What is the recommended empirical management and diagnostic workup for acute urethritis?

Approach to Urethritis

Diagnostic Confirmation First

Before initiating treatment, confirm urethritis using at least one objective criterion: mucopurulent/purulent urethral discharge on examination, Gram stain showing ≥5 white blood cells per oil-immersion field, positive leukocyte esterase on first-void urine, or ≥10 white blood cells per high-power field on urine microscopy. 1, 2

• Symptoms alone (dysuria, itching, urethral discomfort) without objective laboratory findings are insufficient to diagnose urethritis and do not justify antimicrobial therapy 1, 2
• The Gram stain is the preferred rapid diagnostic test because it simultaneously confirms urethritis and distinguishes gonococcal from non-gonococcal infection with >95% sensitivity and >99% specificity 2
• Intracellular gram-negative diplococci indicate gonococcal urethritis; ≥5 leukocytes without diplococci suggest non-gonococcal urethritis 2

Mandatory Microbiological Testing

All patients with confirmed or suspected urethritis must be tested for both N. gonorrhoeae and C. trachomatis using nucleic acid amplification tests (NAATs) on first-void urine or urethral swab. 3, 1, 2

• NAATs are more sensitive than culture for C. trachomatis and do not require viable organisms 3, 2
• Testing for specific pathogens is essential because both infections are reportable and a specific diagnosis improves compliance and partner notification 3

Key Pathogen Prevalence in Non-Gonococcal Urethritis:

• C. trachomatis: 23-55% of cases 3, 1, 2
• Ureaplasma urealyticum: 20-40% of cases 1, 2
• Mycoplasma genitalium: 17-33% of cases 1, 2
• Trichomonas vaginalis: 2-5% of cases 1, 2

First-Line Empiric Treatment Algorithm

When Diagnostic Tools Are Available and Gram Stain Can Be Performed:

If Gram stain shows intracellular gram-negative diplococci (gonococcal urethritis):

• Ceftriaxone 250 mg IM single dose PLUS either azithromycin 1 g orally single dose OR doxycycline 100 mg orally twice daily for 7 days 1, 4, 2

If Gram stain shows ≥5 WBCs without diplococci (non-gonococcal urethritis):

• Azithromycin 1 g orally single dose OR doxycycline 100 mg orally twice daily for 7 days 3, 1, 2
• Azithromycin provides superior activity against M. genitalium compared to doxycycline 3, 4, 2

When Diagnostic Tools Are Unavailable or Patient Is High-Risk for Loss to Follow-Up:

Treat empirically for both gonorrhea and chlamydia with ceftriaxone 250 mg IM single dose PLUS doxycycline 100 mg orally twice daily for 7 days (or azithromycin 1 g orally single dose). 3, 1, 4

• High-risk patients include adolescents with multiple partners or anyone unlikely to return for follow-up 3, 1, 2
• Medications should be dispensed on-site and the first dose directly observed to maximize adherence 3, 4

Alternative Regimens for Non-Gonococcal Urethritis

When first-line agents are contraindicated: 3, 2

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

Critical caveat: Fluoroquinolones should never be used for gonorrhea due to widespread resistance 4, 2

Partner Management (Non-Negotiable)

All sexual partners within the preceding 60 days must be evaluated and treated with the same regimen, regardless of symptoms or test results. 1, 4, 2

• Failure to treat partners is the leading cause of persistent or recurrent urethritis 1, 2
• Both patient and all partners must abstain from sexual intercourse for 7 days after treatment initiation and until symptoms have completely resolved 3, 1, 4
• Partners should receive treatment for both gonorrhea and chlamydia even if the index patient tests positive for only one pathogen 4

Follow-Up Strategy

Patients should return for evaluation ONLY if symptoms persist or recur after completing therapy. 1, 4, 2

• Routine test-of-cure is not required for asymptomatic patients who completed the recommended regimen 4, 5
• Repeat testing should not be performed less than 3 weeks after treatment due to risk of false-positive results 5
• Persistent symptoms without objective signs (discharge, elevated WBC count) are insufficient to justify retreatment 1, 2
• All patients treated for sexually transmitted urethritis should have repeat screening in 3 months 5

Management of Treatment Failure

If symptoms persist after initial therapy: 1, 2

1. Re-confirm objective signs of urethritis before retreating (discharge, Gram stain, urine microscopy)
2. Assess for reinfection and treatment compliance
3. Test for Trichomonas vaginalis using NAAT on first-void urine or urethral swab 1, 2
4. Consider testing for herpes simplex virus 1
5. Consider tetracycline-resistant Ureaplasma urealyticum 4

Comprehensive STI Screening

All patients with urethritis should receive HIV counseling/testing and syphilis serology at the time of diagnosis. 1, 2

Critical Complications to Prevent

Untreated urethritis, especially due to C. trachomatis, can lead to: 1, 2

• Epididymitis
• Reactive arthritis (Reiter syndrome)
• Transmission to female partners with risk of pelvic inflammatory disease

Common Pitfalls to Avoid

• Never treat for gonorrhea alone without chlamydia coverage because co-infection is common 4
• Never use azithromycin 1 g as monotherapy for suspected gonococcal urethritis because it is insufficiently effective against gonorrhea 4
• Never delay treatment while awaiting laboratory results in patients with confirmed urethritis or those at high risk of loss to follow-up 4, 2
• Never use gentamicin or nitrofurantoin for urethritis as they have no role in STI management 4
• Never defer treatment in high-risk patients even when objective criteria are absent, as they are unlikely to return for follow-up 3, 2

Special Age Considerations

• Men <35 years: STI pathogens (C. trachomatis or N. gonorrhoeae) are the most common causes 2
• Men >35 years: Consider gram-negative enteric organisms (e.g., E. coli) especially with recent urinary instrumentation, surgery, or anatomic abnormalities 2