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Pacific Islanders have hyperendemic rates of Chlamydia trachomatis (Ct) sexually transmitted infections (STIs) and remain underrepresented in research. Using metagenomic shotgun sequencing, we investigated the impact of azithromycin (AZ) treatment on microbial communities, function and the resistomes of paired vaginal, endocervical and rectal microbiomes among three cohorts of women in Fiji: Ct-infected women treated at baseline who cleared or had persistent infection at follow-up compared to uninfected, untreated women at either time point. Several species were significantly associated with Ct persistence: endocervical Neisseria gonorrhoeae (Ng); and rectal Ng and species associated with biofilm formation. Women with Ct clearance and persistent were also significantly more likely to have high-risk (hr)HPV types at follow-up compared to uninfected, untreated women. Three distinct microbiome phylotypes were identified based on Bray-Curtis hierarchical clustering with evidence for genital-to-rectal and rectal-to-genital transmission among all cohorts. The AZ resistance gene ermB in L. iners (Ln) was significantly higher in the endocervix of both treatment cohorts at follow-up compared to baseline, while the tetracycline resistance gene tetM was highly prevalent among all cohorts at both time points. G. vaginalis (Gv) had a high prevalence of the AZ resistance gene ermX in the rectum of all cohorts. These Gv strains were associated with moderate/high biofilm formation. Both Ln and Gv increased in abundance post-treatment, which could perpetuate Ct persistence and increase the risk for other STIs. Nonsynonymous mutations in the Ct rplV gene were highly prevalent in the Ct persistent cohort in all anatomic sites at both time points and mapped to mutations associated with AZ resistance. Our results reveal perturbing effects of azithromycin treatment with increased risk of hrHPV, Ng and other STIs, and azithromycin resistance among co-infecting pathogens with potential homotypic resistance in Ct that may impact successful treatment of Ct, indicating the need for novel therapeutic strategies to treat Ct and protect and restore the microbiome.