Antibiotic resistance risk assessments

1. Risk assessment for food-producing animals

If your application relates to the use of an antibiotic in food-producing animals, you should prepare a qualitative risk assessment addressing the possible contribution of the proposed use pattern to antibiotic resistance in foodborne microorganisms and human pathogens, and the risk of consequent disease in susceptible humans.

1.1. Summary of the risk profile

In your risk assessment, you should summarise the:

• hazard characterisation
• exposure characterisation
• impact characterisation
• assessment of the uncertainty of the data used in risk assessment
• benefits of use of the antibiotic in Australian animal health
• risk characterisation.

These are discussed in more detail below.

1.1.1. Hazard characterisation

A hazard characterisation details the antibiotic-resistant microorganisms or their resistance-transferable genetic elements (that have the potential to transfer to humans) within an animal species, arising from the use of an antibiotic in an animal species.

Firstly, you should:

• state how much of the antibiotic you expect will be used in Australia, and in which geographic and/or farming areas it will be used
• list relevant microorganisms (target animal pathogens, food-borne microorganisms)
• characterise the hazard with respect to
  • the known mechanism(s) and genetics of resistance pathways in relevant microorganisms
  • details of the microbial resistance patterns in relevant microorganisms in vitro, such as
    • minimal inhibitory concentrations (MICs) of antibiotic against relevant microorganisms – include data from contemporary Australian isolates where available
    • the estimated development rate of expression of resistance, such as indicated from in vitro studies of passaged microorganisms in the presence of the antibiotic (where such information is available)
  • details of the microbial resistance patterns in relevant microorganisms that have emerged with the use of the product, the antibiotic or related substances
• identify the proposed use of the product and the target animal species
  • major food-producing species (mass medication) – for example, cattle, sheep, pigs and poultry
  • major food-producing species (individual animal treatment) – for example, cattle, sheep, pigs and poultry
  • other food-producing species (mass medication or individual animal treatment) – buffalo, deer, fish, goat, kangaroo, rabbit, bee, crustaceans, molluscs and other minor species.

Secondly, you should supply overseas data or Australian data, or both, where available. These data may include changes that have been identified in MICs of the antibiotic against isolates of relevant microorganisms collected from clinical cases, field trials, or changes identified after other uses of the antibiotic or related substances.

You should provide evidence of in vitro cross-resistance in relevant microorganisms with other antibiotics in

• the same antibiotic class
• other antibiotic classes.

If overseas or Australian data are not available, you should justify this with relevant scientific argument:

• Assess the potential exposure of gut flora to the antimicrobial (or its metabolites) according to the following levels of exposure:
  • High – in-feed or in-water medication as group treatment – the antimicrobial substance and/or its metabolites are present in the gastrointestinal tract in concentrations high enough to have an impact on microbial flora after administration
  • Low – parenteral treatment or individual oral treatment – the antimicrobial substance and/or its metabolites are present in the gastrointestinal tract after administration
  • None – the antimicrobial substance and/or its metabolites are not present in the gastrointestinal tract
• If the antibiotic (or metabolites) is likely to be present as an active substance in the large intestine of target animal species, describe the:
  • Known or predicted antibiotic concentrations in colonic contents, where available
  • Expected effects of the antibiotic on colonic microorganism content (including anaerobes) and resistance patterns in relevant microorganisms in target animals or animal products – if not available, provide relevant scientific argument
• Describe the hazard that may be expected to arise from the proposed use pattern and the quantities and distribution of use
• Categorise the probability of hazard when the product is used according to the proposed use pattern (negligible, low, medium or high)

1.1.2. Exposure characterisation

An exposure characterisation states the amount and frequency of exposure of susceptible humans to antibiotic-resistant microorganisms (or their transferable genetic elements) from animal sources.

You should describe:

• routes of exposure
• levels of carriage of food-borne microorganisms in populations of the target animal species
• the potential for contamination of food commodities on farms (such as eggs or milk), at abattoirs (such as meat) or at other relevant locations of harvest
• the potential for contamination and amplification along the food chain, including processing, storage, distribution and preparation
• contamination prevention programs along the food chain, providing details of:
  • the effectiveness and reliability of codes of practice and Hazard Analysis and Critical Control Points (HACCP) programs relating to contamination
  • the effectiveness and reliability of process controls to destroy or inhibit microorganisms
  • microorganism survival and potential for growth, reduction or dilution in food along the food chain (processing, storage, distribution and preparation) with respect to temperature, time, pH, water activity and microbial interaction
• the intended use of foods and consumption patterns
• the probability and extent of human exposure in the general human population (negligible, low, medium or high).

You should also give details of:

• the demonstrated establishment of antibiotic-resistant microorganisms (of animal origin) in the general human population and in susceptible humans
• factors that are believed to influence food-borne microorganism distribution and secondary spread from a point source to a range of susceptible humans (including characterisation, variability and distribution)
• populations of susceptible humans with respect to relevant microorganisms
• the probability of spread to susceptible humans (negligible, low, medium or high)
• the probability and extent of exposure of susceptible humans to resistant microorganisms from animal sources (negligible, low, medium or high).

1.1.3. Impact characterisation

An impact characterisation is the evaluation of infections (caused by antibiotic-resistant pathogens of animal origin) in susceptible humans.

You should rank the antibiotic with regard to the perceived or known clinical importance of the class of antibiotics to humans. Table 1 is based on the Expert Advisory Group on Antimicrobial Resistance (EAGAR) document titled EAGAR importance ratings and summary of antibiotic uses in humans in Australia (2006 – no longer readily available) and may be used as a guide.

In your impact characterisation, you should also:

• present a dose-response analysis – a description of the relationship between the frequency and magnitude of exposure of humans (dose) to antibiotic-resistant, food-borne microorganisms and the severity and/or frequency of the impact (response), including an estimate of the critical threshold of exposure required to cause infection in susceptible humans
• describe the severity, morbidity and mortality of antibiotic-resistant diseases
• state the expected numbers of infections and deaths
• outline the impact on human health and quality of life, including the range of susceptible humans expected to be affected
• categorise the probability of antibiotic-resistant infection development in susceptible humans (negligible, low, medium or high).

1.1.4. Assessment of the uncertainty of the data used in the risk assessment

You should assess how much of the uncertainty of the data used in the risk assessment is due to inherent variability and measurement error, and how much is due to lack of information or understanding.

1.1.5. Benefits of use of the antibiotic in Australian animal health

You should describe the:

• benefits of use of the antibiotic in Australian animal health
• groups that benefit from taking the risk of using the antibiotic
• groups that bear the risk and would benefit from risk management
• risk-benefit distribution in Australian society, including the relative importance of the class of antibiotics in animals and humans.

1.1.6. Risk characterisation

A risk characterisation states the probability of disease due to infection in susceptible humans after exposure to antibiotic-resistant microorganisms (or their transferable genetic elements) of animal origin and the severity of the impact of exposure on susceptible humans.

You should justify your risk characterisation.

1.2. Summary of the risk assessment

You should summarise the risk profile, including a 3 x 4 matrix such as the example given in Table 2.

Place a tick in each column that characterises the hazard, the exposure and the impact. For example, if the hazard is high, the exposure is low and the impact is negligible, a tick is placed in the ‘high’ column for hazard, in the ‘low’ column for exposure and in the ‘negligible’ column for impact.

Separate risk summaries may be necessary for different bacterial species.

1.3. Recommendation

You should present a recommendation in support of the proposed use pattern of the antibiotic, providing suggestions for risk management, including mitigation and minimisation.

2. Risk assessment for non-food-producing animals

For antibiotics to be used in non-food-producing animals, a risk assessment should address risks associated with the potential transfer of antimicrobial-resistant bacteria or their genetic material from non-food-producing animals, such as companion animals, to humans.

A risk assessment for non-food-producing animals should be qualitative and based on scientific argument and data. Overseas data, Australian data or both should be supplied where available.

You should cover the following points in the risk assessment:

• The identification of relevant microorganisms of zoonotic potential
• The identification of relevant microorganisms that may be found in the animals’ faeces (for example, Campylobacter species, Escherichia coli, Enterococcus species, Salmonella species), urine (for example, E. coli), skin or nares (for example, Staphylococcus intermedius, S. aureus) or saliva
• Consideration of possible routes of exposure, including:
  • direct contact with animal faeces
  • indirect contact with animal faeces (through grooming or stroking animals or being licked by animals)
  • direct or indirect contact with resistant bacterial pathogens on the animal’s skin or nares, or in the animal’s mouth or urine
• Consideration of different exposure risks for different human population groups. Separate risk summaries may be necessary for:
  • members of the general public
  • specific population groups that are in frequent and sometimes prolonged contact with companion animals (such as families with pets, veterinary staff, kennel staff, elderly persons in retirement homes or hospitalised patients in contact with ‘pets-as-therapy’ animals)
  • young children with higher risks associated with poor hygiene
• Consideration of horses as potential food-producing animals (if horses are a target species)