Treatment Approaches for Refractory Mycoplasma genitalium Infection

Mycoplasma genitalium is an increasingly recognized sexually transmitted infection (STI) associated with urethritis, cervicitis, and pelvic inflammatory disease. Its management, though, is complicated by rapid expansion of antimicrobial resistance. Because M. genitalium lacks a cell wall, treatment options are limited to macrolides, tetracyclines, and fluoroquinolones. Widespread macrolide resistance, along with rising fluoroquinolone and dual-class resistance, has made refractory infection a common and challenging clinical scenario. Current guidelines recommend staged, resistance guided-therapy using a doxycycline lead-in followed by azithromycin for macrolide-susceptible infection or moxifloxacin for macrolide-resistant infection. However, access to macrolide resistance testing remains inconsistent; fluoroquinolone resistance testing is largely unavailable in routine practice, and correlations between resistance markers and clinical failure are incomplete. This review summarizes contemporary standard-of-care treatment strategies and emerging approaches for resistant or refractory M. genitalium infection. It also highlights critical gaps in diagnostic capacity, clinical trial data, and the antimicrobial development pipeline for STIs.