Contribution of ParC -and GyrA- mutations to fluoroquinolone treatment failures in Mycoplasma genitalium: a systematized review

While macrolide resistance in Mycoplasma genitalium is consistently associated with mutations in the 23S rRNA gene, enabling macrolide resistance-guided therapies, the correlation between genotype and fluoroquinolone resistance is less definitive. We aim to estimate the contribution of ParC -and GyrA- mutations in M. genitalium to fluoroquinolone resistance through a systematized review of the scientific literature.

On May 2025, a Boolean search was performed in PubMed for manuscripts reporting fourth-generation fluoroquinolone-based treatment outcomes in M. genitalium infections harboring ParC mutations at S83 and/or D87. Concurrent GyrA mutations were also recorded. Sixteen studies were included in the review, accounting for 376 M. genitalium infections. Most treatment failures were associated with the S83I variant in ParC, where 43% of cases receiving fluoroquinolones failed. While the rate of treatment failure estimated among S83R variants was slightly higher (50%), this mutation was much less frequently identified. On the other hand, no treatment failures were identified associated with mutations S83N, D87G and D87H. Concomitant GyrA mutation M95I or variations affecting D99 significantly increased the rate of treatment failure up to three-fold. Sitafloxacin was significantly more effective than moxifloxacin in the presence of resistance mutations.

This descriptive review provides compilated and preliminary data regarding the contribution of parC and gyrA mutations to fluoroquinolone resistance, to be considered in diagnostic assay designs. This may ultimately lead therapeutic decision-making guidance.