Epidemiology of antimicrobial resistance and the effect of interventions in food-producing animals

Abstract

This thesis explores the animal-human interface of the emerging antimicrobial resistance (AMR) problem. It focuses on two relevant bacterial species imposing a burden for human health: methicillin-resistant Staphylococcus aureus (MRSA) and (extended-spectrum beta-lactamase (ESBL)/AmpC-producing) Escherichia coli. This work strengthens the level of evidence on the relation between veterinary antimicrobial use (AMU) and AMR by relying on longitudinal studies and quantitative AMU data. Two intervention studies in veal calves, pigs, and their farmers and family members are presented together with the evaluation of a country-wide AMU reduction. Additionally, a meta-analysis on molecular characteristics of ESBL/AmpC-producing E. coli contributes information on potential attribution by animal and environmental reservoirs. Part I presents a 3-arm intervention study on livestock-associated (LA)-MRSA in veal calf farming. Results show that farm environments contaminated with MRSA might enhance the acquisition of LA-MRSA through airborne transmission. In farms applying a protocol for cleaning and disinfection of stables, a transitory LA-MRSA spread in the air was observed, apparently leading to higher LA-MRSA carriage in veal calves, and farmers. More stringent biosecurity conditions reduced LA-MRSA carriage in animals and humans. Farms at which AMU was reduced showed a decreased carriage of LA-MRSA in animals and humans over time. Part II presents a longitudinal study in pig farming to control LA-MRSA and ESBL-producing E. coli carriage. AMU decreased 44% during the study period. LA-MRSA in pigs slightly decreased while ESBL carriage showed a more substantial drop. Higher LA-MRSA and ESBL carriage were positively related to increasing AMU. The incidental use of cephalosporins was the most striking risk factor for LA-MRSA and ESBL carriage in pigs. AMU in animals was shown to be a risk factor for MRSA in farmers. A risk factor analysis showed an increased spread of LA-MRSA and ESBLs in farms receiving external supply of animals from other premises, and in farms with less stringent biosecurity conditions or less rigid animal contact structures. In Part III trends in AMU and AMR in commensal E. coli in livestock are evaluated over a 10 year-period in the Netherlands. The nationwide AMU reduction was associated to decreasing E. coli resistance levels for most antimicrobial drugs, especially for the veal calf and pig sectors. Drug use history and co-selection of resistance were key elements for perpetuation of resistance. In Part IV, a meta-collection of 3646 ESBL/AmpC-producing E. coli isolates was created from 27 Dutch studies in different reservoirs. Results showed an existing, but limited, E. coli molecular similarity between most animal reservoirs, and the open human population and patients in clinical settings. E. coli from human farming communities shared basically the same molecular profiles with bacteria isolated from their animals . Transmission and dissemination of resistance seemed to occur beyond domesticated animals and humans, without apparent direct selective pressure to antimicrobials (e.g. in wild birds and surface water). These results call for controlled intervention studies, preferably over prolonged periods of time, and advocate for a prudent AMU. In light of the multiple AMR transmission reservoirs, this problem needs a holistic “One Health” approach.