What is the best course of treatment for a 22-year-old male with dysuria (painful urination) and discharge, who has tested negative for chlamydia, gonorrhea, and has a negative urine culture?

Treatment of Dysuria and Discharge with Negative Testing

Treat this patient empirically for non-gonococcal urethritis (NGU) with doxycycline 100 mg orally twice daily for 7 days, as this represents the first-line therapy for culture-negative urethritis in sexually active young men. 1, 2, 3

Diagnostic Confirmation

Before initiating treatment, confirm that urethritis is actually present by documenting at least one of the following objective findings:

• Mucopurulent or purulent urethral discharge on examination 4
• ≥5 white blood cells per oil immersion field on Gram stain of urethral secretions 4
• Positive leukocyte esterase test on first-void urine OR ≥10 WBCs per high-power field on microscopic examination of first-void urine 4

Critical caveat: If none of these objective signs are present, defer treatment and retest for N. gonorrhoeae and C. trachomatis with close follow-up, as symptoms alone without documented inflammation are insufficient for treatment 4. However, the absence of pyuria does not exclude sexually transmitted urethritis, as urethral swabs and first-catch urine have low sensitivity (29-62%) for detecting polymorphonuclear leukocytes in various pathogens 1.

Recommended Treatment Regimen

Doxycycline 100 mg orally twice daily for 7 days is the preferred first-line therapy 1, 2, 3:

• This regimen has replaced azithromycin 1 g single dose as first-line due to emerging antimicrobial resistance concerns, particularly with Mycoplasma genitalium 1, 3
• Doxycycline should be taken with adequate fluids to reduce esophageal irritation risk 2
• If gastric irritation occurs, administer with food or milk, as absorption is not significantly affected 2

Alternative regimen if doxycycline cannot be used:

• Azithromycin extended course: 500 mg orally as a single dose on day 1, then 250 mg daily for 4 additional days (total 5 days) 1, 3
• This extended azithromycin regimen is preferred over the traditional 1 g single dose to reduce resistance development 3

Likely Etiologies in This Clinical Scenario

With negative testing for chlamydia, gonorrhea, and negative urine culture, the most probable causes include:

• Mycoplasma genitalium - implicated in up to one-third of NGU cases 4
• Ureaplasma urealyticum - another common cause of nonchlamydial NGU 4, 2
• Trichomonas vaginalis - occasionally causes NGU 4
• Herpes simplex virus - can cause NGU in some cases 4

Important note: Specific diagnostic tests for M. genitalium and U. urealyticum are not routinely indicated in initial management because detection is difficult and would not alter first-line therapy 4. However, testing for M. genitalium becomes important if symptoms persist after initial treatment 1, 3.

Essential Management Steps

Partner management:

• Refer all sexual partners from the preceding 60 days for evaluation and treatment 4, 1
• Partners should receive the same empiric treatment regimen even if asymptomatic 4

Sexual abstinence:

• Instruct the patient to abstain from sexual intercourse until 7 days after therapy is initiated 4
• Both patient and partners must complete treatment before resuming sexual activity 4

Follow-up instructions:

• Return for evaluation only if symptoms persist or recur after completing therapy 4
• Symptoms alone without objective signs of urethral inflammation are not sufficient basis for re-treatment 4

Management of Persistent or Recurrent Symptoms

If symptoms persist after completing the initial 7-day doxycycline course:

• First, assess compliance and re-exposure: If the patient did not complete treatment or was re-exposed to an untreated partner, re-treat with the initial regimen 4

• If compliant and no re-exposure occurred:

  • Perform wet mount examination and culture of intraurethral swab for T. vaginalis 4
  • Consider testing for M. genitalium if not previously done, as this pathogen shows extremely high treatment failure rates (60-70%) with standard regimens 1, 3, 5
  • Treat with metronidazole 2 g orally single dose PLUS erythromycin base 500 mg orally four times daily for 7 days 4

• For confirmed M. genitalium with macrolide resistance: Consider moxifloxacin 400 mg daily for 7-14 days 1

Common Pitfalls to Avoid

• Do not treat based on symptoms alone without documenting objective signs of urethritis, as this leads to unnecessary antibiotic exposure 4
• Avoid azithromycin 1 g single dose as first-line therapy due to resistance concerns, particularly with M. genitalium 1, 3
• Do not perform routine testing for U. urealyticum or M. genitalium in initial management, as it does not change first-line treatment 4
• Ensure partner treatment to prevent reinfection, which is a major cause of persistent symptoms 4, 1