Translating antibiotic prescribing into antimicrobial resistance in the environment: a hazard characterisation case study

The global movement to combat the rise in antibiotic-resistant infections aims to reduce antibiotic use and misuse in humans and in food production. The environment receives antibiotics through a combination of direct application, such as in aquaculture and fruit production, as well as indirect release through sewage and animal manure. Antibiotic concentrations in many sewage-impacted rivers are predicted to be sufficient to drive antimicrobial resistance selection. Here we examine the potential for macrolide and fluoroquinolone prescribing in England to drive resistance selection in the River Thames catchment, England. We show that 63% and 73% of the length of the modelled catchment is chronically exposed to putative resistance-selecting concentrations of macrolides and fluoroquinolones, respectively. Our results reveal that macrolide and fluoroquinolone prescribing would need to decline by 77% and 85%, respectively, to protect freshwaters from resistance selection. We anticipate our model will provide a starting point for a more sophisticated national-scale assessment of the relationship between antibiotic prescribing and resistance selection in the environment. Improved antibiotic stewardship, alone, is unlikely to alleviate the identified challenge. Action is needed to substantially reduce antibiotic prescribing alongside innovation in sewage-treatment to reduce the discharge of antibiotics and resistance genes. Greater confidence is needed in current risk-based targets for antibiotics, particularly in mixtures, to better inform environmental risk assessments and mitigation.


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The drive to reduce antibiotic use and misuse in human medicine had gained considerable 37 traction since 2013 when Professor Dame Sally Davies, the Chief Medical Officer (CMO) for 38 England and Chief Medical Advisor to the UK government published her Annual Report [1]. 39 In Volume 2 of this report, she highlighted the "challenges and opportunities facing us in the 40 prevention, diagnosis and management of infectious diseases", which included the move to  The River Thames catchment (i.e., Thames Basin) in southern England was selected for this 97 study as it is the most highly populous catchment in the United Kingdom (nearly 4 million 98 people). It also might be seen as a realistic worst-case scenario, as on average, this part of     and ungauged sites and to assist regional water resources and catchment management. The 173 LF2000-WQX software is a geographical information-based system that combines 174 hydrological models with a range of water-quality models, including a catchment-scale represented by a non-specific dissipation process assuming first-order kinetics., Antibiotics 186 were assumed to persist in the river for at least one day, thereby providing a realistic worst-187 case scenario.

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In summary, LF2000-WQX was parameterised with the highest monthly fluoroquinolone and 190 macrolide prescription rate for each of the four CCGs (see bolded rates in Table 4).

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Macrolide and fluoroquinolone loss was accounted for upon excretion (32.2% and 64.2%, 192 respectively) and before discharge from STPs into the receiving river (50%). As such, the

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This study aimed to understand the degree of resistance selection that might be occurring in 232 the River Thames catchment under current macrolide and fluoroquinolone prescribing 233 practice by the NHS as well as after foreseeable and aspirational reductions in prescribing.

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The objective was to estimate the level of reduction needed in NHS antibiotic prescribing that 235 might be necessary to substantially reduce the macrolide and fluoroquinolone-resistance 236 selection burden created in the river environment.   Hence, a target of 100% would be unrealistic and necessitate even more dramatic reductions 267 in antibiotic use or zero effluent discharge.

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The sensitivity analysis revealed that macrolide prescriptions must decline by 77% to protect 270 90.4% of the length of the Thames catchment from macrolide resistance selection (Table 6; 271 Fig 4a). Even at this much-reduced prescription rate, there were still 13 reaches with a total 272 length of 8.5 km (0.6%) remaining 'critical' for macrolide resistance selection (Fig 4a).

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Fluoroquinolone prescriptions would need to be reduced by 85% to alleviate the selection 274 risk in 90% of the catchment (Table 6; Fig 4b). The results do not reflect the granular differences in prescribing that are seen between small 316 CCGs as there would be no way to attribute an antibiotic user to a particular STP confidently.

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It is expected that if such an effort were possible, it would highlight elevated antibiotics in   where the authors and an expert panel explored the 'appropriateness' of antibiotic 460 prescription, the authors found that substantially higher proportions of patients received 461 antibiotics than was deemed 'appropriate', with the respiratory ailments showing the largest 462 contrast between actual and ideal: acute cough (41% vs 10%, respectively), bronchitis 463 (82%:13%); sore throat (59%:13%); rhinosinusitis (88%:11%); and acute otitis media in 2-to 464 18-year-olds (92%:17%) [94]. Such a reduction in prescribing will be beneficial to reducing 465 resistance selection in humans, but, as shown in this paper, might not go far enough (Table   466 8).    Although not immediately within the scope of this paper, it is relevant to highlight that any This study explores the reduction in macrolide and fluoroquinolone prescribing needed to 506 alleviate the modelled hazard from antibiotic resistance selection in sewage-impacted rivers.

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It is unclear if the projected reductions in antibiotic pollution of 77 to 85% could be achieved 508 solely through reduced prescribing by the NHS. Environmental targets could be more readily 509 achieved by a holistic, integrated AMR action plan, which constrains and optimises antibiotic 510 prescribing, while also addressing the chronic release of antimicrobials, biocides, metals and 511 resistance genes from STP effluent.