Non-Gonococcal Urethritis (NGU)

Definition

Epidemiology

• An estimated 2.8 million cases of urethritis occur annually in the US; the majority are NGU.
• NGU is more common in younger, sexually active individuals (highest prevalence < 24 years).
• Coinfection with gonorrhea is common; up to 40-50% of NGU cases have no identifiable causative organism.

Etiology

• C. trachomatis is more prevalent in younger men.
• M. genitalium has emerged as an increasingly recognized pathogen, with clinical significance comparable to chlamydia.
• Ureaplasma urealyticum should be considered when no other pathogen is found, particularly in young men with few sexual partners.

Pathophysiology

Clinical Features

• Often asymptomatic (symptoms are less prominent than in gonococcal urethritis)
• Dysuria (usual)
• White, mucopurulent or purulent urethral discharge (can appear 1-6 weeks after sexual contact)
• Urine may appear clear but contain "threads" or pus cells
• Urethral itching/stinging, penile tip irritation

• Usually asymptomatic
• Vaginal discharge or urethrotriginitis
• May present as cervicitis or ascend to cause pelvic inflammatory disease (PID)

Clinical features alone cannot reliably distinguish NGU from gonococcal urethritis; coinfection is common.

Diagnosis

Diagnostic Criteria (any one of the following):

1. Mucoid, mucopurulent, or purulent discharge on examination
2. Urethral Gram stain showing ≥2 WBCs per oil immersion field (current CDC threshold - older guideline used ≥5 WBCs/hpf, which missed significant cases)
3. Positive leukocyte esterase on first-void urine
4. >10 WBCs/hpf on first-void urine microscopy

Gram Stain Interpretation

• Gram-negative intracellular diplococci = N. gonorrhoeae (gonococcal)
• ≥2 WBCs per oil immersion field without intracellular diplococci = NGU
• Sensitivity of Gram stain is highly provider-dependent and collection-method dependent

Nucleic Acid Amplification Test (NAAT) - Gold Standard

• First-catch (first-void) urine is the preferred specimen in men for NAAT
• High sensitivity and specificity for C. trachomatis, N. gonorrhoeae, T. vaginalis, and M. genitalium
• Should be performed whenever Gram stain is unavailable, or when ≥2 WBCs are present without intracellular diplococci
• In women: urine, endocervical, or vaginal swabs can be used

Additional Testing

• Concurrent testing for gonorrhea, HIV, and syphilis is recommended with any NGU diagnosis
• NAAT for M. genitalium should be obtained in persistent or recurrent NGU
• Wet mount microscopy can identify trichomoniasis but is less sensitive than NAAT (~50-65%)

Treatment

First-Line Treatment for NGU

Note: Doxycycline is now preferred over azithromycin for NGU because azithromycin's median cure rate has dropped from 85% historically to ~40% in recent studies, largely due to M. genitalium resistance.

Alternative Regimens (for C. trachomatis):

• Erythromycin base 500 mg PO four times daily for 7 days
• Erythromycin ethylsuccinate 800 mg PO four times daily for 7 days
• Levofloxacin 500 mg PO once daily for 7 days
• Ofloxacin 300 mg PO twice daily for 7 days

Treatment by Specific Organism

• Doxycycline 100 mg PO twice daily x 7 days (preferred)
• OR Azithromycin 1 g PO single dose
• Abstain from intercourse for 7 days after single-dose therapy or until 7-day course is complete
• 3-month retest recommended (not test-of-cure, but re-screening)

• Two-stage approach: Doxycycline 100 mg PO twice daily x 7 days followed by Moxifloxacin 400 mg PO once daily x 7 days
• If macrolide sensitivity confirmed on resistance testing: doxycycline x 7 days followed by azithromycin (1 g initial dose, then 500 mg once daily x 3 more days)
• Moxifloxacin has shown 100% cure rates in early reports

• Metronidazole 2 g PO single dose
• OR Tinidazole 2 g PO single dose

Persistent or Recurrent NGU

• Treatment failure (especially M. genitalium resistance to doxycycline or azithromycin)
• Non-compliance with initial treatment
• Re-exposure to an untreated sex partner
• Resistant M. genitalium or T. vaginalis infection

• Obtain urine NAAT for M. genitalium and T. vaginalis
• If M. genitalium confirmed: two-stage doxycycline + moxifloxacin regimen (see above)
• Consider chronic pelvic pain syndrome as an alternative diagnosis if pelvic pain is prominent
• Urologic evaluation rarely identifies a specific cause in persistent cases

Complications

• Epididymitis (common)
• Orchitis
• Prostatitis (prostate may also serve as a reservoir for relapse)
• Urethral stricture (potential late complication)
• Reiter syndrome (reactive arthritis, uveitis, urethritis) - associated with C. trachomatis

• Cervicitis
• Pelvic inflammatory disease (PID)
• Fallopian tube scarring
• Infertility
• Pelvic pain

• Neonatal conjunctivitis (ophthalmia neonatorum)
• Neonatal pneumonia (C. trachomatis)

Partner Management

• All sex partners with whom the patient had sexual contact in the preceding 60 days should be referred for evaluation, testing, and presumptive treatment.
• Treat both partners - reinfection is probable if the partner is not treated.
• Retesting of both partners at 3 months is recommended.
• Patients should abstain from intercourse until treatment is complete and symptoms resolve.

EAU Guideline Recommendations (Summary)

• Gram stain of urethral discharge for preliminary diagnosis
• NAAT on first-void urine (preferred) or urethral smear before empirical treatment
• Delay treatment until NAAT results available if symptoms are mild
• Urethral swab culture prior to treatment if NAAT is positive for gonorrhea (for resistance profiling)
• Pathogen-directed treatment based on local resistance data
• Always treat sexual partners

Key Points Summary