Diagnostic Work-Up and Treatment for Suspected Mycoplasma genitalium Urethritis
Immediate Diagnostic Confirmation
For a patient with urethral discharge, dysuria, and Gram stain showing ≥5 leukocytes per high-power field without intracellular gram-negative diplococci, you should immediately obtain nucleic acid amplification tests (NAATs) for both Chlamydia trachomatis and Mycoplasma genitalium, with resistance testing for M. genitalium if available, and initiate empiric treatment with azithromycin 500 mg on day 1, then 250 mg on days 2-5. 1, 2
The absence of intracellular gram-negative diplococci effectively rules out gonococcal urethritis (which has >99% specificity when present), making this a case of nongonococcal urethritis (NGU). 3 The presence of ≥5 WBCs per oil immersion field confirms urethritis and warrants treatment. 1, 4
Specific Diagnostic Testing Required
Order NAATs for C. trachomatis and M. genitalium on either urethral swab or first-void urine specimen, as these are the two most likely pathogens in nonchlamydial NGU. 4, 5
Request macrolide resistance mutation testing for M. genitalium if your laboratory offers it, as 62% of M. genitalium infections may harbor macrolide resistance-mediating mutations (MRMM). 2, 6
Obtain comprehensive STI screening including syphilis serology and HIV testing, as all patients diagnosed with a new STD should receive testing for other STDs. 7, 3
Consider testing for Trichomonas vaginalis using NAAT if symptoms persist after initial treatment, particularly since this can cause persistent urethritis. 7, 5
Empiric Treatment Strategy
First-Line Treatment
Azithromycin 500 mg orally on day 1, then 250 mg orally on days 2-5 is the preferred regimen when M. genitalium is suspected. 2 This extended azithromycin course has a higher cure rate (85-95% for macrolide-susceptible infections) compared to single-dose therapy. 2, 8
The extended 5-day azithromycin regimen is superior to the single 1-gram dose for M. genitalium, with all 20 patients in one study achieving microbiological cure with the 1.5g over 5 days regimen. 8
Avoid doxycycline as monotherapy if M. genitalium is strongly suspected, as it has only a 30-40% cure rate for this organism, though it remains effective for chlamydial urethritis. 2, 8
Critical Caveat About Azithromycin
While CDC guidelines from 2006 recommend either azithromycin 1g single dose or doxycycline 100mg twice daily for 7 days for NGU 1, more recent European guidelines specifically warn against single-dose azithromycin without resistance testing, as this approach selects for macrolide-resistant M. genitalium strains in the population. 2 The extended 5-day azithromycin course represents a compromise between efficacy and resistance prevention.
Management of Treatment Failure
If Symptoms Persist After Azithromycin
Re-document urethritis using the same microscopic criteria (≥5 WBCs per oil immersion field) before prescribing additional antibiotics. 1
Obtain test of cure for M. genitalium no earlier than 3 weeks after starting treatment, as the organism may persist asymptomatically for 89-186 days after symptom resolution. 5, 6
Prescribe moxifloxacin 400 mg orally once daily for 7-14 days if M. genitalium persists or if macrolide resistance is documented. 2 This is effective as second-line therapy, though fluoroquinolone resistance is increasing. 2
If Symptoms Persist After Doxycycline (If Used)
M. genitalium is detected in 41% of men with persistent or recurrent urethritis after doxycycline treatment. 8
Switch to azithromycin 500 mg day 1, then 250 mg days 2-5 if doxycycline was used initially, as azithromycin is significantly more effective for M. genitalium eradication. 8
Partner Management
Refer all sexual partners from the preceding 60 days for evaluation and treatment with the same regimen, even if asymptomatic. 1, 5
Female partners have a 67% positivity rate when the male partner has M. genitalium, and all should be treated presumptively. 8
Instruct the patient to abstain from sexual intercourse until 7 days after therapy is initiated AND symptoms have resolved AND partners have been adequately treated. 1
Key Clinical Pitfalls to Avoid
Do not assume symptom resolution equals microbiological cure with M. genitalium—the organism can persist asymptomatically for months (median 143 days, range 21-228 days) after azithromycin treatment, particularly with macrolide-resistant strains. 6
Do not use single-dose azithromycin 1g as first-line therapy when M. genitalium is suspected, despite older CDC recommendations, as the extended 5-day course has superior efficacy and may reduce resistance selection. 2, 8
Do not prescribe additional antibiotics for persistent symptoms without re-documenting urethritis, as extending antimicrobial duration without objective signs of inflammation has not demonstrated value. 7, 1
Do not overlook reinfection or non-compliance as causes of persistent urethritis before escalating to second-line therapy. 7, 5