Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

95. Sexually Transmitted Diseases

Leroy C. Knodel


KEY CONCEPTS

 Images All recommended treatment regimens for gonorrhea include antibiotic therapy directed against Chlamydia species because of the high prevalence of coexisting infections, unless chlamydia has been ruled out.

 Images Parenteral penicillin is the treatment of choice for all syphilis infections. For patients who are penicillin allergic, few well-studied alternative agents are available, and all are oral medications that require 2 to 4 weeks of therapy to be effective. Patient compliance and thus efficacy are a concern when alternative regimens must be used.

 Images Chlamydia genital tract infections represent the most frequently reported communicable disease in the United States. In females, these infections are frequently asymptomatic or minimally symptomatic and, if left untreated, are associated with the development of pelvic inflammatory disease and attendant complications such as ectopic pregnancy and infertility. As a result, all sexually active females aged 20 to 25 years and sexually active women with multiple sexual partners should be screened annually for this infection.

 Images Oral acyclovir, famciclovir, and valacyclovir are effective in reducing viral shedding, duration of symptoms, and time to healing of first-episode genital herpes infections, with maximal benefits seen when therapy is initiated at the earliest stages of infection. The benefit of these agents for recurrent infections has not been demonstrated. Patient-initiated, single-day antiviral therapy started within 6 to 12 hours of prodromal symptom onset offers an alternative to continuous suppressive therapy of recurrent infection in some individuals.

 Images Metronidazole and tinidazole are the only agents currently approved in the United States to treat trichomoniasis. Although a single 2-g dose of either agent is widely used for compliance and other reasons, the alternative 7-day metronidazole regimen may be a better choice if sexual partners of treated individuals cannot be treated concurrently.


The spectrum of sexually transmitted diseases (STDs) has broadened from the classic venereal diseases—gonorrhea, syphilis, chancroid, lymphogranuloma venereum, and granuloma inguinale—to include a variety of pathogens known to be spread by sexual contact (Table 95–1). Because of the large number of infected individuals, the diversity of clinical manifestations, the changing drug-susceptibility patterns of some pathogens, and the high frequency of multiple STDs occurring simultaneously in infected individuals, the diagnosis and management of patients with STDs are much more complex today than they were even a decade ago.14

TABLE 95-1 Sexually Transmitted Diseases

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Despite a higher reported incidence of most major STDs in men, the complications of STDs generally are more frequent and severe in women. In particular, serious effects on maternal and infant health during pregnancy are well documented.1,4 Damage to reproductive organs, increased risk of cancer, complications associated with pregnancy, and transmission of disease to the fetus or newborn are associated with several STDs. As a result of the physiologic, psychosocial, and economic consequences of STDs, and because of the increasing prevalence of some viral STDs, such as human immunodeficiency virus (HIV) and genital herpes, for which curative therapy is not available, there is continuing research into STDs and the primary prevention of these diseases.25

With the exception of HIV infection, which is reviewed in detail in Chapter 103, the most frequently occurring STDs in the United States are discussed in this chapter. For other less common STDs, only recommended treatment regimens are presented. The most current information on the epidemiology, diagnosis, and treatment of STDs provided by the U.S. Centers for Disease Control and Prevention (CDC) can be obtained at the CDC Website (www.cdc.gov).

Numerous interrelated factors contribute to the epidemic nature of STDs. Sociocultural, demographic, and economic factors, together with patterns of sexual behavior, host susceptibility to infection, changing properties of the causative pathogens, disease transmission by asymptomatic individuals, and environmental factors, are important determinants of the frequency and distribution of STDs in the United States and worldwide.

Age is one of the most important demographic determinants of STD incidence. Two thirds of STD cases each year occur in persons in their teens and twenties, the peak years of sexual activity. With increasing age, the incidence of most STDs decreases exponentially. In sexually active teenagers, STD rates are highest in the youngest, suggesting that physiologic differences may contribute to increased susceptibility.25

Age-specific rates of STDs are higher in men than in women; however, reported rates may not represent true gender differences but rather may reflect greater ease of detection in men. In recent years, the ratio of male-to-female cases for most STDs has declined, possibly reflecting improvements in the diagnosis of STDs in asymptomatic women or changes in female sexual behavior following the availability of improved methods of contraception. Although some racial disparity exists for rates of STD infection, it is possible that this is a reflection of socioeconomic differences.15

The single greatest risk factor for contracting STDs is the number of sexual partners. As the number of sexual partners increases, the risk of being exposed to someone infected with an STD increases. Sexual preference also plays a major role in the transmission of STDs. For all major STDs, rates are disproportionately greater in men who have sex with men (MSM) than in heterosexuals. In addition, a number of less common STDs, including several caused by enteric protozoans and bacterial pathogens, occur primarily in MSM. The major risk factors for MSM appear to be related to the greater number of sexual partners and the practice of unprotected anal–genital, oral–genital, and oral–anal intercourse. In addition, prostitution and illicit drug use are associated with a higher incidence of most STDs.15

Some of the most serious sequelae of STDs are associated with congenital or perinatal infections. Most neonatal infections are acquired at birth, after infant passage through an infected cervix or vagina. Neonatal Chlamydia trachomatisNeisseria gonorrhoeae, and herpes simplex virus (HSV) infections are associated with this type of spread. For pregnant women with syphilis, infection is usually transmitted transplacentally, producing a congenital infection. Depending on the organism, neonatal infections can manifest in a variety of ways, produce significant morbidity, and in some cases result in infant death.14

Other than complete abstinence, the most effective way to prevent STD transmission is by maintaining a mutually monogamous sexual relationship between uninfected partners. Short of this, use of barrier contraceptive methods, such as the male and female condoms, diaphragm, cervical cap, vaginal sponges, and vaginal spermicides alone or in combination, provides varying degrees of protection from a number of STDs. When used correctly and consistently, male latex condoms with or without spermicide are more effective than natural skin condoms in protecting against STD transmission, including HIV, gonorrhea, chlamydia, trichomoniasis, HSV, and human papillomavirus (HPV). When lubrication is desired with latex condoms, water-based products, such as K-Y jelly, are recommended because oil-based agents (e.g., petroleum jelly) can weaken latex condoms and reduce their effectiveness. For latex-allergic individuals, other synthetic condoms (e.g., polyurethane) appear to possess efficacy against STD transmission similar to latex condoms. The female condom is a lubricated polyurethane sheath with a diaphragm-like ring on each end that can be used as a protective device for women with male sexual partners who do not desire to use a condom. Limited data suggest that the female condom blocks penetration of viruses, including HIV; for nonviral STDs, the female condom provides STD protection similar to the male condom.1,3,5,6 At one time, use of nonoxynol-9, a vaginal spermicide with cytolytic activity, was advocated to reduce the transmissibility of several STDs. This was based in large part on in vitro and animal data. However, nonoxynol-9 does not reduce the risk of transmission of common STDs and actually can increase the risk of HIV transmission. Frequent use of nonoxynol-9 damages vaginal, cervical, and rectal epithelium, leading to increased transmissibility of HIV and possibly other STDs. Diaphragms may protect against cervical gonorrheal, chlamydial, and trichomonal infections.1,58

The varied spectrum of clinical syndromes produced by common STDs is determined not only by the etiologic pathogen(s) but also by differences in male and female anatomy and reproductive physiology. For a number of STDs, the signs and symptoms overlap sufficiently to prevent accurate diagnosis without microbiologic confirmation. Frequently, symptoms are minimal or absent despite the presence of infection. Table 95–2 lists common clinical syndromes associated with STDs.14

TABLE 95-2 Selected Syndromes Associated with Common Sexually Transmitted Pathogens

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GONORRHEA

Epidemiology and Etiology

The gram-negative diplococcus N. gonorrhoeae is the causative organism of gonorrhea. Although the rate of reported cases in the United States has remained relatively stable over the past decade, over 300,000 cases were reported in 2010. However, because of the increasing incidence of resistance to available antibiotics, there is concern that this number may dramatically increase in the future.1,9 Of concern also are the substantial number of infections that remain undiagnosed and unreported.1,9 Humans are the only known natural host of this intracellular parasite. Because of its rapid incubation period and the large number of infected individuals with asymptomatic disease, gonorrhea is difficult to control.1,1015

Although the risk of a female acquiring a cervical infection after a single episode of vaginal intercourse with an infected male partner is high and increases with multiple exposures, the risk of transmission from an infected female to an uninfected male is not as great following a single act of coitus. No data are available on the risk of transmission after other types of sexual contact.1014

Pathophysiology

On contact with a mucosal surface lined by columnar, cuboidal, or noncornified squamous epithelial cells, the gonococci attach to cell membranes by means of surface pili and are then pinocytosed. The virulence of the organism is mediated primarily by the presence of pili and other outer membrane proteins. After mucosal damage is established, polymorphonuclear (PMN) leukocytes invade the tissue, submucosal abscesses form, and purulent exudates are secreted.1015

Clinical Presentation

Individuals infected with gonorrhea can be symptomatic or asymptomatic, have complicated or uncomplicated infections, and have infections involving several anatomic sites. Interestingly, most of the symptomatic patients who are not treated become asymptomatic within 6 months, with only a few becoming asymptomatic carriers of the disease.1013 The most common clinical features of gonococcal infections are presented in Table 95–3.

TABLE 95-3 Presentation of Gonorrhea Infections

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Complications associated with untreated gonorrhea appear more pronounced in women, likely a result of a high percentage who experience signs and symptoms that are nonspecific and minimally symptomatic. As a result, many women do not seek treatment until after the development of serious complications, such as pelvic inflammatory disease (PID). Approximately 15% of women with gonorrhea develop PID. Left untreated, PID can be an indirect cause of infertility and ectopic pregnancies. In 0.5% to 3% of patients with gonorrhea, the gonococci invade the bloodstream and produce disseminated disease. Disseminated gonococcal infection (DGI) is three times more common in women than in men. The usual clinical manifestations of DGI are tender necrotic skin lesions, tenosynovitis, and monoarticular arthritis.1,1014

Diagnosis

Diagnosis of gonococcal infections can be made by gram-stained smears, culture, or methods based on the detection of cellular components of the gonococcus (e.g., enzymes, antigens, DNA, or lipopolysaccharide [LPS]) in clinical specimens. Various stains have been used to identify gonococci microscopically, with the Gram stain the most widely used in clinical practice. Gram-stained smears are positive for gonococci when gram-negative diplococci of typical kidney bean morphology are identified within PMN leukocytes.1,1014 In the presence of equivocal smears (extracellular gonococcal forms that can be nonpathogenic, commensal Neisseria, or gram-negative diplococci of atypical morphology), culture is mandatory. In urethral smears from men with symptomatic urethritis, the smear is highly sensitive and specific, and is considered diagnostic for infection. Because of their low sensitivity, gram-stained smears are not recommended in the diagnosis of endocervical, rectal, cutaneous, and asymptomatic male urethral infections. Because of the presence of nonpathogenic Neisseria in the pharynx, the Gram stain is not useful in the diagnosis of pharyngeal infection.1,10,1214

Although no longer considered the most sensitive of diagnostic tests for gonorrhea, culture is considered the test of choice because of its high specificity in medicolegal situations (e.g., suspected abuse, rape); in diagnosing anorectal, pharyngeal, and conjunctival infections; and in screening populations with a low prevalence. Anatomic sites to be cultured depend on the individual’s sexual preferences and body areas exposed. In women, because the urethra and other sites are rarely the sole locus of infection, cervical cultures produce the highest yield and frequently are performed in conjunction with rectal cultures. Urethral cultures are recommended in women who have had hysterectomies and heterosexual men.1,1014

Because technical constraints and cost preclude the use of culture techniques in many office settings and clinics, alternative methods of diagnosis have been developed, including enzyme immunoassay (EIA), DNA probe techniques, and nucleic acid amplification techniques (NAATs). With the exception of Gram stain for symptomatic gonococcal urethritis, these tests offer increased sensitivity and/or specificity over both Gram stain and culture.10,13,14,16 Additionally, many of these tests can provide a more rapid means of diagnosis than culture. Of particular clinical importance is the high sensitivity of NAATs for detecting N. gonorrhoeae using noninvasive specimens (e.g., self-collected urine specimens, vaginal swabs). As a result, NAAT is considered the standard of care for the diagnosis of gonorrhea. This technology is also being used to concurrently test for C. trachomatis using a single specimen. However, a major drawback of NAATs is their inability to provide resistance data on isolated gonococcal strains. In cases of documented treatment failure, antimicrobial susceptibility testing is recommended.1,1416

TREATMENT

Images In 2010 the CDC issued an update to their recommended treatment regimens for gonorrhea. This update eliminated oral cephalosporins from the recommended treatment regimens for gonorrhea, leaving parenteral ceftriaxone as the only recommended agent for treating gonorrhea14 (Table 95–4). The ceftriaxone-based regimens are the only regimens that have well-documented efficacy in the treatment of urethral, cervical, rectal, and pharyngeal infections. Coexisting chlamydial infection, which is documented in up to 50% of women and 20% of men with gonorrhea, constitutes the major cause of postgonococcal urethritis, cervicitis, and salpingitis in patients treated for gonorrhea for whom concurrent chlamydial infection has not been ruled out.1,14 As a result, concomitant treatment with azithromycin or doxycycline is recommended in all patients treated for gonorrhea. If a cefixime-based regimen is used to treat gonorrhea, it is recommended that patients return in 1 week for a test of cure. While azithromycin (2 g) as a single dose appears highly effective in eradicating both gonorrhea and chlamydia, it is not recommended as a preferred alternative to ceftriaxone because of concerns regarding the development of resistance. In cephalosporin-allergic individuals, azithromycin (2 g) is currently the only alternative available to treat gonorrhea.1,14,17,18

TABLE 95-4 Treatment of Gonorrhea

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Although oral therapy with cefixime may offer a more patient acceptable alternative to intramuscular ceftriaxone, the declining susceptibility of gonorrheal isolates in the United States to cefixime has resulted in its move from a recommended regimen of choice to an alternative regimen. Additionally, only ceftriaxone is effective in treating pharyngeal gonorrhea and eradicating both gonorrhea and incubating syphilis in a patient coinfected with both organisms. The latter is particularly beneficial in areas with a high rate of syphilis.1,10,1215

Pregnant women infected with N. gonorrhoeae should be treated with ceftriaxone. For presumed or diagnosed concurrent C. trachomatis infection, azithromycin or amoxicillin is the preferred treatment.1,10,11

Ceftriaxone is the recommended therapy for DGI, gonococcal meningitis, endocarditis, and any type of gonococcal infection in children. In cases of DGI, patients should be hospitalized and treated with ceftriaxone or one of the alternative parenteral cephalosporin antibiotics (see Table 95–4). Although marked improvement is usually noted within 48 hours of initiating therapy, treatment should be continued for at least 7 days.1,13,14 Gonococcal ophthalmia is highly contagious in adults and neonates and requires ceftriaxone therapy. Single-dose therapy is adequate for gonococcal conjunctivitis, although some physicians recommend continuing therapy until cultures are negative at 48 to 72 hours. Topical antibiotics are not sufficiently effective when used alone for ocular infections and are not necessary with appropriate systemic therapy. Infants with any evidence of ocular infection should be evaluated for signs of DGI.1,10,1314,19


Clinical Controversy…

Some clinicians advocate that a single 2-g dose of azithromycin should be the treatment of choice for gonorrhea because it is also effective in eradicating concomitant chlamydial infection. However, because of concerns regarding the development of resistance and the relatively high incidence of GI side effects, azithromycin monotherapy is not recommended as a first-line therapy.

Treatment of gonorrhea during pregnancy is essential to prevent ophthalmia neonatorum. Gonococcal infection in newborns results primarily from passage through an infected birth canal, but it also can be transmitted in utero. Ophthalmia neonatorum is the most common ophthalmic infection in newborns (1.6% to 12%), although membranes of the vagina, pharynx, or rectum also can become colonized. Conjunctival involvement usually develops within 7 days of delivery and is characterized by intense, bilateral conjunctival inflammation with chemosis. If not treated promptly, corneal ulceration and blindness can develop. Because the law in most states requires neonatal prophylaxis with topical ocular antimicrobials, gonococcal ophthalmia neonatorum is rare in the United States. The CDC recommends that erythromycin (0.5%) ophthalmic ointment be instilled in each conjunctival sac immediately postpartum.1,1014,19

Evaluation of Therapeutic Outcomes

In the past, persistence of gonorrhea symptoms a short time following treatment with a recommended regimen against gonorrhea usually indicated reinfection rather than treatment failure and, as such, reflected the need for improved patient education and sex partner referral. However, with antimicrobial resistance increasingly being reported in recent years, reinfection can no longer be assumed as the cause. As a result, the CDC recommends that all apparent treatment failures be assessed using culture and sensitivity testing. Persistence of symptoms also can be due to other infectious causes, such as C. trachomatis.1,1015 While the CDC does not recommend routine follow-up of patients treated with a recommended regimen, it is recommend that any patient treated with an alternative regimen be tested for cure 1 week following treatment.

SYPHILIS

Epidemiology and Etiology

During the 2000s, the number of reported cases of primary and secondary syphilis in the United States has remained relatively constant at around 14,000.9 Of these newly diagnosed cases, two-thirds are reported in MSM. In addition to being highly contagious, syphilis is of major concern because, if left untreated, it can progress to a chronic systemic disease that can be fatal or seriously disabling.2029Syphilis usually is acquired by sexual contact with infected mucous membranes or cutaneous lesions, although on rare occasions it can be acquired by nonsexual personal contact, accidental inoculation, or blood transfusion. The causative organism of syphilis is Treponema pallidum, a spirochete. The risk of acquiring syphilis from an infected individual after a single sexual encounter is approximately 50% to 60%. After sexual contact, the organism penetrates the intact mucous membrane or a break in the cornified epithelium, and spirochetemia occurs.21,24,2529

There is strong evidence of an association between syphilis and HIV infection. Syphilis, similar to other sexually transmitted genital ulcer diseases, can increase the risk of acquiring HIV in exposed individuals. In addition, immunologic defects in HIV-infected individuals can produce an atypical serologic response to syphilis. In particular, the possibility of delayed seroreactivity, markedly elevated serologic titers, and increased false-positive results could complicate the diagnosis, as well as assessment of treatment efficacy, in HIV-positive individuals infected with syphilis. Furthermore, anecdotal evidence suggests that compromised immune function can result in an accelerated progression of syphilis, particularly to neurosyphilis, requiring more aggressive antibiotic therapy in comparison with an immunocompetent host. As a result of this association, the CDC recommends that all patients diagnosed with syphilis be tested for HIV infection.1,20,2224,26,27

Clinical Presentation

The clinical presentation of syphilis is varied with progression through multiple stages possible in untreated or inadequately treated patients (Table 95–5).

TABLE 95-5 Presentation of Syphilis Infections

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Primary Syphilis

The primary stage, characterized by the appearance of a chancre on cutaneous or mucocutaneous tissue exposed to the organism, is highly infectious. Even without treatment, chancres persist only for 1 to 8 weeks before healing spontaneously. Because syphilitic chancres can be confused with other infectious etiologies, appropriate diagnostic testing is important.2024,26,28

Secondary Syphilis

The secondary stage of syphilis is characterized by a variety of mucocutaneous eruptions resulting from widespread hematogenous and lymphatic spread of T. pallidum. Skin lesions can be either generalized or localized to a small portion of the body and, with the exception of follicular lesions, are nonpruritic. Generalized lymphadenopathy also is seen in the majority of patients, as are nonspecific symptoms such as mild and transitory malaise, fever, pharyngitis, headache, anorexia, and arthralgia. If untreated, secondary syphilis disappears in 4 to 10 weeks; however, lesions can recur at any time within 4 years.2028

Latent Syphilis

By definition, persons with a positive serologic test for syphilis but with no other evidence of disease have latent syphilis. Latent syphilis is further divided into early and late latency. During early latency, the patient is considered potentially infectious because of the 25% risk of spontaneous mucocutaneous relapse. The U.S. Public Health Service defines early latency as 1 year from the onset of infection, although other investigators propose a longer interval, such as 2 to 4 years. With the exception of pregnancy in which the mother can pass the disease to the fetus, late latency is considered noninfectious, although the patient remains a host.1,2028

Most untreated patients with late latent syphilis have no further sequelae; however, approximately 25% to 30% progress either to neurosyphilis or to late syphilis with clinical manifestations other than neurosyphilis. Treatment of all patients with latent syphilis is essential because there is no way to predict which patients will have progression of their disease.2028

Tertiary Syphilis and Neurosyphilis

If left untreated, syphilis can slowly produce an inflammatory reaction in virtually any organ in the body. Manifestations of this disease progression were referred to previously as tertiary syphilis. These clinical manifestations now are differentiated into two subgroups based on the presence or absence of CNS involvement: neurosyphilis or tertiary syphilis (i.e., gumma and cardiovascular syphilis).1,2028

Currently, the term neurosyphilis encompasses any patient with cerebrospinal fluid (CSF) abnormalities consistent with CNS infection. Approximately 40% of patients with primary or secondary syphilis exhibit such abnormalities, although most remain asymptomatic. Persistence of CSF abnormalities into late latency is associated with a greater risk of progression to symptomatic neurosyphilis. Although data are conflicting, some investigators suggest that HIV-infected patients are at greater risk of developing symptomatic neurosyphilis than patients with intact immune systems.1,2028

Rarely seen, the most common manifestations of disease progression from late latency are benign gumma formation and cardiovascular syphilis. The gumma, a nonspecific granulomatous lesion, is the classic lesion of late syphilis and develops in 50% of patients with disease progression. These chronic, destructive lesions characteristically infiltrate the skin, bone, soft tissue, and liver but can be found in any organ or tissue. Gummas of critical organs, such as the heart or brain, can be fatal.1,2024,27

Congenital Syphilis

In pregnant women with syphilis, T. pallidum can cross the placenta at any time during pregnancy. The risk of fetal infection is greatest in pregnant women with primary and secondary syphilis and declines in pregnant women with late disease. Transmission of syphilis during pregnancy occurs primarily transplacentally and can result in fetal death, prematurity, or congenital syphilis. Symptoms can be seen during the first months of life (early congenital syphilis) or later in childhood or adolescence (late congenital syphilis). Manifestations of early congenital syphilis resemble those of secondary syphilis, whereas those of late congenital syphilis correspond to the tertiary stage in adults.20,2224

Diagnosis

Because T. pallidum is difficult to culture in vitro, diagnosis is based primarily on microscopic examination of serous material from a suspected syphilitic lesion or on results from serologic testing. In primary syphilis, diagnosis is established by the presence of T. pallidum on dark-field microscopic examination of material from cutaneous lesions and enlarged lymph nodes in patients with secondary syphilis. In incubating syphilis, confirmation frequently is by dark-field microscopic examination because serologic tests can be unreactive early in the disease. Another method of direct microscopic examination, the direct fluorescent-antibody (test) for T. pallidum (DFA-TP), which uses monoclonal or polyclonal antibodies specific for T. pallidum, has greater specificity and sensitivity than dark-field examination, and does not require the immediate examination of fresh specimens.2429

Serologic tests are the mainstay in the diagnosis of syphilis and traditionally are categorized as nontreponemal or treponemal. Common nontreponemal tests include the Venereal Disease Research Laboratory (VDRL) slide test, rapid plasma reagin (RPR) card test, unheated serum reagin (USR) test, and the toluidine red unheated serum test (TRUST). Nontreponemal tests, which are inexpensive and easily performed, rely on the detection of treponemal antibodies directed against an alcoholic solution of cardiolipin, lecithin, and cholesterol contained in these tests. A positive nontreponemal test can indicate the presence of any stage of syphilis or congenital syphilis, although incubating syphilis and very early primary syphilis produce a negative reaction; however, because they are nonspecific tests, false-positive reactions occur, making them inappropriate to confirm the diagnosis alone. Transiently false-positive results can be seen in patients with acute febrile illnesses, after immunizations, and during pregnancy. Chronic false-positive results are commonly associated with heroin addiction, aging, chronic infections, autoimmune diseases, and malignant disease. In some cases, false-positive reactions are familial and are related to abnormal serum globulin levels.2329

Nontreponemal tests are used primarily as screening tests; however, because T. pallidum antibody titers also can be quantitated by testing serial dilutions of the patient’s serum for reactivity, they are useful in following the progression of the disease, recovery after therapy, and possible reinfection. Because antibody titers vary to some extent between tests, it is important that sequential serologic testing be performed using the same method each time. In patients treated successfully for primary and secondary syphilis, nontreponemal tests almost always will return to seronegativity. If these tests are going to return to negative in patients with early latent syphilis, they will do so within the first 4 years after adequate therapy; patients with disease of longer duration usually remain seropositive for life. In addition to their use in serologic testing, nontreponemal tests often are used on CSF to diagnose neurosyphilis.2329

In some patients with secondary syphilis, a prozone phenomenon occurs that produces a negative VDRL test despite the presence of high reaginic antibody titers. This is corrected by diluting the patient’s serum prior to testing.26,27 For HIV-positive individuals with syphilis, the reactivity of nontreponemal tests can vary depending on the stage of the HIV infection. In the early stages, reaginic titers higher than in non–HIV-infected patients have been seen, resulting in the prozone phenomenon. During the later stages of HIV infection, however, when immune function deteriorates to a greater extent, serologic responses can be reduced or delayed. As a result, the diagnosis of syphilis in HIV-infected individuals can be more difficult.1,2429

In diagnosing all stages of syphilis, treponemal tests are more sensitive than nontreponemal tests. Because these tests are technically more demanding and are more expensive, they are used primarily as confirmatory rather than as screening tests. For many years, the fluorescent treponemal antibody absorption (FTA-ABS) test was the most frequently used treponemal test. The FTA-ABS test uses the T. pallidum antigen to detect specific antibodies to treponemal organisms. However, the FTA-ABS test has largely been replaced by card assays such as the T. pallidum hemagglutination assay (TPHA), the microhemagglutination assay for antibodies to T. pallidum (MHA-TP), and the T. pallidum particle agglutination assay (TPPA) which can be automated and are less expensive to perform. Despite adequate antibiotic therapy for any stage of syphilis, the antibody tests usually remain reactive for life and therefore are not useful in assessing serologic response to therapy, relapse, or reinfection.1,2429

Several EIAs for T. pallidum have become available and are gaining wide use as confirmatory tests. Polymerase chain reaction (PCR)-based tests also are being investigated, particularly in situations in which serologic testing has poor sensitivity and specificity (e.g., congenital syphilis, early primary syphilis, and neurosyphilis). Additionally, multiplex PCR tests that can identify the presence of T. pallidum, herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2), and Haemophilus ducreyi from genital ulcer specimens are under study. The CDC recommends that all patients diagnosed with syphilis be tested for HIV infection.1,2224,29

TREATMENT

Table 95–6 presents the CDC’s treatment recommendations.1 Parenteral penicillin G is the treatment of choice for all stages of syphilis. Because T. pallidum multiplies slowly, single doses of short- or intermediate-acting penicillins do not provide the prolonged, low-level exposure to penicillin required for eradication of the treponeme. As a result, benzathine penicillin G is the only penicillin effective for single-dose therapy.1,2228

TABLE 95-6 Drug Therapy and Follow-up of Syphilis

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The recommended treatment for syphilis of less than 1 year’s duration is benzathine penicillin G 2.4 million units as a single dose. Although the relapse rate for this regimen is less than 3%, some investigators advocate that 2.4 million units be administered once a week for two consecutive weeks. In patients with syphilis of longer than 1 year’s duration and normal CSF examination, benzathine penicillin G is administered weekly for three successive doses. Although not specifically recommended by the CDC, this three-dose regimen is used by some experts to treat HIV-infected patients with syphilis of less than 1 year’s duration based on data suggesting a greater risk of treatment failure with single-dose therapy.1,2428

Patients with abnormal CSF findings should be treated as having neurosyphilis. Preferred regimens for neurosyphilis provide treatment over 10 to 14 days with parenteral penicillin G administered every 4 hours. Benzathine penicillin G alone in standard weekly doses and procaine penicillin G in doses under 2.4 million units do not consistently provide treponemicidal levels in the CSF and have resulted in treatment failures. Because T. pallidumresistance to penicillin has not emerged, the primary need for alternative drugs in treating syphilis is for penicillin-allergic patients.1,2428

Images Alternative regimens recommended for penicillin-allergic patients are doxycycline 100 mg orally twice daily or tetracycline 500 mg orally four times daily for 2 to 4 weeks depending on the duration of syphilis infection. These regimens should be used only in cases of documented penicillin allergy, and given concerns regarding patient compliance with these regimens, follow-up serologic testing is of particular importance.1,2428

Other antibiotics used successfully in treating syphilis include various β-lactam antibiotics; however, none offers significant advantages over benzathine penicillin G. Even though ceftriaxone is considered effective in eradicating incubating syphilis when given as a single 125-mg dose, higher doses and more frequent administration (e.g., 1,000 mg daily for 8 to 10 days) appear necessary for more advanced syphilis, and treatment failures are reported in HIV-infected patients. Although azithromycin 2 g as a single dose produces good results in patients with early syphilis, treatment failures and resistance to azithromycin are reported.1,21,2428


Clinical Controversy…

Some experts even prefer to treat all patients with syphilis of less than 1 year’s duration with the three-dose regimen because single-dose therapy is not consistently effective in eradicating treponemes from the CSF; this is of primary concern in patients with undiagnosed CSF involvement, such as in HIV-infected individuals.

For pregnant patients, penicillin is the treatment of choice at the dosage recommended for that particular stage of syphilis. To ensure treatment success and prevent transmission to the fetus, some experts advocate an additional IM dose of benzathine penicillin G 2.4 million units 1 week after completion of the recommended regimen. In women allergic to penicillin, safe and effective alternatives are not available; therefore, skin testing should be performed to confirm a penicillin allergy. It is recommended that women with positive skin tests undergo penicillin desensitization and receive the appropriate treatment regimen for their stage of disease.1,2224

Most patients treated for primary and secondary syphilis experience the Jarisch-Herxheimer reaction after treatment. This benign, self-limiting reaction is characterized by flulike symptoms, such as transient headache, fever, chills, malaise, arthralgia, myalgia, tachypnea, peripheral vasodilation, and aggravation of syphilitic lesions. The exact mechanism of the reaction is unknown, although proposed etiologies, including immunologic mechanisms and release of endotoxin or other toxic treponemal products, are not substantiated. The Jarisch-Herxheimer reaction is independent of the drug and dose used and should not be confused with penicillin allergy. It usually begins within 2 to 4 hours of initiating therapy, peaks at 8 hours, and is complete within 12 to 24 hours. Most reactions can be managed symptomatically with analgesics, antipyretics, and rest. Steroids and antihistamines have been administered prior to initiation of syphilitic therapy but are of limited value.1,2224

Evaluation of Therapeutic Outcomes

Table 95–6 lists the CDC recommendations for serologic follow-up of patients treated for syphilis.1 Quantitative nontreponemal tests should be performed at 6 and 12 months in all patients treated for primary and secondary syphilis and at 6, 12, and 24 months for early and late latent disease. The CDC recommends more frequent monitoring of HIV-infected individuals (i.e., 3, 6, 9, 12, and 24 months after therapy). In general, the time to reach seronegativity is proportional to the duration of the disease. Table 95–6 also includes specific testing recommendations for other stages of syphilis. Despite adequate therapy, some patients can remain seropositive based on nontreponemal test results. In these cases, stabilization of low antibody titers is indicative of adequate therapy. For women treated during pregnancy, monthly quantitative nontreponemal tests are recommended in those at high risk of reinfection.2224

CHLAMYDIA TRACHOMATIS

Epidemiology and Etiology

Based on CDC data for 2010, over 1.3 million cases of chlamydia infection were reported, making it the most frequently reported infectious disease in the United States.1,9 Because of the silent nature of many infections, the presumptive treatment of many cases, and the underreporting of many cases, it is estimated that more than double this number of cases actually occur annually. Chlamydial infections also are the primary causes of nongonococcal urethritis (NGU), accounting for as much as 50% of such infections.1,3034

Pathophysiology

C. trachomatis is an obligate intracellular parasite that shares properties of both viruses and bacteria. Like viruses, chlamydiae require cellular material from host cells for replication; however, unlike viruses, chlamydiae maintain their cellular identity throughout development. Although C. trachomatis lacks a cell-wall peptidoglycan, its major outer membrane is similar to gram-negative bacteria. At least 18 serovars (subspecies) of C. trachomatis exist, of which only the lymphogranuloma venereum strains produce potentially invasive infections. The remaining serovars are involved primarily with superficial infection of epithelial cells.3034

The risk of transmissibility of chlamydia after exposure is unknown but is believed to be less than that following exposure to N. gonorrhoeae. Coinfection with chlamydia occurs in a substantial number of individuals with gonorrhea and all individuals diagnosed with N. gonorrhoeae should be assumed also to have C. trachomatis present, if chlamydial infection has not been ruled out.1 Of major concern is that chlamydial infections are associated with a significantly increased risk of acquiring HIV infection. In addition to genital infections, ocular infections in adults owing to autoinoculation and infants owing to vaginal delivery through an infected birth canal are reported. Pharyngeal and rectal infections can develop secondary to orogenital or receptive anal intercourse, respectively, with an infected individual.1,3037

Clinical Presentation

In comparison with gonorrhea, chlamydial genital tract infections are more frequently asymptomatic, and when present, symptoms tend to be less noticeable. Urethral discharge usually is less profuse and more mucoid or watery than the urethral discharge associated with gonorrhea.3134 Table 95–7 summarizes the usual clinical presentation of chlamydial infections.

TABLE 95-7 Presentation of Chlamydia Infections

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Similar to gonorrhea, chlamydia can be transmitted to an infant during contact with infected cervicovaginal secretions. Nearly two-thirds of infants acquire chlamydial infection after endocervical exposure, with the primary morbidity associated with seeding of the infant’s eyes, nasopharynx, rectum, or vagina. In exposed infants, neonatal conjunctivitis develops in as many as 50%, and pneumonia develops in up to 16%. Inclusion conjunctivitis in newborns is usually self-limited, but it can result in scarring and micropannus of the cornea. Interstitial pneumonitis occurring secondary to carriage in the nasopharynx typically is mild, but it can be severe and require hospitalization.1,3134,36

Diagnosis

Images Because of the high rate of asymptomatic disease and the high prevalence of chlamydial infection in sexually active females 25 years of age or younger and sexually active women with new sex partners or multiple sex partners, the CDC recommends routine annual screening in these individuals. Laboratory confirmation of chlamydial infection is important because of the relative lack of specificity of symptoms when present.1

Cell culture is the reference standard against which all other diagnostic tests are measured. Because chlamydiae are obligate intracellular parasites, specimens for culture must be obtained from endocervical (women) or urethral (men) epithelial cell scrapings rather than from urine or urethral discharges. Although tissue culture techniques have close to 100% specificity, the sensitivity is reported to be as low as 70% in part because of problems of improper specimen collection, transport, or processing. Because of the technical demands, expense, and length of time until results are available (3 to 7 days), culture is not used widely for diagnostic purposes today. However, culture remains the diagnostic standard in medicolegal cases such as sexual assault and child abuse because of its high specificity and ability to detect only viable organisms.3134,3740

Tests that detect chlamydial antigens and nucleic acid provide more rapid results, are technically less demanding to perform, are less costly, and in some situations have greater sensitivity than culture. Commonly used nonculture tests for detection of C. trachomatis are the enzyme immunosorbent assay (EIA), DNA hybridization probe, and NAATs.32,34,37,39

Although still widely used both as rapid office tests and as laboratory-based tests, EIA methods for diagnosis of C. trachomatis are no longer recommended because of their poor sensitivity in comparison to NAATs. NAATs, which can detect small amounts of chlamydial DNA, are highly sensitive and specific for detecting infection in urogenital and anal specimens, as well as in urine. Use of self-collected vaginal or anal specimens or first-void urine samples offers greater patient acceptability, particularly when used to screen asymptomatic individuals. A further advantage of tests that can screen urine for the presence of infection is that up to 30% of women are reported to have urethral infection only, which would be missed using a test on endocervical samples. Because of their ability to detect as little as a single gene copy in a specimen, nucleic acid residues that persist following successful antibiotic therapy of a chlamydial infection can result in a false-positive test for several weeks following eradication of the organism.33,34

TREATMENT

A number of antimicrobials, including tetracyclines, macrolides, azithromycin, and some fluoroquinolones, display good in vitro and in vivo activity against C. trachomatis. In most clinical trials, cure rates exceeding 90% are reported for these agents. All these antimicrobials also appear to have good efficacy against Ureaplasma urealyticum, the second most common cause of NGU.3134

Azithromycin 1 g orally as a single dose and doxycycline 100 mg orally twice daily for 7 days are the regimens of choice for the treatment of uncomplicated chlamydial infections1 (Table 95–8). Because of its prolonged serum and tissue half-life, azithromycin is the only single-dose therapy that is effective in treating C. trachomatis. Of the fluoroquinolones, ofloxacin and levofloxacin are included in the CDC recommendations, but neither appears to offer an advantage over other first-line nor alternative therapies. Although ciprofloxacin and some other fluoroquinolones have activity against C. trachomatis and U. urealyticum, high dosages have not consistently eradicated chlamydial infections.1,3137

TABLE 95-8 Treatment of Chlamydial Infections

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For pregnant women with chlamydial urogenital infections, treatment can reduce the risk of pregnancy complications and transmission to the newborn significantly. Because the use of tetracyclines and fluoroquinolones is contraindicated during pregnancy, azithromycin and amoxicillin are the recommended drug treatments (see Table 95–8). When compliance with a multiday regimen is a concern, azithromycin is the preferred treatment in women, regardless of pregnancy status. It is recommended that posttreatment cultures be obtained for pregnant patients treated for chlamydial infections to ensure eradication of the infection. Persons treated for chlamydia should abstain from sexual intercourse for 7 days following the initiation of treatment.1,3437,41,42

C. trachomatis transmission during perinatal exposure can result in infections of the eye, oropharynx, lungs, urogenital tract, and rectum of the neonate or infant. Despite its efficacy in preventing gonococcal ophthalmia, topical erythromycin ointment (0.5%) appears less effective in preventing chlamydial ophthalmia. Additionally, topical therapy has no effect on nasal carriage or colonization of other parts of the infant’s body, so the potential for other infections, including pneumonia, remains. Because of the high percentage of treatment failures, topical therapy is not recommended to treat ophthalmia caused by C. trachomatis. Instead, an oral erythromycin regimen is recommended.1,3134

Evaluation of Therapeutic Outcomes

Treatment of chlamydial infections with the recommended regimens is highly effective; therefore, posttreatment laboratory testing is not recommended routinely unless symptoms persist or there are other specific concerns (e.g., pregnancy). Posttreatment tests should not be performed for at least 3 weeks following completion of therapy.1 When posttreatment tests are positive, they usually represent noncompliance, failure to treat sexual partners, or laboratory error rather than inadequate therapy or resistance to therapy. Infants with pneumonitis should receive follow-up testing because erythromycin is only 80% effective, and a second course of therapy can be necessary.1,3134

GENITAL HERPES

Epidemiology and Etiology

Genital herpes infections represent the most common cause of genital ulceration seen in the United States. More than 50 million Americans have genital herpes, and this number is increasing by at least 500,000 each year.1,4348Because of its morbidity, recurrent nature, and potential for complications, as well as its ability to be transmitted asymptomatically, genital herpes is of major public health importance.4554 Similar to syphilis and other STDs, the presence of genital herpes lesions is associated with an increased risk of acquiring HIV following exposure.1,4349

Pathophysiology

Herpes comes from the Greek word meaning “to creep” and is used to describe two distinct but antigenically related serotypes of HSV. HSV-1 is associated most commonly with oropharyngeal disease, and HSV-2 is associated most closely with genital disease; however, each virus is capable of causing clinically indistinguishable infections in both anatomic areas.4345,48

Humans are the sole known reservoir for HSV. Infection is transmitted via inoculation of virus from infected secretions onto mucosal surfaces (e.g., urethra, oropharynx, cervix, and conjunctivae) or through abraded skin. Evidence that the virus survives for a limited time on environmental surfaces suggests the possibility of fomitic transfer as a nonvenereal route of transmission.4345,48

The cycle of HSV infection occurs in five stages: primary mucocutaneous infection, infection of the ganglia, establishment of latency, reactivation, and recurrent infection. After viral inoculation, HSV infection is associated with cytoplasmic granulation, ballooning degeneration of cells, and production of mononucleated giant cells. Initially, the cellular response is predominantly PMN, followed by a lymphocytic response. Replication occurs with viral spread to contiguous cells and peripheral sensory nerves. Latency then is established in sensory or autonomic nerve root ganglia. Latency appears to be lifelong, interrupted only by reactivation of the viral infection. It is unclear what factors are important in maintaining latency, but immune responses and emotional and physical stresses appear important in reactivating latent virus.4345,48

Clinical Presentation

The signs and symptoms of genital herpes infection are influenced by many factors, including previous exposure to HSV, viral type, and host factors such as age and site of infection. Because a high percentage of initial and recurrent infections are asymptomatic, and because viral shedding can occur in the absence of apparent lesions or symptoms, identification and education of individuals with genital herpes are essential in controlling its transmission.4352 A summary of the clinical presentation of genital herpes is provided in Table 95–9.

TABLE 95-9 Presentation of Genital Herpes Infections

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Complications

Complications from genital herpes infections result from both genital spread and autoinoculation of the virus and occur most commonly with primary first episodes. Lesions at extragenital sites, such as the eye, rectum, pharynx, and fingers, are not uncommon. CNS involvement is seen occasionally and can take several forms, including an aseptic meningitis, transverse myelitis, or sacral radiculopathy syndrome.4352

A major concern is the effect of genital herpes on neonates exposed during pregnancy. Neonatal herpes is associated with a high mortality and significant morbidity. It is transmitted to the newborn primarily through exposure to HSV in the birth canal but, in rare cases, also is transmitted transplacentally. The risk of transmission during birth appears much greater for first-episode primary infections than for recurrent infections. Neonatal herpes infection has a case-fatality rate of approximately 50%, with a large proportion of surviving infants experiencing significant morbidity, including permanent neurologic damage.43,44,48

Diagnosis

Confirmation of a genital herpes infection can be made only with laboratory testing. Tissue culture is the most specific (100%) and sensitive method (80% to 90%) of confirming the diagnosis of first-episode genital herpes; however, culture is relatively insensitive in detecting HSV in ulcers in the latter stages of healing and in recurrent infections, as a result, in part, of reduced viral load. Viral culture is expensive and time-consuming, and improper collection or transport of specimens can result in false-negative results. In most situations, HSV isolation on tissue culture takes 48 to 96 hours. Following isolation, it is recommended that typing of the virus be performed because of prognostic implications (HSV-1 is associated with a lower rate of asymptomatic and symptomatic recurrence). In instances in which rapid detection is necessary, such as an impending birth, other detection methods can be more useful. Amplified culture techniques that combine cell culture for 24 hours and subsequent staining for HSV antigen have sensitivities and specificities only slightly less than those of culture.4348,5355

Several serologic tests capable of distinguishing HSV-1 and HSV-2 antibodies are available. These tests detect antibodies to type-specific HSV-1 and HSV-2 proteins gG-1 and gG-2, respectively. Although antibody formation begins immediately following a primary herpes infection, complete seroconversion (i.e., complete antibody development) can take several months. Until the full expression of all antigenic determinants of HSV-1 and HSV-2 occurs, these tests are not useful in differentiating HSV-1 and HSV-2 infection. Older antibody detection tests, some of which are still marketed, are unable to distinguish between HSV-1 and HSV-2 owing to the considerable cross-reactivity between the two serotypes. Given the high prevalence of HSV-1 antibody in the adult population, accurate interpretation of positive results is not possible.4348,5355

PCR assays that detect HSV DNA and differentiate HSV-1 and HSV-2 infections are more sensitive than culture and are considered the diagnostic test of choice for suspected CNS infections (i.e., HSV encephalitis and HSV meningitis). PCR assays are highly sensitive in detecting asymptomatic viral shedding.4348,5355

Although the diagnosis of genital herpes can be confirmed only by laboratory tests, less stringent diagnostic criteria (e.g., characteristic physical findings or clinical history) frequently are used in clinical practice. A presumptive diagnosis of genital herpes commonly is made based on the presence of dark-field-negative, vesicular, or ulcerative genital lesions. A prior history of similar lesions or recent sexual contact with an individual with similar lesions also is useful in making the diagnosis. Other STDs, including chancroid, lymphogranuloma venereum, and granuloma inguinale, and causes such as trauma, allergic reactions, and bacterial or fungal infections are considered in the differential diagnosis.4348,5355

TREATMENT

The most achievable goals in the management of genital herpes are to relieve symptoms and to shorten the clinical course, to prevent complications and recurrences, and to decrease disease transmission. Although research has focused primarily on the treatment of active infection and suppression of recurrences, increasing emphasis is being placed on various approaches, including immunotherapy that might provide protection from disease transmission or possibly eliminate established latency.4748

Palliative and supportive measures are the cornerstone of therapy for patients with genital herpes. Pain and discomfort usually respond to warm saline baths or the use of analgesics, antipyretics, or antipruritics; good genital hygiene can prevent the development of bacterial superinfection.

Images Specific chemotherapeutic approaches to treating genital herpes include antiviral compounds, topical surfactants, photodynamic dyes, immune modulators, vaccines, and interferons. Few of these have undergone extensive evaluation, however, and only the antiviral agents have demonstrated any consistent clinical efficacy. The most recent CDC recommendations for the treatment of genital herpes include the antiviral agents acyclovir, valacyclovir, and famciclovir1 (Table 95–10). The overall efficacy of these agents in treating genital HSV infection appears comparable, although patient compliance can be improved with regimens requiring less frequent dosing.1,43,44

TABLE 95-10 Treatment of Genital Herpes

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First-Episode Infections

Oral formulations of acyclovir, famciclovir, and valacyclovir have demonstrated efficacy in reducing viral shedding, duration of symptoms, and time to healing of first-episode genital herpes infections, with maximal benefits seen when therapy is initiated at the earliest stages of infection. Table 95–10 lists the recommended acyclovir, famciclovir, and valacyclovir oral regimens for first-episode infections. In immunocompromised patients or those with severe symptoms or complications necessitating hospitalization, parenteral acyclovir can be beneficial; however, the IV regimen has been associated with renal, GI, bone marrow, and CNS toxicity, particularly in patients with renal dysfunction receiving high doses. No antiviral regimen is known to prevent latency or alter the subsequent frequency and severity of recurrences in humans.1,4348,51,52,5659

Recurrent Infections

There are two approaches to management of recurrent episodes: episodic or chronic suppressive therapy. Episodic therapy is initiated early during the course of the recurrence, preferably within 6 to 12 hours of the onset of prodromal symptoms but no more than 24 hours after the appearance of lesions. In most patients, appreciable effects on symptomatology are not seen. Patients with prolonged episodes of recurrent infection or severe symptomatology are most likely to benefit from episodic therapy. Table 95–10 lists the recommended acyclovir, famciclovir, and valacyclovir suppressive regimens. One concern with episodic therapy is that some patients continue to shed virus despite the absence of lesions or presence of prodromal symptoms. Because of the relative mildness and brevity of recurrent infections, parenteral administration of acyclovir usually is not justifiable.1,4348,51,52,5659

Suppressive therapy with recommended antivirals reduces the frequency and severity of recurrences in 70% to 80% of patients experiencing frequent recurrences. Asymptomatic viral shedding is markedly reduced in patients receiving suppressive therapy; however, the extent to which this decreases disease transmission to sexual partners remains to be determined. Despite antiviral suppressive therapy, low-level virus shedding still occurs. However, this virus shedding may be less than that seen in patients treated episodically for recurrences, and thus may be associated with a lower risk of disease transmission. Because the frequency of recurrences tends to diminish over time, periodic “drug holidays” are advocated to assess changes in the underlying recurrence rate and determine if continued suppressive therapy is warranted.1,4348,51,52,5659


Clinical Controversy…

The role of antiviral agents in the treatment of most recurrent genital herpes episodes is controversial. Because signs and symptoms of recurrent infections generally are milder and of shorter duration than those of first-episode infections in immunocompetent hosts, demonstration of clinically important therapeutic benefits is difficult. However, as episodic, asymptomatic viral shedding is common in HSV-2 infection, suppressive therapy in combination with use of condoms provides some protection to uninfected sexual partners.

Resistant HSV isolates have been identified in some patients experiencing breakthrough recurrences while taking acyclovir. Although there is concern about the development of resistant strains with suppressive therapy, clinical trials have found no evidence of cumulative toxicity or significant resistance in patients treated continuously with the recommended antivirals.4348

Selected Populations

Immunocompromised patients are at greatest risk for severe and recurrent HSV infections. Acyclovir, valacyclovir, and famciclovir have been used to prevent reactivation of infection in patients seropositive for HSV who undergo transplantation procedures or induction chemotherapy for acute leukemia. Immunocompromised individuals, such as patients with acquired immunodeficiency syndrome (AIDS), who fail treatment or prophylaxis with recommended antiviral doses frequently demonstrate improved response with higher doses. If resistance is suspected or confirmed with recommended first-line antivirals, foscarnet is usually effective. However, its use is associated with a greater risk of serious adverse effects. Lesional application of an extemporaneous compounded cidofovir (1%) gel or trifluridine ophthalmic solution appears to offer some benefits also.1,4348

The safety of acyclovir, famciclovir, and valacyclovir during pregnancy is not established, although considerable experience with acyclovir in pregnant patients has produced no evidence of teratogenic effects. Because of the high maternal and infant morbidity associated with first-episode primary genital infections or severe recurrent infections at or near term, many clinicians advocate the use of systemic acyclovir as the standard of care in such cases; however, the effectiveness of such therapy is unknown. The use of acyclovir to suppress recurrent episodes near term is more controversial primarily because of the lack of data demonstrating significant benefits in this situation.1,4348,6063

With the increasing prevalence of genital herpes worldwide, the potential exists for widespread use and misuse of acyclovir, valacyclovir, and famciclovir, resulting in development of resistant HSV isolates. In vitro resistance to these three agents usually is mediated by alterations in viral thymidine kinase; most resistant isolates are either thymidine kinase-deficient or have altered thymidine kinase. The incidence and clinical implications of HSV resistance require further study particularly with respect to immunocompromised hosts, in whom resistance can develop with greater frequency and be of greater clinical importance. Unlike acyclovir, valacyclovir, and famciclovir, foscarnet does not require the presence of thymidine kinase to be effective.4348

Numerous agents for the prophylaxis and treatment of genital herpes infections are being studied. Neither topical nor systemic interferons have demonstrated consistent beneficial effects in genital HSV infections; however, a reduction in pain and time of healing of lesions has been reported with an interferon preparation incorporated into a gel containing nonoxynol-9. Other treatments under investigation include cidofovir and immune modulators such as imiquimod and resiquimod.4348 Agents that can eliminate ganglionic latency and prevent recurrent HSV infections are not expected to be available in the near future. Development of vaccines capable of protecting against HSV infection has proved challenging given the relative lack of protection offered by humoral and cell-mediated immunity in preventing naturally occurring recurrent infections. Safety concerns with live attenuated virus vaccines resulted in research focused primarily on recombinant protein vaccines that have exhibited relatively poor immunogenicity. Use of heterologous vaccines (bacillus Calmette–Guérin and influenza vaccines) to stimulate the immune system in patients with recurrent genital herpes has proved of no significant benefit.4348,64

Evaluation of Therapeutic Outcomes

Available antiviral compounds are of greatest benefit in patients experiencing first-episode primary infections, immunocompromised patients, and patients with frequent or severe recurrent infections. Antivirals, however, are palliative and not curative, and patients receiving these agents should be monitored closely for adverse drug effects. CDC guidelines suggest that discontinuation of suppressive therapy after 1 year should be considered to assess for possible changes in the patient’s intrinsic pattern of recurrence. In many patients, decreases in recurrence rates and the severity of symptoms occur over time. However, some clinicians prefer to continue suppressive therapy indefinitely because it significantly reduces asymptomatic viral shedding, a potential benefit in reducing the risk of disease transmission to uninfected sexual partners.1,4348

TRICHOMONIASIS

Epidemiology and Etiology

Trichomonas vaginalis, a flagellated, motile protozoan is responsible for 3 to 5 million cases of trichomoniasis annually in the United States. Humans are host to two other Trichomonas species, Trichomonas tenax and Trichomonas hominis, but T. vaginalis is the only species thought to be pathogenic. Although infection by nonsexual contact is reported, it is rare. Contamination of inanimate objects and spread of infection via communal bathing or contact with infected bath or toilet articles is possible because T. vaginalis can survive for up to 45 minutes on moist surfaces. Neonatal infections also represent another possible nonvenereal route of disease transmission.6569

Coinfection with other STDs is not unusual in patients diagnosed with trichomoniasis. Women infected with T. vaginalis are three times more likely to have gonorrhea than those who do not have trichomoniasis; approximately 20% of men with gonococcal urethritis also have trichomoniasis.6569 In patients treated appropriately for genital C. trachomatis or U. urealyticum infection, persistent urethritis can result from coexisting trichomonal infection. Although not well documented, the inflammatory response produced by trichomoniasis may increase the risk of acquiring HIV.1,6570

Pathophysiology

Trichomonads typically can be isolated from the vagina, urethra, and paraurethral ducts and glands in the majority of infected women. Infrequently, they are recovered from the endocervix. Extragenital sites are epidemiologically important because infection can persist and result in reinfection of the vagina if local therapy alone is used. This may account for the higher relapse rates reported for local versus systemic therapy. After attachment to the vaginal or urethral mucosa, trichomonads usually elicit an inflammatory response that manifests as a discharge containing large numbers of PMN leukocytes.6574

Clinical Presentation

Trichomonal infections are reported more commonly in women than in men. In part this might be because of the smaller number of organisms found in the male urethra making detection more difficult, greater disease transmission rates from males to females, and the nature of male infections, which have a high spontaneous cure rate even in the absence of treatment.66,67,7072,75 The typical clinical presentation of trichomoniasis in males and females is presented in Table 95–11.

TABLE 95-11 Presentation of Trichomonas Infections

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Diagnosis

T. vaginalis produces nonspecific symptoms also consistent with bacterial vaginosis; as a result, laboratory diagnosis is required. Because T. vaginalis requires a pH range of 4.9 to 7.5 for survival, a vaginal discharge pH of greater than 5 usually indicates the presence of either T. vaginalis or Gardnerella vaginalis, a common cause of bacterial vaginosis. The simplest and most reliable means of diagnosis is a wet-mount examination of the vaginal discharge.67,7072,75 Trichomoniasis is confirmed if characteristic pear-shaped, flagellating organisms are observed. The wet mount is only about 60% to 80% sensitive in detecting the presence of trichomonads, with lower sensitivities reported in men and in women with low-grade, subacute, or chronic infections.6870,72,74

Although the presence of trichomonads may be reported on a Papanicolaou smear (Pap), the sensitivity of this cytologic technique is less than for wet mount and also is associated with a high number of false-positive and false-negative results. Stained smears of cervical specimens have been used in diagnosis, but they are less sensitive and more time-consuming than the wet mount and therefore are not recommended. Culture techniques for trichomonads are highly specific and more sensitive than the wet mount, but they are not useful in rapid diagnosis because up to 48 hours or longer is necessary for growth. Cultures can be necessary, however, to confirm the diagnosis in the absence of a positive wet mount or to determine antimicrobial susceptibility in intractable cases.1,6572,74,75

Newer diagnostic tests such as monoclonal antibody or DNA probe techniques, as well as PCR tests that can detect small amounts of trichomonal DNA, have been developed. These office-based tests are highly sensitive and specific for detecting infection in both vaginal specimens and urine. However, these tests are still not widely used.6569

In males, demonstration of trichomonads in urethral specimens or urine sediment by wet mount is difficult, and diagnosis depends largely on culture. Specimens from males should be taken prior to first voiding because the small number of trichomonads in males may be reduced by micturition.6571

TREATMENT

Recommended and alternative treatment regimens for T. vaginalis include either metronidazole or tinidazole, both of which produce high cure rates in these infections. In only a few cases have T. vaginalisisolates been resistant to standard metronidazole or tinidazole doses. In these instances, longer courses of therapy or doses higher than those recommended routinely as initial therapy usually produce a cure.1,6569,72,75,76

Table 95–12 provides treatment recommendations for trichomonas infections.1 The standard therapy for trichomoniasis is either metronidazole or tinidazole 2 g orally as a single dose; cure rates are comparable with the recommended alternative regimen of metronidazole 500 mg twice daily for 7 days. When sexual partners are treated simultaneously, cure rates greater than 95% are reported. If sexual partners are not treated concurrently, cure rates are somewhat lower. In limited clinical testing, single metronidazole doses of less than 1.5 g are associated with high failure rates.1,6569,72,75,76

TABLE 95-12 Treatment of Trichomoniasis

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Advantages of single-dose therapy over the multidose alternative regimen include better patient compliance, lower total dose, lower cost, and shorter exposure of the patient’s GI and urogenital anaerobic bacterial flora to the drug. As a result of the latter, the likelihood of developing pseudomembranous colitis or symptomatic candidal vulvovaginitis is decreased.6569,72 Because high doses of metronidazole have mutagenic effects in bacteria and oncogenic effects in mice, a reduced time of exposure in humans can be beneficial. There is no conclusive evidence for either of these effects in humans after short-term therapy with recommended doses. GI complaints (e.g., anorexia, nausea, vomiting, and diarrhea) are more common with the single 2-g dose of either metronidazole or tinidazole, occurring in 5% to 10% of treated patients. Some patients also complain of a bitter metallic taste in the mouth with metronidazole. Patients intolerant of the single 2-g dose because of GI adverse effects usually tolerate the alternative metronidazole multidose regimen.6569,72,75,76

Images To achieve maximal cure rates and prevent relapse with either metronidazole or tinidazole as a single 2-g dose, simultaneous treatment of infected sexual partners is necessary. In women treated with the alternative 7-day course, however, relapse rates are not appreciably different regardless of whether or not sexual partners are treated. It is speculated that in men, spontaneous resolution of trichomonal infection or a reduction in the number of trichomonads below the inoculum necessary to transmit disease may occur during the 7 days of a female’s therapy. In patients who fail to respond to an initial course of metronidazole therapy, a second course of therapy with metronidazole 500 mg twice daily for 7 days or a single 2-g dose of tinidazole is recommended. Patients refractory to a second course of treatment usually respond to a regimen using higher dosages of either agent (i.e., 2 to 4 g daily for 5 to 14 days). Good response rates also are reported for metronidazole 2 to 3 g orally plus either a single 500-mg tablet administered intravaginally or intravaginal metronidazole gel (0.75%) for 7 to 14 days.61,6569,71,76,77 Topical vaginal therapy alone is associated with low cure rates because infections involving the urethra or periurethral glands are unaffected and can serve as the source of reinfection.67 Use of IV metronidazole can be warranted for rare cases of intolerance to oral medication or infections resistant to high-dose oral metronidazole. Sexual partners of all patients who require retreatment also should be treated or retreated because the majority of apparent treatment failures appear to be caused by reinfection or noncompliance.6569

Concerns regarding the use of metronidazole in women who are pregnant or breast-feeding have been raised. Because metronidazole is secreted in breast milk, it is recommended that breast-feeding be interrupted for 12 to 24 hours after maternal ingestion of a single 2-g dose. Metronidazole (pregnancy category B) and tinidazole (pregnancy category C) are contraindicated during the first trimester of pregnancy based on FDA-approved labeling. Although some experts recommend avoiding use of either agent throughout pregnancy, others advocate the use of metronidazole during any stage of pregnancy because of the potential adverse pregnancy outcomes associated with trichomoniasis. Currently no consensus exists on whether or how to treat trichomonas infections in pregnant women.1,6569

Various local therapies for trichomoniasis have been proposed, particularly for pregnant patients. Clotrimazole vaginal suppositories, 100 mg at bedtime for 1 to 2 weeks, relieve symptoms in many women and produce cure rates of 50% or greater. An alternative therapy is gentle douching with either a diluted solution of vinegar or a 1% zinc sulfate solution until symptoms improve and then less frequently thereafter. This therapy generally provides some symptomatic improvement but few cures. Although once recommended, povidone-iodine douches should be avoided during pregnancy because of the risk of fetal thyroid suppression.6569

Several other nitroimidazole antibiotics related to metronidazole and tinidazole (e.g., nimorazole, ornidazole, and carnidazole) are being investigated worldwide for the treatment of trichomoniasis. Unfortunately, none of these agents differs significantly from metronidazole or tinidazole in terms of efficacy (i.e., cross-resistance is high) or toxicity against metronidazole-susceptible strains of T. vaginalis.6569

EVALUATION OF THERAPEUTIC OUTCOMES

Follow-up is considered unnecessary in patients who become asymptomatic after treatment with recommended therapy. When patients remain symptomatic, it is important to determine if reinfection has occurred. In these cases, a repeat course of therapy, as well as identification and treatment or retreatment of infected sexual partners, is recommended. In situations in which reinfection can be excluded, a relative resistance to metronidazole or tinidazole should be assumed, and an alternative regimen should be prescribed. Culture and sensitivity are warranted for infections unresponsive to alternative regimens.

HUMAN PAPILLOMAVIRUS AND OTHER STDS

Several STDs other than those just discussed occur with varying frequency in the United States and throughout the world. Although an in-depth discussion of these diseases is beyond the scope of this chapter, Table 95–13 lists recommended treatment regimens.1 Of notable importance among these other STDs, however, is genital HPV infection, the most common viral STD in the United States. More than 100 HPV types have been characterized by genomic makeup, with approximately 30 types associated with genital tract lesions.7981 Of these, types 6 and 11 are associated most commonly with the development of low-grade dysplasia manifested as exophytic genital warts. In most individuals, genital infection with HPV is subclinical, and patients with visible acuminate warts represent less than 1% of all infected individuals. When present, genital warts can be large and multifocal, producing variable degrees of discomfort. Based on HPV DNA detection methods, most warts will regress spontaneously within 1 to 2 years of their initial appearance. However, reinfection is common in young, sexually active populations.1,78,79

TABLE 95-13 Treatment Regimens for Miscellaneous Sexually Transmitted Diseases

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Infection with several HPV types, particularly HPV-16 and HPV-18, is considered the major risk factor for the development of cervical neoplasia, the second most common cancer in women worldwide. Although epidemiologic, virologic, and clinical data strongly support this association, HPV infection alone is insufficient to cause cervical cancer development because only a small percentage of infected women develop the disease. It appears that the interplay of host immune defenses, genetic factors, and infection with HPV types containing a more aggressive variant all contribute to the risk of developing cervical neoplasia.78,79

The Pap smear is the most frequently used and cost-effective diagnostic test for detecting clinical and subclinical (i.e., no visible signs of condylomata) HPV in women. However, Pap smears are neither specific for HPV nor useful in detecting latent infections. Frequently, visual inspection of genital surfaces under magnification can assist in making the diagnosis. Various tests for detecting HPV DNA, RNA, or capsid protein also are available, and unlike the Pap smear do not require subjective interpretation of the results. The HPV-specific tests are only approved in women with abnormal Pap smears or women older than 30 years of age. However, use of HPV DNA testing as a routine screening test in lieu of Pap smears is expected in the near future. In women identified to have high-risk HPV infections by these tests, follow-up cytology would be performed.78,79

No consensus exists on the best approach to treating patients with genital HPV infection, particularly because most cases appear to be transient with spontaneous regression of lesions. A number of treatments are recommended (see Table 95–13), but none is clearly superior to the others. Treatment generally is directed toward patients with manifestations of genital warts, with the goal of removing or destroying these lesions and grossly infected surrounding tissue. Because such treatment neither stops viral expression in surrounding tissue nor eliminates viral latency, recurrence of lesions is not uncommon.78,79

Two HPV vaccines are marketed in the United States. Cervarix, a bivalent vaccine for HPV-16 and -18, and Gardasil, a quadrivalent vaccine for HPV-6, -11, -16, and -18. Both vaccines are indicated for preventing cervical precancers and cervical cancer in females 9 to 26 years of age. In addition, Gardasil is indicated in males between the ages of 9 and 26 years for the prevention of genital warts caused by HPV-6 and -11, and for the prevention of anal cancer caused by HPV-16 and -18. Clinically important differences in the magnitude and duration of the immune response, as well as prevention of HPV infections and cervical cancer remain to be determined.8083

ABBREVIATIONS

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