What is the differential diagnosis (Ddx) for a 25-year-old male with painless, odorless, yellowish penile discharge, considering sexually transmitted infections (STIs)?

Differential Diagnosis for Painless, Odorless, Yellowish Penile Discharge in a 25-Year-Old Male

The most likely diagnoses are nongonococcal urethritis (NGU) caused by Chlamydia trachomatis or gonococcal urethritis caused by Neisseria gonorrhoeae, with chlamydia being more consistent with the painless presentation. 1

Primary Infectious Etiologies

Most Common Pathogens

• Chlamydia trachomatis is the leading cause of NGU, accounting for 15-55% of cases, and typically presents with mucoid or mucopurulent discharge that can be painless 1, 2
• Neisseria gonorrhoeae causes gonococcal urethritis with purulent discharge, though it can occasionally be asymptomatic or minimally symptomatic 1
• The yellowish color suggests purulent or mucopurulent material, which is characteristic of both gonococcal and nongonococcal urethritis 1, 3

Other Bacterial Causes

• Mycoplasma genitalium causes approximately one-third of nonchlamydial NGU cases and presents similarly to chlamydia 1, 2, 4
• Ureaplasma urealyticum accounts for 20-40% of NGU cases 1
• These organisms are difficult to detect and do not alter initial empiric therapy 1

Less Common Pathogens

• Trichomonas vaginalis causes 2-5% of NGU cases and should be considered if initial treatment fails 1, 2, 4
• Herpes simplex virus occasionally causes NGU but typically presents with genital lesions 1
• Adenovirus is a rare cause of urethritis 2

Diagnostic Approach

Confirm Urethritis

• Document mucopurulent or purulent urethral discharge on examination 1, 5
• Perform Gram stain of urethral swab showing ≥5 white blood cells per oil immersion field 1, 5
• If urethral Gram stain is unavailable, examine first-void urine showing ≥10 white blood cells per high-power field or positive leukocyte esterase test 1, 2, 3

Identify Specific Pathogen

• Gram stain to identify intracellular Gram-negative diplococci confirms gonococcal urethritis 1, 5
• If Gram-negative intracellular diplococci are absent, diagnose as NGU 1
• Nucleic acid amplification tests (NAATs) on first-void urine or urethral swab for both N. gonorrhoeae and C. trachomatis are the preferred diagnostic method due to superior sensitivity 1, 5, 3

Additional Testing

• Syphilis serology should be performed in all patients with sexually transmitted urethritis 1
• HIV counseling and testing is recommended 1
• Culture for N. gonorrhoeae with susceptibility testing is essential due to emerging antibiotic resistance 4

Empiric Treatment Recommendations

Because both chlamydia and gonorrhea are common and testing results may not be immediately available, treat empirically for both organisms. 1, 2, 3

First-Line Regimen

• Ceftriaxone 250 mg IM single dose PLUS doxycycline 100 mg orally twice daily for 7 days 1, 6, 7, 2, 3
• This combination covers both gonococcal and nongonococcal urethritis, including chlamydia 2, 3

Alternative Regimens

• If doxycycline is contraindicated: azithromycin 1 gram orally as a single dose can be used for chlamydia, though doxycycline is preferred due to better efficacy 6, 8
• Erythromycin base 500 mg orally 4 times daily for 7 days is an alternative for NGU 1

Critical Pitfalls to Avoid

Partner Management

• All sexual partners from the preceding 60 days must be evaluated and treated to prevent reinfection 1, 5, 9
• Expedited partner treatment (providing prescriptions for untested partners) is advocated by the CDC and approved in many states 2
• Patients should abstain from sexual intercourse for 7 days after treatment initiation and until partners complete treatment 3

Coinfection Considerations

• Always test for syphilis, as antimicrobial agents used for urethritis may mask or delay symptoms of incubating syphilis 1, 6
• Asymptomatic infections are common with both gonorrhea and chlamydia, so partner notification is essential even if partners are asymptomatic 1

Follow-Up

• Patients should return if symptoms persist or recur after completing therapy 1
• Repeat testing should not be performed less than 3 weeks after treatment due to risk of false-positive results 3
• All patients treated for STIs should have repeat screening in 3 months due to high reinfection rates 3, 10

Treatment Failure

• If symptoms persist after initial treatment, consider re-treatment if patient was noncompliant or re-exposed to untreated partner 1
• If compliance was adequate, test for T. vaginalis and consider extended therapy with alternative regimen (erythromycin 500 mg orally 4 times daily for 14 days) 1
• Persistent symptoms may indicate M. genitalium infection, which requires different antimicrobial therapy 1, 4