Towards precision management of Mycoplasma genitalium: a real-world cohort study identifying key predictors for treatment failure and the superiority of sequential therapy

Background The management of Mycoplasma genitalium (MG) infection is challenged by rising macrolide resistance, leading to high failure rates with azithromycin. Evidence on the long-term effectiveness of alternative initial regimens, particularly sequential therapy, and easily obtainable predictors for poor outcomes remains scarce. Methods We conducted a retrospective cohort study at a tertiary hospital in China (2018-2024). Sexually active adults with nucleic acid amplification test (NAAT)-confirmed MG infection and available treatment records were included. The primary outcomes were treatment failure (persistent infection at 8 weeks, ultimate failure) and recurrence. Multivariable logistic regression and Kaplan-Meier survival analyses were employed to assess the impact of initial antibiotic regimens (azithromycin, quinolones, doxycycline-quinolone sequential therapy), demographics, and co-infections. Results Among 1, 192 MG-positive patients, 474 completed follow-up. After adjustment, doxycycline-quinolone sequential therapy was associated with significantly lower odds of ultimate treatment failure (adjusted odds ratio [aOR]=0.36, 95%CI:0.21-0.61) and recurrence (aOR=0.37, 95%CI:0.18-0.75) compared to azithromycin. Survival analysis confirmed a faster median time to clearance with sequential therapy (7 vs. 10 weeks, p=0.001) and a marked “long-tail” effect in the azithromycin group (mean clearance time: 94.2 vs. 28.0 weeks). Co-infection with Chlamydia trachomatis (CT) was the strongest independent predictor for all adverse outcomes (aOR for ultimate failure=3.21, 95%CI:1.88-5.48), followed by male sex. Conclusions In this real-world cohort, doxycycline-quinolone sequential therapy demonstrated superior long-term effectiveness over azithromycin for MG infection. CT co-infection and male sex were key risk predictors. These findings advocate for a paradigm shift towards risk-stratified initial therapy, prioritizing sequential regimens for high-risk patients to improve cure rates while supporting antimicrobial stewardship.