What is the first‑line treatment for an adult with uncomplicated Mycoplasma urinary‑tract infection, and what alternatives should be used in pregnancy, breastfeeding, or tetracycline intolerance?

Mycoplasma Urinary Tract Infection Treatment

Critical Clarification: Mycoplasma Does Not Cause Typical UTIs

Mycoplasma genitalium and Ureaplasma urealyticum cause urethritis and cervicitis, not urinary tract infections (cystitis or pyelonephritis). 1, 2 These organisms infect the urethra and genital tract through direct mucosal contact during sexual activity, not the bladder or kidneys like typical uropathogens. 1, 2

• Standard UTI antibiotics (nitrofurantoin, fosfomycin, trimethoprim-sulfamethoxazole) are not effective against Mycoplasma species and should never be used for these infections. 3, 4
• If you suspect a true urinary tract infection (dysuria with frequency, urgency, suprapubic pain), the pathogen is almost certainly E. coli, Klebsiella, or Staphylococcus saprophyticus—not Mycoplasma. 5

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First-Line Treatment for Mycoplasma Genitalium Urethritis/Cervicitis

Azithromycin 500 mg orally on day 1, then 250 mg orally daily on days 2–5 (total 1.5 g over 5 days) is the recommended first-line regimen for uncomplicated Mycoplasma genitalium infection without known macrolide resistance. 1, 2

Why This Regimen?

• The extended 5-day azithromycin course achieves 85–95% cure rates in macrolide-susceptible infections, significantly higher than the outdated 1 g single-dose regimen. 1, 2, 6
• Doxycycline alone has only 30–40% efficacy against M. genitalium and should not be used as monotherapy. 1, 2, 6
• Pre-treatment with doxycycline 100 mg twice daily for 7 days followed by azithromycin may reduce organism load and decrease macrolide resistance selection, but this is not universally recommended as first-line. 2

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Alternative Regimens and Special Populations

Pregnancy

Azithromycin 500 mg on day 1, then 250 mg daily on days 2–5 remains the safest option during pregnancy. 1, 2 Fluoroquinolones (moxifloxacin) are contraindicated in pregnancy due to cartilage toxicity risk. 1, 2

Breastfeeding

Azithromycin is compatible with breastfeeding and should be used at the same dosing schedule. 1, 2 Small amounts enter breast milk but are not harmful to infants.

Tetracycline Intolerance or Allergy

If the patient cannot tolerate doxycycline (which is only used as adjunctive pre-treatment), proceed directly to azithromycin 500 mg/250 mg extended regimen. 1, 2 Alternatively, josamycin 500 mg three times daily for 10 days can be used where available (not FDA-approved in the United States). 1

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Second-Line Treatment for Macrolide-Resistant or Treatment-Failure Cases

Moxifloxacin 400 mg orally once daily for 7 days is the recommended second-line therapy for macrolide-resistant M. genitalium or azithromycin treatment failure. 1, 2

Important Caveats

• Macrolide resistance is increasing globally (now 30–50% in some regions) due to widespread single-dose azithromycin use without test-of-cure. 2, 6
• Fluoroquinolone resistance is also emerging; moxifloxacin failure has been documented in cases with dual macrolide and fluoroquinolone resistance mutations. 6
• Always obtain nucleic acid amplification testing (NAAT) with macrolide resistance mutation testing before treatment when available. 2 This allows resistance-guided therapy and prevents unnecessary moxifloxacin exposure.

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Third-Line Options for Persistent Infection

For infections persisting after both azithromycin and moxifloxacin failure, doxycycline 100 mg twice daily for 14 days may achieve 40–70% cure rates. 2

• Pristinamycin 1 g four times daily for 10 days has approximately 75% efficacy but is not available in the United States. 2
• Minocycline 100 mg twice daily for 14 days is an alternative tetracycline with slightly better Ureaplasma activity than doxycycline. 7

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Complicated Infections (Pelvic Inflammatory Disease, Epididymitis)

Moxifloxacin 400 mg orally once daily for 14 days (not 7 days) is required for complicated M. genitalium infections involving the upper genital tract. 1, 2

• Symptoms of complicated infection include abdominal/pelvic pain, dyspareunia (women), or testicular pain/swelling (men). 1, 2
• Hospitalization and parenteral therapy are rarely needed unless the patient is systemically ill or unable to tolerate oral medications. 1, 2

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Ureaplasma Urealyticum Urethritis

Doxycycline 100 mg orally twice daily for 7 days is effective for Ureaplasma urealyticum urethritis and is the preferred first-line agent. 5, 8

• Alternatively, clarithromycin or azithromycin can be used if doxycycline is contraindicated. 8
• Erythromycin 500 mg four times daily for 7 days is an older alternative but has higher gastrointestinal side effects. 5
• Tetracycline-resistant Ureaplasma strains exist; if symptoms persist after doxycycline, extend erythromycin to 14 days or switch to azithromycin. 5, 7

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Critical Pitfalls to Avoid

• Do not treat asymptomatic Mycoplasma/Ureaplasma colonization. Testing and treatment are indicated only for symptomatic urethritis, cervicitis, or epidemiologically linked exposure. 2
• Do not use single-dose azithromycin 1 g. This outdated regimen has lower efficacy and drives macrolide resistance. 2, 6
• Do not use fluoroquinolones as first-line therapy. Reserve moxifloxacin for documented macrolide resistance or treatment failure to preserve its efficacy. 2
• Always treat sexual partners simultaneously to prevent reinfection; partners should receive the same regimen even if asymptomatic. 5, 1, 2
• Perform test-of-cure NAAT 3–5 weeks after treatment completion for all M. genitalium infections to detect persistent infection and guide further therapy. 2