What is the most likely diagnosis and appropriate first‑line treatment for a 26‑year‑old male presenting with pyuria, dysuria at the onset of micturition, and a colourless penile discharge?

Most Likely Diagnosis and First-Line Treatment

The most likely diagnosis is non-gonococcal urethritis (NGU), and the recommended first-line empiric treatment is ceftriaxone 250 mg IM single dose PLUS doxycycline 100 mg orally twice daily for 7 days. 1

Clinical Reasoning and Diagnosis

Classic Presentation of Urethritis

This 26-year-old male presents with the triad of urethritis:

• Pyuria (many pus cells in urine) 1, 2
• Dysuria at the start of micturition (urethral inflammation causes pain at onset of voiding) 1, 2
• Colorless penile discharge (mucopurulent or clear discharge is characteristic) 1, 2, 3

Distinguishing Gonococcal vs Non-Gonococcal Urethritis

In sexually active men aged <35 years, urethritis is most commonly caused by Chlamydia trachomatis or Neisseria gonorrhoeae. 1 However, the clinical presentation provides important clues:

• Colorless discharge more strongly suggests NGU (chlamydial or mycoplasmal), whereas gonococcal urethritis typically produces profuse purulent (yellow-green) discharge 2, 3
• Burning at the start of urination is consistent with urethral inflammation from either etiology 1, 2
• Many pus cells (>5 polymorphonuclear leukocytes per oil immersion field on Gram stain, or ≥10 WBCs per high-power field on urinalysis) confirms urethritis 1, 2, 3

Differential Diagnosis Considerations

The European Association of Urology guidelines emphasize that urethral infections are commonly transmitted via sexual contact, and it is crucial to differentiate between gonococcal urethritis (GU) and non-gonococcal urethritis (NGU). 1 NGU has various infectious etiologies including:

• Chlamydia trachomatis (20-50% of NGU cases) 4
• Mycoplasma genitalium (10-30% of NGU cases) 1, 4
• Ureaplasma urealyticum 1, 4
• Trichomonas vaginalis 1, 4
• Less commonly: HSV, adenovirus 4

Diagnostic Workup

Essential Immediate Testing

Before initiating treatment, the following diagnostic procedures should be performed: 1

1. Gram-stained smear of urethral exudate or intraurethral swab to diagnose urethritis (>5 polymorphonuclear leukocytes per oil immersion field) and for presumptive diagnosis of gonococcal infection 1

2. Nucleic acid amplification test (NAAT) on intraurethral swab or first-void urine for N. gonorrhoeae and C. trachomatis 1, 2

3. First-void uncentrifuged urine examination for leukocytes if urethral Gram stain is negative 1

4. Syphilis serology and HIV counseling/testing 1

Diagnostic Criteria

A diagnosis of urethritis can be made if at least one of the following is present: 2, 3

• Mucopurulent or purulent urethral discharge on examination 2
• Gram stain showing ≥2 WBCs per oil immersion field 2
• First-void urinalysis showing ≥10 WBCs per high-power field 2, 3
• Positive leukocyte esterase on first-void urine 2, 3

First-Line Empiric Treatment

Recommended Regimen

For epididymitis/urethritis most likely caused by gonococcal or chlamydial infection in men <35 years: 1

• Ceftriaxone 250 mg IM in a single dose 1, 5
• PLUS
• Doxycycline 100 mg orally twice daily for 10 days 1

Alternative first-line regimen (per recent guidelines): 2, 3

• Ceftriaxone 250 mg IM single dose 2, 3, 5
• PLUS
• Doxycycline 100 mg orally twice daily for 7 days 2, 3

Rationale for Dual Therapy

Empiric therapy must cover both N. gonorrhoeae and C. trachomatis because: 1, 3, 5

• Coinfection rates are high (up to 30-40%) 3, 5
• Clinical presentation alone cannot reliably distinguish between the two 2, 3
• Treatment delays while awaiting culture results can lead to complications 1
• Fluoroquinolones are no longer recommended due to widespread gonococcal resistance 5

Alternative Regimens

If the patient has severe tetracycline allergy or other contraindications: 1

• Ofloxacin 300 mg orally twice daily for 10 days (only if local resistance <10%) 1
• OR Levofloxacin 500 mg orally once daily for 10 days 1

However, do NOT use fluoroquinolones for empirical treatment if: 1

• The patient is from a urology department 1
• The patient has used fluoroquinolones in the last 6 months 1
• Local resistance rates are ≥10% 1

Adjunctive Therapy and Management

Symptomatic Relief

As an adjunct to antimicrobial therapy, recommend: 1

• Bed rest until fever and local inflammation subside 1
• Scrotal elevation (if epididymitis is present) 1
• Analgesics for pain control 1

Sexual Activity Restrictions

Patients treated for urethritis should: 2

• Abstain from sexual intercourse for 7 days after starting treatment 2
• Continue abstinence until all symptoms have fully resolved 2
• Ensure sexual partners have been adequately treated before resuming intercourse 2

Partner Management and Follow-Up

Contact Tracing

Patients with confirmed or suspected N. gonorrhoeae or C. trachomatis should be instructed to refer sexual partners for evaluation and treatment. 1 All sexual contacts from the preceding 60 days should be notified, examined, and treated with the same regimen 3, 5

Follow-Up Evaluation

Failure to improve within 3 days of initiating treatment requires reevaluation of both the diagnosis and therapy. 1 Specifically:

• Reassess for treatment compliance 4
• Consider reinfection from untreated partners 4
• Evaluate for resistant organisms (particularly M. genitalium) 4
• Rule out alternative diagnoses (testicular torsion, tumor, abscess) 1

Swelling and tenderness that persist after completion of antimicrobial therapy should be evaluated comprehensively, with differential diagnosis including tumor, abscess, infarction, testicular cancer, tuberculosis, and fungal epididymitis 1

Repeat Testing

Do NOT perform repeat testing less than 3 weeks after treatment completion because nucleic acid amplification tests can yield false-positive results during this period 2

Patients treated for a sexually transmitted infection should have repeat screening in 3 months due to high reinfection rates 2, 3, 5

Critical Pitfalls to Avoid

Common Errors in Management

1. Do NOT delay empiric treatment while awaiting laboratory results in patients with confirmed urethritis and marked symptoms 4

2. Do NOT use azithromycin 1 gram single dose as first-line therapy without M. genitalium testing and test-of-cure, as this will select for macrolide-resistant strains 4

3. Do NOT use fluoroquinolones empirically given widespread gonococcal resistance 1, 5

4. Do NOT assume urethritis is solely infectious—noninfectious causes exist, though they are less common in young sexually active men 1

5. Do NOT forget to screen for other STIs including syphilis and HIV, as urethritis is associated with increased HIV concentration in semen 1, 3

When to Consider Alternative Diagnoses

If symptoms do not improve after 3 days of appropriate therapy, consider: 1

• Epididymitis (unilateral testicular pain and tenderness, palpable epididymal swelling) 1
• Testicular torsion (surgical emergency, more common in adolescents, sudden severe pain) 1
• Prostatitis (perineal pain, obstructive voiding symptoms, tender prostate on DRE) 3
• Resistant organisms (particularly macrolide-resistant M. genitalium) 4

Special Considerations for This Patient

Age-Specific Risk Factors

In sexually active men aged <35 years, sexually transmitted pathogens (C. trachomatis and N. gonorrhoeae) are the most common causes of urethritis. 1 This patient's age places him squarely in this high-risk category.

Colorless Discharge Significance

The colorless (clear) discharge is more consistent with NGU than gonococcal urethritis, but empiric dual therapy is still mandatory because clinical features alone cannot reliably distinguish between etiologies 2, 3

Pyuria Without Bacteriuria

Many pus cells in urine with urethritis is expected, as urethral inflammation produces leukocytes that appear in first-void urine 1, 2, 3 This does NOT indicate a urinary tract infection requiring different antibiotic coverage.