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Campylobacter 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 cmeRABC , which encodes an efflux pump conferring high levels of combined resistance to fluoroquinolones and macrolides in Campylobacter strains isolated from poultry ( n = 75) and children ( n = 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 cmeRABC operon and identified a potential genetic bottleneck for the cmeA and cmeB genes. While most cmeB alleles segregate by species, alleles associated with high resistance to fluoroquinolones and macrolides were found in both Campylobacter jejuni and Campylobacter coli . We inferred that the likely ancestry of these alleles was from C. jejuni and was later acquired by C. coli through recombination. Publicly accessible global genomic data from 16,120 Campylobacter genomes identified these mutations in approximately 6% of C. jejuni and C. coli isolates globally, with higher prevalence in samples from poultry in many countries, including Peru. Our findings suggest that these extensively drug-resistant Campylobacter strains originated from C. jejuni in poultry.IMPORTANCEAntimicrobial resistance in Campylobacter 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 Campylobacter jejuni and spread to C. coli 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 Campylobacter ., Competing Interests: The authors declare no conflict of interest.

Objectives: Antimicrobial resistant (AMR) Campylobacter is a global health threat; however, there is limited information on genomic determinants of resistance in low- and middle-income countries. We evaluated genomic determinants of AMR using a collection of whole genome sequenced Campylobacter jejuni and C. coli isolates from Iquitos, Peru., Methods: Campylobacter isolates from two paediatric cohort studies enriched with isolates that demonstrated resistance to ciprofloxacin and azithromycin were sequenced and mined for AMR determinants., Results: The gyrA mutation leading to the Thr86Ile amino acid change was the only gyrA mutation associated with fluoroquinolone resistance identified. The A2075G mutation in 23S rRNA was present, but three other 23S rRNA mutations previously associated with macrolide resistance were not identified. A resistant-enhancing variant of the cmeABC efflux pump genotype (RE-cmeABC) was identified in 36.1% (35/97) of C. jejuni genomes and 17.9% (12/67) of C. coli genomes. Mutations identified in the CmeR-binding site, an inverted repeat sequence in the cmeABC promoter region that increases expression of the operon, were identified in 24/97 C. jejuni and 14/67 C. coli genomes. The presence of these variants, in addition to RE-cmeABC, was noted in 18 of the 24 C. jejuni and 9 of the 14 C. coli genomes., Conclusions: Both RE-cmeABC and mutations in the CmeR-binding site were strongly associated with the MDR phenotype in C. jejuni and C. coli. This is the first report of RE-cmeABC in Peru and suggests it is a major driver of resistance to the principal therapies used to treat human campylobacteriosis in this setting., (Copyright © 2024. Published by Elsevier Ltd.)

Background: There is a need to evaluate antibiotic use, duration of therapy, and stewardship in low- and middle-income countries to guide the development of appropriate stewardship programs that are global in scope and effectively decrease unnecessary antibiotic use., Methods: We prospectively collected information on illness occurrence and antibiotic use from a cohort of 303 children. We evaluated the incidence, duration of therapy, and appropriateness of antibiotic prescriptions by 5 main antibiotic prescribers (physicians and nurses, pharmacists, nursing assistants, self-prescriptions, and neighbors or family members)., Results: Ninety percent of children received an antibiotic during follow-up, and on average, by the end of follow-up a child had spent 4.3% of their first 5 years of life on antibiotics. The most frequent prescribers were physicians/nurses (79.4%), followed by pharmacists (8.1%), self-prescriptions (6.8%), nursing assistants (3.7%), and family or neighbors (1.9%). Of the 3702 courses of antibiotics prescribed, 30.9% were done so for the occurrence of fever, 25.3% for diarrhea, 2.8% for acute lower respiratory disease, 2.7% for dysentery, and 38.2% for an undetermined illness. Courses exceeding the recommended duration were common for the principal diseases for which treatment was initiated, with 27.3% of courses exceeding the recommended length duration, representing a potential reduction in 13.2% of days on which this cohort spent on antibiotics., Conclusions: Stewardship programs should target medical personnel for a primary care stewardship program even in a context in which antibiotics are available to the public with little or no restrictions and appropriate duration should be emphasized in this training., Competing Interests: Potential conflicts of interest. F. S. reports payment or honoraria from Universidad Peruana Cayetano Heredia for lecture at undergraduate and graduate level and Universidad Cientifica del Sur for lecture at undergraduate level. J. M. C. reports grants or contracts outside of the submitted work paid to the university from CDC-U01GH002270 Conducting Integrated Infectious Disease and Public Health Research in Peru, NIH-R03AI158576 Genomic Epidemiology of Campylobacter to Improve Disease Control in Low- and Middle-Income Countries, NIH-R03AI151564-01 Global Geospatial Mapping and Modeling of Household-level Covariates of Infectious Disease Transmission and Child Health, NASA/JHU 16-GEO16-0047 Environmental Determinants of Enteric Infectious Disease: a GEOSS platform for analysis and risk assessment with COVID-19 supplement, BMGF SL12449 Enterics for Global Health (EFGH): Multisite Shigella surveillance study to prepare for the implementation of vaccine trials for Shigella, and intramural funds to department for high resolution hydrological models for mapping and predicting infectious disease transmission globally and in the Commonwealth of Virginia – UVA Engineering in Medicine Seed Grant and GIDI-UP Summer Research Grant – UVA Global Infectious Diseases Institute. F. S., M. P. O., M. N. K., and P. P. Y. report grants or contracts outside of the submitted work paid to the University of Virginia from NIAID - 5R01AI158576-02, NIAID - 1R21AI163801-01A1, and CGH - 5U01GH002270-02. C. R. reports payment or honoraria from Universidad Nacional de la Amazonia Peruana for lecture at undergraduate and graduate level. All other authors report no potential conflicts. The aforementioned sponsors had no role on the study design, analysis or manuscript preparation. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The objective of this study was to determine the phenotypic patterns of antibiotic resistance and the epidemiology of drug-resistant Campylobacter spp. from a low-resource setting. A birth cohort of 303 patients was followed until 5 years of age. Stool samples from asymptomatic children ( n = 10,008) and those with diarrhea ( n = 3,175) were cultured for Campylobacter Disk diffusion for ciprofloxacin (CIP), nalidixic acid (NAL), erythromycin (ERY), azithromycin (AZM), tetracycline (TE), gentamicin (GM), ampicillin (AMP), amoxicillin and clavulanic acid (AMC), ceftriaxone (CRO), chloramphenicol (C), and trimethoprim-sulfamethoxazole (TMS) was determined. Antibiotic resistances in Campylobacter jejuni and non- C. jejuni isolates from surveillance and diarrhea samples were compared, and the association between personal macrolide exposure and subsequent occurrence of a macrolide-resistant Campylobacter spp. was assessed. Of 917 Campylobacter isolates, 77.4% of C. jejuni isolates and 79.8% of non- C. jejuni isolates were resistant to ciprofloxacin, while 4.9% of C. jejuni isolates and 24.8% of non- C. jejuni isolates were not susceptible to azithromycin. Of the 303 children, 33.1% had been diagnosed with a Campylobacter strain nonsusceptible to both azithromycin and ciprofloxacin. Personal macrolide exposure did not affect the risk of macrolide-resistant Campylobacter Amoxicillin and clavulanic acid (94.0%) was one of the antibiotics with the highest rates of susceptibility. There is a high incidence of quinolone- and macrolide-resistant Campylobacter infections in infants under 24 months of age. Given the lack of association between personal exposure to macrolides and a subsequent Campylobacter infection resistant to macrolides, there is a need to evaluate the source of multidrug-resistant (MDR) Campylobacter This study provides compelling evidence to propose amoxicillin/clavulanic acid as a treatment for campylobacteriosis., (Copyright © 2019 Schiaffino et al.)