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Campylobacter  spp. are the most frequent agent of human gastroenteritis worldwide, and the spread of multidrug-resistant strains makes the clinical treatment difficult. The current study presents the resistome analysis of 39,798  Campylobacter jejuni  and 11,920  Campylobacter coli  genomes available in public repositories. Determinants of resistance to β-lactams (Be) and tetracyclines (Te) were the most frequent for both species, with resistance to quinolones (Qu) as the third most important on  C. jejuni  and to aminoglycosides (Am) on  C. coli . Moreover, resistance to Te, Qu, and Am was frequently found in co-occurrence with resistance to other antibiotic families. Geographical differences on clonal complexes distribution were found for  C. jejuni  and on resistome genotypes for both  C. jejuni  and  C. coli  species. Attending to the resistome patterns by isolation source, three main clusters of genomes were found on  C. jejuni  genomes at antimicrobial resistance gene level. The first cluster was formed by genomes from human, food production animals (e.g., sheep, cow, and chicken), and food (e.g., dairy products) isolates. The higher incidence of  tet(O) , associated with tetracycline resistance, and the  gyrA  (T86I) single-nucleotide polymorphism (SNP), associated with quinolone resistance, among genomes from this cluster could be due to the intense use of these antibiotics in veterinary and human clinical settings. Similarly, a high incidence of  tet(O)  genes of  C. coli  genomes from pig, cow, and turkey was found. Moreover, the cluster based on resistome patterns formed by  C. jejuni  and  C. coli  genomes of human, turkey, and chicken origin is in agreement with previous observations reporting chicken or poultry-related environments as the main source of human campylobacteriosis infections. Most clonal complexes (CCs) associated with chicken host specialization (e.g., ST-354, ST-573, ST-464, and ST-446) were the CCs with the highest prevalence of determinants of resistance to Be, Qu, and Te. Finally, a clear trend toward an increase in the occurrence of Te and Qu resistance determinants on  C. jejuni , linked to the spread of the co-occurrence of the  bla   OXA– 61  and  tet(O)-tet(O/W/O)  genes and the  gyrA  (T86I) SNP, was found from 2001 to date in Europe.

Whole Resistome Analysis in Campylobacter jejuni and C. coli Genomes Available in Public Repositories