What is the next step in managing a 21-year-old male with symptoms of penile ache, urinary frequency, and urgency, without dysuria, and a normal urine culture and analysis, considering the potential for sexually transmitted infections (STIs)?

Management of Urethritis with Normal Urine Culture

In a 21-year-old male with penile ache, urinary frequency, and urgency but normal urine culture and analysis, you should immediately initiate empiric treatment for sexually transmitted urethritis with doxycycline 100 mg orally twice daily for 7 days, plus ceftriaxone 500 mg IM single dose to cover both chlamydia and gonorrhea. 1

Why Standard Urine Testing Misses STI-Related Urethritis

• Normal urine culture and analysis does NOT rule out sexually transmitted urethritis in young men. In sexually active men under 35 years, the most common causes of urethritis are Chlamydia trachomatis and Neisseria gonorrhoeae, which originate from urethral pathogens rather than urinary tract bacteria. 2

• Standard urinalysis frequently misses STI-related urethritis because these infections may not produce significant pyuria, and urine culture is designed to detect bladder infections, not urethral sexually transmitted pathogens. 2

• Neither nonculture tests nor tissue culture isolation are sufficiently sensitive to rule out chlamydial infection based solely on a negative test result. 3

Proper Diagnostic Approach

Before or concurrent with treatment, obtain:

• Urethral swab testing using nucleic acid amplification testing (NAAT) for N. gonorrhoeae and C. trachomatis on intraurethral swab or first-void urine. 2

• A urethral Gram stain showing ≥5 polymorphonuclear leukocytes per oil immersion field confirms urethritis. 1

• The leukocyte esterase test (LET) can screen for urethritis in sexually active young males, with sensitivities ranging from 46% to 100%, though patients with positive results still require specific testing for C. trachomatis and N. gonorrhoeae. 3

Treatment Protocol

First-line empiric therapy (start immediately without waiting for test results):

• Doxycycline 100 mg orally twice daily for 7 days PLUS ceftriaxone 500 mg IM single dose (or cefixime 400 mg orally single dose if IM not feasible). 1, 4

• This dual therapy covers both nongonococcal urethritis (primarily chlamydia, Ureaplasma urealyticum, Mycoplasma genitalium) and gonorrhea. 1

Alternative regimens if doxycycline is contraindicated:

• Erythromycin base 500 mg orally 4 times daily for 7 days OR erythromycin ethylsuccinate 800 mg orally 4 times daily for 7 days. 1

Critical Clinical Pitfalls

• Do not wait for test results to initiate treatment. The CDC explicitly recommends starting treatment immediately in symptomatic young men, as delays increase transmission risk and potential complications. 1

• The absence of dysuria does not exclude urethritis. Many STI-related urethral infections are asymptomatic or present with minimal symptoms like frequency, urgency, or penile discomfort without classic burning. 1

• Penile ache and urinary frequency/urgency without dysuria is consistent with urethritis. The presence of a "wet feeling in underwear" (urethral discharge) is a hallmark of urethritis, even when dysuria is absent. 1

Partner Management

• All sexual partners within the preceding 60 days require evaluation and empiric treatment with the same chlamydia-effective regimen, even if the patient's specific etiology remains unknown. 1

• For symptomatic patients, partners with last sexual contact within 30 days of symptom onset should be prioritized. 3

• Patients must abstain from sexual intercourse until both they and their partners complete treatment and are symptom-free. 3

Follow-Up Strategy

• Patients should return for evaluation only if symptoms persist or recur after completing therapy. 1

• If no improvement occurs within 3 days of starting treatment, re-evaluate the diagnosis and consider:

  • Treatment failure due to non-compliance or re-exposure to untreated partner 3
  • Tetracycline-resistant U. urealyticum (extend treatment to 14 days with erythromycin base 500 mg orally 4 times daily) 3
  • Alternative diagnoses including Trichomonas vaginalis (requires wet mount examination and culture) 3

• If symptoms persist beyond 3 months despite appropriate treatment, consider chronic prostatitis/chronic pelvic pain syndrome and refer to urology for further evaluation. 1

Why This Approach Prioritizes Morbidity and Mortality

• Untreated chlamydial and gonococcal urethritis leads to serious complications including epididymitis, prostatitis, and transmission to sexual partners who may develop pelvic inflammatory disease and infertility. 1

• Early empiric treatment prevents these complications and interrupts transmission chains, particularly important given that C. trachomatis causes only 23-55% of NGU cases, with other pathogens like U. urealyticum (20-40%) and M. genitalium also contributing. 1

• The high specificity (97% to >99%) of positive tests in symptomatic young men with urethritis justifies immediate empiric treatment even before confirmatory testing. 3