M. genitalium infections explain 15–25% of symptomatic male NGU and causes sexually transmitted urethritis, cervicitis, and PID in women. The bacterium is extremely difficult to isolate by culture, and consequently, the knowledge about antimicrobial resistance and its underlying molecular mechanisms has been slow to accumulate.

In the few randomised trials of M. genitalium conducted to date, doxycycline has been compared with a 1 g single dose of azithromycin, and together with results from open trials, it is evident that doxycycline is inefficient in eradicating M. genitalium with eradication rates around 35%. The eradication rate after azithromycin 1 g single dose has most often been significantly higher, but differs greatly between studies. Remarkably, older studies appear to have higher eradication rates than the more recent ones, and in the latest study from the US, no significant difference between doxycycline and azithromycin efficacy could be detected.

Although several mutations have been associated with increased macrolide MIC in strains selected by passage in the presence of macrolides, only mutations in the 23S rRNA gene at position 2058 and 2059 ( E. colinumbering) have been detected in patients failing azithromycin treatment.

A number of rapid methods for detection of such mutations directly from clinical samples have been developed and have proved to be clinically useful in directing treatment. Pre-treatment mutations have been found in between 10–15% of contemporary samples where doxycycline is used as the primary NGU treatment and is most commonly around 40% in settings where azithromycin is the primary drug. However, in Greenland where chlamydial infections are extremely common and azithromycin is used liberally, mutations have been found in nearly 100% of the specimens tested.

At present, moxifloxacin is the only second line antibiotic that has a proven high efficacy against macrolide resistant M. genitalium. However, price and safety profile as well as the emergence of multidrug resistant strains emphasises the urgent need for clinical trials with alternative drugs.