FMM/RAS/298: Strengthening capacities, policies and national action plans on prudent and responsible use of antimicrobials in fisheries Risk analysis of antimicrobial use in aquaculture Peter Smith peter.smith@nuigalway.ie Aquatic AMR Workshop 1: 10-11 April 2017, Mangalore, India
Components of risk analysis Hazard Identification Definition of risk Risk assessment Risk management Risk communication
Risk analysis - definitions Hazard Resistant microorganisms or resistance determinants that have emerged as a result of the use of a specific antimicrobial agent in aquatic animals Risk The infection of a host with a bacterium in which resistance has emerged due to antimicrobial agent usage in aquatic animals, and which results in the loss of benefit of antimicrobial therapy when used to manage that infection
Risks The largest risk associated with the use of antibiotics in aquatic animals is its impact on the therapy of aquatic animals There is very strong evidence that the use of antibiotics in aquaculture has resulted in a significant reduction of the therapeutic agents that can be used to treat aquatic animals
Risks The most politically important risk associated with the use of antibiotics in aquatic animals is its impact on the therapy of humans There is currently no evidence that the use of antibiotics in aquaculture has resulted in any significant reduction of the range of therapeutic agents that can be used to control any human infections
Risks to human medicine The lack of evidence of an impact cannot be used to argue that there is no impact The fear that aquacultural use may, will or does impact on human medicine has led to Attempts to limit the range of antibiotics that should be available to aquaculture Reduced market acceptance of aquaculture products A decline in research into antibiotic use into aquaculture The publication of some poor quality science
Risks to human medicine Two exposure pathways Movement of resistant bacteria Movement of transferable resistance determinants genetic elements that can move between bacterial species and potentially decrease the antibiotic susceptibility of bacteria that acquire them
Movement of resistant bacteria 1. Presence in the aquaculture environment of bacteria capable of infecting humans (zoonotic aquatic species or terrestrial contamination) 2. Selection of resistant variants of these bacteria as a result of antimicrobial use in aquaculture 3. Movement of these resistant bacteria to the human environment (via aquaculture products or water) 4. Infection of humans 5. Adverse effects resulting from the failure of any necessary antimicrobial agent therapy in humans
Presence in the aquaculture environment of bacteria capable of infecting humans Relatively few zoonotic aquatic species Vibrio parahaemolyticus? antibiotic therapy of no value in humans Vibrio vulnificus? - antibiotic therapy not used in aquatic host Motile Aeromonads? Terrestrial contamination Bigger problem in fresh water human waste disposal Salmonella spp?
Assessment of risks associated with movement of resistant bacteria Qualitative assessment Risks probably low Definitely very much lower than those associated with antibiotic use in land-based animals Quantitative assessments May be possible with respect to specific bacterial species emerging as a result of the use of a specific drug in specific aquatic animals
Caution Antibiotic resistant human pathogens in aquatic products at the point of sale may arise from Terrestrial contamination of in-flow water Post-harvesting contamination of the product Using point of sale data will overestimate the risk associated with antimicrobial agent usage in aquatic animals
Movement of resistance determinants Resistance determinants have travelled through the global microbiome since before man started to use antibiotics The totality of resistance determinants in an environment has been termed the environmental resistome The size of the resistome has been greatly increased by the selective pressure resulting from our use and misuse of antimicrobial agents The environmental resistome is the ultimate source of the resistance determinants in those bacteria that infect humans
Movement of resistance determinants Entry assessment Selection for increased frequency of resistance determinants in the locality of aquatic farms The bit in the middle Survival and dissemination in the environmental resistome Exposure assessment Movement of resistance determinants from the environmental resistome to bacteria infecting humans and resulting in an adverse effect on therapy
What data should we collect to perform an entry assessment? We could obtain data on the concentrations and spatial/temporal footprint in the vicinity of aquaculture units of: Phenotypically resistant bacteria Antibiotics Resistance determinants
Entry assessment Phenotypically resistant bacteria - most studied but of little relevance to this risk A very small percentage of aquatic bacteria can be grown in the laboratory Difficulty in defining or detecting resistance in aquatic bacteria Difficulty in assigning causality factors other than antibiotics may lead to increases in phenotypic resistance
Entry assessment Antibiotics Detectable concentrations have been detected in the local environment of aquatic farms. Highest concentrations have been reported in sediments Significant variation between studies in concentrations, distribution and persistence Difficulties in assessing the biological activity and selective pressure exerted by antibiotics in the environment
Entry assessment Resistance determinants Elevated frequencies have been found in aquatic farm environments Few studies - most not linked to antibiotic use Problems with standardising methods and data reporting
Frequency of resistance determinants in bacteria cultured from the same sites in Chile Bacteria studied Site flo R tet A Buschmann et al. (2012) 24 Aquaculture 17% 17% 24 Control 8% 13% Shah et al. (2014) 100 Aquaculture 0% 2.5% 100 Control 0% 0%
The environmental resistome What factors influence the maintenance of elevated frequencies or concentrations of resistance determinants in the environmental resistome? Direct selection by antibiotics Indirect selection by linked genes Rates of transfer to new bacterial hosts Fate of bacterial hosts unlinked to resistance determinants
The environmental resistome The use of antibiotics in Humans Terrestrial animals and plants Aquatic animals All contribute resistance determinants to the environmental resistome All contribute antibiotics to the environment
The environmental resistome Current interpretations of the available data suggest that the environmental resistome is the most significant global reservoir of resistance determinants and is the ultimate source of resistance determinants in those bacteria that infect humans The risk to human therapies associated with an increase in the environmental resistome is of equal importance in Risk Analysis of antibiotic use in Humans and hospitals Terrestrial animal and plants Aquatic animals
This environmental resistome, its mobilization, and the conditions that facilitate its entry into human pathogens are at the heart of the current public health crisis in antibiotic resistance. Understanding the origins, evolution, and mechanisms of transfer of resistance elements is vital to our ability to adequately address this public health issue. Gaze WH 1, Krone SM, Larsson DG, Li XZ, Robinson JA, Simonet P, Smalla K, Timinouni M, Topp E, Wellington EM, Wright GD, Zhu YG Influence of humans on evolution and mobilization of environmental antibiotic resistome. Emerg Infect Dis. 2013 Jul;19(7). doi: 10.3201/eid1907.120871.
Components of risk analysis associated with resistance determinants Hazard Identification done Definition of risk done Risk assessment partial first step in a long journey for which we so far lack a map Risk management? Risk communication?
Management of risk associated with resistance determinants We are currently facing the challenge of managing a risk when We have not been able to generate any evidence-based quantitative or qualitative assessment of the size of that risk We are not even clear about what evidence would help
Thank you for your attention