Antimicrobial Resistance Crisis in STIs: Gonorrhea and M. genitalium on the Brink of Untreatability

Antimicrobial resistance (AMR) in sexually transmitted infections (STIs), especially Neisseria gonorrhoeae and Mycoplasma genitalium , is a growing global health crisis. These pathogens are developing resistance to first-line treatments like ceftriaxone and macrolides, risking untreatable infections. This review examines resistance trends, treatment challenges, and emerging solutions. A systematic analysis of epidemiological data, molecular studies, and clinical trials was performed. Key resistance markers (e.g., penA mosaics in N. gonorrhoeae , 23S rRNA mutations in M. genitalium ) and treatment outcomes were assessed. Data sources included WHO reports, peer-reviewed studies (2010–2024), and phase II/III trials of new drugs like zoliflodacin and gepotidacin. N. gonorrhoeae resists all previously effective antibiotics, with ceftriaxone-resistant strains (e.g., FC428 clone) spreading via penA -60.001 alleles. Dual resistance to ceftriaxone/azithromycin is emerging. M. genitalium shows high macrolide (23S rRNA mutations) and fluoroquinolone ( parC/gyrA mutations) resistance (>50% in some regions), complicating therapy. While zoliflodacin and gepotidacin show promise, pre-existing resistance (e.g., GyrB D443N) threatens efficacy. Third-line options (pristinamycin, sitafloxacin) have limited availability and effectiveness. The AMR crisis in STIs requires urgent action, including improved surveillance, resistance-guided therapy, and rapid diagnostics. Investment in new antibiotics and alternative approaches (e.g., doxycycline prophylaxis) is crucial. Global public health efforts are needed to curb resistance and prevent untreatable STIs. • Sexually transmitted infections (STIs) remain a major global public health challenge. • M. genitalium exhibits increasing resistance to antibiotics. • N. gonorrhoeae has progressively acquired resistance to all previously recommended antibiotics.