Urethritis

Urethritis is inflammation of the urethra, usually from infection. It is classified as gonococcal (Neisseria gonorrhoeae) or non-gonococcal (NGU), and the latter is the commoner. It is a leading reason for men to attend sexual health clinics. In women, urethritis is part of the urethral syndrome, cervicitis or cystitis and is often asymptomatic.

Causes:

• Gonococcal urethritis: N. gonorrhoeae.
• Non-gonococcal urethritis (15 to 40% chlamydial, 10 to 30% idiopathic or unidentified):
• Chlamydia trachomatis (the commonest identified cause, 15 to 40%).
• Mycoplasma genitalium (10 to 25%, growing resistance to macrolides and fluoroquinolones).
• Ureaplasma urealyticum (uncertain role), Trichomonas vaginalis (1 to 20%), herpes simplex virus (2 to 3%), adenovirus (2 to 4%, with conjunctivitis), enteric bacteria (E. coli, H. influenzae in men who have insertive anal intercourse), Neisseria meningitidis (urethral meningococcal infection), Haemophilus species, and Treponema pallidum.
• Non-infectious: trauma (catheterisation, instrumentation), chemical irritants (spermicides, soaps, douches), allergic reaction, Reiter/reactive arthritis, Behçet disease, foreign body, urethral stricture, and urethral tumour.

Epidemiology:

• Gonorrhoea and chlamydia are the most common bacterial STIs, with peak incidence in 15 to 24 year-olds. Many infections are asymptomatic (chlamydia in 50% of men, 70 to 90% of women; gonorrhoea in 10 to 40% of men, 50% or more of women). Transmission is by vaginal, anal or oral sex, and perinatally.
• Complications: epididymo-orchitis, prostatitis, urethral stricture (after long-standing infection), pelvic inflammatory disease, tubal infertility, ectopic pregnancy, chronic pelvic pain, reactive arthritis, disseminated gonococcal infection, and increased HIV transmission.

Risk factors: new or multiple partners, unprotected sex, previous STI, age under 25, men who have sex with men, drug use, and partner with STI.

Men

• Gonococcal: incubation 2 to 7 days. Acute onset of purulent or mucopurulent urethral discharge (yellow-green, copious), severe dysuria, meatal erythema and oedema. Discharge is often noticed first thing in the morning.
• Non-gonococcal: incubation 1 to 5 weeks. Gradual onset, scant to moderate white, clear or mucoid discharge (worse in the morning, the "morning drop"), mild dysuria or urethral itching and discomfort. Up to 50% have no symptoms.
• Complications: epididymitis (unilateral scrotal pain and swelling), prostatitis, balanitis, urethral stricture, and reactive arthritis (arthritis, conjunctivitis and urethritis, 1 to 3% after NGU, HLA-B27 association).

Women

• Dysuria, frequency and urgency (acute urethral syndrome with sterile pyuria), often with cervicitis: vaginal discharge, intermenstrual or postcoital bleeding, lower abdominal pain, dyspareunia. Many are asymptomatic. Urethral discharge on pressure of the urethra against the pubic symphysis may be present.

Extragenital and disseminated disease

• Pharyngeal and rectal infection (usually asymptomatic, proctitis with discharge, pain, tenesmus). Conjunctivitis from autoinoculation.
• Disseminated gonococcal infection (0.5 to 3%): fever, migratory polyarthralgia, tenosynovitis, vesiculopustular skin lesions, and septic arthritis, usually in women (especially menstruation or pregnancy) and in complement deficiency.

Differential diagnosis: cystitis, prostatitis, balanitis, epididymitis, urethral stricture, genital herpes, reactive arthritis, urethral diverticulum, interstitial cystitis, and vaginitis.

Red flags: testicular pain or swelling, fever, pelvic pain with cervical motion tenderness, joint symptoms or rash, persistent symptoms after treatment, pregnancy, and a child with urethritis (consider sexual abuse).

Men

• Urethral discharge on examination (milk the urethra), or urethral smear with Gram stain showing 2 or more polymorphonuclear leukocytes per oil immersion field (5 or more in some criteria), and intracellular Gram-negative diplococci (diagnostic of gonorrhoea in symptomatic men with 95% sensitivity). First-void urine microscopy with 10 or more WBC per high power field supports urethritis.
• Nucleic acid amplification tests (NAAT) on first-void urine (first 10 to 20 mL, at least 1 to 2 hours since last void) or urethral swab for N. gonorrhoeae, C. trachomatis, and M. genitalium (with macrolide resistance mutation testing), T. vaginalis in high-prevalence settings.
• Gonococcal culture with antimicrobial susceptibility testing before treatment (urethral swab, plus pharyngeal and rectal swabs as indicated) to monitor resistance.
• Leukocyte esterase dipstick on first-void urine is a rapid screen (sensitivity 80 to 90%).

Women

• NAAT on self- or clinician-collected vulvovaginal swab (preferred, sensitivity 90%+), endocervical swab or first-void urine for gonorrhoea, chlamydia, trichomonas and M. genitalium. Wet mount, pH and Gram stain for vaginitis (bacterial vaginosis, candidiasis). Pregnancy test.
• Pelvic examination for cervicitis (mucopurulent discharge, friable cervix) and pelvic inflammatory disease.

Extragenital sites: NAAT of pharyngeal and rectal swabs in people who have receptive oral or anal sex.

Additional

• HIV, syphilis, hepatitis B and C serology (and hepatitis A/B vaccination status), and at-risk screening for other STIs.
• Urine culture to exclude UTI. Joint aspirate, blood cultures and skin lesion swabs in suspected disseminated gonococcal infection.
• HSV PCR from lesions, and adenovirus testing in recurrent NGU with conjunctivitis.
• Persistent or recurrent urethritis: test for M. genitalium, trichomonas, HSV, and consider urethroscopy for stricture or foreign body.

Treat promptly (syndromic treatment at the first visit when tests are delayed in symptomatic patients), treat partners, and abstain from sex for 7 days after therapy and until partners are treated.

Gonococcal urethritis (uncomplicated)

• Ceftriaxone 500 mg IM single dose (1 g in patients over 150 kg), the recommended therapy (older regimens used 250 mg). Given with doxycycline 100 mg twice daily for 7 days if chlamydia is not excluded.
• Alternatives (allergy or unavailability): gentamicin 240 mg IM plus azithromycin 2 g orally (single dose), cefixime 800 mg orally (less effective), spectinomycin 2 g IM, or zoliflodacin and gepotidacin (newer agents). Test of cure by NAAT 2 weeks (culture if clinical failure or pharyngeal infection) after treatment.
• Pharyngeal gonorrhoea: ceftriaxone 500 mg IM, with test of cure at 2 weeks. Rectal: same regimen.
• Disseminated gonococcal infection: hospital admission, ceftriaxone 1 g IM or IV every 24 hours for 7 days (joint drainage, complete resolution of symptoms), step down to oral cefixime 400 mg twice daily after 24 to 48 hours of improvement. Meningitis or endocarditis needs longer (10 to 14 days, up to 4 weeks) and cefotaxime/ceftriaxone 1 to 2 g IV every 12 hours.

Non-gonococcal urethritis

• First line: doxycycline 100 mg orally twice daily for 7 days (superior to azithromycin for chlamydia, especially rectal infection).
• Alternative: azithromycin 1 g orally single dose, followed by 500 mg daily for 2 days (azithromycin 1 g single dose has a rising failure rate with M. genitalium resistance).
• Persistent or recurrent NGU (symptoms persisting after 3 weeks, or recurrence): test for M. genitalium and trichomonas. For M. genitalium: doxycycline 100 mg twice daily for 7 days followed by moxifloxacin 400 mg once daily for 7 to 10 days (macrolide-resistant or resistance testing not available), or azithromycin 1 g then 500 mg daily for 3 days (if macrolide-susceptible). Pristinamycin 1 g four times daily for 10 days, and minocycline are alternatives.
• Trichomonas: metronidazole 2 g single dose (men) or 500 mg twice daily for 7 days (women, preferred), tinidazole 2 g single dose.
• Other causes: HSV (valaciclovir 500 mg twice daily for 5 to 10 days), adenovirus (self-limiting).

Women

• Chlamydial infection: doxycycline 100 mg twice daily for 7 days, or azithromycin 1 g single dose (pregnancy: azithromycin 1 g, or amoxicillin 500 mg three times daily for 7 days). Gonorrhoea: ceftriaxone 500 mg IM single dose. Treat cervicitis and pelvic inflammatory disease according to guidelines (ceftriaxone 500 mg IM single dose, doxycycline 100 mg twice daily plus metronidazole 400 to 500 mg twice daily for 14 days).

Complications

• Epididymo-orchitis in men under 35 (likely STI): ceftriaxone 500 mg IM single dose plus doxycycline 100 mg twice daily for 10 to 14 days. Reactive arthritis: NSAIDs, intra-articular steroids, and sulfasalazine 1 to 3 g daily for persistent disease. Urethral stricture: urethral dilation or urethrotomy.

Partner management and prevention

• Partner notification and treatment for all partners in the preceding 2 weeks (symptomatic men) or 60 days (asymptomatic, last partner), with expedited partner therapy where permitted. Refrain from sexual contact until both partners are treated and symptoms resolved (7 days after treatment).
• Retest for chlamydia and gonorrhoea at 3 months after treatment, because reinfection is common. Test of cure for gonorrhoea, pharyngeal infection, pregnancy, and persistent symptoms.
• HIV pre-exposure prophylaxis counselling for those at risk (tenofovir/emtricitabine 300/200 mg daily or cabotegravir injections), doxycycline post-exposure prophylaxis (200 mg within 72 hours of condomless sex) for selected MSM (reduces chlamydia and syphilis but not clearly gonorrhoea, with possible effect on resistance), vaccination (HPV, hepatitis A and B, meningococcal B vaccine offering partial protection against gonorrhoea), consistent condom use, and routine STI screening in high-risk groups.
• Counselling and sexual history, and safeguarding assessment for adolescents and children.

Follow-up

• Review at 1 to 2 weeks for persistent symptoms. If symptoms persist after adherence and partner treatment, perform repeat testing and consider resistant organisms, reinfection, and non-infectious causes. Screen for syphilis and HIV again at 3 months.