What is the differential diagnosis and treatment approach for a male presenting with symptoms of a sexually transmitted infection (STI)?

Differential Diagnosis of STI in Males

When a male presents with symptoms suggestive of an STI, the primary differential diagnosis includes urethritis (gonococcal or non-gonococcal), epididymitis, genital ulcer disease, and genital warts, with the specific diagnosis guided by presenting symptoms and age-based risk stratification.

Clinical Presentation-Based Differential Diagnosis

Urethritis (Most Common Presentation)

Urethritis is characterized by mucopurulent or purulent urethral discharge and/or dysuria, though asymptomatic infections are common 1.

Primary pathogens:

• Neisseria gonorrhoeae (gonococcal urethritis) 1
• Chlamydia trachomatis (most frequent cause of non-gonococcal urethritis, accounting for 23-55% of cases) 1
• Ureaplasma urealyticum and Mycoplasma genitalium (implicated in up to one-third of non-chlamydial NGU cases) 1
• Trichomonas vaginalis and HSV (less common causes) 1

Diagnostic approach:

• Gram-stained smear of urethral exudate showing ≥5 polymorphonuclear leukocytes per oil immersion field confirms urethritis 1
• Gram-negative intracellular diplococci on Gram stain suggests gonococcal infection 1
• Nucleic acid amplification testing (NAAT) on first-void urine or urethral swab for N. gonorrhoeae and C. trachomatis 1
• If urethral Gram stain is negative, examine first-void urine for leukocytes 1

Epididymitis (Age-Stratified Etiology)

In sexually active men <35 years, epididymitis is most often caused by C. trachomatis or N. gonorrhoeae 1.

In men >35 years or those with recent urinary instrumentation, Gram-negative enteric organisms predominate 1.

Special population: Among men who have sex with men (MSM) who are insertive partners during anal intercourse, E. coli can cause sexually transmitted epididymitis 1.

Clinical features:

• Unilateral testicular pain and tenderness 1
• Palpable swelling of the epididymis and hydrocele 1
• Usually accompanied by urethritis (often asymptomatic) 1

Critical differential: Testicular torsion must be ruled out emergently, especially in adolescents, when pain onset is sudden and severe 2.

Genital Ulcer Disease

Primary causes in males:

• Treponema pallidum (syphilis) - painless ulcer with indurated borders 1
• Haemophilus ducreyi (chancroid) - painful ulcer 3
• Herpes simplex virus - painful vesicular lesions 4, 5

Note: Efficacy of azithromycin for chancroid in women has not been established due to small numbers in clinical trials 3.

Genital Warts

Caused by HPV types 6 or 11 1.

Other HPV types (16,18,31,33,35) are associated with dysplasia but not visible warts 1.

Diagnostic Workup Algorithm

Initial Evaluation for All Suspected STIs

1. Urethral assessment:

   • Gram stain of urethral exudate or intraurethral swab 1
   • NAAT for N. gonorrhoeae and C. trachomatis on urethral swab or first-void urine 1

2. Mandatory additional testing:

   • Syphilis serology 1
   • HIV counseling and testing 1

3. For MSM, test extragenital sites:

   • Rectal and oropharyngeal specimens for N. gonorrhoeae and C. trachomatis 1

Age-Based Risk Stratification for Epididymitis

• <35 years: Presume sexually transmitted etiology (C. trachomatis, N. gonorrhoeae) 1
• >35 years: Consider enteric organisms, especially with history of urinary instrumentation or anatomical abnormalities 1

Treatment Approach

Urethritis

Empiric therapy is indicated before culture results are available 1.

For gonococcal or suspected gonococcal urethritis:

• Ceftriaxone 250 mg IM single dose PLUS doxycycline 100 mg orally twice daily for 10 days 1, 2

For non-gonococcal urethritis:

• Doxycycline 100 mg orally twice daily for 10 days 1
• Alternative: Azithromycin (though resistance is increasing) 3

Epididymitis

For sexually transmitted epididymitis (age <35 years):

• Ceftriaxone 250 mg IM single dose PLUS doxycycline 100 mg orally twice daily for 10 days 1, 2

For enteric organism-related epididymitis (age >35 years) or penicillin allergy:

• Ofloxacin 300 mg orally twice daily for 10 days OR levofloxacin 500 mg orally once daily for 10 days 1, 2

Adjunctive therapy:

• Bed rest, scrotal elevation, and analgesics until fever and inflammation subside 1, 2

Genital Ulcer Disease

For chancroid:

• Azithromycin is FDA-approved for genital ulcer disease in men due to H. ducreyi 3

Critical caveat: Azithromycin at recommended doses should not be relied upon to treat syphilis 3. All patients with sexually transmitted urethritis or cervicitis require serologic testing for syphilis at diagnosis 3.

Follow-Up and Partner Management

Follow-Up Timing

Reevaluation is necessary if no improvement occurs within 3 days of treatment initiation 1, 2.

Persistent symptoms after completing therapy require comprehensive evaluation for:

• Tumor, abscess, infarction, testicular cancer 1, 2
• Tuberculous or fungal epididymitis 1, 2

Partner Notification and Treatment

Sex partners should be evaluated and treated if contact occurred within 60 days preceding symptom onset 1, 2.

For symptomatic male urethritis, a 30-day exposure period is sufficient 1.

Patients must avoid sexual intercourse until they and their partners complete treatment and are symptom-free 1, 2.

Common Pitfalls and Caveats

Antimicrobial Resistance Concerns

High-dose, short-course antimicrobials for non-gonococcal urethritis may mask or delay symptoms of incubating syphilis 3. Always perform syphilis serology at initial diagnosis 3.

Frequent screening in high-prevalence populations (e.g., MSM on HIV PrEP) increases antimicrobial consumption and resistance risk 6.

Reinfection vs. Treatment Failure

Patients who "fail" therapy and have persistent positive tests are most likely reinfected by untreated partners 1. This underscores the critical importance of partner treatment 1.

Special Populations

HIV-positive patients with uncomplicated epididymitis receive the same treatment as HIV-negative patients 1, 2.

However, fungi and mycobacteria are more likely causes in immunosuppressed patients 1, 2.

Hospitalization Indications

Consider hospitalization for epididymitis when:

• Severe pain suggests alternative diagnoses (torsion, testicular infarction, abscess) 1
• Patient is febrile 1
• Concern for non-compliance with antimicrobial regimen 1

Diagnostic Limitations

Despite comprehensive testing, 25-40% of genital infection causes may not be specifically identified 1.

Chlamydia tests for asymptomatic males have variable sensitivity (46-100%) 1.