Could the effect of antimicrobials on antimicrobial resistance be saturated at high antimicrobial consumption? A comparison of the MORDOR and ResistAZM studies

Background and objectives Antimicrobial resistance poses a considerable threat in high-antimicrobial-consumption populations, such as men who have sex with men (MSM) taking HIV pre-exposure prophylaxis. While the ResistAZM trial found no increase in macrolide resistance genes in MSM with gonorrhea after azithromycin treatment, the MORDOR trial observed an increase in these genes after mass azithromycin distribution. We hypothesized that this could be due to saturation of the resistome. To test this hypothesis, we compared the abundance of macrolide resistance determinants in anorectal samples between the baselines of the two trials. Methods Shotgun metagenome reads from the anorectal baseline samples from the ResistAZM (n=42) and MORDOR (n=30) trials were analyzed using AMRPlusPlus. Non-host reads were mapped to the MEGARes database to detect antibiotic resistance genes (ARG). AMR was normalized using cumulative sum scaling, and ARG abundance was estimated. Results Macrolide, lincosamides and streptogramins (MLS) determinants were approximately 10-fold more abundant in the ResistAZM than the MORDOR samples (p = <0.001). Conclusions The findings are compatible with our hypothesis. Thus, in populations with high antimicrobial use, the relationship between antimicrobial consumption and AMR may be diminished due to saturation. These findings are vital for future studies investigating the resistogencity of novel interventions, such as doxycycline post-exposure prophylaxis, in populations with high preceding consumption of antimicrobials.