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

• ResistAZM vs MORDOR trials showed azithromycin's impact on resistome. • Saturation hypothesis: Baseline resistome saturated in ResistAZM trial. • Macrolide resistance genes 10× more abundant in ResistAZM than MORDOR. • High-antimicrobial consumption populations, baseline resistome may be attenuated. 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. Shotgun metagenome reads from the anorectal baseline samples from the ResistAZM (n = 42) and MORDOR (n = 30) trials were analyzed using AMRPlusPlus. Nonhost reads were mapped to the MEGARes database to detect antibiotic resistance genes (ARG). Antimicrobial resistance (AMR) was normalized using cumulative sum scaling, and ARG abundance was estimated. Macrolide, lincosamides, and streptogramins determinants were approximately 10-fold more abundant in the ResistAZM than the MORDOR samples (P ≤ 0.001). 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. [Display omitted] [ABSTRACT FROM AUTHOR]