Diseases Characterized by Urethritis and Cervicitis

Urethritis

Urethritis, as characterized by urethral inflammation, can result from infectious and noninfectious conditions. Symptoms, if present, include discharge of mucopurulent or purulent material, dysuria, or urethral pruritis. Asymptomatic infections are common. Although N. gonorrhoeae and C. trachomatis are well established as clinically important infectious causes of urethritis, Mycoplasma genitalium has also been associated with urethritis (240-243). If clinic-based diagnostic tools (e.g., Gram-stain microscopy, first void urine with microscopy, and leukocyte esterase) are not available, patients should be treated with drug regimens effective against both gonorrhea and chlamydia. Further testing to determine the specific etiology is recommended because both chlamydia and gonorrhea are reportable to health departments and a specific diagnosis might improve partner notification and treatment. Culture, nucleic acid hybridization tests, and NAATs are available for the detection of both N. gonorrhoeae and C. trachomatis. Culture and hybridization tests require urethral swab specimens, whereas NAATs can be performed on urine specimens. Because of their higher sensitivity, NAATs are preferred for the detection of C. trachomatis (197).

Etiology

Several organisms can cause infectious urethritis. The presence of Gram-negative intracellular diplococci (GNID) on urethral smear is indicative of gonorrhea infection, which is frequently accompanied by chlamydial infection. Nongonoccocal urethritis (NGU), which is diagnosed when examination findings or microscopy indicate inflammation without GNID, is caused by C. trachomatis in 15%–40% of cases; however, prevalence varies by age group, with a lower burden of disease occurring among older men (244). Complications of NGU among males infected with C. trachomatis include epididymitis and Reiter’s syndrome. Documentation of chlamydial infection is essential because of the need for partner referral for evaluation and treatment.

In most cases of nonchlamydial NGU, no pathogen can be detected. M. genitalium, which appears to be sexually transmitted, is associated with both symptoms of urethritis and urethral inflammation and accounts for 15%–25% of NGU cases in the United States (240-243). T. vaginalis, HSV, and adenovirus also can cause NGU, but data supporting other Mycoplasma species and Ureaplasma as etiologic agents are inconsistent (244-247). Diagnostic and treatment procedures for these organisms are reserved for situations in which these infections are suspected (e.g., contact with trichomoniasis, genital lesions, or severe dysuria and meatitis, which might suggest genital herpes) or when NGU is not responsive to therapy. Enteric bacteria have been identified as an uncommon cause of NGU and might be associated with insertive anal intercourse (244).

Confirmed Urethritis

Clinicians should attempt to obtain objective evidence of urethral inflammation. However, if clinic-based diagnostic tools (e.g., Gram-stain microscopy) are not available, patients should be treated with drug regimens effective against both gonorrhea and chlamydia.

Urethritis can be documented on the basis of any of the following signs or laboratory tests:

• Mucopurulent or purulent discharge on examination.
• Gram stain of urethral secretions demonstrating ≥5 WBC per oil immersion field. The Gram stain is the preferred rapid diagnostic test for evaluating urethritis and is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection. Gonococcal infection is established by documenting the presence of WBC containing GNID.

TABLE 1. Oral desensitization protocol for patients with a positive skin test*

Note: Observation period was 30 minutes before parenteral administration of penicillin.
* Reprinted with permission from the New England Journal of Medicine (Wendel GO, Jr, Stark BJ, Jamison RB, Melina RD, Sullivan TJ. Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med 1985;312:1229–32.).
† Interval between doses, 15–30 minutes; elapsed time, 4–8 hours; cumulative dose, 1.3 million units.
§ The specific amount of drug was diluted in approximately 30 mL of water and then administered orally.

• Positive leukocyte esterase test on first-void urine or microscopic examination of first-void urine sediment demonstrating ≥10 WBC per high-power field.

If none of these criteria are present, testing for N. gonorrhoeae and C. trachomatis using NAATs might identify additional infections (248). If the results demonstrate infection with either of these pathogens, the appropriate treatment should be given and sex partners referred for evaluation and treatment. If none of these criteria are present, empiric treatment of symptomatic males is recommended only for men at high risk for infection who are unlikely to return for a follow-up evaluation. Such patients should be treated with drug regimens effective against gonorrhea and chlamydia. Partners of patients treated empirically should be evaluated and treated, if indicated.

Nongonococcal Urethritis

Diagnosis

All patients who have confirmed or suspected urethritis should be tested for gonorrhea and chlamydia. Testing for chlamydia is strongly recommended because of the increased utility and availability of highly sensitive and specific testing methods (e.g., NAATs) and because a specific diagnosis might enhance partner notification and improve compliance with treatment, especially in the exposed partner.

Treatment

Treatment should be initiated as soon as possible after diagnosis. Azithromycin and doxycycline are highly effective for chlamydial urethritis; however, infections with M. genitalium respond better to azithromycin (249,250). Single-dose regimens have the advantage of improved compliance and directly observed treatment. To maximize compliance with recommended therapies, medications should be dispensed on-site in the clinic, and the first dose should be directly observed.

To minimize transmission, men treated for NGU should be instructed to abstain from sexual intercourse for 7 days after single-dose therapy or until completion of a 7-day regimen, provided their symptoms have resolved. To minimize the risk for reinfection, men should be instructed to abstain from sexual intercourse until all of their sex partners are treated.

Persons who have been diagnosed with a new STD should receive testing for other infections, including syphilis and HIV.

Follow-Up

Patients should be instructed to return for evaluation if symptoms persist or recur after completion of therapy. Symptoms alone, without documentation of signs or laboratory evidence of urethral inflammation, are not a sufficient basis for retreatment. Providers should be alert to the possibility of chronic prostatitis/chronic pelvic pain syndrome in male patients experiencing persistent pain (perineal, penile, or pelvic), discomfort, irritative voiding symptoms, pain during or after ejaculation, or new-onset premature ejaculation lasting for >3 months.

Unless a patient’s symptoms persist or therapeutic noncompliance or reinfection is suspected by the provider, a test-of-cure (i.e., repeat testing 3–4 weeks after completing therapy) is not recommended for persons with documented chlamydia or gonococcal infections who have received treatment with recommended or alterative regimens. However, because men with documented chlamydial or gonococcal infections have a high rate of reinfection within 6 months after treatment (251,252), repeat testing of all men diagnosed with chlamydia or gonorrhea is recommended 3–6 months after treatment, regardless of whether patients believe that their sex partners were treated (251).

Partner Referral

A specific diagnosis might facilitate partner referral. Therefore, testing for gonorrhea and chlamydia is encouraged. Because a substantial proportion of female partners of males with nonchlamydial NGU are infected with chlamydia, partner management is recommended for males with NGU regardless of whether a specific etiology is identified. All sex partners within the preceding 60 days should be referred for evaluation, testing, and empiric treatment with a drug regimen effective against chlamydia. Expedited partner treatment and patient referral are alternative approaches to treating partners (71).

Recurrent and Persistent Urethritis

Objective signs of urethritis should be present before the initiation of antimicrobial therapy. In persons who have persistent symptoms after treatment without objective signs of urethritis, the value of extending the duration of antimicrobials has not been demonstrated. Persons who have persistent or recurrent urethritis can be retreated with the initial regimen if they did not comply with the treatment regimen or if they were reexposed to an untreated sex partner. Persistent urethritis after doxycycline treatment might be caused by doxycycline-resistant U. urealyticum or M. genitalium. T. vaginalis is also known to cause urethritis in men; a urethral swab, first void urine, or semen for culture or a NAAT (PCR or TMA) on a urethral swab or urine can be performed. If compliant with the initial regimen and re-exposure can be excluded, the following regimen is recommended while awaiting the results of the diagnostic tests.

Studies involving a limited number of patients who experienced NGU treatment failures have demonstrated that Moxifloxacin 400 mg orally once daily for 7 days is highly effective against M. genitalium (253,254). Men with a low probability of T. vaginalis (e.g., MSM) are unlikely to benefit from the addition of metronidazole or tinidazole.

Urologic examinations usually do not reveal a specific etiology for urethritis. A four-glass Meares-Stamey lower-urinary-tract localization procedure (or four-glass test) might be helpful in localizing pathogens to the prostate (255). A substantial proportion of men with chronic nonbacterial prostatitis/chronic pelvic pain syndrome have evidence of urethral inflammation without any identifiable microbial pathogens. Estimates vary considerably depending on the source and sensitivity of the assay, but one study demonstrated that in 50% of men with this syndrome, ≥5 WBCs per high-power field were detected in expressed prostatic secretions (256). Referral to a urologist should be considered for men who experience pain for more than 3 months within a 6-month period.

If men require treatment with a new antibiotic regimen for persistent urethritis and a sexually transmitted agent is the suspected cause, all partners in the past 60 days before the initial diagnosis and any interim partners should be referred for evaluation and appropriate treatment.

Special Considerations

HIV Infection

Gonococcal urethritis, chlamydial urethritis, and nongonococcal, nonchlamydial urethritis might facilitate HIV transmission. Patients who have NGU and also are infected with HIV should receive the same treatment regimen as those who are HIV negative.

Cervicitis

Two major diagnostic signs characterize cervicitis: 1) a purulent or mucopurulent endocervical exudate visible in the endocervical canal or on an endocervical swab specimen (commonly referred to as mucopurulent cervicitis or cervicitis) and 2) sustained endocervical bleeding easily induced by gentle passage of a cotton swab through the cervical os. Either or both signs might be present. Cervicitis frequently is asymptomatic, but some women complain of an abnormal vaginal discharge and intermenstrual vaginal bleeding (e.g., after sexual intercourse). A finding of leukorrhea (>10 WBC per high-power field on microscopic examination of vaginal fluid) has been associated with chlamydial and gonococcal infection of the cervix. In the absence of inflammatory vaginitis, leukorrhea might be a sensitive indicator of cervical inflammation with a high negative predictive value (257,258). Although some specialists consider an increased number of polymorphonuclear leukocytes on endocervical Gram stain as being useful in the diagnosis of cervicitis, this criterion has not been standardized. In addition, it has a low positive-predictive value (PPV) for infection with C. trachomatis and N. gonorrhoeae and is not available in most clinical settings. Finally, although the presence of GNID on Gram stain of endocervical fluid is specific for the diagnosis of gonococcal cervical infection, it is not a sensitive indicator, because it is observed in only 50% of women with this infection.

Etiology

When an etiologic organism is isolated in the presence of cervicitis, it is typically C. trachomatis or N. gonorrhoeae. Cervicitis also can accompany trichomoniasis and genital herpes (especially primary HSV-2 infection). However, in most cases of cervicitis, no organism is isolated, especially in women at relatively low risk for recent acquisition of these STDs (e.g., women aged >30 years). Limited data indicate that infection with M. genitalium and BV and frequent douching might cause cervicitis (259-263). For reasons that are unclear, cervicitis can persist despite repeated courses of antimicrobial therapy. Because most persistent cases of cervicitis are not caused by relapse or reinfection with C. trachomatis or N. gonorrhoeae, other factors (e.g., persistent abnormality of vaginal flora, douching [or exposure to other types of chemical irritants], or idiopathic inflammation in the zone of ectopy) might be involved.

Diagnosis

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

As discussed, NAAT should be used for diagnosing C. trachomatis and N. gonorrhoeae in women with cervicitis; this testing can be performed on either vaginal, cervical, or urine samples (197). A finding of >10 WBC in vaginal fluid, in the absence of trichomoniasis, might indicate endocervical inflammation caused specifically by C. trachomatis or N. gonorrhoeae (264,265).

Treatment

Several factors should affect the decision to provide presumptive therapy for cervicitis or to await the results of diagnostic tests. Treatment with antibiotics for C. trachomatis should be provided for those women at increased risk for this common STD (e.g., those aged ≤25 years, those with new or multiple sex partners, and those who engage in unprotected sex), especially if follow-up cannot be ensured and if a relatively insensitive diagnostic test is used in place of NAAT. Concurrent therapy for N. gonorrhoeae is indicated if the prevalence of this infection is >5% (those in younger age groups and those living in certain facilities).

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

Recurrent and Persistent Cervicitis

Women with persistent cervicitis should be reevaluated for possible reexposure to an STD. If relapse and/or reinfection with a specific STD has been excluded, BV is not present, and sex partners have been evaluated and treated, management options for persistent cervicitis are undefined; in addition, the utility of repeated or prolonged administration of antibiotic therapy for persistent symptomatic cervicitis remains unknown. Women who receive such therapy should return after treatment so that a determination can be made regarding whether cervicitis has resolved. Research is needed on the etiology of persistent cervicitis including the potential role of M. genitalium (266). In women with persistent symptoms that are clearly attributable to cervicitis, referral to a gynecologic specialist can be considered.

Follow-Up

Follow-up should be conducted as recommended for the infections for which a woman is treated. If symptoms persist, women should be instructed to return for re-evaluation because women with documented chlamydial or gonococcal infections have a high rate of reinfection within 6 months after treatment. Therefore, repeat testing of all women with chlamydia or gonorrhea is recommended 3-6 months after treatment, regardless of whether their sex partners were treated (267).

Management of Sex Partners

Management of sex partners of women treated for cervicitis should be appropriate for the identified or suspected STD. Partners should be notified and examined if chlamydia, gonorrhea, or trichomoniasis was identified or suspected in the index patient; these partners should then be treated for the STDs for which the index patient received treatment. To avoid reinfection, patients and their sex partners should abstain from sexual intercourse until therapy is completed (i.e., 7 days after a single-dose regimen or after completion of a 7-day regimen). Expedited partner treatment and patient referral (see Partner Management) are alternative approaches to treating male partners of women that have chlamydia or gonococcal infections (68,69,71).

Special Considerations

HIV Infection

Patients who have cervicitis and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. Treatment of cervicitis in HIV-infected women is vital because cervicitis increases cervical HIV shedding. Treatment of cervicitis in HIV-infected women reduces HIV shedding from the cervix and might reduce HIV transmission to susceptible sex partners (268-270).

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