What is the recommended treatment for Mycoplasma genitalium infection in a non‑pregnant adult?

Treatment for Mycoplasma genitalium

For non-pregnant adults with confirmed Mycoplasma genitalium infection, treat with doxycycline 100 mg orally twice daily for 7 days followed immediately by resistance-guided therapy: azithromycin 500 mg on day 1, then 250 mg daily on days 2-5 if macrolide-susceptible, or moxifloxacin 400 mg once daily for 7 days if macrolide-resistant or resistance status unknown. 1, 2, 3

When to Test and Treat

Testing should be focused to avoid inappropriate antibiotic use:

• Test for M. genitalium in men with persistent or recurrent urethritis after standard chlamydia/gonorrhea treatment, women with cervicitis or mucopurulent cervical discharge, patients with proctitis, and those with pelvic inflammatory disease or epididymitis 1, 3
• Test sexual partners of patients diagnosed with M. genitalium 1, 3
• Do not test asymptomatic patients, including pregnant women without known exposure, as treatment of asymptomatic infection is not indicated and promotes resistance 1, 3

First-Line Treatment Algorithm

The sequential two-step approach maximizes cure rates while minimizing resistance selection:

Step 1: Doxycycline Pre-Treatment

• Doxycycline 100 mg orally twice daily for 7 days reduces bacterial load by approximately 2.6 log₁₀ copies, decreasing the risk of macrolide resistance selection during subsequent azithromycin therapy 2
• Doxycycline alone achieves only 30-40% cure rates, so it must be followed by definitive therapy 1

Step 2: Resistance-Guided Therapy

If macrolide resistance testing is available:

• Macrolide-susceptible infections: Azithromycin 500 mg orally on day 1, then 250 mg daily on days 2-5 (total 2.5 g over 5 days) achieves 85-95% cure rates 1, 2
• Macrolide-resistant infections: Moxifloxacin 400 mg orally once daily for 7 days achieves 92% cure rates 1, 2

If resistance testing is unavailable (most U.S. settings):

• Moxifloxacin 400 mg orally once daily for 7 days is recommended as the safer empiric choice given that macrolide resistance now affects 40-70% of M. genitalium infections globally 1, 3
• The CDC recommends moxifloxacin when resistance status is unknown to avoid treatment failure 3

Alternative and Salvage Regimens

When first-line and second-line therapies fail:

• Doxycycline or minocycline 100 mg orally twice daily for 14 days may cure 40-70% of persistent infections 1
• Pristinamycin 1 g orally four times daily for 10 days achieves approximately 75% cure rates for multidrug-resistant infections, though availability is limited 1
• Sitafloxacin 100 mg orally twice daily for 7 days demonstrated 92% cure rates in macrolide-resistant infections in one prospective study 2

Treatment of Complicated Infections

For upper genital tract disease (pelvic inflammatory disease, epididymitis):

• Moxifloxacin 400 mg orally once daily for 14 days (extended duration compared to uncomplicated infection) 1
• Always test and treat concurrently for Chlamydia trachomatis and Neisseria gonorrhoeae, as coinfection rates are substantial and undertreating these organisms leads to treatment failure 4

Pregnancy Considerations

• Azithromycin is first-line treatment for M. genitalium in pregnancy, though optimal dosing remains uncertain 5
• All four international guidelines reviewed recommend azithromycin and advise against moxifloxacin use in pregnancy 5
• Dosing schedules vary: some recommend 1 g single dose, others recommend extended regimens (500 mg day 1, then 250 mg daily for 4 days) 5
• Moxifloxacin is contraindicated in pregnancy due to potential fetal harm 5, 1
• Safety data for pristinamycin in pregnancy is inconsistent and insufficient 5

Partner Management and Sexual Activity

• All sexual partners from the preceding 60 days must be evaluated, tested, and empirically treated with the same regimen as the index patient 4, 1
• Patients must abstain from all sexual intercourse for 7 days after completing the full treatment course and until all partners have been treated to prevent reinfection 1

Test of Cure and Follow-Up

• Test of cure is mandatory 14-90 days after completing the second antibiotic (not after doxycycline alone) 2
• Testing before 14 days may yield false-positive results from residual bacterial DNA 2
• Use nucleic acid amplification testing (NAAT) for test of cure; culture is not clinically available 1, 3
• Retest at 3 months if symptoms recur or reinfection is suspected 1

Critical Pitfalls to Avoid

• Do not use azithromycin 1 g single dose (the standard chlamydia regimen)—this suboptimal dosing drives macrolide resistance selection and has lower cure rates than extended azithromycin regimens 6, 1
• Do not treat asymptomatic patients without known exposure, as this promotes antimicrobial resistance without proven benefit 1, 3
• Do not use doxycycline monotherapy—it achieves only 30-40% cure and must be followed by azithromycin or moxifloxacin 1
• Do not assume partners were treated—directly verify or use expedited partner therapy, as failing to treat partners leads to reinfection in up to 20% of cases 4
• Do not retreat empirically without test of cure—document microbiologic failure before switching to salvage therapy 1, 2

Resistance Considerations

• Macrolide resistance is present in 40-70% of M. genitalium infections in many populations and is strongly associated with azithromycin treatment failure 6, 1
• Fluoroquinolone resistance is emerging, with first cases of moxifloxacin failure due to coexistent macrolide and fluoroquinolone resistance mutations reported 6
• Resistance-guided therapy using macrolide resistance assays reduces treatment failure and minimizes resistance selection (only 2.6% developed macrolide resistance with guided therapy vs. higher rates with empiric azithromycin) 2
• Currently, no FDA-approved macrolide resistance tests are widely available in the United States, necessitating empiric moxifloxacin in most settings 3