Diseases Characterized by Urethritis and Cervicitis

Urethritis

Urethritis, as characterized by urethral inflammation, can result from infectious and noninfectious conditions. Symptoms, if present, include dysuria; urethral pruritis; and mucoid, mucopurulent, or purulent discharge. Signs of urethral discharge on examination can also be present in persons without symptoms. Although N. gonorrhoeae and C. trachomatis are well established as clinically important infectious causes of urethritis, Mycoplasma genitalium has also been associated with urethritis and, less commonly, prostatitis (470-474). If point-of-care diagnostic tools (e.g., Gram, methylene blue [MB] or gentian violet [GV] stain microscopy, first void urine with microscopy, and leukocyte esterase) are not available, drug regimens effective against both gonorrhea and chlamydia should be administered. Further testing to determine the specific etiology is recommended to prevent complications, re-infection, and transmission because a specific diagnosis might improve treatment compliance, delivery of risk reduction interventions, and partner notification. Both chlamydia and gonorrhea are reportable to health departments. NAATs are preferred for the detection of C. trachomatis and N. gonorrhoeae, and urine is the preferred specimen in males (394). NAAT-based tests for the diagnosis of T. vaginalis in men have not been cleared by FDA; however, some laboratories have performed the CLIA-compliant validation studies (475) needed to provide such testing.

Etiology

Several organisms can cause infectious urethritis. The presence of Gram-negative intracellular diplococci (GNID) or MB/GV purple intracellular diplococci on urethral smear is indicative of presumed gonorrhea infection, which is frequently accompanied by chlamydial infection. NGU, which is diagnosed when microscopy of urethral secretions indicates inflammation without GNID or MB/GV purple intracellular diplococci, 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 (476). Documentation of chlamydial infection as the etiology of NGU is essential because of the need for partner referral for evaluation and treatment to prevent complications of chlamydia, especially in female partners. Complications of C. trachomatis-associated NGU among males include epididymitis, prostatitis, and reactive arthritis.

M. genitalium, which can be sexually transmitted, is associated with symptoms of urethritis as well as urethral inflammation and accounts for 15%–25% of NGU cases in the United States (470-473). However, FDA-cleared diagnostic tests for M. genitalium are not available.

T. vaginalis can cause NGU in heterosexual men, but the prevalence varies substantially by region of the United States and within specific subpopulations. In some instances, NGU can be acquired by fellatio (i.e., oral penile contact), sometimes because of specific pathogens such as HSV, Epstein Barr Virus, and adenovirus (476); data supporting other Mycoplasma species and Ureaplasma as etiologic agents are inconsistent. Diagnostic and treatment procedures for these organisms are reserved for situations in which these infections are suspected (e.g., contact with trichomoniasis, urethral lesions, or severe dysuria and meatitis, which might suggest genital herpes) or when NGU is not responsive to recommended therapy. Enteric bacteria have been identified as an uncommon cause of NGU and might be associated with insertive anal intercourse (476). The importance of NGU not caused by defined pathogens is uncertain; neither complications (e.g., urethral stricture and epididymitis) nor adverse outcomes in sex partners have been identified in these cases.

Diagnostic Considerations

Clinicians should attempt to obtain objective evidence of urethral inflammation. However, if point-of-care diagnostic tests (e.g., Gram, MB or GV, or Gram stain microscopy) are not available, all men should be tested by NAAT and treated with drug regimens effective against both gonorrhea and chlamydia.

In the setting of compatible symptoms, urethritis can be documented on the basis of any of the following signs or laboratory tests:

  • Mucoid, mucopurulent, or purulent discharge on examination.
  • Gram stain of urethral secretions demonstrating ≥2 WBC per oil immersion field (477). The Gram stain is a point-of-care diagnostic test for evaluating urethritis that is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection. MB/GV stain of urethral secretions is an alternative point-of-care diagnostic test with performance characteristics similar to Gram stain; thus, the cutoff number for WBC per oil immersion field should be the same (478). Presumed gonococcal infection is established by documenting the presence of WBC containing GNID in Gram stain or intracellular purple diplococci in MB/GV smears; men should be presumptively treated and managed accordingly for gonorrhea (GC) infection (see Gonococcal Infections).
  • Positive leukocyte esterase test on first-void urine or microscopic examination of sediment from a spun first-void urine demonstrating ≥10 WBC per high power field.

In settings where Gram stain or MB/GV smear is available, men who meet criteria for urethritis (microscopy of urethral secretions with >2 WBC per oil immersion field and no intracellular gram negative or purple diplococci) should receive NAAT testing for C. trachomatis and N. gonorrhoeae and can be managed as recommended (see Nongonococcal Urethritis). Men evaluated in settings in which Gram stain or MB/GV smear is not available (i.e., gonococcal infection cannot be ruled out at the point of care) who meet at least one criterion for urethritis (i.e., urethral discharge, positive LE test on first void urine, or microscopic exam of first void urine sediment with > 10 WBC per hpf) should be tested by NAAT and treated with regimens effective against gonorrhea and chlamydia.

If symptoms are present but no evidence of urethral inflammation is present, NAAT testing for C. trachomatis and N. gonorrhoeae might identify infections (479). If the results demonstrate infection with these pathogens, the appropriate treatment should be given and sex partners referred for evaluation and treatment. If none of these clinical criteria are present, empiric treatment of symptomatic men is recommended only for those men at high risk for infection who are unlikely to return for a follow-up evaluation or test results. Such men should be treated with drug regimens effective against gonorrhea and chlamydia.

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Nongonococcal Urethritis

Diagnostic Considerations

NGU is a nonspecific diagnosis that can have many infectious etiologies. NGU is confirmed in symptomatic men when staining of urethral secretions indicates inflammation without Gram negative or purple diplococci. All men who have confirmed NGU should be tested for chlamydia and gonorrhea even if point-of-care tests are negative for evidence of GC. NAATs for chlamydia and gonorrhea are recommended because of their high sensitivity and specificity; a specific diagnosis can potentially reduce complications, re-infection, and transmission (394). Testing for T. vaginalis should be considered in areas or populations of high prevalence.

Treatment

Presumptive treatment should be initiated at the time of NGU diagnosis. Azithromycin and doxycycline are highly effective for chlamydial urethritis. NGU associated with M. genitalium currently responds better to azithromycin than doxycycline, although azithromycin efficacy might be declining (See Mycoplasma genitalium).

Recommended Regimens
  • Azithromycin 1 g orally in a single dose
    OR
  • Doxycycline 100 mg orally twice a day for 7 days
Alternative Regimens
  • Erythromycin base 500 mg orally four times a day for 7 days
    OR
  • Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days
    OR
  • Levofloxacin 500 mg orally once daily for 7 days
    OR
  • Ofloxacin 300 mg orally twice a day for 7 days

As a directly observed treatment, single-dose regimens might be associated with higher rates of compliance over other regimens. To maximize compliance with recommended therapies, medications should be dispensed onsite in the clinic, and regardless of the number of doses involved in the regimen, the first should be directly observed.

Other Management Considerations

To minimize transmission and reinfection, men treated for NGU should be instructed to abstain from sexual intercourse until they and their partner(s) have been adequately treated (i.e., for 7 days after single-dose therapy or until completion of a 7-day regimen and symptoms resolved). Men who receive a diagnosis of NGU should be tested for HIV and syphilis.

Follow-Up

Men should be provided results of the testing obtained as part of the NGU evaluation, and those with a specific diagnosis of chlamydia, gonorrhea, or trichomonas should be offered partner services and instructed to return 3 months after treatment for repeat testing because of high rates of reinfection, regardless of whether their sex partners were treated (480,481) (see Chlamydia, Follow-Up and Gonorrhea, Follow-Up).

If symptoms persist or recur after completion of therapy, men should be instructed to return for re-evaluation. 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 possible diagnosis of chronic prostatitis/chronic pelvic pain syndrome in men experiencing persistent perineal, penile, or pelvic pain or discomfort, voiding symptoms, pain during or after ejaculation, or new-onset premature ejaculation lasting for >3 months. Men with persistent pain should be referred to a urologist.

Management of Sex Partners

All sex partners of men with NGU within the preceding 60 days should be referred for evaluation, testing, and presumptive treatment with a drug regimen effective against chlamydia. EPT is an alternative approach to treating female partners for CT in the absence of signs and symptoms of PID (95). If N. gonorrhea or T. vaginalis is documented, all partners should be evaluated and treated according to the management section for their respective pathogen. To avoid reinfection, sex partners should abstain from sexual intercourse until they and their partner(s) are adequately treated.

Persistent and Recurrent NGU

The objective diagnosis of persistent or recurrent NGU should be made before considering additional antimicrobial therapy. In men who have persistent symptoms after treatment without objective signs of urethral inflammation, the value of extending the duration of antimicrobials has not been demonstrated. Men who have persistent or recurrent NGU can be retreated with the initial regimen if they did not comply with the treatment regimen or were re-exposed to an untreated sex partner.

Recent studies have shown that the most common cause of persistent or recurrent NGU is M. genitalium, especially following doxycycline therapy (277,278). Azithromycin 1 g orally in a single dose should be administered to men initially treated with doxycycline. Certain observational studies have shown that moxifloxacin 400 mg orally once daily for 7 days is highly effective against M. genitalium. Therefore, men who fail a regimen of azithromycin should be retreated with moxifloxacin 400 mg orally once daily for 7 days. Higher doses of azithromycin have not been found to be effective for M. genitalium in cases of azithromycin failure (280).

T. vaginalis is also known to cause urethritis in men who have sex with women. Although no NAAT for T. vaginalis detection in men has been FDA-cleared in the United States, several large reference laboratories have performed the necessary CLIA validation of a urine-based T. vaginalis NAAT for men for clinical use. Trichomonas NAAT testing is more sensitive than culture (475). In areas where T. vaginalis is prevalent, men who have sex with women and have persistent or recurrent urethritis should be presumptively treated with metronidazole 2 g orally in a single dose or tinidazole 2 g orally in a single dose; their partners should be referred for evaluation and appropriate treatment. Persons with persistent or recurrent NGU after presumptive treatment for M. genitalium or T. vaginalis should be referred to a urologist.

Special Considerations

HIV Infection

NGU might facilitate HIV transmission. Persons with NGU and HIV should receive the same treatment regimen as those who are HIV negative.

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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) 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 the major diagnostic signs of inflammatory vaginitis, leukorrhea might be a sensitive indicator of cervical inflammation with a high negative predictive value (i.e., cervicitis is unlikely in the absence of leucorrhea) (482,483). The criterion of using an increased number of WBCs on endocervical Gram stain in the diagnosis of cervicitis has not been standardized and therefore is not helpful. 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 gram negative intracellular diplococci on Gram stain of endocervical fluid may be specific for the diagnosis of gonococcal cervical infection when evaluated by an experienced laboratorian, it is not a sensitive indicator of 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) (484). Limited data indicate that infection with M. genitalium or BV and frequent douching might cause cervicitis (257-259,261,265,485-487). For reasons that are unclear, cervicitis can persist despite repeated courses of antimicrobial therapy. Because most persistent cases of cervicitis are not caused by recurrent 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.

Diagnostic Considerations

Because cervicitis might be a sign of upper-genital–tract infection (endometritis), women with a new episode of cervicitis should be assessed for signs of PID and should be tested for C. trachomatis and for N. gonorrhoeae with NAAT; such testing can be performed on either vaginal, cervical, or urine samples (394) (see Chlamydia and Gonorrhea Diagnostic Considerations).Women with cervicitis also should be evaluated for the presence of BV and trichomoniasis, and if these 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, NAAT or other FDA approved diagnostic test) (see Trichomoniasis, Diagnosis). A finding of >10 WBC per high power field in vaginal fluid, in the absence of trichomoniasis, might indicate endocervical inflammation caused specifically by C. trachomatis or N. gonorrhoeae (488,489). Although HSV-2 infection has been associated with cervicitis, the utility of specific testing (i.e., PCR, culture or serologic testing) for HSV-2 is unknown. FDA-cleared diagnostic tests for M. genitalium are not available.

Treatment

Several factors should affect the decision to provide presumptive therapy for cervicitis. Presumptive treatment with antimicrobials for C. trachomatis and N. gonorrhoeae should be provided for women at increased risk (e.g., those aged <25 years and those with a new sex partner, a sex partner with concurrent partners, or a sex partner who has a sexually transmitted infection), especially if follow-up cannot be ensured or if testing with NAAT is not possible. Trichomoniasis and BV should also be treated if detected (see Bacterial Vaginosis and Trichomoniasis). For women at lower risk of STDs, deferring treatment until results of diagnostic tests are available is an option. If treatment is deferred and NAATs for C. trachomatis and N. gonorrhoeae are negative, a follow-up visit to see if the cervicitis has resolved can be considered.

Recommended Regimens for Presumptive Treatment*
  • Azithromycin 1 g orally in a single dose
    OR
  • Doxycycline 100 mg orally twice a day for 7 days

*Consider concurrent treatment for gonococcal infection if patient is at risk for gonorrhea or lives in a community where the prevalence of gonorrhea is high.

Other Considerations

To minimize transmission and reinfection, women treated for cervicitis should be instructed to abstain from sexual intercourse until they and their partner(s) have been adequately treated (i.e., for 7 days after single-dose therapy or until completion of a 7-day regimen) and symptoms have resolved. Women who receive a diagnosis of cervicitis should be tested for HIV and syphilis.

Follow-Up

Women receiving treatment should return to their provider for a follow-up visit, allowing the provider to determine whether cervicitis has resolved. For women who are not treated, a follow-up visit gives providers an opportunity to communicate results of tests obtained as part of the cervicitis evaluation. Additional follow-up should be conducted as recommended for the infections identified. Women with a specific diagnosis of chlamydia, gonorrhea, or trichomonas should be offered partner services and instructed to return in 3 months after treatment for repeat testing because of high rates of reinfection, regardless of whether their sex partners were treated (480). If symptoms persist or recur, women should be instructed to return for re-evaluation.

Management of Sex Partners

Management of sex partners of women treated for cervicitis should be appropriate for the specific STD identified or suspected. All sex partners in the past 60 days should be referred for evaluation, testing, and presumptive treatment if chlamydia, gonorrhea, or trichomoniasis was identified or suspected in the women with cervicitis. EPT or other effective partner referral strategies (see Partner Services) are alternative approaches to treating male partners of women who have chlamydia or gonococcal infection (93-95). To avoid reinfection, sex partners should abstain from sexual intercourse until they and their partner(s) are adequately treated.

Persistent or Recurrent Cervicitis

Women with persistent or recurrent cervicitis despite having been treated should be reevaluated for possible re-exposure or treatment failure to gonorrhea or chlamydia. If relapse and/or reinfection with a specific STD have 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. The etiology of persistent cervicitis including the potential role of M. genitalium (490) is unclear. M. genitalium might be considered for cases of clinically significant cervicitis that persist after azithromycin or doxycycline therapy in which re-exposure to an infected partner or medical nonadherence is unlikely. In settings with validated assays, women with persistent cervicitis could be tested for M. genitalium with the decision to treat with moxifloxacin based on results of diagnostic testing (491). In treated women with persistent symptoms that are clearly attributable to cervicitis, referral to a gynecologic specialist can be considered.

Special Considerations

HIV Infection

Women with cervicitis and HIV infection should receive the same treatment regimen as those who are HIV negative. Cervicitis increases cervical HIV shedding. Treatment of cervicitis in women with HIV infection reduces HIV shedding from the cervix and might reduce HIV transmission to susceptible sex partners (492-496).

Pregnancy

Diagnosis and treatment of cervicitis in pregnant women does not differ from that in women that are not pregnant. For more information, see Cervicitis, sections on Diagnostic Considerations and Treatment.

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