The impact of antimicrobial persistence and co-selection on resistance

Summary

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Antimicrobial compounds are arguably one of the most powerful discovered drugs in the history of human medicine. However, the success of antimicrobial compounds has ultimately contributed to their own downfall due to the emergence of antimicrobial resistant bacteria. Their use, including too frequent and careless use, has led to the increasing development of antimicrobial resistant bacteria. As a result, treating bacterial infections has become more challenging and can lead to treatment failure. Furthermore, the development of new antimicrobials has also become increasingly difficult, both for scientific and economic reasons.

Any use of antimicrobials selects for antimicrobial resistant bacteria. Antimicrobial usage in livestock farming is substantial and it is considered one of the main drivers of antimicrobial resistance. It is estimated that global antimicrobial use in livestock farming is around 100,000 tons per year, while only milligrams to grams per animal are needed for treatment. As a result, a reservoir of antimicrobial resistant bacteria is created. From this reservoir, these antimicrobial resistant bacteria can potentially transmit to the environment or humans through various pathways. These antimicrobial resistant bacteria can eventually cause infections, leading to health problems. It is therefore important to investigate whether the selection for resistant bacteria in livestock farming can be reduced. For this reason, stewardship programs have been introduced to promote more responsible antimicrobial use. In that light, the aim of this thesis is to reconsider the classification of antimicrobials through scientific research on selective concentrations, antimicrobial stability, and the unintended selection of resistance to so-called critically important antimicrobials.

In this thesis, studies report that some antimicrobials are very stable and that concentrations of these antimicrobials are able to remain in the farm environment. Even more worrying is that the concentrations of these residues are at concentrations, where selection of antimicrobial resistance still occurs. Furthermore, we modelled the effect of these residues on the occurrence of co-selection and has found that co-selection is increased when persistent antimicrobials are used in an commercial farm environment. Lastly, in this thesis we  addressed the problem of cross-resistance, which means that antimicrobials select for the same type of resistance, between antimicrobials belonging to the same class such as flumequine and enrofloxacin.

The main conclusion of this thesis is that antimicrobial residues of persistent antimicrobials remain in the farm environment, exerting prolonged selective pressure for antimicrobial resistant bacteria. This effect is shown by the observed increase in non-wildtype bacteria over a longer time following the use of persistent antimicrobials compared to non-persistent antimicrobials. Additionally, the findings suggest that these persistent residues may play a significant role in the development of co-resistance and cross-resistance among bacteria.