| Summary: | <i>Mycoplasma genitalium</i> is recognized as a remarkable pathogen since azithromycin-resistant strains and treatment failure have been increasingly reported. Nevertheless, international guidelines still recommend azithromycin as a first-line treatment and moxifloxacin as a second-line treatment. We performed a systematic review and meta-analysis to validate the efficacy and safety of both drugs in the initial treatment of <i>M. genitalium</i>. We systematically searched the EMBASE, PubMed, Scopus, Ichushi, and CINAHL databases up to December 2021. We defined efficacy as clinical and microbiologic cure, and safety as persistent diarrhea. Overall, four studies met the inclusion criteria: one showed clinical cure (azithromycin treatment, n = 32; moxifloxacin treatment, n = 6), four showed microbiologic cure (n = 516; n = 99), and one showed safety (n = 63; n = 84). Moxifloxacin improved the microbiologic cure rate compared with azithromycin (odds ratio [OR] 2.79, 95% confidence interval [CI], 1.06–7.35). Clinical cure and safety did not show a significant difference between azithromycin and moxifloxacin treatments (OR 4.51, 95% CI 0.23–88.3; OR 0.63, 95% CI 0.21–1.83). Our meta-analysis showed that moxifloxacin was more effective than azithromycin at eradicating <i>M. genitalium</i> infections and supports its preferential use as a first-line treatment.
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