Sexually Transmitted Infections: Chlamydia, Gonorrhea, Pelvic Inflammatory Disease, and Syphilis
Lydia A. Shrier
Sexually transmitted infections (STIs) are epidemic among adolescents in the United States. Of the approximately 19 million new cases of STIs identified each year, almost one-half occur in young people ages 15 to 24 years (1). Adolescent girls (15 to 19 years) have the most reported cases of chlamydia and gonorrhea compared to any other age–sex group, followed by young women (20 to 24 years) (2). Using nationally representative data, a recent study found that approximately one in four (24.1%) U.S. adolescent girls ages 14 to 19 years has at least one of five STIs: human papillomavirus (HPV) infection, chlamydia, gonorrhea, herpes simplex virus type 2 (HSV-2) infection, and trichomoniasis (3).
The high prevalence of STIs in teens is the result of many behavioral, biologic, social, and epidemiologic factors. Adolescents are more likely than adults to engage in a variety of sexual risk behaviors, including sexual intercourse with multiple and high-risk sexual partners; inconsistent, incorrect, or lack of condom use; and risky sexual practices such as rectal intercourse (often to preserve virginity). Early onset of sexual activity predisposes adolescents to STIs due to lack of immunity from prior exposure and, in girls, cervical ectopy (extension of endocervical columnar epithelium onto the exocervix). Sexual violence, secrecy, poor sexuality education, lack of ability to pay for services and treatment, lack of access, discomfort with facilities and services designed for adults, and concerns about confidentiality may increase the rates of STI acquisition and augment the dearth of preventive services and prompt treatment for adolescents (4).
Many pediatricians are not aware of confidentiality laws existing in every state that permit adolescents to consent to their own health care related to STIs; in a survey by the American Academy of Pediatrics, 28% of pediatricians identified “issues with confidentiality” as a barrier to care for adolescent patients (5). Increased health facilities for teenagers and the advent of noninvasive STI testing (6) have permitted better diagnosis and reporting, and the recognition of asymptomatic infections in males and females has resulted in increased screening, factors that have also contributed to higher reported rates in adolescents. Adolescent girls infected with Chlamydia trachomatis and Neisseria gonorrhoeae are at particular risk of upper genital tract infections including pelvic inflammatory disease (PID) and the possible sequelae of infertility, ectopic pregnancy, and chronic pain. Although the highest numbers of chlamydial and gonococcal infections occur in young women between 15 and 24 years of age (2), very young teenagers who are sexually active have an especially high risk of acquiring these pathogens. The health consequences and costs associated with the high prevalence of STIs are substantial, yet they remain largely hidden (4).
More widespread screening to detect asymptomatic infections of N. gonorrhoeae and C. trachomatis and improved recognition of the symptoms of upper genital tract infections are needed to enhance the health care of teenage women. The finding of one STI should lead to the diagnostic suspicion of other potential STIs, including syphilis and HIV. All adolescent girls should be immunized against some of the most common types of HPV using one of two vaccines currently available. Given the risk of transmitting and acquiring hepatitis B infection during the adolescent years, all adolescents should have completed the vaccination series to prevent this infection. Family planning clinics should provide adequate screening and treatment for STIs, and STI clinics should counsel their clients about appropriate methods of contraception if pregnancy is not desired. Potential effects of contraceptives on STIs are considered in Chapter 24.
Hlamydia Trachomatis Infections
With 1,210,523 cases reported to the Centers for Disease Control and Prevention (CDC) in 2008, C. trachomatis continues to be the most commonly reported infectious disease in the United States (2). The highest rates are reported from the southern United States and among women, especially those who are 15 to 19 years old (3,275.8 per 100,000 females) and 20 to 24 years old (3,179.9 per 100,000 females). Chlamydial infections in women may result in PID and subsequent chronic pelvic pain, ectopic pregnancy, and tubal infertility. The rates of reported chlamydial infection have been increasing since the 1990s, due at least in part to increased screening, use of more sensitive tests, and increased reporting (2,7). Where large-scale screening programs have been instituted, such as in the West and Midwest and in programs such as the National Job Training Program, prevalence rates have declined (7). However, chlamydial infections are usually asymptomatic and screening is not universal, so the rate of new chlamydial infections each year in the United States is closer to an estimated 2.8 million (1).
It is estimated that sexually active women younger than 20 years old have chlamydial infection rates two- to threefold higher than adult women. According to data from the 2003–2004 National Health and Nutrition Examination Survey (NHANES), the prevalence of chlamydial infection among girls 14 to 19 years of age in the United States is 3.9% without regard to history of sexual activity and 7.1% among those who report ever having oral, vaginal, or anal sex (8). Prevalence figures for chlamydia vary depending on the population studied, with rates from 2.7% in sexually active adolescent patients of two suburban pediatric
private practices to as high as 20.8% in young women entering the National Job Training Program (2,8,9,10,11,12,13,14,15,16) (Table 18-1).
private practices to as high as 20.8% in young women entering the National Job Training Program (2,8,9,10,11,12,13,14,15,16) (Table 18-1).
Table 18-1 Prevalence of Urogenital Infection with Neisseria Gonorrhoeae and Chlamydia Trachomatis in Different Female Adolescent Samples | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Several factors contribute to or indicate an increased risk of chlamydial infection among adolescent girls, including increased number of sexual partners, inconsistent condom use, nonwhite race, having a partner ≥2 years older, and marijuana use (17). Many adolescent girls have a significant cervical ectropion, the columnar cells of which are exposed to the vaginal environment, and are thus more easily colonized with C. trachomatis. If the patient has an ectropion, the presence of infecting C. trachomatis is also more easily detected. Oral contraceptives have been reported to be associated with chlamydial infections in some studies, but not others. Oral contraceptives may affect the prevalence by contributing to the persistence of the ectropion. Adolescents also may be at increased risk of developing a chlamydial infection because of their “immunologic immaturity” and lower levels of antichlamydial antibodies. Younger age (17) is also an independent predictor of STIs, including C. trachomatis.
Although in STI clinics patients may present with signs and symptoms of chlamydial infection, in lower-risk settings such as college health centers, most patients are asymptomatic and detected only by screening tests. Results of a randomized controlled trial of chlamydial screening indicated that routine screening can reduce the incidence of PID by as much as 60% (18). Because more adolescents with endocervical infection with C. trachomatis go on to develop salpingitis than do adult women, screening in this age group is particularly important. The U.S. Preventive Services Task Force (USPSTF) and the CDC recommend at least annual screening for young sexually active women (younger than 25 [19] or 26 [20] years of age). Unfortunately, an analysis of national data reported by commercial and Medicaid health plans to the Healthcare Effectiveness Data and Information Set (HEDIS) found that in 2007 only 41.6% of “sexually active” young women had received annual screening for chlamydia (21); however, the HEDIS measures underestimate the percentage screened because the population of young women identified as “sexually active” includes adolescents with prescriptions for oral contraceptives (which could be for a menstrual disorder) and those who have had a pregnancy test ordered. In young populations with a high prevalence of C. trachomatis, twice-yearly screening may be warranted (22,23). It is also prudent to consider screening young women after a change in sexual partners and with any suggestive symptoms (24).
C. trachomatis is a major etiologic agent in perihepatitis or Fitz-Hugh-Curtis syndrome, with or without concurrent salpingitis (25,26). The patient typically presents with right upper quadrant pain, often pleuritic, and laboratory evaluation reveals an increased erythrocyte sedimentation rate (ESR); the patient may have a positive genital or urine test for C. trachomatis (note that endocervical tests can be negative in patients with upper genital tract chlamydial infection). Ultrasonography may be necessary to exclude biliary tract disease in patients with this type of pain. Liver function tests are usually normal in chlamydial perihepatitis, in contrast to the elevated liver function tests that may accompany gonococcal perihepatitis.
Recurrent chlamydial infections are problematic because of the increased incidence of resulting tubal damage and subsequent infertility. Adolescents are at particularly high risk for recurrent chlamydial infection (27,28,29). In one study, adolescents younger than 15 years of age had an eightfold increased risk, those 15 to 19 years of age had a fivefold increased risk, and young adults 20 to 29 years had a twofold increased risk of recurrent C. trachomatis infection, compared to older women (28). Recurrence occurred in 54% of adolescents younger than 15 years and 30% of those 15 to 19 years old. A comprehensive analysis of data from 10 community-based health centers found a rate of recurrent C. trachomatis infections of 42.1 per 1000 person-months among nulliparous young women ages 14 to 19 years (30); median time to recurrence was 5.2 months. Over one-half (52.9%) of all chlamydial diagnoses were recurrent
infections. Although reinfection is the most common cause of repeat chlamydial infection in adolescent girls, treatment failure must also be considered. One study of adolescent girls found that 13.7% of repeat chlamydial infections were possible or probable treatment failures despite the use of an appropriate antibiotic regimen (31).
infections. Although reinfection is the most common cause of repeat chlamydial infection in adolescent girls, treatment failure must also be considered. One study of adolescent girls found that 13.7% of repeat chlamydial infections were possible or probable treatment failures despite the use of an appropriate antibiotic regimen (31).
C. trachomatis is an obligate intracellular parasite of primarily squamocolumnar epithelial cells. Serotypes D through K have been associated with inclusion conjunctivitis, pneumonia, and vaginitis, most commonly in infants; nongonococcal urethritis and epididymitis in men; and mucopurulent cervicitis, salpingitis, urethritis, endometritis, and perihepatitis in women. Both men and women may have conjunctivitis, reactive arthritis, and rectal infections. Cervical infection with C. trachomatis has been associated with spontaneous abortion, intrauterine infection of the fetus, premature rupture of membranes, preterm labor, low birth weight, stillbirth, and postabortion and postpartum endometritis (32,33). Chlamydial DNA or antigen is found in the fallopian tubes of a high percentage of women with tubal infertility (34). Current or past chlamydial infection may cause uterine inflammation that impairs embryo implantation or facilitates immune rejection after uterine transfer of in vitro–fertilized embryos (35).
Transmission of C. trachomatis occurs via direct contact with infective material. Men who become infected with non-LGV strains will generally develop nongonococcal urethritis 1 to 3 weeks after infection. Perinatal chlamydial infection involves mucous membranes of the eye, oropharynx, urogenital tract, and rectum, and may present with or without symptoms. C. trachomatis is the most frequently identified infectious cause of ophthalmia neonatorum, which typically develops 5 to 12 days after birth. C. trachomatis may also cause a subacute, afebrile pneumonia in infants ages 1 to 3 months.
Diagnosis
Female patients may be tested for C. trachomatis with nucleic acid amplification tests (NAATs), including polymerase chain reaction (PCR; Amplicor, Roche), transcription-mediated amplification (TMA; Aptima, Gen-Probe), and strand displacement amplification (SDA; BDProbeTec ET, Becton Dickinson); nonculture, non-NAATs, including direct immunofluorescent smears (DFA, MicroTrak), enzyme immunoassays (Chlamydiazyme, Abbott; IDEIA, Dako), and DNA probes (PACE 2, Gen-Probe; Hybrid Capture II, Digene); and culture (36). Whereas culture and nonculture, non-NAATs require specimens to be from the endocervix or the endourethra, NAATs can be performed on urine, vaginal, rectal, oropharyngeal, and ThinPrep Papanicolaou (Pap) specimens as well.
Because NAATs are more sensitive and specific than other test types (37,38,39,40), the CDC recommends their use for the detection of C. trachomatis infections in the reproductive tract of both men and women with and without symptoms (41). The preferred NAAT specimen type from females is a vaginal swab, which can be collected by the patient or the clinician. Vaginal swab specimens are at least as sensitive and specific as endocervical swab specimens (17,42,43,44,45,46,47), may be obtained whether or not a pelvic examination is being performed, and are cost effective for the prevention of PID (48). An endocervical swab specimen is an acceptable alternative (e.g., per patient preference or when a liquid cytology sample is being sent for both Pap and STI testing, although liquid cytology samples may be more likely to result in inhibition of amplification or contamination than other specimen types). Female urine specimens are also acceptable, but do not offer advantages over vaginal swab specimens and may be less sensitive than either vaginal or endocervical swabs (45,46). In several studies, both adolescent and adult women prefer self-collecting vaginal swabs or urine specimens over a clinician obtaining genital swabs during the pelvic examination (44,49,50,51).
PCR (Amplicor, Roche), TMA (Aptima GC/CT Combo 2 and Aptima CT, Gen-Probe), and SDA (BDProbeTec, Becton Dickinson) are all available for detecting C. trachomatis in both endocervical swabs and female urine specimens, and TMA and SDA may be used on vaginal swab specimens as well. The U.S. Food and Drug Administration (FDA) recently approved a second PCR (RealTime, Abbott) for the detection of C. trachomatis in endocervical swab, vaginal swab, and female urine specimens from symptomatic individuals, and vaginal swab and female urine from asymptomatic individuals. The ligase chain reaction (LCR) assay (LCx, Abbott) is no longer available. In a large study of women attending family planning, obstetric and gynecology, teen, and STI clinics, the sensitivities and specificities of TMA for C. trachomatis were 96.6% to 98.3% and 96.5% to 97.6%, respectively, for patient-collected vaginal swabs, and 96.7% to 97.2% and 95.2% to 97.1%, respectively, for clinician-collected vaginal swabs, using a reference standard of at least two positive NAATs (46). In this study, either patient-collected or clinician-collected vaginal swabs detected an equivalent number of infections as endocervical swabs and more infections than first-catch urine specimens (46). Compared to TMA, SDA is less sensitive for the detection of C. trachomatis in vaginal swabs (81.5%) (52). In clinical trials comparing real-time PCR to two commercially available NAATs, sensitivity was 92.5% to 94.7% and specificity was 99.0% to 99.8% for clinician- and patient-collected vaginal swabs obtained from symptomatic women (53).
Compared with culture, the sensitivity of the Amplicor PCR is 82.6% for endocervical swab specimens and 84.4% for urine specimens (54). When chlamydial infection is defined as a positive culture or two positive NAATs, the sensitivity and specificity of the Amplicor PCR on urine have been high, 97.1% and 99.8%, respectively (55). TMA is similarly highly sensitive and specific on endocervical and urine specimens (sensitivities, 91.4% to 100%; specificities 99.5% to 100% [55,56]). Compared to positive endocervical culture or two positive nonculture tests, the sensitivity and specificity of SDA was 92.8% and 98.8% in endocervical swabs and 80.5% and 98.4% in urine specimens, respectively (57). For the real-time PCR, the sensitivity and specificity in urine specimens from symptomatic women is high (92.6% and 99.5%, respectively) (53). Depending on the prevalence of C. trachomatis infection in the population under study and the reference standard being used, sensitivities of the NAATs may be lower than reported in the package inserts or in previous studies (17,42,43,44).
NAATs may also be used to test for rectal and pharyngeal chlamydial infections. Because rectal and pharyngeal specimens have not
been cleared by the FDA for testing with NAATs, laboratories need to establish performance specifications to comply with Clinical Laboratory Improvement Amendments of 1988 (CLIA) before reporting results (41). NAAT sensitivities for the detection of C. trachomatis from rectal swabs range from 91.4% to 100%, with specificities ranging from 88.8% to 98.5% (58). In studies of women attending STI clinics, 13% to 20% of chlamydial infections would have been missed if specimens had not been obtained from the rectum (58,59). However, little is known about the prevalence of rectal chlamydial infections in younger female patients, especially those not at high risk (receptive anal sex, infection with gonorrhea, sexually assaulted, anorectal symptoms). Proctitis may be seen in women as part of the anorectal syndrome of lymphogranuloma venereum, a chronic chlamydial infection that is seen primarily in Africa, Asia, and South America (60). In contrast to rectal chlamydial infections, pharyngeal infections with C. trachomatis appear to be relatively uncommon and unlikely to occur exclusive of coexisting genital chlamydial infection (61).
been cleared by the FDA for testing with NAATs, laboratories need to establish performance specifications to comply with Clinical Laboratory Improvement Amendments of 1988 (CLIA) before reporting results (41). NAAT sensitivities for the detection of C. trachomatis from rectal swabs range from 91.4% to 100%, with specificities ranging from 88.8% to 98.5% (58). In studies of women attending STI clinics, 13% to 20% of chlamydial infections would have been missed if specimens had not been obtained from the rectum (58,59). However, little is known about the prevalence of rectal chlamydial infections in younger female patients, especially those not at high risk (receptive anal sex, infection with gonorrhea, sexually assaulted, anorectal symptoms). Proctitis may be seen in women as part of the anorectal syndrome of lymphogranuloma venereum, a chronic chlamydial infection that is seen primarily in Africa, Asia, and South America (60). In contrast to rectal chlamydial infections, pharyngeal infections with C. trachomatis appear to be relatively uncommon and unlikely to occur exclusive of coexisting genital chlamydial infection (61).
Cell culture involves inoculation of McCoy cells and identification of characteristic intracytoplasmic inclusions with fluorescent antibody stain after 48 to 72 hours of growth. Care must be taken when cultures are obtained to use a Dacron swab and to scrape the endocervix to obtain cells as C. trachomatis is an intracellular organism. Compared to NAATs, culture is suboptimal for most testing situations because of its relatively low sensitivity (80% to 90% at best), difficulties associated with transport and laboratory technique, and relatively high cost. In addition, culture will not detect nonviable organisms of the lower genital tract even when viable organisms coexist in the upper genital tract. Although culture should not be used in routine clinical practice, some laboratories need to maintain the capability to perform C. trachomatis culture for research, evaluating rare types of chlamydial infections, diagnosis in children, and reference standards (41). Because NAATs are more sensitive than culture, have specificities approaching that of culture (100%), and may be performed on noninvasive specimens, the CDC is developing recommendations that recognize that NAATs as well as culture can be used for forensic purposes (41). Compared to culture, NAATs appear advantageous for use in children being evaluated for suspected sexual abuse (62). According to the 2010 CDC treatment guidelines (20), NAATs can be used to detect C. trachomatis in vaginal or urine specimens from girls being evaluated for STIs. Specimens should be kept for additional testing if necessary. Culture continues to be the preferred method for extragenital sites in these girls.
Regardless of the test used, a positive result for C. trachomatis must be considered a true positive and the patient treated appropriately. Although any tests for C. trachomatis, even culture in rare instances, can yield false-positive results, repeat confirmatory testing is no longer recommended following a positive NAAT result for C. trachomatis infection (41), except in prepubertal girls in whom sexual abuse is being considered (see Chapters 1, 4, and 30). It may be difficult to interpret a negative result on a second test (which may be wrong), laboratories often do not have additional assays with which to perform confirmatory testing, and it is costly to conduct additional testing without clear benefit to the patient or provider (41).
Reactive Arthritis
Reactive arthritis frequently follows genitourinary infection with C. trachomatis or N. gonorrhoeae, or enteric infection with Shigella, Salmonella, or Yersinia. Other STI pathogens such as mycoplasmas may also induce a reactive arthritis (80). The arthritis is accompanied by urethritis and ocular abnormalities, a triad previously referred to as Reiter syndrome. Evidence of chlamydial infection has been found in 42% to 69% of patients with this reactive arthritis syndrome (40). Reactive arthritis is associated with HLA-B27 and -B7 determinants. The joints affected are primarily knees, ankles, feet, and wrists in an oligo- or monoarticular pattern; sacroiliitis and spondyloarthropathies can also occur. Ocular problems include iritis and conjunctivitis. Dermatologic findings include keratosis blennorrhagica, mucocutaneous lesions, erosive vulvitis, nail changes, and oral ulcers. Treatment should aim at the detection and antimicrobial therapy of the genital infection and the use of nonsteroidal anti-inflammatory agents for the reactive arthritis. The eyes should be carefully monitored by an ophthalmologist and treated with topical and systemic agents as indicated (81).
Treatment
The following regimens are recommended for the treatment of C. trachomatis cervical and urethral infections in adolescent and adult women (20): azithromycin 1 g orally in a single dose or doxycycline 100 mg orally two times a day for 7 days. Alternate regimens include erythromycin base 500 mg four times a day for 7 days, erythromycin ethylsuccinate 800 mg four times a day for 7 days, ofloxacin 300 mg two times a day for 7 days, or levofloxacin 500 mg orally once a day for 7 days.
Azithromycin and doxycycline have similar efficacy and side effects, which are primarily gastrointestinal (82). In general, azithromycin is preferred for adolescents because it can be administered by a health professional in a single oral dose. Although azithromycin is more costly from the perspective of the public health clinic, for the third-party payer and for the health care system as a whole, it is more cost effective than doxycycline owing to improved compliance with the single dose and subsequent reduction in costly sequelae from infection (83). Erythromycin is less efficacious than either azithromycin or doxycycline and is often poorly tolerated due to gastrointestinal side effects. Ofloxacin has similar efficacy to azithromycin and doxycycline (84). Levofloxacin has similar pharmacology and in vitro microbiologic activity to ofloxacin and thus may be used for treatment of chlamydial infections, although it has not been fully evaluated (85). Other quinolones either do not adequately treat C. trachomatis or have not been fully evaluated. Quinolones are more expensive than the other alternative regimens and they cannot be used in pregnancy or lactation. Quinolones are no longer recommended for the treatment of gonococcal infections (86), so they cannot be used as a single-medication regimen for patients being treated for both C. trachomatis and N. gonorrhoeae.
Children should be treated with erythromycin 50 mg/kg/d in four divided doses for 14 days (children <45 kg and younger than 8 years), azithromycin 1 g orally in a single dose (children ≥45 kg and younger than 8 years, and children 8 years or older), or doxycycline 100 mg twice a day for 7 days (children 8 years or older) (20). Clindamycin is effective against C. trachomatis in vitro, results in clinical and bacteriologic cure, and may be used in pregnant women, but is significantly more costly than the recommended regimens (87).
Pregnant patients are treated with azithromycin 1 g orally in a single dose or amoxicillin 500 mg three times a day for 7 days (20). Alternative regimens include erythromycin base 500 mg four times a day for 7 days, erythromycin base 250 mg four times a day for 14 days, erythromycin ethylsuccinate 800 mg four times a day for 7 days, or erythromycin ethylsuccinate 400 mg four times daily for 14 days (20). Erythromycin estolate has been associated with hepatotoxicity and should not be used in pregnant women. If erythromycin is to be used, the lower-dose 14-day regimens
may be appropriate if there is concern that the patient may experience intolerable gastrointestinal side effects. Doxycycline and quinolones are contraindicated in pregnancy.
may be appropriate if there is concern that the patient may experience intolerable gastrointestinal side effects. Doxycycline and quinolones are contraindicated in pregnancy.
Patients being treated for chlamydial infection should be examined for other STIs and their sexual partner(s) should receive adequate diagnosis and treatment at the same visit. It is important to remember that C. trachomatis can remain asymptomatic in the cervix for months and probably years (88,89), and pinpointing the source can be problematic in some adolescents. Thus, the recommendation is to evaluate and treat partners within 60 days of the onset of symptoms or identification of the infection in the asymptomatic patient. If the last sexual intercourse was more than 60 days previously, the last partner should be assessed and treated. Patients and their partners should abstain from intercourse until they have all completed the treatment course (7 days after single-dose azithromycin or after completing a 7- or 14-day multidose regimen) and are without symptoms. As for all STIs, patients should be thoroughly counseled about practicing abstinence, limiting the number of sexual partners, avoiding concurrent sexual relationships, and using condoms.
When it is challenging to evaluate and counsel partners directly or through referral to an appropriate site of care, the CDC, the Society for Adolescent Health and Medicine, and the American Academy of Pediatrics recommend considering expedited partner therapy (EPT) to increase the likelihood that partners of patients infected with gonorrhea and/or chlamydia will be treated (20,90,91). In the most common form of EPT, patient-delivered partner therapy (PDPT), infected patients provide their partners with medications or prescriptions without the partners being evaluated or counseled by a health care provider. Adolescent and young adult women prefer PDPT to partner notification and referral (92). Compared to partner referral, PDPT is associated with a similar or greater reduction in recurrent infection with gonorrhea or chlamydia (93,94). Patient-delivered medications and prescriptions should be given along with clear instructions and warnings about taking medications in pregnancy, advice to be evaluated medically, and counseling regarding safer sex behaviors. Although EPT is explicitly permitted or potentially allowed in most of the United States, there remains uncertainty about the legal status of EPT in some jurisdictions (95). More information on state-specific legality of the practice is available at http://www.cdc.gov/std/ept/legal (96).
Because of the high risk of reexposure to an untreated partner or exposure to a new infected partner, the possibility of nonadherence, the risk of persistent chlamydial infection despite treatment (31,89), and the substantial morbidity associated with chlamydial infection in young women, clinicians should retest infected adolescents approximately 3 months after treatment (97). In addition, it is prudent to test all women treated for infection with C. trachomatis whenever they present for medical care over the ensuing 3 to 12 months (97). In general, nonpregnant patients treated for chlamydial infection with azithromycin, doxycycline, or a quinolone do not need a test of cure. A test of cure may be considered 3 weeks after completing a course of erythromycin because poor adherence to the dosing schedule and gastrointestinal side effects may impede receipt of the full course of treatment. Repeat testing 3 weeks after completing treatment should also be considered in patients with persistent or recurrent symptoms and/or suspected reexposure. In addition, repeat testing 3 weeks after completing treatment should be performed in all pregnant patients owing to serious sequelae of persistent chlamydia infection in pregnant women and neonates. NAATs are the preferred test type for test-of-cure and rescreening purposes, but if performed less than 3 weeks after completing treatment, NAATs may give false-positive results due to continued excretion of dead organisms. Retesting with nonamplified tests may yield false-negative results in cases of persistent infection with low numbers of chlamydial organisms.
Gonococcal Infections
Following implementation of a national program in the mid-1970s to reduce gonococcal disease, the annual estimated number of infections with N. gonorrhoeae declined from over 1 million in 1976 to 1980 (442 to 456 cases per 100,000) to 327,665 in 1997 (120.2 cases per 100,000) (2). However, further declines in the reported rates of gonococcal infections have been small; 336,742 cases were reported in 2008, a rate of 111.6 cases per 100,000 (2). Adolescent and young adult women continue to have higher rates of gonorrhea than any other sex–age group (636.8 cases per 100,000 for women 15 to 19 years and 608.6 per 100,000 for women 20 to 24 years) (2). Gonorrhea disproportionately affects African Americans, independent of socioeconomic status (98); young, African American women therefore have the highest gonorrhea rates of any group (2,934.6 per 100,000 15- to 19-year-old black women, followed by 2,777.0 per 100,000 20- to 24-year-old black women) (2).
The incubation period for N. gonorrhoeae is approximately 1 week, with symptoms generally appearing within 10 days after exposure (99,100). Although it has been estimated that 75% to 90% of all gonococcal infections in women and 10% to 40% of infections in men are asymptomatic (99), on careful questioning, many of these patients do, in fact, have symptoms. Screening endocervical tests indicate that the asymptomatic rate of gonorrhea ranges from 0% to 13% in adolescent women, depending on the clinical setting. Adolescents seen in private practices in the suburbs (9) and older high school students (14) tend to have lower rates than middle adolescents in inner city schools (16), pregnant teens (11), or adolescents entering a juvenile detention facility (101) (Table 18-1). Risk markers (variables that are associated with infection but not in the causal pathway) for gonorrhea include a history of sexual abuse; sexual behaviors such as early onset of sexual intercourse, high numbers of casual partners, selection of partners at high risk of gonorrhea, and “survival sex” (sex for food, money, drugs, or shelter); and health behaviors such as failure to recognize symptoms, delay in seeking treatment, delay in notifying partners, nonuse of barrier contraception, and noncompliance with therapy (102,103,104).
The USPSTF and the CDC recommend gonorrhea screening for all young sexually active women at increased risk for infection (e.g., history of gonococcal infection, other STIs, new or multiple partners, inconsistent condom use, commercial sex work, drug use, residence in a community with a high prevalence of gonorrhea) (20,105,106). The optimal interval for gonorrhea screening in nonpregnant young women is not known (106) and consistent recommendations do not exist (107). Screening for gonorrhea among sexually active women at low risk for infection is not recommended.
Diagnosis
As for C. trachomatis, NAATs are preferred for the detection of N. gonorrhoeae genital infections in both symptomatic and
asymptomatic women (41). Currently, PCR (Amplicor, Roche; RealTime, Abbott), TMA (Aptima, Gen-Probe, Inc.), and SDA (BDProbeTec ET, Becton Dickinson) are available for testing of endocervical swabs; RealTime PCR, TMA, and SDA assays may be performed with female urine specimens; and RealTime PCR and TMA are FDA approved for detecting gonorrhea on vaginal swabs, the preferred specimen type for both screening and diagnostic testing (41). Because the sensitivity is unacceptably low, Amplicor PCR for gonorrhea on female urine specimens is not FDA approved and the LCR test (LCx, Abbott) for gonorrhea is no longer available for use with any specimen type (108).
asymptomatic women (41). Currently, PCR (Amplicor, Roche; RealTime, Abbott), TMA (Aptima, Gen-Probe, Inc.), and SDA (BDProbeTec ET, Becton Dickinson) are available for testing of endocervical swabs; RealTime PCR, TMA, and SDA assays may be performed with female urine specimens; and RealTime PCR and TMA are FDA approved for detecting gonorrhea on vaginal swabs, the preferred specimen type for both screening and diagnostic testing (41). Because the sensitivity is unacceptably low, Amplicor PCR for gonorrhea on female urine specimens is not FDA approved and the LCR test (LCx, Abbott) for gonorrhea is no longer available for use with any specimen type (108).
Specimens, especially of urine, can contain amplification inhibitors that result in false-negative results on NAATs (109,110). False-positive results may occur because of contamination or because the primers used with some NAATs for N. gonorrhoeae may cross-react with nongonococcal Neisseria species (109,111). In general, repeat testing of NAAT results positive for gonorrhea is not recommended because it does not improve the positive predictive value of the test, may yield falsely negative results, and incurs unnecessary costs (41,112). However, if it is known that a particular assay has clinical reactivity with nongonococcal Neisseria species, repeat testing of a positive specimen with a different NAAT is warranted, especially in cases of alleged rape or childhood sexual abuse (41,62).
NAATs perform better than other tests for detection of gonorrhea in the rectum and the pharynx; the exception is PCR, which has demonstrated suboptimal specificity for the detection of gonorrhea in the pharynx (121). Pharyngeal swab specimens should be tested using a NAAT that has demonstrated minimal cross-reactivity with nongonococcal Neisseria species. Because the FDA has not approved NAATs for use with rectal or pharyngeal specimens, laboratories must meet performance specifications in compliance with CLIA before results can be reported for patient care (41).
N. gonorrhoeae, a fastidious gram-negative intracellular diplococcus, may be cultured using a selective (e.g., Thayer-Martin or Martin-Lewis) or nonselective (e.g., chocolate agar) medium. Specimens for culture must be transported under anaerobic conditions to maintain the viability of organisms. Although culture is no longer recommended for routine gonorrhea testing, some reference laboratories will need to continue to evaluate gonorrhea cultures to monitor trends in resistance to antimicrobial treatment. Culture and antimicrobial susceptibility testing is recommended in cases of suspected or documented treatment failure (20) and for surveillance.
There is currently no adequate point-of-care test for gonorrhea. Gram stains of endocervical specimens are not recommended for testing for N. gonorrhoeae infection among women because the sensitivity is low (99,122,123) and skilled microscopy must be performed to ensure adequate specificity (77). Gram stains of pharyngeal specimens are not recommended because the pharynx can be colonized with N. meningitidis and commensal Neisseria species (124).
Urogenital Gonococcal Infection
The endocervix is the primary site of urogenital gonococcal infection. In 70% to 90% of cases, the urethra is also infected. Patients with urogenital gonococcal infection may be asymptomatic or they may present with vaginal discharge, dysuria, urinary frequency, dyspareunia, irregular or heavy vaginal bleeding, and/or suprapubic pain. On examination, the cervix may appear normal or it may be friable and tender to palpation with a purulent discharge. Purulent exudate may be expressed from the urethra, periurethral (Skene) glands, or Bartholin gland ducts. Labial pain and swelling may be present with a Bartholin gland abscess (see Fig. 18-1), which is usually treated with incision and drainage using a Ward catheter. Marsupialization may be necessary for recurrent infections. Treatment for gonorrhea can be instituted on the basis of symptoms and risk for infection, although the diagnosis should be confirmed by with a positive NAAT result. Although the urethra, Skene glands, and Bartholin gland ducts are frequently also infected, they are rarely the only site of infection and therefore do not need to be tested (99).
 Figure 18-1. Bartholin gland abscess. |
Treatment of Asymptomatic Infections, Contacts, Urethritis, and Cervicitis
Treatment of N. gonorrhoeae must take into account the sites infected, the prevalence of antibiotic resistance, the high rate of coexisting C. trachomatis infections in adolescents, allergies, pregnancy, and the likelihood of compliance. Important variations currently identified in the United States are plasmid-mediated penicillin resistance (β-lactamase–producing N. gonorrhoeae), plasmid-mediated tetracycline resistance, and chromosomally mediated resistance to penicillin or tetracycline (125). Quinolone resistance, established in Asia and the Pacific, has emerged across the United States, first among men who have sex with men (125,126,127,128), and then among heterosexual men. In 2007, based on data from the Gonococcal Isolate Surveillance Project (GISP) demonstrating quinolone resistance in more than 5% of gonococcal isolates from nearly all GISP sites, the CDC recommended that quinolones no longer be used for treatment of gonococcal infections and associated conditions (e.g., PID) (129). As a result, the options for treatment of gonorrhea are limited to one class of antibiotics, the cephalosporins. Resistance to ceftriaxone is rare (20,130) but increasing. Clinicians
treating patients with suspected or documented cephalosporin treatment failure should perform N. gonorrhoeae culture and susceptibility testing, consult a specialist for guidance on management, and report the case to the CDC through their state and local public health departments. Notification and treatment of partners of these patients should be a public health priority.
treating patients with suspected or documented cephalosporin treatment failure should perform N. gonorrhoeae culture and susceptibility testing, consult a specialist for guidance on management, and report the case to the CDC through their state and local public health departments. Notification and treatment of partners of these patients should be a public health priority.
The CDC recommends that one of the following regimens be used for treatment of uncomplicated urogenital gonococcal infection (20): ceftriaxone 250 mg intramuscularly (IM) single dose or, if not an option, cefixime 400 mg orally in a single dose or 400 mg by suspension (200 mg/5 mL) plus treatment for C. trachomatis. Note that there are three key revisions to previous gonorrhea treatment recommendations. First, the dose of ceftriaxone is now 250 mg, not 125 mg. The rationale for this recommendation includes the increasingly widespread distribution of isolates with decreased susceptibility to cephalosporins in vitro, reports of ceftriaxone treatment failures, the increased efficacy of the 250-mg dose in pharyngeal infection (which often goes unrecognized), and the value of having a single dosing recommendation for treatment regardless of the anatomic site of infection (20). Second, a preference for ceftriaxone is asserted over cefixime. Cefixime 400 mg orally does not provide as high or as sustained a bactericidal level as ceftriaxone 250 mg intramuscularly, and is less efficacious against pharyngeal infection (92.3%, 95% confidence interval [CI]: 74.9% to 99.1%). Third, routine treatment for chlamydial infection is recommended when treatment for gonococcal infection is being provided (20). Patients with N. gonorrhoeae are frequently also infected with C. trachomatis, especially those of a young age (131). In addition, most N. gonorrhoeae are susceptible to the preferred chlamydial treatment regimens (doxycycline and azithromycin), so routine cotreatment may limit the development of antimicrobial resistance (132). Finally, there is some evidence that azithromycin may augment the efficacy of oral cephalosporins in the treatment of pharyngeal infection (133).
Ceftriaxone can be mixed with 1% lidocaine (without epinephrine) to reduce patient discomfort with the injection (134). History and nature of allergy to penicillin and cephalo-sporins should be obtained before initiating treatment. Fortunately, the cross-reactivity between third-generation cepha-losporins and penicillin is rare. Cefpodoxime 400 mg may be an appropriate oral alternative for uncomplicated urogenital but not pharyngeal infections (135). Cefuroxime axetil 1 g orally may be efficacious against uncomplicated urogenital and rectal infections, but has less favorable pharmacodynamics compared to cefpodoxime and is not efficacious against pharyngeal infections (20). Intramuscular spectinomycin is effective for uncomplicated urogenital and rectal gonococcal infections, but it is expensive, has low efficacy against pharyngeal infection, and is no longer available in the United States (136). Although a single oral dose of azithromycin 2 g has an efficacy of 99.2% for urogenital infections and 100% for pharyngeal infection, it is not recommended because the dose is costly and poorly tolerated. Azithromycin 1 g alone is also efficacious against gonorrhea but it is not recommended because there have been documented treatment failures. In addition, regardless of dose, azithromycin should be used sparingly because N. gonorrhoeae readily develops resistance to macrolides (137).
A serologic test for syphilis should be sent at the time of therapy. If the initial test result is negative, a follow-up blood test 1 month later may be considered if the patient was treated with spectinomycin or a quinolone. HIV counseling and availability of testing as well as individual counseling about risk reduction and “safer sex” are important parts of care. Patients are instructed to abstain from sexual relations for 7 days. Since treatment failure is rare with the recommended regimens, test-of-cure is not necessary. However, a rescreening test for gonorrhea done 3 to 4 months after treatment allows the opportunity to test for reinfection. Among teens with an N. gonorrhoeae infection in our clinics, 23% developed one or more additional infections with N. gonorrhoeae and 19% developed a chlamydial infection in the ensuing 8 to 14 months of follow-up (138). Persistent symptoms also call for culturing and conducting susceptibility testing of any identified N. gonorrhoeae isolates.
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