Urethritis, Vulvovaginitis, and Cervicitis

Etiologic Agents

Organisms associated with STIs are the most significant etiologic agents in urethritis. Newer, more sensitive molecular diagnostic testing modalities for STIs have advanced the understanding of specific pathogens that cause urethritis.

Epidemiology

Population-based data from 2001 to 2004 for those 15–24 years old in the US, derived from the National Health and Nutrition Examination Survey (NHANES), showed a prevalence of C. trachomatis in 1.7% of males and 3.2% of females (2005–2008 data); N. gonorrhoeae in 0.3% of males and 0.6% of females (1999–2008 data); and T. vaginalis in 0.9% of males and 1.5% of females. Other NHANES data from 2003 to 2004 found that sexually experienced females aged 14–19 had higher prevalence rates than the general population for C. trachomatis (7.1% vs. 3.9%), T. vaginalis (3.6% vs. 2.5%), and N. gonorrhoeae (2.5% vs. 1.3%). Recent 2018 data from the Centers for Disease Control and Prevention (CDC) revealed increasing rates of STIs between 2014 and 2018 among 15–19 years old AYA for both C. trachomatis (increase of 31% for males and 12% for females) and N. gonorrhoeae (increase of 44% for males and 27% for females). Data from the 2001 to 2002 enrollment in the National Longitudinal Study of Adolescent Health found the prevalence of M. genitalium among 18–27-year-old males and females to be 1% compared to 0.4% for N. gonorrhoeae , 4.2% for C. trachomatis , and 2.3% for trichomoniasis.

Meta-analysis of global studies conducted between 2009 and 2016 evaluating the estimated incidence and prevalence of C. trachomatis , N. gonorrhoeae , and T. vaginalis in women and men 15–49 years old showed that trichomoniasis has the highest number of incident cases worldwide. The prevalence in women was 3.8% for chlamydia, 0.9% for gonorrhea, and 5.3% for trichomonas and in men 2.7% for chlamydia, 0.7% for gonorrhea, and 0.7% for trichomonas. The estimated prevalence in 2016 within the European region for 15- to 40-year-old males and females combined was 3.2% for C. trachomatis ; 0.3% for N. gonorrhoeae , and 1.6% for T. vaginalis .

Regarding M. genitalium , a meta-analysis of global studies utilizing NAAT between 2001 and 2016 for males and females older than age 13 found the prevalence varied by setting: 1.31% in a random sampling of the general population (US and Europe); 1.58% from a community-based non-random sampling representing enrollment outside of healthcare settings (Europe, Russia); a higher prevalence of 3.66% in healthcare clinic based studies for men who have sex with men (US and Europe); and even higher rates of 18.4% among commercial sex workers in a community-based setting from Germany.

Sexual practices and behaviors can influence the epidemiology of urethritis. Urethritis due to C. trachomatis, N. gonorrhoeae, or HSV among adolescent women correlates with having new sex partners. Adenovirus and HSV-1 have been associated with oral-genital contact and having a male partner, whereas M. genitalium and C. trachomatis have been associated with vaginal sex. Overall, rates of STIs are higher among those seeking care for a concern about having an STI, ^, incarcerated individuals, young men who have sex with men, and high risk youth. High risk behaviors include use of injection drugs, early onset of sexual activity, having multiple partners, and not using condoms.

Ethnic/racial differences have been demonstrated. NHANES data from 2013 to 2016 found that the prevalence of T. vaginalis was highest among Black men and women; lowest among non-Hispanic Whites and higher in individuals with lower income and less education. ^, Similar ethnic and racial differences have been found for other sexually transmitted diseases. ^{, , , , ,}

Urethritis due to STI pathogens also can occur in prepubertal boys and, less frequently, in prepubertal girls. In this age group, transmission commonly results from sexual abuse with genital-to-genital contact ( Chapter 54 ).

Clinical Manifestations and Differential Diagnosis

Symptomatic urethritis in adolescent males is commonly characterized by dysuria, urethral discharge, or urethral pruritus. In a study of 19- to 65-year-old men at an STI clinic, confirmed urethritis was most likely to be found when the presenting symptoms included urethral discharge and/or dysuria both of which increased the relative risk of being diagnosed with clinical urethritis by 2-fold. Discharge can be mucoid, mucopurulent, or purulent. Gonococcal urethritis compared with NGU usually has a shorter incubation period, more acute onset, and more profuse discharge ( Table 51.1 ). Discharge in patients with NGU can be so scant that it is only noticed in the morning or is apparent as crusting on the meatus or as stains in underwear. Urethral infection with N. gonorrhoeae and the various organisms causing NGU also can be asymptomatic.

Urethritis must be differentiated from UTI, particularly in adolescent boys with dysuria but no discharge. In contrast to UTI, frequency, hematuria, and urgency are uncommon in urethritis. ^, However, if the male adolescent is sexually active, pyuria is more likely to be caused by urethritis than UTI. A focused STI history (see Chapter 49 ) and thorough medical history can help establish relative risks of urethritis and UTI.

In adolescent girls, dysuria is the cardinal feature of urethritis, which must be differentiated from acute bacterial cystitis and vulvovaginitis ( Table 51.2 ). The literature differentiates internal and external dysuria. Internal dysuria is pain that is felt internally during voiding while external dysuria is discomfort that is felt as urine passes over the labia. Internal dysuria with pain only at the end of urination, urinary frequency, and isolation of >10 ⁵ uropathogens per mL of voided urine suggest acute bacterial cystitis. Isolation of ≤10 ⁵ uropathogens per mL suggests acute urethritis due to STI pathogens or vulvovaginitis. External dysuria can occur with vulvovaginitis and genital lesions. Female adolescents can have vaginitis alone or a concurrent UTI and may not be able to adequately distinguish between internal and external dysuria. ^, Any female patient suspected of having urethritis requires an STI-directed history and physical examination to identify other STI syndromes (e.g., pelvic inflammatory disease [PID]).

In prepubertal boys and girls, urethritis due to STI pathogens can manifest with dysuria and urethral or vaginal discharge. There may be vague lower abdominal pain, unwillingness to void, and in boys, irritation in the distal urethra or meatus. Dysuria in a prepubertal child is much more likely to be caused by UTI, vulvovaginitis unrelated to an STI, or another urologic abnormality. Sexual abuse should always be considered with symptoms of urethritis.

Laboratory Findings and Diagnosis

Males

Guidelines from the US and Europe including the CDC, International Union against Sexually Transmitted Infections (IUSTI), and British Association for Sexual Health and HIV (BASHH) all recommend obtaining objective evidence of urethral inflammation when considering urethritis in symptomatic patients. Urethritis is documented by the presence of urethral discharge or WBCs in a urethral or urine specimen ( Box 51.1 ). ^, Compared with the urethral smear, urine dip for leukocyte esterase (LE) is less sensitive and specific. ^, However, LE is an option to assist in the clinical assessment when microscopy is not available.

BOX 51.1

CDC Diagnostic Criteria for Urethritis

Adapted from Workowski KA, Bachmann LH, Chan PA, et al. Sexually transmitted infections treatment guidelines, 2021. MMWR Recomm Rep . 2021;70(4):1–187

• Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2018 . Atlanta: U.S. Department of Health and Human Services; 2019. https://doi.org/10.15620/cdc.79370

Presence of any one of the following:

• Visibly abnormal urethral discharge

• Gram stain of a urethral smear showing at least 2 WBCs/HPF ^a

  a Gram stain: ≥2 WBCs/HPF for high prevalence setting and ≥5 WBCs/HPF for low prevalence setting.

• Positive leukocyte esterase (LE) test result from first-void urine ^b

  b For a male <60 years of age without other urinary tract disease that could cause pyuria.

• ≥10 WBCs/HPF on a spun first-void urine sediment

There is controversy in the literature regarding the cutoff point for the number of white blood cells per high-power field (WBC/HPF) used in the diagnosis of urethritis. ^, The IUSTI and BASHH guidelines have a cutoff of ≥5 WBCs/HPF on Gram stain or methylene blue-stained urethral smears rather than the ≥2 WBC indicated by the CDC. ^{, ,} The 2021 CDC guidelines indicate that the diagnostic cutoff for WBCs could be raised to 5 WBCs/HPF in clinical settings with a lower prevalence of STIs. One study concluded that it may not be possible to establish a universal cut off since the number of WBC/HPF varies by the how the sample is obtained and the prevalence of organisms causing urethritis in different settings. Although more men with presumptive C. trachomatis and M. genitalium will be identified with the lower cut off, there will also be an increase in the number of individuals without an STI who are misclassified and have unnecessary presumptive treatment.

For males, specimens are obtained to document the presence of urethritis and to identify the infecting organism(s). The definitive diagnosis is enhanced if the patient has not voided recently; examination in the morning before voiding is ideal, although 2–4 hours is conventional. ^{, ,} A meatal swab specimen of discharge can be taken for Gram stain/smear. The finding of gram-negative intracellular diplococci shaped like kidney beans ( Fig. 51.1 ) is sensitive and specific in diagnosing presumptive gonococcal urethritis. If the Gram stain/smear is equivocal, negative, or unavailable and the other criteria for urethritis are met, NAAT for the common pathogens causing urethritis is indicated. ^{, ,} In all patients, even if N. gonorrhoeae is demonstrated by Gram stain, co-infection with other STIs can occur. A first-voided urine or a urethral specimen should be obtained for detection of C. trachomatis by NAAT. ^{, , ,}

Recommendations about testing for M. genitalium in symptomatic patients are evolving. The BASHH and IUSTI guidelines recommend NAAT testing for M. genitalium for all cases of symptomatic urethritis. ^, The CDC guidelines do not recommend testing for M. genitalium as part of the initial work up but rather testing in cases of persistent or recurrent NGU. A NAAT test for M. genitalium was recently approved by the US Food and Drug Administration (FDA).

The diagnosis of T. vaginalis is more challenging in men than women. Wet mount preparation of a urethral smear detects only 30% of T. vaginalis infections in men. Culture can be performed on urine, semen, or urethral specimens and appears to yield better results if multiple sites are tested. ^, The InPouch culture system (BioMed Diagnostics, San Jose, CA) is equivalent to the gold standard Diamond media. However, studies have shown that NAAT is superior to a wet mount preparation or culture to detect T. vaginalis in men. ^, There is one NAAT test (Cepheid Xpert TV Assay [Cepheid, Sunnyvale, CA]) that is FDA approved and used in Europe on male urine specimens. Other in-house-developed NAAT tests or those that only have approval for women may be used in laboratories that have conducted validation procedures on specimens from men. ^, Specific testing of men for T. vaginalis should be considered for cases of persistent NGU, especially in high-prevalence areas or populations for men who have sex with women. ^,

Cultures for U. urealyticum are not readily available and, although labs may have developed their own NAAT tests, none are currently FDA approved. Routine testing for this organism is not recommended in a 2018 position statement by the European STI Guidelines editorial board. Rather, management relies on the exclusion of other causes.

Females.

Since it is difficult to differentiate between dysuria caused by UTI and STI/vaginitis symptoms in females, evaluation of dysuria includes all of these possible etiologies. Clean catch urinalysis will indicate whether pyuria, nitrite, or hematuria is present, and urine culture should be performed if urinalysis is abnormal. ^, Sterile pyuria is indicative of a possible STI. Since simultaneous UTI and STI can occur in sexually active females, diagnosing a UTI does not preclude the need for further evaluation. Genital examination is an important part of the evaluation to assess the need for additional testing related to urethral or vulvar pathology. This includes HSV lesions or candida vulvovaginitis, which may cause symptoms of dysuria. ^,

In sexually active patients, endocervical, vaginal, or urine specimens should be obtained for N. gonorrhoeae , C. trachomatis, and T. vaginalis . ^, Vaginal specimens are the preferred specimen and can be collected by the healthcare personnel or the patient. ^, Unlike males, microscopy for identifying N. gonorrhoeae is not recommended because of poor sensitivity. Although T. vaginalis can be diagnosed by a variety of methods, including wet mount of vaginal secretions, NAAT testing is the most sensitive test and the recommended option among US and European organizations. ^{, , ,} The IUSTI guidelines include recommendations for NAAT testing for M. genitalium if there are signs or symptoms of PID, cervicitis, or cervical/vaginal discharge with risk factors for STIs, while BASHH recommends testing with signs and symptoms of PID and considering testing for signs and symptoms of mucopurulent cervicitis (MPC). ^, CDC guidelines recommend testing for M. genitalium in women with recurrent cervicitis and consideration for testing in cases of PID.

Management, Empiric, and Definitive Therapy

Because of increasing antibiotic resistance for various STI pathogens worldwide, and in particular for N. gonorrhoeae, C. trachomatis, and M. genitalium , treatment recommendations for urethritis are evolving. ^{, ,} Resistance rates vary by country, gender, age, and sexual orientation. ^, Increasing resistance to both azithromycin and ceftriaxone has impacted treatment recommendations for N. gonorrhoeae , C. trachomatis , and M. genitalium . ^, Macrolide resistance is thought to be due to the extensive use of single-dose azithromycin. Of concern are recently reported cases in the UK of N. gonorrhoeae resistant to both ceftriaxone and azithromycin. In addition to azithromycin resistance which impacts the first-line treatment options for C. trachomatis and M. genitalium , quinolone resistance has impacted the second-line treatment for M. genitalium . ^,

Treatment with 1 g of azithromycin can induce mutations associated with macrolide resistance, which would also render the previously recommended longer 5-day course (1.5 g) for M. genitalium ineffective. ^, Use of doxycycline rather than azithromycin for presumptive STI treatment followed by therapy, guided by antibiotic susceptibility test results, increases cure rates for M. genitalium . In one study, subsequent high-dose azithromycin (2.5 g [1 g on day 1 and 500 mg daily for 3 days]) for macrolide-sensitive infections or moxifloxacin (400 mg daily for 7 days) for macrolide-resistant infections was found to have microbial cure 95.4% and 92.0% of the time, respectively. It has been postulated that pretreatment with doxycycline, although not curative in most cases of M. genitalium , may decrease the bacterial load and improve cure rates with subsequent macrolide or quinolone treatment. The relevance of currently identified quinolone resistance markers is unclear since their presence is not always associated with clinical treatment failure.

Overall, more judicious use of antibiotics has been recommended. ^, These data have informed recently revised guidelines in both Europe and the US. ^{, , , , ,} However, enacting some of the new recommendations may be hampered, in part, by the current availability of testing for M. genitalium and antibiotic resistance testing.

The following approach to treatment of urethritis is derived from review of the currently available CDC, BASHH, ^{, ,} and IUSTI ^{, ,} guidelines. Immediate presumptive diagnosis of urethritis for symptomatic male patients can be based on presence of urethral discharge on exam, Gram stain results, or demonstration of WBCs in a urine specimen. ^{, , , ,} Empiric treatment without objective signs of urethritis is not generally recommended. ^{, ,} Patients with evidence of N. gonorrhoeae urethritis by Gram stain can be presumptively diagnosed as having gonorrhea; however, NAAT testing for N. gonorrhoeae still should be performed along with NAAT for C. trachomatis . ^{, ,} Current BASHH recommendations also include sending a urethral specimen for N. gonorrhoeae culture to assess for antimicrobial resistance prior to treatment and USTI guidelines list this approach as the ideal. CDC recommends N. gonorrhoeae culture for susceptibility testing in the context of suspected or documented treatment failure. When sending NAAT for M. genitalium , ideally testing should be performed simultaneously for determination of macrolide resistance. ^{, ,} Testing for quinolone resistance should be considered if M. genitalium testing is positive and infection was acquired in the Asia-Pacific region.

Treatment based on susceptibility test results is preferred, but treatment prior to obtaining results is discussed in the guidelines particularly for patients with severe symptoms. The first-line treatment recommendations are outlined in Table 51.3 . All three organizations recommend 7-day treatment with doxycycline for C. trachomatis except in the case of pregnancy when azithromycin remains the recommendation due to contraindications for use of doxycycline. However, there are significant differences among the three organizations’ recommendations for N. gonorrhoeae treatment. Unlike the IUSTI guidelines in which dual therapy with high-dose ceftriaxone plus high-dose azithromycin is the first-line recommendation, BASHH and CDC recommend monotherapy. CDC recommends ceftriaxone with a higher dose for individuals weighing >150 kg. BASHH recommends ceftriaxone when antimicrobial susceptibility is unknown prior to treatment and includes single-dose monotherapy with ciprofloxacin as a first-line treatment option if the organism is shown to be susceptible. Azithromycin as part of dual therapy with another antibiotic is only recommended as part of an alternative regimen in the BASHH and CDC guidelines. The IUSTI treatment guideline for gonorrhea only recommends single-dose ceftriaxone under specific conditions including absence of local ceftriaxone resistance; mandatory test of cure; lack of availability of azithromycin; or patient inability to take oral medication. In addition, IUSTI recommends concurrent use of 7 days of doxycycline when C. trachomatis has not been excluded by NAAT. CDC guidelines also recommend adding doxycycline to treat C. trachomatis if not excluded, while BASHH discusses treatment of suspected C. trachomatis co-infection. Unlike the BASHH guidelines, use of single-dose ciprofloxacin, when C. trachomatis is demonstrated to be susceptible, is listed as an alternative rather than first treatment option in the IUSTI guideline and is included for cases of drug allergy in the CDC guidelines.

For NGU, all three guidelines recommend first-line treatment with doxycycline for 7 days. This therapy will effectively treat both C. trachomatis and U. urealyticum . Depending on which European guideline (BASHH or IUSTI) is being used, if the patient has M. genitalium due to a macrolide-susceptible organism, a 3–5-day course of azithromycin is recommended. Per BASHH guidelines, azithromycin ideally should be given within 14 days of completing doxycycline therapy. If the M. genitalium strain is macrolide resistant, a 7–10-day course of moxifloxacin (400 mg daily) is recommended.

If there is persistent or recurrent NGU, repeat testing for N. gonorrhoeae , C. trachomatis , and M. genitalium should be conducted along with testing for T. vaginalis . If not done previously, macrolide resistance for M. genitalium should be included when available. Recommended treatment per BASHH and IUSTI guidelines includes coverage for M. genitalium , T. vaginalis , and possible BV associated bacteria using azithromycin and metronidazole if doxycycline was the initial treatment and moxifloxacin with metronidazole if azithromycin was the initial therapy. A newer drug—pristinamycin, which is not available in the US—may be a possible treatment for those who remain positive for M. genitalium infection.

CDC guidelines regarding persistent/recurrent NGU recommend treatment based on diagnostic testing including available susceptibility test results. M. genitalium infection should be suspected as a cause of persistent/recurrent NGU when testing is not available. When M. genitalium NAAT results are available and following completion of a 7-day course of doxycycline treatment, 4 days of azithromycin is indicated if the organism is macrolide sensitive, or 7 days of moxifloxacin if macrolide resistant. If resistance testing is unavailable, a 7-day course of moxifloxacin is recommended after 7 days of doxycycline. A 7-day course of doxycycline prior to moxifloxacin therapy is recommended to improve eradication of M. genitalium . Testing for T. vaginalis and presumptive treatment with single-dose metronidazole or tinidazole is also recommended in areas where T. vaginalis is prevalent for men who have sex with women.

Immediate follow-up and repeat testing for N. gonorrhoeae or C. trachomatis urethritis are not recommended by CDC if appropriate treatment is completed, signs and symptoms disappear, and no re-exposure to an untreated partner occurs. However, because of the high rate of reinfection after initial treatment, repeat testing for N. gonorrhoeae and C. trachomatis is recommended at 3 months. There is no similar follow-up recommendation for M. genitalium . The BASHH and IUSTI guidelines recommend test of cure in all patients for N. gonorrhoeae and M. genitalium even if they are asymptomatic. N. gonorrhoeae testing should occur at least 2 weeks after treatment and M. genitalium after at least 3 weeks. Test of cure is not needed for C. trachomatis urethritis if treated with first-line therapy. If symptoms persist despite good adherence and no re-exposure and the person meets diagnostic criteria for persistent or recurrent NGU, further management is indicated. Patients who do not respond to therapy should be referred to a urologist.

Female patients with findings suggesting bacterial cystitis can be treated presumptively for UTI. However, if urethritis is suspected, treatment should be guided by STI testing results and per CDC, BASHH, and IUSTI guidelines. If symptoms of dysuria due to vulvovaginitis are found, treatment should be directed at the cause.

Complications

Complications of urethritis include disseminated gonococcal infection (0.5%–3%) and reactive arthritis syndrome (i.e., Reiter syndrome). In male patients, epididymo-orchitis and, rarely, prostatitis and balanoposthitis can occur. ^{, , , , ,} Female patients with N. gonorrhoeae , C. trachomatis , and M. genitalium infection are at risk for PID and infertility. ^{, , ,} M. genitalium has been associated with cervicitis, preterm birth and spontaneous abortion. ^{, ,} STIs associated with urethritis increase susceptibility to HIV infection.

Prevention

Consistent use of condoms is the most effective means of preventing and reducing transmission of the STIs associated with urethritis. Sexual partners should be contacted for assessment and treatment.

Vulvovaginitis in the Prepubertal Age Group