Objectives Mycoplasma genitalium (MG) causes urethritis and is associated with cervicitis, pelvic inflammatory disease and preterm delivery. Antimicrobial resistance is widespread and cure rates are declining. Lefamulin, a novel pleuromutilin, may be effective in cases of treatment failure.

Methods Under compassionate access in Australia and a pilot open-label parallel arm randomised clinical trial in the USA, patients with urogenital MG infection and microbiological treatment failure or contraindications to moxifloxacin were treated with lefamulin monotherapy (600 mg orally two times per for 7 days) or sequential doxycycline-lefamulin (doxycycline 100 mg orally two times per day for 7 days followed by lefamulin for 7 days) (1:1 randomisation in the USA). Two additional regimens were also evaluated in Australia: combination therapy with doxycycline plus lefamulin for 7 days and extended lefamulin therapy with doxycycline for 7 days followed by lefamulin for 14 days. Microbiological cure (negative MG NAAT) was assessed 21–35 days after completing lefamulin. Sustained cure was assessed 42–49 days after treatment.

Results Seventeen heavily pretreated Australian (seen between October 2020 and December 2023) and 11 US cases (recruited between April 2022 and February 2023; 5 randomised to lefamulin monotherapy, 6 randomised to sequential doxycycline-lefamulin) received lefamulin-containing regimens. Sequential doxycycline-lefamulin demonstrated microbiological cure 21–35 days post-treatment in 6 of 12 (50%) Australian and US patients. Three of five (60%) US patients but none of five (0%) Australian patients were cured with lefamulin monotherapy. Combination therapy with doxycycline and lefamulin was ineffective (n=0/2), but extended lefamulin therapy cured two of three (67%). Gastrointestinal side effects occurred in 77% (Australia) and 91% (USA).

Conclusion While cure rates were low, lefamulin was effective in some individuals with MG treatment failure. Additional antibacterial agents for multidrug-resistant infections are needed.