What is the best course of action for a male patient with persistent pruritus (itching) inside the penis for 2 weeks, with negative sexually transmitted disease (STD) tests and no known past medical history?

Management of Persistent Penile Pruritus with Negative STD Testing

For a male patient with 2 weeks of internal penile itching and negative STD tests, the most likely diagnosis is non-infectious urethritis or a localized dermatological condition, and treatment should begin with topical hydrocortisone for symptomatic relief while pursuing further diagnostic evaluation to exclude non-STD causes. 1, 2

Immediate Diagnostic Considerations

The negative STD panel does not exclude all causes of penile pruritus. You must now systematically evaluate for:

• Non-gonococcal urethritis (NGU) - Even with negative initial STD tests, urethritis can be present without discharge. Confirm urethritis by examining for ≥5 polymorphonuclear leukocytes per oil immersion field on urethral swab or ≥10 WBC per high-power field on first-void urine microscopy 3, 4

• Contact dermatitis or irritant balanitis - "Over-treatment balanitis" from excessive hygiene or soap use is a common cause of persistent penile itching without infection 5

• Fixed drug eruption - If the patient recently started any medications (especially antibiotics like trimethoprim-sulfamethoxazole), this can cause intense penile itching and burning 6

• Localized scabies - Rare but documented cases of scabies isolated to the genital region can occur even in immunocompetent patients, presenting as continuous pruritus 7

Essential Next Steps in Evaluation

Obtain a detailed history focusing on:

• Recent medication use (within past 2-4 weeks) to identify potential fixed drug eruption 6
• Hygiene practices - excessive washing with soap can cause irritant dermatitis 5
• Sexual contacts within the past 60 days, as some organisms causing NGU may not be detected on standard STD panels 4
• Presence of any visible lesions, discharge, or dysuria 1

Physical examination must include:

• Inspection of the entire penile shaft, glans, and urethral meatus for erythema, excoriation, nodules, or vesicles 8, 9
• Examination for urethral discharge (even minimal mucoid discharge suggests urethritis) 4
• Digital rectal exam to assess for prostate tenderness if any voiding symptoms are present 1

Laboratory testing should include:

• Urinalysis with microscopy on first-void urine to detect pyuria suggesting urethritis 1, 4
• Nucleic acid amplification testing (NAAT) for Chlamydia trachomatis if not already performed, as it is more sensitive than culture 3, 4
• Consider testing for Mycoplasma genitalium and Ureaplasma urealyticum, which cause 20-40% of NGU cases but are not detected on standard STD panels 3

Treatment Algorithm

If Urethritis is Confirmed (≥5 WBC on urethral smear or ≥10 WBC on urine microscopy):

Treat empirically for non-gonococcal urethritis:

• First-line: Doxycycline 100mg orally twice daily for 7 days 4
• Alternative: Azithromycin 1g orally as a single dose (particularly effective against Mycoplasma genitalium) 4
• Partners within the preceding 60 days must be treated, and the patient should abstain from sexual activity for 7 days after treatment initiation 4

If No Urethritis is Found (Normal Urinalysis and No Discharge):

Initiate symptomatic treatment with topical therapy:

• Hydrocortisone 1% cream applied to the affected area 3-4 times daily for external genital itching 2
• Discontinue all soaps and irritants; clean with water only 5
• If a recent medication is identified, discontinue it immediately and treat as fixed drug eruption with topical corticosteroids 6

If Symptoms Persist Beyond 2-4 Weeks Despite Treatment:

• Consider empiric treatment for scabies with permethrin 5% cream applied from neck down and washed off after 8-14 hours, OR ivermectin 200 mcg/kg orally repeated in 2 weeks 3, 7
• Perform penile punch biopsy if diagnostic uncertainty persists, particularly to exclude malignancy or chronic inflammatory conditions like lichen planus 10

Critical Pitfalls to Avoid

• Do not assume all penile itching is STD-related - The majority of persistent penile pruritus with negative STD tests is due to contact dermatitis, over-hygiene, or non-chlamydial NGU 5

• Do not overlook medication history - Fixed drug eruptions can occur 15 minutes to several days after drug exposure and cause intense genital itching that mimics infection 6

• Do not miss localized scabies - While rare, scabies can present with isolated genital pruritus even without typical body distribution 7

• Do not delay biopsy if uncertainty persists - Penile biopsy in a clinical setting is safe with minimal complications (17% minor complications in one series) and is indicated when diagnosis remains unclear after 2-4 weeks 10

Follow-Up Strategy

• Reassess at 1 week if symptoms persist or worsen despite initial treatment 3
• Re-evaluate at 4 weeks if symptoms continue, considering alternative diagnoses and potential need for biopsy 1, 10
• If urethritis was treated, test-of-cure is not needed if asymptomatic, but consider repeat testing at 3-6 months due to high reinfection rates 4