineum (17). After a week, about 50% of patients develop inguinal
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lymphadenopathy that is most frequently unilateral. Women are less likely to develop lymphadenopathy (36). Lymph nodes may become fluctuant and may spontaneously rupture. The combination of a painful ulcer and suppurative lymphadenopathy is almost pathognomonic for chancroid.
Definitive diagnosis of H. ducreyi requires isolation of the organism in special culture media that is not commonly available. The sensitivity of culture is <80% (37). A Gram stain revealing short, wide gram-negative rods in chains or clusters is suggestive of the diagnosis but the sensitivity and specificity of Gram stain is generally felt to be poor (38). There is no FDA-approved PCR test for chancroid. Given these diagnostic limitations, the CDC treatment guidelines suggest that a probable diagnosis of chancroid can be based on the following criteria: one or more painful genital ulcers; T. pallidum is not identified on dark-field examination of the ulcer exudates and serologic testing for syphilis is negative at least 7 days after onset of the ulcers; the presentation, ulcer appearance and, if present, lymphadenopathy are typical for chancroid; and, HSV culture of the ulcer exudates is negative.
The recommended treatments for chancroid include: azithromycin 1 g orally as a single dose; ceftriaxone 250 mg intramuscularly in a single dose; ciprofloxacin 500 mg orally twice daily for 3 days; or erythromycin base 500 mg orally 3 times daily for 7 days (2). Little data is available regarding the efficacy of the short-term ceftriaxone and azithromycin regimens in HIV-infected patients. Some experts prefer erythromycin therapy in HIV-infected patients. Pregnant or lactating women and patients less than 18 years of age should avoid ciprofloxacin.
Clinical re-evaluation should be performed between 3 to 7 days after initiation of therapy. Symptoms rapidly improve within 3 days of initiating therapy and clinical improvement of ulcers is usually evident in 7 days. Large ulcers may take over 2 weeks to heal. Healing of lymphadenopathy is slower and large fluctuant lymph nodes may require aspiration or incision and drainage (39). Response to therapy may be slow or inadequate in uncircumcised men or HIV-infected patients and these patients should be followed more closely (40, 41, 42). Overall, the cure rate with recommended therapy in HIV-negative patients is ≥92% and in HIV-positive patients is ≥76% (40, 41, 42, 43).
Patients should be counseled to notify their recent sexual partners so that they may receive clinical evaluation and therapy if indicated. All persons who have had sexual contact with the patient within 10 days of the development of symptoms of chancroid should be empirically treated for chancroid even if no abnormalities are detected on examination. The patient should be provided HIV and syphilis testing at time of diagnosis and instructed to return for repeat testing in 3 months (2).
Granuloma Inguinale (Donavonosis)
Granuloma inguinale is caused by the intracellular, encapsulated, short gram-negative bacillus, Klebsiella granulomatis. The disorder is found most commonly in tropical and subtropical areas, especially in the Western Pacific, and is rare in the United States. The incubation period is between 8 days and 12 weeks. It can present as large ulcerative lesions, erythematous papules with overlying granulation tissue, large papules resembling severe condyloma acuminatum, or expanding plaques of scar tissue (16). Most commonly it is a slowly progressive disorder with large, painless, friable ulcers with heaped up borders and “beefy” vascular bases. Lymphadenopathy is rare. Without treatment, granuloma inguinale is a slowly destructive process that can result in serious sequelae for the genitourinary tract. The organism is difficult to culture and diagnosis relies on histopathology. A sample of tissue from the leading edge of an ulcer is placed between a slide and cover slip, crushed (crush preparation), and stained. The diagnosis of granuloma inguinale is made by identification of rods within cytoplasmic vacuoles of macrophages (Donovan bodies).
The CDC-recommended treatment is doxycycline 100 mg orally twice daily for at least 3 weeks and until the lesions have completely healed (2,44). Alternative regimens include: ciprofloxacin 750 mg twice daily for at least 3 weeks; erythromycin base 500 mg 4 times a day for at least 3 weeks; azithromycin 1 g weekly for at least 3 weeks; or trimethoprim-sulfamethoxazole one double strength tablet twice daily for at least 3 weeks. The 2003 World Health Organization (WHO) Sexually Transmitted Infections Management Guidelines also recommended a 1 g dose of azithromycin followed by azithromycin 500 mg daily until symptoms resolve (44). Therapy should be continued until all lesions have re-epithelialized. In patients with HIV-infection, pregnant patients, or patients with slow improvement, gentamicin 1 mg/kg intravenously every 8 hours can be added. The erythromycin-based regimen is preferred in pregnancy. The benefit of empiric drug therapy for sexual contacts is not clear, but all sexual contacts within 60 days of the patient's symptom onset should be evaluated clinically and offered therapy.
Lymphogranuloma Venereum
Chlamydia trachomatis serovars L1, L2, and L3 are the causative organisms of lymphogranuloma venereum (LGV). Until recently, LGV was infrequently seen in the Western world and was chiefly seen in South and Central America, the Caribbean, Southeast Asia, India, and areas of Africa. In 2003, an outbreak was noted among MSM in the Netherlands in association with proctitis. Investigation revealed 30 cases in 2003 and 62 cases in 2004 (1). Since then cases and case clusters of LGV proctitis have been
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reported in Canada, Great Britain, Europe, and in large metropolitan areas in the United States. These cases have been linked primarily with serovar L2, and often associated with HIV and hepatitis C infections (1,45,46). Transmission has been associated with unprotected sex and high-risk sexual activity.
The incubation period is between 3 to 40 days. In the inguinal syndrome, the initial manifestation of disease is a painless papule at the site of inoculation, which erodes to for a small ulcer that heals in a few days. Patients develop painful inguinal adenopathy 7 to 30 days later, which often leads them to seek medical attention. By this time, the ulcerative lesion has usually resolved, and most patients will not recall the presence of an ulcer (16). The groove sign that is associated with LGV is caused by bulky lymphadenopathy that occurs on either side of the inguinal ligament but spares the area just overlying it. The major differential diagnosis is chancroid, which can produce similarly large nodes and buboes.
The anogenitorectal syndrome is generally characterized by bloody rectal discharge, tenesmus, fever, and even constipation. Evaluation reveals an ulcerative proctocolitis sometimes progressing to perirectal abscesses, rectal fissures, and rectal strictures resembling Crohn disease (47, 48, 49, 50). Because of these unusual clinical presentations, LGV cases are often managed initially by gastroenterologists or surgeons for other disorders (see Chapter 98). Screening for LGV should be incorporated into the evaluation of new lower gastrointestinal (GI) disorders in MSM.
Clinicians suspecting LGV infection should obtain a swab of an ulcer or an aspirate of a lymph node and test for Chlamydia trachomatis by culture, direct immunofluorescence, or nucleic acid detection. Chlamydia trachomatis nucleic acid amplification tests are not FDA-approved for use on rectal samples. Unfortunately, additional testing needed to differentiate L serovars of Chlamydia trachomatis is not widely available. Complement fixation or microimmunofluorescence serologic testing for LGV can provide additional data to support a clinical diagnosis of LGV, but are limited by lack of standardization, possible cross reactivity with other Chlamydia serovars, and lack of validation in the anogenitorectal syndrome. A list of labs with serologic tests that may provide titers is available on the CDC website (http://www.cdc.gov/std/lgv-labs.htm). Clinicians should contact the CDC at 404-639-2059 and local health departments if they identify a probable case of anogenitorectal LGV.
Recommended treatment is doxycycline 100 mg orally twice daily for 21 days. Erythromycin base 500 mg orally four times daily for 21 days is an alternative regimen that should be offered to pregnant or lactating women. Sexual contacts of the patient within 30 days of the development of symptoms should have clinical evaluation and urethral and cervical chlamydia testing and be treated with a standard chlamydia regimen (see Chlamydia).
Genital Warts
Genital warts are caused by infection with human papillomavirus (HPV). In the United States, the prevalence of external genital warts is 1% in sexually active men and women 18 to 49 years of age (51). The prevalence of external genital warts varies by the population screened and medical setting. Rates have been reported as low as 0.6% to 0.8% in health maintenance organizations and as high as 13% in STD clinics. Rates as high as 10% to 20% have been reported when assessing both symptomatic and asymptomatic infection through sensitive HPV DNA direct-detection methods. Since many subtypes of HPV infection do not cause visible genital warts, many patients remain unaware of their infection. Risk factors for HPV infection in women include younger age, number of sexual partners, frequency of sexual intercourse, having a sex partner with genital warts, and in some studies failure to use condoms (51, 52, 53, 54). In men, risk factors for genital warts include younger age, number of sex partners, failure to use condoms, previous STDs, and greater cigarette use (54,55). The relationship between oral contraceptive use and genital warts remains unclear (56, 57, 58). Patients with HIV or other forms of immunosuppression may be at higher risk for genital HPV infection (59,60).
HPV is a nonenveloped, double-stranded DNA virus. Over 70 HPV types have been identified, including over 30 that can infect the genital tract. HPV types 6 and 11 are the most common types causing visible genital warts and are rarely associated with cancers. They have been associated with laryngeal papillomatosis in infants born to women with genital warts. HPV subtypes 16, 18, 31, and 45 rarely cause visible warts and are closely associated with the development of cervical cancer and other genital cancers (61, 62, 63, 64).
The natural history of HPV infection is variable. Genital warts may persist, enlarge, or spontaneously resolve. Spontaneous regression is more often associated with young age, and persistence is more common in immunosuppressed patients, such as those with HIV (65). HIV-infected patients have a higher prevalence (approximately a threefold increase compared to HIV-negative women) of external genital warts and generally have a lower clearance rate with topical therapies and a higher rate of wart recurrence (66,67). Transmission of genital warts is primarily by sexual contact. HPV is thought to enter through minor breaks in the epithelial surface and thereby infect the basal cell layer (68). Given the tendency of HPV to latent infection, the incubation period can be from months to years following acquisition.
Genital warts are most often asymptomatic but can be associated with pruritus, urethral or postcoital bleeding, irritation, and urethral or vaginal discharge (68). Genital warts can be located on the penis, vulva, scrotum, perineum, perianal skin, cervix, vagina, urethra, anus, and
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mouth. Perianal warts can occur in patients without a history of anal sex; intra-anal warts occur primarily in men and women who have had anal intercourse (69,70). HPV 6 and 11 are infrequently associated with the development of squamous carcinomas but visible warts are occasionally caused by HPV 16, 18, and others that are high risk for malignant transformation. Another complication of external genital warts in children of infected women is juvenile recurrent respiratory papillomatosis (RRP). It is estimated to have a prevalence in the United States between 1.69 to 2.59 per 100,000 based on a study evaluating the rates in two U.S. cities (71). In a recent retrospective cohort study, risk of RRP was strongly associated with a maternal history of genital warts, but Cesarean delivery was not protec-tive (72).
Genital warts are classified by their morphologic appearance: condylomata acuminata are cauliflower-like lesions usually occurring on moist surfaces; papular warts are dome-shaped lesions that are usually 1 to 4 mm in size and located on dry skin; keratotic genital warts have a thickened horny surface, occur most frequently on dry skin, and are similar in appearance to common skin warts; flat condylomata are subclinical lesions that are macular or slightly raised and can occur on dry or moist skin. Flat warts are generally not visible on direct examination and are most common on the cervix or in the anogenital area.
Diagnosis of genital warts is by direct examination and can be aided by bright lighting and magnification. Anoscopy is recommended for evaluation of intraanal warts in patients with a history of receptive anal intercourse (69). Visual inspection of the distal urethra and meatus should be performed for symptoms of terminal hematuria or abnormal urinary stream. Urethroscopy should also be considered in these cases. Since oral warts can be sexually transmitted, all patients should be questioned about oral symptoms and should be examined for oral warts (65). A complete examination of the genital tract should always be performed to accurately determine the extent of disease as this may influence treatment options. The use of dilute acetic acid on areas with suspected HPV infection (acetowhite test) is not recommended because of poor positive predictive value (73). HPV typing has not been shown to be of benefit in managing visible genital warts.
If condylomata lata are suspected, syphilis serology can be drawn and dark-field microscopy of fluid obtained from the lesions can be examined for signs of spirochetes. Clinical exam is generally diagnostic for genital warts, but biopsy should be considered when the lesion is atypical; the diagnosis is in doubt; disease progresses during treatment; there are early or frequent recurrences; lesions are pigmented, indurated, ulcerated, or fixed to underlying structures; individual lesions are larger than 1 cm; or, the patient is immunocompromised (65). Biopsy is particularly helpful when malignancy is suspected.
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TABLE 37.2 Differential Diagnosis of External Anogenital Warts |
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Table 37.2 lists the differential diagnosis for genital warts. Bowenoid papulosis is a carcinoma-in-situ that is characterized by rough papules 2 to 4 mm in diameter with red-brown color. Buschke-Lowenstein tumor is a rare, low-grade invasive malignancy associated with HPV types 6 and 11. Bowen disease and squamous cell and basal cell carcinomas are other malignancies that are sometimes confused with genital warts and can be diagnosed by biopsy.
Most current treatment strategies are based on destruction of the clinically visible affected tissue. The exception is imiquimod, which is an immune modulator, and works by enhancing local cellular immune response. However, since infection can persist in histologically normal tissue, viral eradication and prevention of transmission to sexual partners is impossible. The goal of treatment is the alleviation of physical and psychological symptoms attributable to genital warts. The clinician must be aware and counsel the patient that common side effects of treatment are local irritation and erythema and can also include pain, phimosis, preputial tightening, and balanoposthitis. Superficial erosions or ulcerations may facilitate the transmission of other STDs if therapy is not applied as directed or appropriate precautions are not taken (65,69). Ablative therapy has been associated with hypo- and hyperpigmented scars and rarely hypertrophic or depressed scars (74,75). These are less likely if patients are given sufficient time to heal between treatments. Vulvodynia and other chronic pain syndromes have also been associated with ablative therapy (76). Given these risks, the possibility of spontaneous regression, and the limited benefits of treatment, patients should be aware that a decision to defer therapy and continue observation is acceptable.
Treatment can be provided by patient-applied therapy or provider-administered treatment. It is recommended that clinicians providing care for patients with genital
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warts be familiar with the use of at least one patient-applied therapy and one provider-administered therapy. A response to therapy should be evident within 3 months (2). There is insufficient data to suggest that any therapy is routinely superior to another. Clearance and recurrence rates are highly variable for all patient-applied, provider-applied, and surgical therapies (77). The choice of therapy is usually determined by wart size, wart number, anatomic site, morphology, patient preference, cost, convenience, adverse effects, risk of pregnancy, and provider experience.
Topical treatments are more effective on genital warts located on moist skin. In general, the first dose of patient-applied topical therapy should be applied by the clinician to demonstrate the appropriate technique of application and designate the warts to be treated. Podofilox, imiquimod, and podophyllin resin are not recommended for use during pregnancy. Surgical wart treatments are more effective than other modes of therapy in treating patients with extensive disease, oral warts, and disease on internal mucosal surfaces.
Cervical warts require evaluation for squamous intraepithelial lesions and should be managed by an expert. Trichloroacetic acid (TCA) or bichloroacetic acid (BCA) and cryotherapy without use of the cryoprobe are recommended for treatment of vaginal warts. Genital warts presenting at the urethral meatus can be treated with cryotherapy, podophyllin resin, podofilox, or imiquimod. Recommended treatment for anal warts includes cryotherapy, TCA/BCA, and surgical methods. Surgical removal and cryotherapy are the recommended treatments for oral warts. For patients using patient-applied therapy a followup visit several weeks into therapy may be useful to assess adequacy of therapy and side effects of treatment. Risk of recurrent disease is greatest in the first 3 months after therapy.
Patient-Applied Therapy
Podofilox (Condylox) is an antimitotic agent that is the major active ingredient in podophyllin resin. Its use should be limited to a wart area of ≤10 cm2 and a total volume of ≤0.5 mL per day (2). Podofilox 0.5% solution or gel should be applied twice daily for 3 days followed by 4 days without therapy and repeated for up to four cycles if needed. Podofilox should not be applied to areas with open lesions or skin breakdown. Patients should be cautioned to follow directions carefully to avoid systemic toxicity.
Imiquimod (Aldara) is an immune stimulator. It enhances levels of interferon-α, tumor necrosis factor, and interleukin-6 (78,79). Imiquimod 5% cream should be applied 3 times weekly at bedtime (2). The application should be washed off with soap and water after 6 to 10 hours. In men with warts on dry skin, daily treatment may be more effective. Treatment may be continued for up to 16 weeks if needed (2). Patients should be informed of the high cost of imiquimod therapy. Imiquimod may be more effective in women than men (80).
Provider-Administered Therapy
Cryotherapy, usually with liquid nitrogen, destroys warts by cryocytolysis. It should be avoided in patients with cryoglobulinemia or who have poorly controlled diabetes. Use of a cryoprobe is not recommended for the treatment of vaginal warts secondary to the risk of vaginal perforation and fistula formation (2). The skill and experience of the clinician in the application of cryotherapy will greatly affect the associated efficacy and toxicity of treatment. Pain and even blistering is not uncommon. Use of topical or local anesthetics may facilitate treatment application. Cryotherapy is effective for warts on dry and moist skin. Treatments can be repeated every 1 to 2 weeks after adequate healing has occurred.
Podophyllin resin (Podofin) is an antimitotic plant compound that does not have a standardized formulation (81). It is less effective in treating warts on dry skin. Podophyllin use should be limited to a wart area of ≤10 cm2 and a total volume of ≤0.5 mL per session (2). Podophyllin resin 10% to 25% should be applied to warts in a thin layer and allowed to dry thoroughly. Spread of the compound to normal tissues due to over application or incomplete drying can cause significant local irritation. The patient should wash the resin off 1 to 4 hours after application. Application can be repeated weekly. Podophyllin resin should not be applied to areas with open lesions or skin breakdown. Severe systemic toxicity can occur if this agent is inappropriately used.
TCA, Tri-chlor, and BCA cause chemical coagulation of proteins and thereby destroy warts. These agents work best on warts located on moist skin. TCA or BCA 80% to 90% is applied in a thin coat and allowed to dry (2). Application can be repeated weekly as needed. Similarly to podophyllin, over application or incomplete drying can result in spread of the compound and damage to surrounding tissues. TCA/BCA can be neutralized with soap or sodium bicarbonate if needed.
Surgical removal by tangential scissor excision, tangential shave excision, curettage, or electrosurgery has the benefit of producing an immediate wart-free state. Surgical modes of treatment are useful for treating extensive disease but can also be used for wart areas of average size. These techniques generally require local anesthesia.
Alternative Treatments
Intralesional interferon has antiviral immunomodulating effects. However, this requires painful intralesional injections and can be associated with systemic interferon toxicities as well as local reactions. Laser treatments are generally reserved for patients with extensive disease, genital
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warts refractory to other treatments, or intraurethral warts and require operator expertise.
Patient Counseling
Patients diagnosed with genital warts require counseling regarding the natural history of disease and associations between HPV infection and genital cancers. Patients should be aware that genital HPV infection is generally a chronic disease. It is almost always sexually transmitted but the incubation period is long and the new appearance of genital warts does not necessarily imply a new or recent exposure. The efficacy of condoms in prevention of transmission is incomplete. When initiating a sexual relationship with a new partner, disclosure of STD history is encouraged. Patients should be aware that the HPV types that are associated with cancer do not generally cause visible genital warts. HPV types associated with genital warts are unlikely to lead to malignancy. Women should be encouraged to continue regular Papanicolaou smears according to standard recommendations. Patients often perceive the diagnosis of genital warts as stigmatizing. Providing detailed information about the disease, its natural history, and treatment may ease some of the psychological distress associated with a diagnosis of a chronic STD. Counseling should also dispel misconceptions about cancer risks associated with genital warts and allow for a review of appropriate cervical cancer screening. Patients can obtain more information about genital warts and HPV infection on the Internet (http://www.plannedparenthood.org/pp2/portal/files/portal/medicalinfo/sti/pub-sti-genital-warts-hpv.xml,http://www.dph.sf.ca.us/HealthInfo/std_warts.htm) or by contacting the CDC National STD Hot-line 1-800-227-8922.
Urethritis and Cervicitis
Urethritis is characterized by dysuria, urethral discharge, and urethral irritation or pruritus. Urethritis can be caused by several infectious pathogens or can have a noninfectious etiology such as allergy. For treatment purposes, urethritis is generally divided into two categories: gonococcal and nongonococcal urethritis (NGU). The presence of urethritis is confirmed by the clinical finding of muco-purulent discharge, Gram stain of urethral swab with ≥5 white blood cells (WBCs) per oil immersion field, a positive leukocyte esterase test on first-void urine, or ≥10 WBCs per high-power field on microscopy of first-void urine sediment (2). If a patient with urethral symptoms does not meet any of these criteria, they should be evaluated with sensitive diagnostics for gonorrhea and chlamydia but should generally not be offered empiric treatment until results of the evaluation are available. An approach to male urethritis is outlined below (Fig. 37.2).
Mucopurulent cervicitis (MPC) is often asymptomatic but some women may report abnormal discharge or vaginal bleeding. On examination there is mucopurulent or purulent endocervical discharge visible at the cervical os or on endocervical swab. The cervix may also be friable with easy bleeding. Women with evidence of MPC should be carefully evaluated for gonorrhea and chlamydia but the majority of cases do not have an identifiable cause (2). In most women, chlamydia and gonorrhea infection are not characterized by MPC. Other causes of MPC include trichomoniasis and herpes simplex. Conditions such as bacterial vaginosis, and exposures to chemical irritants or douching may also play a role in MPC (82).
Women with clinical evidence of MPC should be evaluated for chlamydia, gonorrhea, trichomonas, and bacterial
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vaginosis. In women with bacterial vaginosis, an absence of vaginal leukorrhea (<5 polymorphonuclear cells on 400X magnification) has a negative predictive value of 92% for chlamydia and 90% for gonorrhea (83). In outbreak settings or in patients at high risk who are unlikely to return for test results, clinicians should consider empiric treatment for gonorrhea and chlamydia.
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FIGURE 37.2. Management of symp-tomatic male urethritis (adapted from Burstein GR, Zenilman JM. Clinical Infect Dis 1999;28, Suppl 1:566–573. ) LET—Leukocyte esterase test. |
Neisseria gonorrhoeae
Gonorrhea causes an estimated 700,000 to 800,00 new infections yearly in the United States (2,84). Surveillance through the CDC demonstrates an incidence in women that peaks between the ages of 15 to 19 years and falls off rapidly after age 24 years. In men, incidence rates peak between ages 20 to 24 years and fall off significantly after age 29. Overall rates of gonorrhea reported to the CDC declined from 1980–1997 but have remained relatively stable since, with similar rates in men and women. Gonorrhea is associated with age, non-Caucasian race, single marital status, illicit drug use, higher numbers of sexual partners, and casual or new sex partners (85, 86, 87,88, 89, 90, 91).
Neisseria gonorrhoeae is a gram-negative diplococcus. It is transmitted exclusively by sexual and perinatal exposure. Risk of transmission appears to be greatest from male-to-female during vaginal intercourse and from female-to-male with multiple episodes of vaginal intercourse (92, 93, 94, 95). Compared to vaginal intercourse, oral sex is believed to be less efficient in the transmission of gonorrhea (96).
The most common manifestations of gonorrhea infection are urethritis in men and cervicitis in women. Male urethritis usually presents 1 to 10 days after exposure and is characterized by purulent discharge and dysuria. A small fraction of men with gonococcal urethritis are asymptomatic (97). If left untreated, most cases of gonococcal urethritis resolve spontaneously after several weeks. Local complications of gonococcal urethritis include epididymitis, penile edema, acute prostatitis, seminal vesiculitis, and periurethral abscesses.
In women, the primary sites of infection are the endocervix and urethra. Unlike men, many women do not develop overt symptoms of infection (98). When present, symptoms usually occur within 10 days and may include abnormal vaginal discharge, dysuria, or abnormal vaginal bleeding. Local complications of gonococcal cervicitis include infection of the Bartholin glands, salpingitis, pelvic inflammatory disease, and perihepatitis (Fitz-Hugh-Curtis syndrome). Long-term complications include infertility and ectopic pregnancy.
Other than the male urethra and the female cervix, gonorrhea can less commonly present at the anorectal area, in the oropharynx, or as disseminated gonococcal infection (DGI). Women and homosexual men most commonly have asymptomatic anorectal gonorrhea infection but can have manifestations such as anal pruritus, purulent discharge, rectal bleeding, or tenesmus (99). Oropharyngeal infection is also most commonly asymptomatic in women and homosexual men (96).
DGI occurs in less than 1% of all gonorrhea infections in the United States (100) and is due to specific N. gonorrhoeae strains that are less likely to cause genital inflammation but more likely to cause bacteremia and disseminated disease (101). The prevalence of these strains in the United States has been decreasing. DGI is characterized by petechial or pustular skin lesions, asymmetric arthralgia, tenosynovitis, or septic arthritis. Some patients develop septic arthritis without associated rash, arthralgias/polyarthritis, or genital disease. Less commonly, DGI is associated with osteomyelitis, endocarditis, meningitis, perihepatitis, and in extreme cases adult respiratory distress syndrome or Waterhouse-Friderichsen syndrome.
The choice of diagnostic test for gonorrhea depends on the site being evaluated. In symptomatic men with urethritis, a Gram stain of urethral discharge has a sensitivity and specificity of ≥94% (102, 103, 104, 105). Diagnosis is made by demonstration of intracellular gram-negative diplococci. To collect the male urethral sample, one hand is placed over the dorsal surface of the penis while the other attempts to move secretions forward through a stripping motion from the base of the penis to the glans. A swab is then inserted approximately 1 cm into the urethra and kept in place for approximately 30 seconds in order to absorb discharge. This sample can be used for Gram stain and gonorrhea culture. Gram stain of endocervical secretions has much lower sensitivity, and is therefore not as valuable.
When obtaining endocervical samples, the ectocervix is first cleaned with a large swab, then a small swab is inserted into the cervical os and allowed to absorb fluids for approximately 30 seconds. When STDs are of concern, samples should be obtained for gonorrhea and chlamydia prior to obtaining samples for Papanicolaou smear. Culture is relatively inexpensive, can be performed at any site, and allows for antibiotic susceptibility testing.
Nucleic acid hybridization techniques have sensitivity and specificity of approximately 85% and 98%, respectively (106). Nucleic acid amplification tests (NAATs), such as ligase chain reaction (LCR) tests and PCR tests, have excellent sensitivity and specificity (approximately 95% and 99%) and allow gonorrhea testing using self-administered vaginal swabs (107,108). LCR also allows for testing using urine specimens. Many clinical settings now use urine NAAT diagnostic probe tests for diagnosis. Nucleic acid amplification tests are expensive, and have not been well assessed in rectal or oropharyngeal gonorrhea detection or in low-prevalence populations (106). They are not currently FDA-approved for use at these sites.
Treatment of gonorrhea depends on the site of infection. In general when treating gonorrhea, it is also recommended to treat chlamydia empirically unless known
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rates of coinfection are low, chlamydia NAAT is available, and the patient is likely to return for results and treatment if needed. When choosing therapy, a clinician must consider geographic trends in antibiotic resistance. As of 2004, quinolone-resistant Neisseria gonorrhoeae(QRNG) was common abroad in parts of Europe, the Middle East, Asia, and the Pacific (2). In the United States, gonorrhea antibiotic resistance and QRNG are monitored by the CDC's Gonococcal Isolate Surveillance Project (GISP). In the United States, QRNG has become prevalent in western states and in the MSM population, in which QRNG rates have been reported from 5% to 12% (109).
Quinolone therapy should be avoided in infections acquired abroad or in California or Hawaii, and in MSM. Quinolones are generally not recommended for pregnant women or children who weigh 45 kg or less.
Recommendations for treatment of gonococcal cervicitis, urethritis, and rectal infection include single doses of cefixime 400 mg orally or ceftriaxone 125 mg intramuscularly. In women and heterosexual men without recent travel to areas with QRNG ≥5%, ciprofloxacin 500 mg orally, ofloxacin 400 mg orally, or levofloxacin 250 mg orally are effective single dose treatments (2). Other single-dose cephalosporins (ceftizoxime 500 mg intramuscularly, cefoxitin 2 g intramuscularly with probenecid 1 g orally, cefotaxime 500 mg intramuscularly, cefpodoxime 400 mg orally, and cefuroxime axetil 1 g orally) and oral quinolones (norfloxacin 800 mg, lomefloxacin 400 mg, and gatifloxacin 400 mg when QRNG is not a consideraton) may also be effective and serve as alternative regimens when recommended regimens are unavailable. Spectinomycin 2 g intramuscularly as a single dose serves as an alternative regimen that is useful in the treatment of patients intolerant of cephalosporins or quinolones, but it may not be available in some areas. Treatment of urogenital and rectal infections with recommended regimens has efficacy >95%, but treatment of oropharyngeal infections is less effective. Azithromycin 2 g orally is effective against uncomplicated gonorrhea of the urethra, cervix, and oropharynx and is also effective against chlamydia. Although this regimen is attractive in MSM who report β-lactam allergy, its use is limited by expense and GI toxicity. In general, treatment of chlamydia coinfection can be accomplished with doxycycline 100 mg orally twice daily for 7 days or azithromycin 1 g orally as a single dose.
Most patients with DGI require hospitalization for initial treatment. The preferred regimen is ceftriaxone 1 g intramuscularly or intravenously daily. Other acceptable regimens include cefotaxime 1 g or ceftizoxime 1 g intravenously every 8 hours, ciprofloxacin 400 mg or ofloxacin 400 mg intravenously every 12 hours, levofloxacin 250 mg intravenously daily, or spectinomycin 2 g intramuscularly every 12 hours. Intravenous or intramuscular therapy should be continued for 1 to 2 days after the patient has improved clinically. Oral therapy with cefixime 400 mg, ciprofloxacin 500 mg, or ofloxacin 400 mg twice daily or levofloxacin 500 mg daily should be continued until the patient has completed a minimum of 7 days of therapy. Intravenous therapy with ceftriaxone 1 to 2 g every 12 hours should be extended to 10 to 14 days for evidence of meningitis or to 4 weeks for evidence of endocarditis. Chlamydia is adequately covered by a 7-day course of levofloxacin or ofloxacin but for other antigonococcal regimens addition of doxycycline 100 mg orally twice daily for a week or azithromycin 1 g orally as a single dose is recommended unless chlamydia NAAT has ruled out infection.
According to the CDC STD treatment guidelines, all sexual contacts within 60 days of symptom onset or diagnosis of gonorrhea should be referred for medical evaluation and treatment of gonorrhea and chlamydia (2). If the patient has not been sexually active in the last 60 days, their last sexual contact should be evaluated and treated. Expedited partner therapy without clinical assessment and counseling should be undertaken only if full evaluation is unattainable. The patient should be counseled to abstain from sexual activity until treatment is complete, symptoms have resolved, and sexual partners have been treated and are symptom-free. Given the often-asymptomatic state of gonorrhea infection in women, screening for women at high risk for infection is important to control local rates of disease. In addition, clinicians should consider rescreening infected patients 3 to 6 months after therapy.
Chlamydia trachomatis
The peak incidence of chlamydia in men and women in the United States is between the ages of 15 and 29 years. Rates of chlamydia infection reported to the CDC have increased, but it is unclear how much of this increase is a result of changes in diagnostics and reporting. Risk factors for chlamydia infection in women include young age, nonwhite race, low socioeconomic status, a new sex partner in the last 90 days, multiple sex partners, and failure to use condoms (110, 111, 112). Risk factors in men are less well defined but younger age, heterosexual sex, and nonwhite race are associated with infection (113, 114, 115).
Chlamydia trachomatis is an obligate intracellular parasite. It exists in two different forms during its life cycle. The extracellular form is metabolically inert and is know as an elementary body. Once it is intracellular, chlamydia transforms into the reticulate body, which is the metabolically active, replicative form. Chlamydia trachomatis infection can cause inclusion conjunctivitis, urethritis, cervicitis, epididymitis, pelvic inflammatory disease (PID), infertility, ectopic pregnancy, reactive arthritis (Reiter syndrome), proctocolitis, and perinatal infections. There is also some evidence that chlamydia infection may increase the risk of HIV acquisition (116). The effects of chlamydia infection
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on cervical HIV-1 viral shedding and transmission remain unclear (117,118).
Asymptomatic genital infection is common in men and women (115,119). In men symptomatic urethritis caused by chlamydia has an incubation period between 7 and 14 days. Men may develop dysuria and penile discharge but the discharge is generally less purulent and less abundant than that associated with gonorrhea. The discharge is clear to gray in color. Epididymitis can occur as a complication of chlamydia infection and is usually unilateral.
The majority of women with cervical or urethral chla-mydia infection are asymptomatic or have only minimal symptoms (119). When present symptoms may include dysuria, discharge, orabnormalbleeding. Women with PID associated with chlamydia tend to have a more subacute course (120) but can have severe PID with associated perihepatitis. Long-term sequelae of symptomatic or asymp-tomatic PID include infertility and ectopic pregnancy.
To collect the male urethral sample, one hand is placed over the dorsal surface of the penis while the other attempts to move secretions forward through a stripping motion from the base of the penis to the glans. A swab is then inserted approximately 1 cm into the urethra and kept in place for approximately 30 seconds in order to absorb discharge. In men, a diagnosis of NGU can be established by the finding of ≥5 WBCs per oil immersion field on Gram stain, a positive leukocyte esterase test on first-void urine, or ≥10 WBCs per oil immersion field in first-void urine sediment without evidence of gram-negative diplococci on Gram stain.
When obtaining endocervical samples, the ectocervix is first cleaned with a large swab, then a small swab is inserted into the cervical os and allowed to absorb fluids for approximately 30 seconds. When STDs are of concern, samples should be obtained for gonorrhea and chlamydia prior to obtaining samples for Papanicolaou smear.
The specific diagnosis of chlamydia requires culture, nucleic acid hybridization, antigen detection, or an amplification assay. Culture is the most specific but can be technically and logistically difficult. Amplification tests like PCR or LCR are the diagnostics of choice for chlamydia given their high sensitivity and specificity (107). In women, LCR and PCR can be used on self-administered swab samples or clinician-obtained swabs (107,108). In men, urine or urethral samples can be used with NAAT. Rectal infection generally should be evaluated with chlamydia culture.
Treatment for chlamydia should be given to all patients with a positive diagnostic evaluation for chlamydia. Given the high rates of gonorrhea and chlamydia coinfection, chlamydia treatment should also be considered in all patients with evidence of gonorrhea infection (see Neisseria Gonorrhoeae). The treatment regimens recommended by the CDC treatment guidelines for uncomplicated urethritis or cervicitis include azithromycin 1 g orally in a single dose or doxycycline 100 mg orally twice daily for 7 days. These two recommended treatments have equal efficacy, but azithromycin treatment has the benefit of being single-dose therapy that may facilitate better compliance (121). Alternative regimens include erythromycin base 500 mg orally four times daily for 7 days, erythromycin ethylsuccinate 800 mg orally four times daily for 7 days, or ofloxacin 300 mg twice daily or levofloxacin 500 mg orally daily for 7 days.
Doxycycline and quinolones are contraindicated in pregnancy. Therefore, during pregnancy patients should be given azithromycin 1 g orally as a single dose or amoxicillin 500 mg orally three times daily for 7 days. Studies comparing these two agents have been small and have not demonstrated clear superiority of either agent (122,123). Alternative regimens in pregnant women include erythromycin base 500 mg orally four times daily for 7 days or 250 mg orally four times daily for 14 days; erythromycin ethylsuccinate 800 mg orally four times daily for 7 days or 400 mg orally four times daily for 14 days. Pregnant women should not be given erythromycin estolate because it has been associated with hepatotoxicity.
Treatment regimens for complicated chlamydia infections are described below for epididymitis and in Chapter 102 for PID.
Patients being treated for chlamydia infection should be instructed to abstain from sexual activities until symptoms have resolved and 7 days have passed since their single-dose azithromycin treatment or they have completed a 7-day course of recommended antibiotic therapy (2). All sex partners in the last 60 days should be evaluated and treated; if the patient's last sex partner was greater than 60 days prior to onset of symptoms or diagnosis of chlamydia, then that sexual contact should be evaluated and treated for chlamydia. Expedited partner therapy without clinical assessment and counseling should be undertaken only if full evaluation is unattainable. The patient should be instructed to abstain from sexual activities with any exposed partner until they have been evaluated and completed treatment.
The CDC recommends that all pregnant women have a test-of-cure for chlamydia with NAAT 3 weeks after completing therapy. Reevaluation earlier than 3 weeks with NAAT should be avoided as the potential for false-positive results secondary to residual dead organisms can cause diagnostic uncertainty. Followup screening tests for chlamydia reinfection are recommended in all women at approximately 3 months after initial diagnosis.
The CDC treatment guidelines and other practice groups recommend screening sexually active adolescent women younger than 25 years of age for chlamydia at least annually. Older women with new or multiple sex partners should also be screened annually for asymptomatic chlamydia infection.
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Nongonococcal Urethritis
Men with clinical or laboratory evidence of urethritis in the absence of gonorrhea infection are diagnosed with NGU. In the United States, 2 million cases of NGU are estimated to occur yearly (124). The etiologic agents of NGU include Chlamydia trachomatis, Mycoplasma genitalium, and probably Trichomonas vaginalis. Data do not definitively link Ureaplasma urealyticum with NGU. Chlamydia is the most common cause of NGU but its prevalence in men with urethritis appears to be declining (125). In recent studies, chlamydia accounted for up to 40% of cases of NGU (126, 127, 128, 129, 130). Data connecting Mycoplasma genitalium infection with symptomatic NGU is growing, and this pathogen may account for 26% to 34% of cases using PCR testing (129,131,132). Trichomonas vaginalis is found in up to 18% of men with NGU screened with trichomonas PCR (133,134). Rarely, HSV may be responsible for the findings of NGU in 6% of cases. NGU also may be associated with organisms and findings of urinary tract infection (UTI) (135). Despite improved diagnostics a significant number of NGU cases have no identifiable etiology (125,136).
Men with symptoms compatible with urethritis should be evaluated for clinical findings that confirm the diagnosis. The patient must have examination findings, urethral Gram stain results, or evidence by urine microscopy or analysis that are compatible with urethritis (seeUrethritis above). All such patients should be evaluated with Gram stain when available. Specific tests for gonorrhea and chlamydia should be performed as outlined above. Testing for ureaplasma and mycoplasma is not routinely available or recommended. Trichomonas cultures of urethral swab and centrifuged urine are recommended only for patients who fail first-line therapy.
Patients with clinical evidence of NGU should be treated with azithromycin 1 g orally as a single dose or with doxycycline 100 mg orally twice daily for 7 days (2). Azithromycin therapy is considerably more expensive than doxycycline therapy but can be given as directly observed therapy. Failure of therapy is higher in patients with nonchlamydial NGU (125,137). Alternative regimens include erythromycin base 500 mg orally four times daily for 7 days, erythromycin ethylsuccinate 800 mg orally four times daily for 7 days, or either ofloxacin at 300 mg twice daily or levofloxacin at 500 mg daily for 7 days. Patients should receive testing for syphilis and HIV.
Patients with recurrent or persistent symptoms should be questioned about compliance with therapy and possible re-exposure. Another possible reason for persistent symptoms is infection with trichomonas (138). Culture for trichomonas infection should be performed. When reevaluating patients with persistent symptoms, clinicians should be aware that urine PCR and LCR tests for chlamydia should not be used for re-evaluation within 3 weeks of treatment as these tests can remain positive after therapy (139). Treatment of recurrent or persistent urethritis in patients without re-exposure or noncompliance with initial treatment should include metronidazole 2 g orally as a single dose with azithromycin 1 g orally as a single dose if not used initially (2).
Patients should be instructed to abstain from sexual activity for 7 days after initiating therapy and until their symptoms have resolved and their sex partners have been adequately treated. Patients should refer all their partners in the last 60 days in for evaluation and treatment. Unless specific testing for chlamydia is negative, all partners should be evaluated and treated for chlamydia. Partners of patients with documented trichomonas urethritis should also be referred for evaluation and treatment with metronidazole. In patients with urethritis in whom neither gonorrhea, chlamydia, nor trichomonas are identified, partner referral for evaluation is not routinely indicated. Recurrent NGU occurs in some patients, and is a clinically vexing problem. In these cases, repeat treatment, including treatment for trichomonas infection, is indicated. Urological evaluation for prostatitis has extremely low yield and is not recommended.
Epididymitis
After puberty, approximately 75% of cases of acute scrotal pain are caused by epididymitis. The most common etiologic agent depends on age group and associated risk factors. Chlamydia and gonorrhea are the most common causes of epididymitis in sexually active men younger than 35 years of age (140); of these chlamydia is more frequently the etiology (141). Men in this age group involved in insertive anal intercourse are also at risk for genitourinary infections caused by enteric bacteria (142,143). Men older than 35 years of age, especially those with diabetes and who have had recent instrumentation of the urinary tract are at greatest risk of enteric bacteria and Pseudomonasspecies although chlamydia and gonorrhea still play an important role. Less common causes of epididymitis include viral, fungal, and mycobacterial pathogens.
Infection generally begins in the urethra or bladder then spreads to the epididymis and sometimes to the testes. The preceding urethral infection due to chlamydia and gonorrhea is asymptomatic in up to 50% (143). The exposure to gonorrhea or chlamydia can occur months before symptoms develop. Patients may report preceding and concurrent dysuria and urethral discharge followed by the gradual onset of unilateral scrotal pain initially localized to the epididymis. If untreated, patients develop fever and progressive diffuse unilateral scrotal pain, edema, and erythema. A reactive hydrocele is not uncommon. The differential diagnosis of epididymitis includes testicular torsion, torsion of the testicular appendage, testicular rupture associated with trauma, traumatic hematoma, inguinal hernia,
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scrotal abscess, hydrocele, varicocele, viral orchitis, testicular neoplasm, Fournier gangrene, Henoch-Schonlein purpura, renal colic, peritonitis, or intraperitoneal hemorrhage with a patent processus vaginalis and a leaking abdominal aortic aneurysm (143).
Testicular torsion and torsion of the testicular appendage are the most common alternative diagnoses (144). Expeditious diagnosis of testicular torsion is critical. The total time of ischemia determines the viability of the testes. Therefore, when evaluating acute scrotal pain, clinicians must consider the history, risk factors, and clinical examination. A history of previous episodes of scrotal pain that resolved without intervention is compatible with intermittent or recurrent testicular torsion (145, 146, 147). Classically the pain of testicular torsion is acute in onset and severe but there is significant overlap in the clinical presentations of the common causes of acute scrotal pain. Physical findings suggestive of testicular torsion include an abnormal axis of the affected testicle, an abnormal position of the epididymis, an abnormal axis of the unaffected testicle, or abnormal elevation of the affected testicle with a palpable twist of the spermatic cord (145). Any findings on history or physical examination that are suggestive of testicular torsion should prompt emergent urosurgical evaluation.
Clinical findings suggestive of epididymitis include: gradual onset of pain; dysuria, urethral discharge, or recent genitourinary instrumentation; a history of UTI, imperforate anus, neurogenic bladder, or genitourinary surgery; fever of >101°F (38.3°C); tenderness and induration at the epididymis; and urinalysis showing ≥10 WBCs per high-power field or ≥10 red blood cells (RBC) per high-power field (145). Patients with three or more of these findings are likely to have epididymitis.
Evaluation of patients with epididymitis should include Gram stain of a urethral swab for evidence of urethritis or gonorrhea, testing for gonorrhea and chlamydia preferably with NAAT for optimal chlamydia sensitivity, and sampling of first-void urine for leukocyte count, leukocyte esterase measurement, and culture (2). Patients with suspected gonorrhea or chlamydia infection should also be screened for syphilis and HIV infection.
Empiric treatment should be initiated at the time of first evaluation. Treatment in patients with a high risk of sexually transmitted epididymitis should include ceftriaxone 250 mg intramuscularly as a single dose with doxycycline 100 mg orally twice daily for 10 days. Ofloxacin 300 mg orally twice daily or levofloxacin 500 mg orally daily for 10 days are also acceptable regimens if the patient has not traveled abroad, has not recently visited California or Hawaii, and is not a homosexual man (2). In patients with epididymitis more likely caused by gram-negative enteric bacteria or patients intolerant of cephalosporins or tetracyclines, treatment with levofloxacin is recommended with the dose, duration, and caveats specified above. Symptomatic treatment should include bed rest, scrotal elevation, and antipyretics/analgesics. Hospital admission should be considered for patients with fever, testicular abscess, toxic appearance, severe pain, immunocompromise, a history of noncompliance, or intolerance of oral intake.
Patients should have significant improvement within 3 days. Patients who fail to improve appropriately or whose symptoms do not completely resolve with treatment should be reevaluated with consideration of the differential diagnosis outlined above and the possibility of quinolone resistant N. gonorrhoeae. Patients may benefit from radiologic imaging and urosurgical evaluation. Treatment failure may indicate error in the initial diagnosis or infection with an antibiotic resistant or atypical organism. Tuberculosis, brucellosis, bacillus Calmette-Guérin (BCG), and fungal infections are rare causes of epididymitis. If gonorrhea or chlamydia infection is suspected or proven, all of the patient's sexual partners in the last 60 days should be referred for medical evaluation and treatment. If the patient's last sexual activity was more than 60 days prior to diagnosis, the patient's last partner should be referred to medical care. The patient and his sexual partners should abstain from sexual activity until symptoms have resolved and treatment has been completed.
Syphilis
Syphilis caused significant morbidity and mortality in the first half of the last century, but after the introduction of penicillin in the 1940s, the rates of disease in the United States declined significantly (148,149). The epidemiology has been characterized by epidemics at 7- to 10-year intervals. In the late 1980s, syphilis was associated with crack cocaine use and sex-for-drugs prostitution (149, 150, 151). More recently, the focus of outbreaks has been in the gay com-munity. Overall, nonwhite minorities are disproportionately affected (148). In addition to the known sequelae of cardiovascular and neurologic disease and the continued morbidity and mortality from congenital syphilis, syphilis facilitates HIV transmission. The HIV epidemic, the concentration of new syphilis cases in specific geographic locations, the disproportionate impact on minority populations, and the availability of new biomedical and public health tools led the CDC to call for a new drive for syphilis elimination. In order to reach this goal, the reported rates of primary and secondary syphilis will need to fall to 0.4 per 100,000 people nationally per year.
Syphilis control requires the rapid treatment of newly identified cases, aggressive contact tracing, and active screening by primary care providers. In most office settings, asymptomatic sexually active patients should be screened for syphilis at their first visit with a nontreponemal serologic test and should be retested at followup visits if they report risk behaviors or have been diagnosed with another STD.
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TABLE 37.3 Outline of the Clinical Stages of Syphilis |
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Clinical Classification
Syphilis is caused by Treponema pallidum. The clinical manifestations of disease vary during the different stages of disease (Table 37.3).
Primary Syphilis
Primary syphilis is classically characterized by the development of a chancre, a painless ulcer with indurated edges and a clean base. A chancre forms 10 to 90 days (average 21 days) after infection. Lesions begin as painless papules at the sites of sexual contact, most commonly on the genitals. Extragenital chancres are infrequent but primarily occur in the mouth (152). Approximately 30% of cases will have multiple lesions. Chancres are frequently associated with painless regional and generalized lymphadenopathy. This painless, initial stage of disease can easily be missed, and up to 60% of patients diagnosed with syphilis have no history of ulcerative lesions (152). (SeeGenital Ulcer Disease for differential diagnosis.)
Secondary Syphilis
Approximately 50% of patients with untreated primary syphilis will develop signs of secondary syphilis. The onset of secondary syphilis is generally between 6 weeks and 6 months after infection. In 15% to 20% of patients, the primary chancre is still present. Secondary syphilis is a systemic disorder, the classic manifestation of which is a maculopapular, follicular, or occasionally pustular rash. The rash can be widespread and often affects the palms and soles. Patchy alopecia may result from follicular involvement on the scalp or along the eyelids. Oral lesions known as mucous patches occur in 5% to 22% of patients and present as gray lesions on an erythematous base (153). Flat, waxy, wart-like lesions usually found in the moist intertriginous regions of the genital or anal areas are known as condylomata lata. Both mucous patches and condylomata lata are highly infectious. Dermatologic manifestations of secondary syphilis will generally resolve within 2 to 6 weeks even without treatment. A quarter of patients will have a recurrence of symptoms within 4 years.
Constitutional symptoms of malaise, low-grade fever, headache, and generalized lymphadenopathy are common in patients with secondary syphilis. Asymptomatic meningitis and cranial nerve palsies may also occur (152). Other infrequent manifestations of secondary syphilis include anorexia, nausea, vomiting, jaundice, granulomatous hepatitis, proteinuria, nephrotic syndrome, acute nephritic syndromes, gastric ulcerations or rugal hypertrophy, ocular inflammation, tinnitus, and sensorineural deafness.
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Latent Syphilis
Latent syphilis is the period of asymptomatic T. pallidum infection that begins with the resolution of secondary symptoms and ends either with treatment or development of signs and symptoms of tertiary disease. The period is divided into two categories: early latent and late latent. The cut-off between these two categories is somewhat arbitrarily set at 1 year. It is within the year of early latent syphilis that 90% of recurrences of secondary symptoms will occur (154). During latent syphilis, recurrences are rare. For this reason persons with early latent syphilis also pose a higher risk of syphilis transmission.
Tertiary Syphilis
Even without appropriate treatment, only one third of patients with syphilis will develop tertiary manifestations. Since the introduction of penicillin, tertiary manifestations have become uncommon and more subtle in their presentation. There are three principal forms of tertiary syphilis: late benign (gummatous) syphilis, cardiovascular syphilis, and neurosyphilis.
Neurosyphilis
Asymptomatic neurosyphilis is defined as a reactive Venereal Disease Research Laboratory (VDRL) test for syphilis in cerebrospinal fluid (CSF) or elevations in CSF WBC or protein concentrations in a syphilitic patient without clinical neurologic or psychiatric abnormalities. The diagnosis of asymptomatic neurosyphilis also requires that other causes of these CSF abnormalities are excluded. These abnormalities in CSF parameters are most commonly detected during primary, secondary, and early latent syphilis. Predictors of CSF abnormalities include a nontreponemal test titer ≥1:32 (see Diagnosis) and in HIV-infected patients, a CD4 count <350 lymphocytes per milliliter (156). Detection of CSF abnormalities in asymptomatic patients is of unclear significance. Use of penicillin in primary and secondary syphilis at doses inadequate for spirochetal eradication in the CNS has nevertheless been associated with remarkably low rates of symptomatic neurosyphilis. Similarly, the presence of CSF abnormalities or mild neurologic complaints in patients with early disease has not been associated with serologic treatment failure after treatment with regimens recommended for early disease (157).
Syphilitic meningitis most commonly occurs during secondary or early latent syphilis and is characterized by severe headache, meningismus, seizures, and cranial nerve involvement. Patients may develop facial palsies, sensori-neural deafness, or optic nerve or primary ocular involvement (152).
Meningovascular syphilis can occur after 2 to 10 years of untreated infection. Clinical findings include headache, irritability, confusion, personality changes, emotional lability, seizures, and altered level of consciousness (158). Vasculitis of small end arteries can produce focal findings specific to areas of involvement.
Tabes dorsalis occurs 5 to 30 years after untreated infection. It affects pupillomotor structures and the posterior columns in the CNS. Patients initially develop lightning pains in their lower extremities and paresthesias. Disease progresses with the onset of sensory ataxia, loss of position and vibratory sense, areflexia, broad-based gait, incontinence, and impotence. Joint changes (Charcot joint) and neuropathic ulcers may develop. Another feature of tabes dorsalis is gastric crises with vomiting, and/or abdominal pain. Some patients also develop the classic Argyll Robertson pupil (small, irregular pupil that accommodates but does not react to light).
General paresis occurs in patients with untreated syphilis 15 to 35 years after infection. It is a complication of untreated syphilis that is characterized by progressive personality changes, irritability, poor judgment, memory loss, and psychotic features.
Pregnancy
In addition to the manifestations and complications above, syphilis has been associated with spontaneous abortion, stillbirth, premature delivery, and perinatal death (159). Syphilis can be transmitted vertically to the neonate and result in serious systemic complications.
Diagnosis
There are several tools that are useful in the diagnosis and staging of syphilis. All patients diagnosed with syphilis by
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dark-field microscopy or serologic testing should be tested for HIV-infection at the time of diagnosis, and in the case of primary and secondary syphilis, at 3 months after diagnosis. Dark-field microscopy and direct fluorescent antibody (DFA-TP) tests are used in early stages of syphilis to identify organisms in primary chancres and condylomata lata. Dark-field microscopy is not available at all centers but is usually available at STD clinics. Patients can usually be referred to one of these clinics for complete evaluation. To obtain a sample, the lesion should be lightly abraded with a gauze pad and then squeezed so that the serous exudate can be collected on a microscope slide or slide cover. Three microscopic samples should be evaluated immediately to avoid drying. Slides should be evaluated at 45X to identify possible organisms. Any suspected organisms should be examined under oil immersion and the 100X objective. Although T. pallidum is a corkscrew shape organism with a characteristic motility, it can be difficult to differentiate from the oral spirochete, T. macrodentium. For this reason oral lesions should not be evaluated with dark-field microscopy. A negative dark-field examination of a genital lesion does not rule out syphilis.
Two different types of serological tests are available for diagnosis of syphilis and are useful during all stages of disease. Nontreponemal tests include VDRL and rapid plasma reagin (RPR). These tests detect nonspecific antibody to reagin, a cardiolipin-lecithin-cholesterol antigen complex. The titers of these tests usually correlate with disease activity. These tests cannot be used by themselves due to their limited sensitivity in early and late syphilis and the occurrence of false positives. For this reason positive nontreponemal tests must be followed with specific treponemal tests to confirm a diagnosis of syphilis.
A patient is considered to have a biologic false-positive test if the nontreponemal test is reactive and a specific treponemal test is consistently nonreactive. The titer of the nontreponemal test is generally less than or equal to 1:8. Biologic false-positive nontreponemal tests are designated as acute if they are present less than 6 months or chronic if present more than 6 months. Conditions associated with a biologic false-positive test include: pneumonia, hepatitis, pregnancy, mononucleosis, measles, malaria, intravenous drug use, rheumatologic disorders, chronic liver disease, Waldenstrom macroglobulinemia, older age, and hereditary biologic false-positive.
Treponemal tests include the fluorescent treponemal antibody absorption (FTA-ABS), T. pallidum particle agglutination, and treponemal enzyme immunoassay (EIA) tests. FTA-ABS and T. pallidum particle agglutination tests detect specific antibodies to T. pallidum. They have higher sensitivity and specificity than nontreponemal tests but are more difficult to perform and are more expensive. False-positive tests are rare but can occur in patients with autoimmune disease, viral infections, and pregnancy (160). There are rare reports of false-negative FTA-ABS tests in HIV-infected patients with syphilis (161). FTA-ABS and T. pallidum particle agglutination should generally be used as confirmatory tests except in cases of suspected primary or tertiary syphilis when the nontreponemal tests may be negative and the treponemal test may be more sensitive.
Treponemal EIA tests are used by some large clinical labs and blood banks. In 2000, approximately 13% of public health laboratories used treponemal EIA tests (162). A positive EIA generally should be followed with a titered nontreponemal test. If the RPR or VDRL is negative, the patient may have partially treated syphilis, previously treated disease, untreated late infection, or a false-positive result. These patients need a careful history and laboratory evaluation with FTA-ABS or TP-PA.
The diagnosis of neurosyphilis in a patient with positive serologic tests for syphilis depends on the results of CSF analysis. Any patient with neurologic or ophthalmic signs or symptoms, evidence of tertiary aortitis or gummas, evidence of serologic treatment failure, or patients with HIV infection and late latent syphilis or syphilis of unknown duration should be evaluated for neurosyphilis with CSF evaluation. CSF examination should also be considered for patients with latent syphilis and serologic titers ≥1:32 or HIV-infected patients with CD4 counts ≤350 lymphocytes per milliliter (156). A positive CSF VDRL is the best laboratory evidence of neurosyphilis. Although its specificity is virtually 100%, its reported sensitivity ranges widely from 10% to 89%. The CSF VDRL is less sensitive in detecting asymptomatic neurosyphilis and tabes dorsalis. However, in patients without other identifiable CNS infections, an elevated protein concentration (>40 mg/dL) or WBC count (>5 mononuclear cells per µL) in the CSF can also indicate CNS syphilis infection. The role of the CSF FTA-ABS test in neurosyphilis diagnosis is controversial. Most studies agree that a nonreactive CSF FTA-ABS is useful for ruling out neurosyphilis, but the significance of a reactive CSF FTA-ABS without other CSF abnormalities is unclear (163, 164, 165).
Treatment and Followup
The treatment of choice for all stages of syphilis is parenteral penicillin G (benzathine, aqueous procaine, or aqueous crystalline). Combinations of benzathine penicillin and procaine penicillin or oral penicillin should not be used. Unfortunately, inadvertent syphilis treatment errors continue to occur due to inappropriate use of Bicillin CR (1.2 million units procaine penicillin G and 1.2 million units benzathine penicillin G) instead of Bicillin LA (2.4 mu benzathine penicillin G) (166). The duration of treatment depends on the stage of disease. Therefore, before deciding on a treatment plan every patient should have a thorough physical examination, including speculum examination in women, to evaluate for evidence of chancres, skin rash, ocular changes, or cardiologic or neurologic
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manifestations. Knowledge of a patient's HIV status is also important.
Primary and Secondary Syphilis
Primary and secondary syphilis should be treated with benzathine penicillin G 2.4 million units intramuscularly (IM) in a single dose (2). Evidence for alternatives to penicillin in nonpregnant, HIV-seronegative patients is limited. Doxycycline 100 mg orally twice daily or tetracycline 500 mg four times daily for 14 days has been used for many years. Less is known about the efficacy of ceftriaxone, but some experts recommend 1 g IM or intravenously (IV) for 8 to 10 days.
Azithromycin 2 g as a single dose has been considered a potential oral option for syphilis treatment (167). Although the potential for directly observed oral therapy makes the use of azithromycin attractive especially in penicillin allergic patients, a considerable rate of in vitro resistance has been demonstrated in the United States, and clinical failures have been reported (168). Therefore, azithromycin should be used with caution and only when alternative regimens are impractical.
Followup of patients should include both physical examination and measurement of nontreponemal test titers. Followup should occur at 6 months and 12 months after treatment. Closer followup may be warranted if patients are treated with nonpenicillin regimens or if they are HIV-positive. Nontreponemal test titers should decline fourfold (2 dilutions) within 6 months after therapy. More than 85% of patients treated for primary or secondary syphilis will eventually revert to a nonreactive nontreponemal serologic test. Approximately 10% of patients appropriately treated will also revert to a negative FTA-ABS (169). If serologic titers have not fallen appropriately, the patient is at risk for treatment failure and at a minimum needs close clinical and serologic followup. Persistant or recurrent symptoms or a fourfold increase in nontreponemal test titer suggest reinfection or treatment failure. Patients with treatment failure should have repeat HIV testing and should be retreated with three weekly IM injections of benzathine penicillin G 2.4 million units, unless CSF evaluation suggests the presence of neurosyphilis.
Latent Syphilis
Recommended treatment of early latent syphilis is benzathine penicillin G 2.4 million units intramuscular injection in a single dose (2). Patients who do not have documented seroconversion within the last year, clear signs of primary or secondary syphilis, and do not have a sex partner with documented primary, secondary, or early latent syphilis must be assumed to have late latent syphilis. These patients should be treated with 3 weekly intramuscular injections of benzathine penicillin 2.4 million units. In nonpregnant, HIV-seronegative patients, alternatives to penicillin therapy are poorly studied. Patients with early latent syphilis may be treated with caution with the alternative regimens listed under Treatment and Followup and Primary and Secondary Syphilis. Patients with late latent syphilis can be treated with either doxycycline 100 mg orally twice daily or tetracycline 500 mg orally four times daily for 28 days.
Clinical and serologic followup should be performed at 6, 12, and 24 months. Approximately 75% of patients treated for early latent syphilis and 44% of patients treated for late latent syphilis will have nonreactive nontreponemal serologic tests 5 years after treatment (171). Treatment failure should be considered for patients whose titers increase fourfold, if an initial titer ≥1:32 fails to decline at least fourfold within 12 to 24 months, or if signs or symptoms of syphilis develop. These patients should have CSF evaluation for neurosyphilis and if negative should be retreated for latent syphilis.
Tertiary Syphilis
Patients with gummatous or cardiovascular syphilis should be evaluated for neurosyphilis. If CSF evaluation is normal, they should be treated with benzathine penicillin 3 weekly IM injections of 2.4 million units (2). Some experts treat patients with evidence of cardiovascular syphilis with neurosyphilis regimens. Doxycycline or tetracycline for 28 days can be considered for treatment of patients with penicillin allergy and without neurosyphilis. Response to treatment of tertiary syphilis has not been well studied.
Neurosyphilis
Patients with abnormalities on CSF examination or with evidence of ocular syphilis should be treated for neurosyphilis. CDC recommended treatment for neurosyphilis is aqueous crystalline penicillin G 3 to 4 million units IV every 4 hours or as a continuous infusion with a daily dose of 18 to 24 million units IV a day for 10 to 14 days (2). An alternative regimen is daily procaine penicillin 2.4 million units IM with probenecid 500 mg orally four times a day for 10 to 14 days. Some experts give one to three additional weekly IM injections of benzathine penicillin 2.4 million units after the IV treatment to achieve a total duration of therapy that is equivalent to late latent treatment. There is less clinical experience with nonpenicillin containing regimens. Ceftriaxone has been recommended by some experts when penicillin cannot be used (172). Some experts recommend ceftriaxone IV or IM 2 g daily for 10 to 14 days.
Patients with elevated CSF cell counts should have repeat CSF evaluation every 6 months until the cell concentration is normal. The cell count should decrease within 6 months, and patients should be retreated if CSF pleocytosis has not resolved after 2 years (2).
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Special Considerations in Pregnancy
Pregnant patients should be treated with penicillin regimens, not with alternative regimens. Pregnant patients with penicillin allergy should be desensitized to penicillin. Some experts recommend 2 weekly doses of intramuscular benzathine penicillin 2.4 million units in pregnant women with primary, secondary, or early latent syphilis. Pregnant patients should be managed with the assistance of an obstetrician.
Jarisch-Herxheimer Reaction
The Jarisch-Herxheimer reaction is an acute febrile reaction that can last several hours and can occur within the first 24 hours of any effective treatment for syphilis. The pathogenesis is unknown but thought to be related to the release of toxin by dying spirochetes. Patients often report headache, myalgias, and worsening cutaneous lesions. Antipyretics may be useful for symptomatic relief. In rare severe reactions patients may develop transient hypotension. In pregnant women, the Jarisch Herxheimer reaction may result in early labor or fetal distress (175). Patients with early stages of syphilis may have a greater risk of developing this reaction and should be informed about this possible side effect of treatment.
HIV-Infected Patients with Syphilis
Although numerous case reports suggest the possibility of a more aggressive course of early syphilis in HIV-infected patients, a recent prospective multicenter, randomized trial comparing manifestations of disease and response to therapy in HIV-infected and uninfected patients with early syphilis found only minor differences in clinical presentation (173). HIV-infected patients had a greater median number of ulcers, and a higher proportion of HIV-infected patients had multiple ulcers. Neurologic signs and symptoms were infrequent in both HIV-infected and uninfected patients.
Although most HIV-infected patients can generally be evaluated and treated with the same diagnostic tests and treatment regimens as HIV-negative patients, clinicians should be aware of several unique considerations. Rarely, false negative serologic tests in the setting of clinical findings suggestive for syphilis in HIV-infected patients may require biopsy of lesions for dark-field examination or direct fluorescent antibody staining. HIV-infected patients with syphilis may also be at somewhat greater risk of developing neurosyphilis even at early stages of disease and may have greater rates of treatment failure with standard treatment regimens (174). A Jarisch-Herxheimer reaction occurs in up to 22% of HIV-infected patients compared to 12% of HIV-negative patients (173).
Current recommendations for treatment do not differ from HIV-negative individuals except that all HIV-infected patients with late latent syphilis or syphilis of unknown duration should have CSF evaluation prior to determination of treatment regimen (2). Recommended followup for HIV-infected patients is at 3, 6, 9, 12, and 24 months after therapy for primary, secondary or early latent syphilis. Patients with late latent syphilis should be re-evaluated serologically at 6, 12, 18, and 24 months after treatment. Patients meeting previously discussed indicators of treatment failure should be reassessed with CSF evaluation and retreated.
Contact Evaluation
Transmission of syphilis occurs through exposure to mucocutaneous syphilitic lesions. Therefore, primary, secondary, and early latent syphilis mark the stages of disease in which sexual partners are at risk of acquiring infection. The CDC STD Treatment Guidelines recommend identifying at-risk sex partners exposed to a patient within 3 months plus the duration of symptoms of primary syphilis, within 6 months plus the duration of symptoms for secondary syphilis, and within 1 year for early latent syphilis (2). Presumptive treatment should be given to all persons regardless of their serology if they have been exposed within 90 days to a case of primary, secondary, or early latent syphilis. If a person has been exposed to primary, secondary, or early latent syphilis greater than 90 days prior to evaluation but serologic tests are not available or followup is in doubt, presumptive treatment should be offered. In cases of syphilis of unknown duration, if the patient has a high titer (≥1:32), partner notification and treatment should follow the guidelines for early syphilis. Persons with a history of exposure to a patient with latent syphilis should be managed based on the results of clinical evaluation and serologic testing.
Specific References
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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