Sharing of <i>cmeRABC</i> alleles between <i>C. coli</i> and <i>C. jejuni</i> associated with extensive drug resistance in <i>Campylobacter</i> isolates from infants and poultry in the Peruvian Amazon

<i>Campylobacter</i> is a serious health threat because of the rapid progressive evolution of antimicrobial resistance and efficient transmission from zoonotic as well as human sources. Resistance to fluoroquinolones and macrolides is particularly concerning as this compromises the two most effective oral antibiotic agents currently available for human campylobacteriosis. Here, we report on the prevalence and worldwide distribution of the operon <i>cmeRABC</i>, which encodes an efflux pump conferring high levels of combined resistance to fluoroquinolones and macrolides in <i>Campylobacter</i> strains isolated from poultry (<i>n</i> = 75) and children (<i>n</i> = 177). These mutations were found to be highly prevalent in isolates from poultry (62.7%) and children (29.4%) in Iquitos, Peru. We investigated the population structure of genes in the <i>cmeRABC</i> operon and identified a potential genetic bottleneck for the <i>cmeA</i> and <i>cmeB</i> genes. While most <i>cmeB</i> alleles segregate by species, alleles associated with high resistance to fluoroquinolones and macrolides were found in both <i>Campylobacter jejuni</i> and <i>Campylobacter coli</i>. We inferred that the likely ancestry of these alleles was from <i>C. jejuni</i> and was later acquired by <i>C. coli</i> through recombination. Publicly accessible global genomic data from 16,120 <i>Campylobacter</i> genomes identified these mutations in approximately 6% of <i>C. jejuni</i> and <i>C. coli</i> isolates globally, with higher prevalence in samples from poultry in many countries, including Peru. Our findings suggest that these extensively drug-resistant <i>Campylobacter</i> strains originated from <i>C. jejuni</i> in poultry.IMPORTANCEAntimicrobial resistance in <i>Campylobacter</i> is a growing public health concern, driven by the rapid evolution and zoonotic transmission of resistant strains. This study focuses on mutations in the cmeABC efflux pump, which confer high resistance to fluoroquinolones and macrolides, the two most effective oral antibiotics for human campylobacteriosis. By analyzing genomes from poultry and children in Iquitos, Peru, as well as global genomic data sets, we identified a significant prevalence of these resistance-associated mutations, particularly in poultry and children. Our findings suggest that these mutations originated in <i>Campylobacter jejuni</i> and spread to <i>C. coli</i> through recombination. Globally, these mutations are found in approximately 6% of isolates, with higher prevalence in poultry in multiple countries. This research underscores the critical role of genomic epidemiology in understanding the origins, evolution, and dissemination of antimicrobial resistance and highlights the need to address poultry as a reservoir for resistant <i>Campylobacter</i>.