What is the recommended treatment for Mycoplasma genitalium?

Treatment for Mycoplasma genitalium

First-line treatment for Mycoplasma genitalium is azithromycin 500 mg orally on day 1, followed by 250 mg daily for days 2-5 (total 1.5 g extended regimen), which achieves 93-99% cure rates while minimizing macrolide resistance development. 1

Diagnostic Testing Before Treatment

• Perform nucleic acid amplification testing (NAAT) to confirm M. genitalium infection before initiating therapy. 1
• Test simultaneously for gonorrhea and chlamydia, as co-infections are common and require different treatment approaches. 1
• If available, obtain macrolide resistance testing to guide antibiotic selection, as resistance now exceeds 50% in many regions. 2, 3, 4

First-Line Treatment Algorithm

For Macrolide-Susceptible or Unknown Resistance Status:

• Azithromycin 500 mg orally on day 1, then 250 mg orally daily for days 2-5 (extended regimen, total 1.5 g). 1, 2, 3
• This extended regimen is superior to the single 1 g dose, with cure rates of 95-99% versus 85-95%. 2, 3, 5
• The extended regimen prevents development of macrolide resistance, whereas the 1 g single dose induces resistance in 100% of treatment failures. 5

Critical Pitfall to Avoid:

Do not use azithromycin 1 g single dose for M. genitalium, despite its listing in older guidelines. 1 This regimen has lower efficacy and drives macrolide resistance development in all treatment failures. 5 The 2024 European Association of Urology guidelines list only the extended regimen. 1

Second-Line Treatment (Macrolide-Resistant Infections)

For Confirmed Macrolide Resistance or Treatment Failure:

• Moxifloxacin 400 mg orally once daily for 7-14 days. 1, 2, 3
• Use 7 days for uncomplicated urethritis/cervicitis. 1, 3
• Use 14 days for complicated infections (pelvic inflammatory disease, epididymitis). 2, 3
• Cure rate is 92% when used as resistance-guided therapy. 4

Important Caveat:

Quinolone resistance is increasing (22% of macrolide-resistant cases have ParC mutations), threatening moxifloxacin efficacy. 4 However, it remains the best second-line option currently available.

Third-Line Treatment (Persistent Infection)

After Both Azithromycin and Moxifloxacin Failure:

• Doxycycline 100 mg orally twice daily for 14 days may cure 40-70% of persistent infections. 3
• Pristinamycin 1 g orally four times daily for 10 days achieves approximately 75-90% cure rates. 2, 3

Why Doxycycline Is Not First-Line:

Doxycycline monotherapy has only 30-40% cure rate for M. genitalium (43% in clinical studies), making it inadequate as initial therapy. 2, 3, 6, 5 However, it does not induce resistance and may have a role in persistent infections. 2, 3

Resistance-Guided Sequential Therapy (Emerging Strategy)

Pre-treatment with doxycycline 100 mg twice daily for 7 days followed by resistance-guided therapy (azithromycin 2.5 g for susceptible strains or moxifloxacin for resistant strains) achieves 95% cure rates. 3, 4 This approach may decrease organism load and reduce macrolide resistance selection. 3

Patient Instructions and Follow-Up

• Patients must abstain from sexual intercourse for 7 days after completing single-dose therapy or until completion of multi-day regimens. 1
• Sexual partners require evaluation and treatment to prevent reinfection, even if asymptomatic. 1
• Test of cure is not routinely recommended if symptoms resolve with first-line therapy. 1
• Patients should return for evaluation if symptoms persist or recur, as this indicates treatment failure requiring resistance testing and alternative therapy. 1
• Repeat testing at 3-6 months is recommended due to high reinfection rates. 1

Key Differences Between Guidelines

The 2024 European Association of Urology guidelines 1 list only azithromycin 500 mg on day 1 (without specifying the extended regimen duration) for M. genitalium, while the 2021 European guideline 3 and 2016 European guideline 2 explicitly recommend the full 5-day extended regimen. The older 2010 CDC guidelines 1 recommend azithromycin 1 g single dose, which is now known to be suboptimal. Follow the extended 5-day azithromycin regimen based on the most recent high-quality evidence. 2, 3, 4, 5