Next Diagnostic Step for Recurrent Dysuria with Negative Gonorrhea/Chlamydia Testing
The next diagnostic maneuver is to test for Mycoplasma genitalium and Trichomonas vaginalis using nucleic acid amplification testing (NAAT) or culture on urethral swab or first-void urine specimens. 1, 2
Confirm Objective Evidence of Urethritis
Before proceeding with additional testing or treatment, you must document objective signs of urethral inflammation 1:
- Perform microscopy on a first-void urine specimen or urethral swab to demonstrate ≥10 white blood cells per high-power field 1
- Check leukocyte esterase on first-void urine as an alternative if microscopy is unavailable 1
- Look for visible urethral discharge (mucopurulent or purulent material) 1
Critical pitfall: Symptoms alone without objective evidence of inflammation are not sufficient to justify retreatment or additional antimicrobial therapy 1. Many patients have persistent symptoms without active urethritis.
Specific Pathogen Testing for Persistent/Recurrent Cases
Once urethritis is confirmed, the CDC guidelines recommend testing for additional organisms that cause non-gonococcal urethritis 1:
Primary Testing Targets:
- Trichomonas vaginalis: Obtain urethral swab, first-void urine, or semen for culture or NAAT (PCR or TMA) 1
- Mycoplasma genitalium: NAAT testing on urethral swab or urine specimen 1, 3, 2
Additional Considerations:
- Herpes simplex virus (HSV): If vesicular lesions, ulcers, or mononuclear leukocytes on microscopy are present 1, 3
- Adenovirus: Consider if viral etiology suspected based on clinical presentation 3
Assess for Treatment Failure Factors
Before attributing symptoms to a new pathogen, evaluate 1:
- Compliance with initial treatment regimen: Did the patient complete the full course of doxycycline or take azithromycin as prescribed?
- Partner treatment status: Was the partner evaluated and treated? Reexposure to untreated partners is a common cause of recurrent symptoms 1
- Timing of sexual activity: Did the patient abstain from intercourse for 7 days after treatment initiation? 1
Empiric Treatment While Awaiting Results
If objective urethritis is confirmed and compliance/reexposure are excluded, the CDC recommends empiric treatment while awaiting M. genitalium and T. vaginalis test results 1:
- Metronidazole 2 g orally single dose OR Tinidazole 2 g orally single dose (for T. vaginalis) 1
- PLUS Azithromycin 1 g orally single dose (if not used initially, for M. genitalium) 1
Important note: Men who have sex with men have low probability of T. vaginalis and are unlikely to benefit from metronidazole/tinidazole 1.
Alternative for Confirmed M. genitalium
If M. genitalium is confirmed and symptoms persist after azithromycin 1, 3:
- Moxifloxacin 400 mg orally once daily for 7-14 days is highly effective, particularly for macrolide-resistant strains 1, 3
Consider Non-Infectious Causes
If all infectious workup is negative and symptoms persist beyond 3 months, consider 1:
- Chronic prostatitis/chronic pelvic pain syndrome: Characterized by persistent perineal, penile, or pelvic pain, irritative voiding symptoms, pain during/after ejaculation, or new-onset premature ejaculation 1
- Four-glass Meares-Stamey test: May help localize pathogens to the prostate in select cases 1