Veterinary Manual of Requirements and Guidelines - Vet MORAG

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Part 10 - Special Data: Antibiotic Resistance

1.   INTRODUCTION

Antibiotic resistance is a global public health and animal health concern that is influenced by both human and non-human antimicrobial usage, with resulting development and spread of antibiotic resistance.

Antibiotic resistance is a property of bacteria that enables them to grow in the presence of antibiotic concentrations that would normally kill or suppress the growth of susceptible bacteria.

Antibiotic resistance occurs naturally in some genera of bacteria and in others it is acquired. The antibiotic resistance of greatest concern is that which is acquired by bacteria through genetic mutations or through movement of antibiotic resistance genes from one bacterium to another. Continued use of an antibiotic in the presence of resistance allows those resistant bacteria to survive and become dominant within the bacterial flora. This selection of resistant bacteria is more likely to occur when the exposure of bacteria to antibiotics is greatest, for example when:

  • there is overuse and inappropriate use of antibiotics (eg by medical practitioners, or veterinarians, or on farms);
  • antibiotics are used at low doses for long periods of time;
  • there is a high bacterial load;
  • there is a high level of resistant bacteria present in the environment or clinical situation.

1.1.   The JETACAR Report

The Joint Expert Technical Advisory Committee on Antibiotic Resistance (JETACAR) reported to the Australian government in 1999 on various aspects of antimicrobial resistance, including those associated with use of antibiotics in food-producing animals. The JETACAR report concluded that there was evidence for:

  • the emergence of resistant bacteria in humans and animals following antibiotic use;
  • the spread of resistant animal bacteria to humans;
  • the transfer of antibiotic-resistance genes from animal bacteria to human pathogens; and
  • resistant strains of animal bacteria causing human disease.

A key recommendation of the JETACAR report, supported by the Australian Government, was that the APVMA would evaluate all new applications for registration of antibiotics for use in animals, major extensions of use, and any reviews of currently registered antibiotics, in accordance with Part 10 Special Data Requirements. This data Part includes a risk analysis associated with antimicrobial resistance.

1.2.   What are the risks?

The use of antimicrobial agents in humans, animals or plants is likely to select for antimicrobial resistance in both target and non-target micro-organisms. Zoonotic organisms can be transferred to humans from animals. It follows that antimicrobial-resistant zoonotic and commensal organisms can also be transferred directly to humans.

The transfer of antimicrobial-resistant non-zoonotic bacteria or their genetic material from animals to humans indirectly via the food chain is known to occur. However, there are limited data to demonstrate the magnitude and importance of such transfer and whether such transfer occurs via consumption of contaminated meat or via contamination of water or vegetables by animal excreta.

The transfer of antimicrobial-resistant bacteria or their genetic material from companion animals to humans is also possible. Transfer of antimicrobial-resistant bacteria or their genetic material from humans to companion animals and back to humans can also occur, as has been demonstrated in the case of methicillin-resistant Staphylococcus aureus (Scott et al, 1988; Cefai et al, 1994; Manian, 2003; Weese et al, 2005). Data demonstrating the magnitude and importance of such transfer are limited. Humans may be exposed to antimicrobial-resistant bacteria from companion animals by the following routes:

  • direct contact with animal faeces – dogs and cats defaecate in public spaces, home gardens or litter trays within homes.
  • indirect contact with animal faeces – anal licking during self-cleaning behaviour by dogs and cats may transfer resistant enteric bacteria to other parts of the animal’s body, such as the coat and mouth. Humans may then be exposed to the resistant bacteria through grooming or stroking the pet, or when the animal licks a family member.
  • direct or indirect contact with resistant bacterial pathogens on the animal’s skin, nares or in the animal’s mouth or urine.

The risk of exposure to antimicrobial-resistant bacteria from companion animals is negligible for members of the general public. However, this risk is considerably higher for members of a pet-owning family or other specific population groups that are in frequent and often prolonged contact with pets. Young children (eg less than 4–5 years of age) may have the highest risk of exposure compared with other family members because they are too young to control their hand-to-mouth actions and to practise adequate hand hygiene (Schutze et al, 1999; LeJeune and Davis, 2004).

The bacterial flora of both food-producing animals and companion animals, whether healthy or diseased, may act as a reservoir of resistance genes. Humans are also a potential reservoir of antimicrobial-resistant micro-organisms. Amplification of antimicrobial resistance may occur in both animal and human reservoirs.

The main risk to be assessed is the probability of diseases occurring in susceptible humans due to infection with antibiotic resistant pathogens arising from proposed changes in the use of antibiotics in animals, and the consequences of such disease.

The level of acceptable risk is that which, when weighed against proposed benefits of use in the target animal species, will not significantly compromise therapeutic use of antibiotics in humans.

2.   OBJECTIVES AND SCOPE

This chapter describes the general requirements for submitting antibiotic resistance data in support of applications for the registration of veterinary chemical products that contain antibiotics as active constituents. This chapter is consistent with the following guidelines and incorporates their requirements for basic information about antimicrobial agents for use in food-producing animals:

This chapter and the FDA/CVM documents both provide guidance on risk assessment in relation to the potential for selection of antimicrobial-resistant bacteria of human health concern.

This chapter retains guidance relating to antimicrobial resistance associated with use of veterinary medicines in companion animals and other non-food-producing species that was provided in the previous edition of Part 10 Special Data Requirements of the old Vet Requirements Series. Greater detail for risk assessments in non-food-producing animals has been provided compared with the previous version.

This chapter outlines the types of studies, data and information that are necessary to characterise the potential for development of antimicrobial resistance associated with the proposed use of antimicrobial products in animals. These studies, data and information cover attributes of the antimicrobial active constituent, the veterinary product, the nature of the resistance, the potential exposure of the gut flora in the target animal species, and risk assessment.

Special considerations may be appropriate for aquaculture products because of fundamental differences in production systems, bacterial populations present, and potential zoonoses.

3.   WHEN IS AN ANTIMICROBIAL RESISTANCE RISK ASSESSMENT REQUIRED?

The APVMA seeks advice from the Expert Advisory Group on Antimicrobial Resistance (EAGAR) of the National Health and Medical Research Council (NH&MRC), on the assessment of the public health risk from development of antibiotic resistance in human pathogens associated with use of antibiotics in animals. In order to assess this risk, applicants must submit data in support of:

  • any proposed use in Australia of a product containing a new antibiotic
  • any proposed extension of use in Australia of a registered product containing an existing approved antibiotic where the APVMA considers that there is likely to be a significant increase in the volume of usage, or that there may be an increased risk to public health as a result of the use of that antibiotic.

The following are examples of situations where there is likely to be a significant increase in the volume of antibiotic usage or an increased risk to public health as a result of the use of that antibiotic:

  • a change in dosage form or use pattern, from use in individual animals to mass medication (eg from injectable to in-feed or in-water dosage forms)
  • an extension of the use pattern to a new major food-producing host species (eg chickens to pigs, sheep to cattle; dogs to cattle)
  • an extension of the use pattern to another major group within the same food-producing species (eg broiler chickens to layers; beef cattle to dairy cattle)
  • an extension of the use pattern from food-producing animals to dogs or cats for the first time for the antibiotic.

Before submitting data, applicants are encouraged to seek clarification from the APVMA on other situations that may be considered a significant increase in the volume of usage, or may pose a public health risk.

4.   DATA REQUIREMENTS

A Part 10 submission should be presented according to the headings which follow. Each item must be addressed by data or relevant scientific argument. However it should be noted that not all requirements might be relevant to all submissions.

The following additional points should be noted:

  • the risk assessment part of the submission should be a qualitative risk assessment with scientific argument in the first instance. The data requirements are for a qualitative risk assessment. Depending on the outcome of this qualitative assessment, applicants then have the option of developing a quantitative risk assessment
  • scientific evidence is required to support the claims made and, where there are citations to scientific literature, copies of these papers must be provided with the submission
  • further questions or requests for data may arise during the APVMA and EAGAR review of the submission
  • absence of evidence for antimicrobial resistance is not evidence of its absence
  • applicants are advised to read the glossary at the end of this chapter.

4.1.   Description of the antibiotic constituent/s of the product

4.1.1.    Name and identification of antibiotic

Provide the following information:

  • Common name
  • Chemical name
  • Chemical Abstract Services (CAS) registry number
  • Chemical structure
  • Manufacturer’s code number and/or synonyms.

4.1.2.    Class of antibiotic

  • State the chemical relationship to other members of the antibiotic’s class and related classes.

4.1.3.    Mechanism and type of antimicrobial action

  • Information on the antimicrobial mechanism of action may be inferred from literature studies, patent information, or specific mechanism of action studies undertaken by the applicant. Characterisation as to concentration-dependent or time-dependent bacterial killing and bacteriostatic versus bactericidal action must be included in this section.

4.1.4.    Antimicrobial activity of the antibiotic

Antimicrobial spectrum

In order to determine the overall spectrum of activity, applicants must provide information that includes data from minimum inhibitory concentration (MIC) tests on a wide variety of micro-organisms, or from literature studies. Where MICs are determined by the applicant, the source of the isolates should be indicated. MICs may be sourced from culture collections, diagnostic laboratories, or other repositories.

Where possible, MIC values should be determined with a validated and controlled method, such as those described by the Clinical and Laboratory Standards Institute (CLSI - formerly known as NCCLS) in documents such as:

Contemporary Australian data should be provided where available and should include:

  • relevant clinical isolates and standard laboratory strains
  • validity of methods including breakpoints
  • MIC frequency tables or histograms.

Post-antibiotic and other antimicrobial effects (where appropriate)

If relevant, describe any additional effects such as first-exposure effects, post-antibiotic effects and sub-MIC effects.

MICs of target animal pathogens (as per product label claim)

Include MICs for target animal pathogens (as per product label claims).

MICs of zoonotic pathogens, food-borne pathogens and commensal organisms

Data must be presented to show MICs of relevant zoonotic pathogens, food-borne pathogens, and commensal organisms. This information may be based on published data or on studies conducted by the applicant.

Depending on the spectrum of activity, appropriate food-borne organisms may include:

  • Salmonella enterica serovars, Campylobacter species particularly C. jejuni and C. coli, Escherichia coli, Enterococcus faecalis, Enterococcus faecium and Klebsiella species.

Wherever possible, the strains included should be selected according to the following guidelines:

  • strains of relevant bacterial species/serotypes should be isolated from the proposed target animal species. When the product is intended for use in a broad range of animal species, the strains should be from the main food-producing species (eg cattle, pigs and poultry).
  • the strain collection should include recent isolates (eg within the last 2 years)
  • information on the tested strains should include:
    • identification at least to the species level
    • the origin, source and date of isolation.

This information may be used as a source of background data for surveillance studies of changes in patterns of antimicrobial resistance.

4.1.5.    Antimicrobial resistance mechanisms and genetics

Information must be provided on the resistance mechanisms and the molecular genetic basis of resistance to the antimicrobial agent. This information may come from literature or from studies conducted by the applicant. Information from analogues or the antibiotic class may be provided in the absence of data on the antimicrobial agent. The information should include:

  • known mechanisms of resistance in animal and human pathogens (eg antimicrobial inactivation, alteration of the target, reduced uptake, efflux of the antimicrobial agent)
  • location of resistance determinants (eg plasmid-mediated versus chromosomal; present on transposon, integron, or phage).

4.1.6.    Occurrence and rate of transfer of antimicrobial resistance genes

Information on the occurrence, or absence, of transfer and rate of transfer of resistance genes must be provided. This information may come from literature or from studies conducted by the applicant.

Specific studies to evaluate the occurrence of genetic transfer may follow a protocol such as found in Antibiotics in Laboratory Medicine, 5th ed., V. Lorian, ed. 2005. Lippincott, Williams and Wilkins, Philadelphia, PA. Relevant issues include:

  • can resistance determinants be transferred among bacteria by transformation, transduction, conjugation or transposition?
  • if resistance determinants can be transferred, what is the rate of transfer?
  • if resistance occurs by point mutation, at what rate do the point mutations occur?

The applicant may consider including data on target animal pathogens, relevant food-borne pathogens, and relevant commensal organisms. Information from analogues may be provided in the absence of data on the antimicrobial agent.

4.1.7.    Occurrence of cross-resistance

Information on cross-resistance to the antimicrobial agent must be provided. This information may come from literature or studies conducted by the applicant. This should include a phenotypic description and, if available, a genotypic description.

4.1.8.    Occurrence of co-resistance / co-selection

Information on co-resistance and co-selection of the antimicrobial agent in question with other antimicrobial agents should be provided by literature information or studies conducted by the applicant. This should include a phenotypic description and, if available, a genotypic description.

4.1.9.    In vitro mutation frequency studies

In vitro mutation frequency studies involving test organisms may be provided by literature information or studies conducted by the applicant. These may follow a protocol such as found in Antibiotics in Laboratory Medicine, 5th ed., V. Lorian, ed. 2005. Lippincott, Williams and Wilkins, Philadelphia, PA.

4.1.10.  Other animal studies

If available, information from other animal studies may be included to help characterise the rate and extent of resistance development associated with the proposed use of the antimicrobial product. This may include data from clinical studies conducted in support of other aspects of the application, or other relevant studies published in the scientific literature.

4.2.   Description of the product(s)

4.2.1.    General

The following attributes of the product must be described:

  • distinguishing name(s)
  • formulation type(s) / pharmaceutical dosage form(s)
  • pack sizes, as per label
  • claims, as per label
  • poisons scheduling
  • label – applicants must include a copy of the draft product label.

4.2.2.    Pharmacokinetic / pharmacodynamic profile of the active constituent after administration of the product(s)

Pharmacokinetic/pharmacodynamic information must be provided, which may include the following:

  • serum / plasma concentrations versus time data
  • maximum concentration (Cmax)
  • time of maximum concentration (Tmax)
  • volume of distribution (VD)
  • clearance (Cl)
  • area under the concentration-time curve (AUC)
  • bioavailability
  • protein binding
  • known or predicted plasma (serum) concentrations especially peaks, troughs after proposed dosing.
  • pharmacokinetic/pharmacodynamic determinant of efficacy (time above MIC, AUC/MIC ratio or peak/MIC ratio), determined either specifically or from what is known for the antibiotic class, and the magnitude of that parameter, determined using free drug concentrations, which results in (i) bacteriostasis and (ii) near maximum killing over 24 hours in vivo.
  • relationship of plasma (serum) and tissue concentrations to MICs for target animal pathogens and indicator bacteria (eg E. coli, Enterococcus spp).

Overseas and/or Australian data should be supplied where available.

4.2.3.    Antimicrobial agent activity in the intestinal tract

Where available, details may be provided on the concentrations of microbiologically-active compound within the intestinal tract contents or the faeces of the target animal(s) when the antimicrobial product is administered according to the proposed directions for use. The activity in question may be due to the parent antimicrobial agent, or to active metabolites.

Where such data are not available, details may be provided by metabolism studies relevant to the intestinal tract.

4.2.4.    Registration status in Australia and overseas

Information on the registration status in Australia and in overseas countries of the product, or products containing the same antimicrobial active constituent, should be presented in the following format:

Country Animal species Approved use patterns Restrictions on use
       

4.3.   Proposed MRLs for food-producing species

Antimicrobial agent residues present in food from food-producing animals may adversely affect the intestinal microflora of consumers. In the case of antimicrobials for use in food-producing animals applicants may propose maximum residue limits (MRLs) and a microbiological acceptable daily intake (ADI). In this case applicants should:

5.   RISK ASSESSMENT

This section is split into risk assessments for food-producing animals and other animals. Only the relevant part should be addressed.

5.1.   Risk Assessment – food-producing animals

If the application relates to use of an antibiotic in food-producing animals, applicants must prepare a qualitative risk assessment addressing the possible contribution of the proposed use pattern to antibiotic resistance in food-borne micro-organisms and human pathogens, and risk of consequent disease in susceptible humans.

With respect to antibiotic resistance, the main risk to be assessed is the probability of disease due to infection in susceptible humans with antibiotic resistant pathogens arising from the proposed use of antibiotics in animals, and the consequences of such disease.

The level of acceptable risk is that which, when weighed against proposed benefits of use in the target animal species, will not significantly compromise therapeutic use of antibiotics in humans.

The risk assessment should include consideration of studies or discussion (where relevant to the target animal species) of the following areas.

5.1.1.    Summary of the risk profile

Summarise the:

  1. hazard characterisation (5.1.2)
  2. exposure characterisation (5.1.3)
  3. impact characterisation (5.1.4)
  4. assessment of the uncertainty of the data used in risk assessment (5.1.5)
  5. benefits of use of the antibiotic in Australian animal health (5.1.6)
  6. risk characterisation (5.1.7)

5.1.2.    Hazard characterisation

Antibiotic-resistant micro-organisms 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.

Applicants must:

  • state how much of the antibiotic they expect will be used in Australia and in which geographic/farm areas.
  • list relevant micro-organisms (target animal pathogens, food-borne micro-organisms).
  • identify the proposed use of the product and the target animal species, using the following table.

    Animal species Specific examples
    Major food-producing species
    (mass medication)     		Cattle, sheep, pigs and poultry
    Major food-producing species
    (individual animal treatment)     		Cattle, sheep, pigs and poultry

    Other food-producing species
    (mass medication or individual animal treatment)

    		 Buffalo , deer, fish, goat, kangaroo, rabbit, bee, crustacea, molluscs and other minor species


  • characterise the hazard with respect to:
    • the known mechanism/s and genetics of resistance pathways in relevant micro-organisms.
    • details of microbial resistance patterns in relevant micro-organisms in vitro:

      - MICs of antibiotic against relevant micro-organisms. Include data from contemporary Australian isolates where available.

      - estimated rate of development of expression of resistance, such as indicated from in vitro studies of passaged micro-organisms in the presence of the antibiotic (where such information is available).
    • details of microbial resistance patterns in relevant micro-organisms which have emerged with the use of the product, the antibiotic or related substances.

    Overseas and/or Australian data should be supplied where available.

    These data may include changes that have been identified in MICs of the antibiotic against isolates of relevant micro-organisms collected from clinical cases, field trials or other uses of the antibiotic or related substances following use of the antibiotic or related substances.

  • evidence should be provided of in vitro cross-resistance in relevant micro-organisms with other antibiotics in:
    • the same antibiotic class
    • other antibiotic classes.

    Overseas and/or Australian data should be supplied. If not available, relevant scientific argument must be supplied.

  • assess the potential exposure of gut flora to the antimicrobial (or its metabolites). The level of exposure may be classified as:

    High potential exposure:

    • in-feed or in-water medication as group treatment; and
    • 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 potential exposure:

    • parenteral treatment or individual oral treatment; and
    • the antimicrobial substance and/or its metabolites are present in the gastrointestinal tract after administration.

    No exposure:

    • 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:
    • known or predicted antibiotic concentrations in colonic contents, where available
    • expected effects of the antibiotic on colonic micro-organism content (including anaerobes) and resistance patterns in relevant micro-organisms in target animals or animal products. If not available, relevant scientific argument must be provided
  • 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, High – see glossary).

5.1.3.    Exposure characterisation

The amount and frequency of exposure of susceptible humans to antibiotic-resistant micro-organisms (or their transferable genetic elements) from animal sources.

Applicants should describe:

  • routes of exposure
  • levels of carriage of food-borne micro-organisms in populations of the target animal species
  • potential for contamination of food commodities on farms (eg eggs, milk) at abattoirs (eg meat) or other relevant locations of harvest
  • potential for contamination and amplification along the food chain including processing, storage, distribution and preparation
  • contamination prevention programs along the food chain including:
    • effectiveness, reliability of Codes of Practice, hazard analysis and critical control points (HACCP) programs relating to contamination
    • effectiveness and reliability of process controls to destroy or inhibit micro-organisms
    • micro-organism survival and potential for growth / reduction / dilution in food along the food chain (processing, storage, distribution and preparation) with respect to temperature, time, pH, water activity, microbial interaction
  • intended use of foods and consumption patterns
  • probability and extent of human exposure in the general human population (Negligible, Low, Medium, High – see glossary)
  • demonstrated establishment of antibiotic-resistant micro-organisms (of animal origin) in the general human population
  • factors that are believed to influence food-borne micro-organism distribution and secondary spread from a point source to a range of susceptible humans (including characterisation, variability, distribution)
  • populations of susceptible humans with respect to relevant micro-organisms
  • probability of spread to susceptible humans (Negligible, Low, Medium, High – see glossary)
  • demonstrated establishment of antibiotic-resistant micro-organisms (of animal origin) in susceptible humans
  • probability and extent of exposure of susceptible humans to resistant micro-organisms from animal sources (Negligible, Low, Medium, High – see glossary).

5.1.4.    Impact characterisation

The evaluation of infections (caused by antibiotic-resistant pathogens of animal origin) in susceptible humans.

Applicants must:

  • rank the antibiotic with regard to the perceived or known clinical importance of the class of antibiotics to humans. The following table is a guide only. The most recent EAGAR importance ratings for antimicrobials can be found at: http://www.nhmrc.gov.au/publications/_files/antirate.pdf

    EAGAR importance rating Description Examples
    High Essential antibiotics for treatment of human infections where there are few or no alternatives for many infections. Have also been called ‘critical’, ‘last-resort’ or ‘last-line’ antibiotics. Antibacterials: Antipseudomonal penicillins, piperacillin-tazobactam, 3rd and 4th generation cephalosporins, carbapenems, monobactams, certain aminoglycosides, oxazolidinones, glycopeptides, fluoroquinolones, streptogramins, antimycobacterials, antileprotics, ansamycins, fusidanes, colistin
    Antifungals:     Polyenes such as nystatin; Allylamines such as terbinafine
    Medium Antibiotics where there are other alternatives available, but fewer than for those classified as Low. Antibacterials: amoxycillin-clavulanate, antistaphylococcal penicillins, 1 st and 2 nd generation cephalosporins, certain aminoglycosides, lincosamides, nitroimidazoles, non-fluorinated quinolones
    Antifungals:     Polyenes such as amphotericin; Imidazoles such as bifonazole, clotrimazole, econazole, isoconazole, ketoconazole, miconazole; Triazoles such as fluconazole; Morpholines such as amorolfine; Griseofulvins
    Low Antibiotics where a reasonable number of alternative agents in different classes are available to treat most infections even if antibiotic resistance develops. Antibacterials: benzylpenicillin, certain aminoglycosides, macrolides, tetracyclines, sulphonamide-trimethoprim combinations, bacitracin, polymyxin B, amphenicols, nitrofurans
    Antifungals:     Thiocarbamates such as tolnaftate
    Nil Classes of antibiotics with no equivalents in human medicine. Polyether ionophores, bambermycins


  • present a dose response assessment — a description of the relationship between the frequency and magnitude of exposure of humans (dose) to antibiotic-resistant food-borne micro-organisms 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 antibiotic-resistant disease severity, morbidity, mortality
  • state the expected numbers of infections and deaths
  • outline the impact on human health and quality of life including the range of the susceptible humans expected to be affected
  • categorise the probability of antibiotic-resistant infection development in susceptible humans (Negligible, Low, Medium, High – see glossary).

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

  • assess the uncertainty due to inherent variability and measurement error
  • assess the uncertainty due to lack of information or understanding.

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

Describe the:

  • benefits of use of the antibiotic in Australian animal health
  • groups that benefit from taking the risk
  • 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.

5.1.7.    Risk characterisation

Probability of disease due to infection in susceptible humans after exposure of humans to antibiotic-resistant micro-organisms (or their transferable genetic elements) of animal origin and the severity of the impact of exposure on susceptible humans.

Characterise the risk with justification.

5.1.8.    Summary of the risk assessment

Summarise the risk profile, including this 3 x 4 matrix.

  Negligible Low Medium High
Hazard        
Exposure        
Impact        

Separate risk summaries may be necessary for different bacterial species.

5.1.9.    Recommendation

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

5.2.   Risk Assessment – non-food-producing animals

For antibiotics to be used in non-food-producing animals, a risk assessment must 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.

For such animals, a risk assessment based on food-borne micro-organisms is not relevant. The risk assessment for antibiotic use in non-food-producing animals will consequently be less detailed, but should follow similar headings, where relevant, to those described in sections 5.1.1 to 5.1.9 for food-producing animals.

A risk assessment for non-food-producing animals should be qualitative and based on scientific argument and data. Overseas and/or Australian data should be supplied where available. The following points should be covered in the risk assessment:

  • identification of relevant micro-organisms of zoonotic potential (see glossary)
  • identification of relevant micro-organisms that may be found in the animals’ faeces (eg Campylobacter spp, E. coli, Enterococcus spp, Salmonella spp), urine (eg E. coli), skin/nares (eg Staphylococcus intermedius, S. aureus) or saliva
  • consideration of possible routes of exposure should include:
    • direct contact with animal faeces
    • indirect contact with animal faeces (through grooming or stroking or licking by animals)
    • direct or indirect contact with resistant bacterial pathogens on the animal’s skin, 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 (eg 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).

6.   GLOSSARY

The definitions in this glossary should be read only in the context of potential antibiotic resistance transfer from animals to humans.

Antibiotic

A chemical agent that will selectively kill or inhibit the growth of susceptible micro-organisms on direct application to living tissue or by oral or parenteral administration.

This definition includes antibacterial agents (including ionophores / polyethers), anti-fungal agents, anti-viral agents, and anti-coccidials with antibacterial activity. Antiseptics and antiparasitics with antibacterial activity may be considered on a case-by-case basis.

This definition excludes disinfectants, anti-neoplastics, immunologicals, direct-fed microbials and enzyme substances.

Antibiotic resistance

Antibiotic resistance is a property of bacteria that enables them to grow in the presence of antibiotic concentrations that would normally kill or suppress the growth of susceptible bacteria.

Breakpoint

Microbiological breakpoint

The antibiotic concentration above which organisms are known, or very likely, to harbour a resistance mechanism.

Susceptible breakpoint

The antibiotic concentration, at the site of action within the target species, at which organisms whose MICs are at or below this concentration are highly likely to respond to treatment with that antibiotic.

Resistant breakpoint

The antibiotic concentration, at the site of action within the target species, at which organisms whose MICs are above this concentration are unlikely to respond to treatment with that antibiotic.

Note: For some antibiotic/organism combinations, the susceptible and resistant breakpoints are identical. For other antibiotic/organism combinations, organism strains whose MICs fall between the susceptible and resistant breakpoint, or are equal to the resistant breakpoint, are likely to respond to higher doses of the antibiotic or at anatomical sites where the antibiotic is more concentrated. These strains are categorised as intermediate.

Disc diffusion test breakpoints

Zone diameters of disc diffusion tests that are determined by calibration against clinical or microbiological breakpoints in the target animal species.

Co-resistance / Co-selection

Co-resistance refers to the presence of several resistance mechanisms in the same organism. Co-selection refers to the selection of multiple antibiotic resistance genes when one gene is selected. This usually occurs because the multiple resistance genes are all part of the same operon and therefore under the control of the same promoter.

Cross-resistance

Resistance to more than one antibiotic or antibiotic class determined by a single mechanism of resistance. Acquisition of a single resistance mechanism confers resistance to a whole class of antibiotics.

Dose / response assessment (in risk assessment)

The relationship between the magnitude of exposure (dose) to a hazard and the severity and/or frequency of the impact (response) (adapted from Codex Alimentarius Commission Procedural Manual 2005).

EAGAR

The Australian government-appointed Expert Advisory Group on Antimicrobial Resistance. EAGAR is a specialist committee of the National Health and Medical Research Council (NH&MRC) in the Department of Health and Ageing. The role of EAGAR is to provide advice on antimicrobial resistance to Australian government agencies such as the APVMA. http://www.nhmrc.gov.au/about/committees/expert/eagar/

EMEA/CVMP

The European Agency for the Evaluation of Medicinal Products – Committee for Veterinary Medicinal Products. http://www.emea.eu.int/index/indexv1.htm.

Exposure characterisation (in risk assessment)

The qualitative and/or quantitative description and evaluation of the likely exposure of susceptible humans to a hazard (adapted from Codex Alimentarius Commission Procedural Manual 2005).

Exposure (in risk assessment)

How much and how often humans are exposed to a hazard in a manner which may produce an impact. With respect to antibiotic resistance, this is the amount and frequency of exposure of susceptible humans to resistant micro-organisms (or their transferable genetic elements) from animal sources.

FDA/CVM

The US Department of Health and Human Services Food and Drug Administration – Center for Veterinary Medicine. http://www.fda.gov/cvm/default.html.

Food-borne micro-organisms

Micro-organisms carried on or in food commodities, that may be potential human pathogens, that may be resistant to antibiotics or that may carry resistance transferable genetic elements, including Salmonella enterica serovars, Campylobacter species particularly C. jejuni and C. coli, Escherichia coli, Enterococcus faecalis, Enterococcus faecium and Klebsiella species.

HACCP program

Hazard Analysis and Critical Control Points program, commonly part of industry quality assurance programs.

Hazard

A biological, chemical or physical agent with the potential to cause an adverse effect on human health (adapted from Codex Alimentarius Commission Procedural Manual 2005). With respect to antibiotic resistance, the hazards are antibiotic resistant micro-organisms 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.

Hazard characterisation

The qualitative and/or quantitative description and evaluation of a hazard.

Human pathogens

Micro-organisms that cause disease in humans.

Impact

One or more adverse effects resulting from exposure to a hazard. With respect to antibiotic resistance, the impact is a disease resulting from infection caused by antibiotic-resistant pathogens in susceptible humans.

Impact characterisation

The qualitative and/or quantitative description and evaluation of the nature of the adverse effects on human health from exposure to a hazard.

Major food-producing species

Cattle (meat and milk), sheep, pigs, poultry (meat- or egg-producing).

Minimum inhibitory concentration (MIC)

The lowest antibiotic concentration that visibly inhibits growth of micro-organisms after in vitro incubation, at a time when an untreated culture becomes readily visible in or on culture medium. The MIC is usually expressed in terms of results for 90% (MIC90) or 50% (MIC50) of the isolates tested.

Minor food-producing species

Animal species that are not major food-producing animal species, including buffalo, deer, fish (other than ornamental fish), goat, kangaroo, rabbit, bee, crustacean and mollusc.

Non-food-producing animal species

Horse, dog, cat, ornamental fish and others.

Other food-producing species (with minor contribution to human diets)

Buffalo, deer, goat, kangaroo, rabbit, bee and others.

Post-antibiotic effect

Inhibitory effects on micro-organism growth that occur after removal of certain antibiotics present at or above MICs.

Probability

The likelihood or chance that an effect will follow, when an event occurs. In qualitative terms, probability can be categorised (adapted from OMAFRA 1996) as:

Negligible – probability is extremely low or negligible

Low – probability is low but clearly possible

Medium – probability is likely

High – probability is very likely or certain.

Qualitative analysis

Use of a narrative form or descriptive scales to describe the characteristics of, and likelihood of, each event arising and its consequences.

Quantitative analysis

Use of numerical data to describe the characteristics of, and likelihood of, each event arising and its consequences.

Risk

The probability of an adverse effect and the severity of that effect, consequential to exposure to a hazard (adapted from Codex Alimentarius Commission Procedural Manual 2005). With respect to antibiotic resistance, the risk being assessed is the probability of disease due to infection of susceptible humans with antibiotic-resistant pathogens arising from the use of antibiotics in animals and the consequences of infections caused by such pathogens in susceptible humans.

Risk analysis

A process consisting of three components: risk assessment, risk management and risk communication (Codex Alimentarius Commission Procedural Manual 2005).

Risk assessment

A scientifically based process, generally consisting of the following steps (adapted from Codex Alimentarius Commission Procedural Manual 2005):

  1. hazard identification,
  2. hazard characterisation,
  3. exposure characterisation,
  4. impact characterisation and
  5. risk characterisation.

Risk characterisation

The qualitative and/or quantitative evaluation, including attendant uncertainties, of the probability of exposure and the severity of the impact of exposure of susceptible humans to the hazard (adapted from Codex Alimentarius Commission Procedural Manual 2005).

Risk communication

The interactive exchange of information and opinions throughout the risk analysis process concerning risk, risk-related factors and risk perceptions, among risk assessors, risk managers, consumers, industry, the academic community and other interested parties, including the explanation of risk assessment findings and the basis of risk management decisions (Codex Alimentarius Commission Procedural Manual 2005).

Risk management

The process of weighing policy alternatives in the light of the results of risk assessment and, if required, selecting and implementing appropriate control options, including regulatory measures (adapted from Codex Alimentarius Commission Procedural Manual 2005).

Susceptible humans

Those humans most likely to succumb to an infection caused by a relevant micro-organism eg food-borne salmonella infections may occur in the general human population but enterococcal infections are more likely to occur in hospitalised or immunocompromised human patients.

VICH

International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Products. http://vich.eudra.org/.

Zoonotic

Transferable from animals to humans. Relevant zoonotic micro-organisms include Salmonella enterica serovars, and Campylobacter species particularly C. jejuni and C. coli. Micro-organisms that are potentially zoonotic include Escherichia coli, and Klebsiella spp. Enterococcus faecalis and Enterococcus faecium of animal origin are generally considered commensal organisms that are host specific.

7.   REFERENCES

  • Antibiotics in Laboratory Medicine , 5th ed., V. Lorian, ed. 2005. Lippincott, Williams and Wilkins, Philadelphia , PA.
  • Australian/ New Zealand Standard Risk Management AS/NZS 4360:1995 (Amendment 2, amended Jan 1998).
  • Cefai C, Ashurst S, Owens C (1994). Human carriage of methicillin-resistant Staphylococcus aureus linked with pet dog. Lancet 344: 539–540.
  • Codex Alimentarius Commission Procedural Manual (15th edition). Joint FAO / WHO Food Standards Programme, Rome 2005.
  • Commonwealth Department of Health and Aged Care and the Commonwealth Department of Agriculture, Fisheries and Forestry – Australia. The Use of Antibiotics in Food-Producing Animals: Antibiotic-Resistant Bacteria in Animals and Humans. Report of the Joint Expert Advisory Committee on Antibiotic Resistance (JETACAR). September 1999. www.health.gov.au/internet/wcms/publishing.nsf/Content/
    2A8435C711929352CA256F180057901E/
  • EMEA/CVMP VICH guideline number 27: Guidance on pre-approval information for registration of new veterinary medicinal products for food producing animals with respect to antimicrobial resistance.
  • FDA/CVM guideline #152: Evaluating the safety of antimicrobial new animal drugs with regard to their microbiological effects on bacteria of human health concern.
  • LeJeune JT, Davis MA (2004). Outbreaks of zoonotic enteric disease associated with animal exhibits. J Am Vet Med Assoc 224: 1440–1445.
  • Manian FA (2003). Asymptomatic nasal carriage of mupirocin-resistant, methicillin-resistant Staphylococcus aureus (MRSA) in a pet dog associated with MRSA infection in household contacts. Clin Infect Dis 36: e26–28.
  • OMAFRA (Ontario Ministry of Agriculture Food and Rural Affairs). Risk assessment models of the Ontario Ministry of Agriculture, Food and Rural Affairs. Document 2 – A general model for food safety risk assessment April 1996.
  • Schutze GE, Sikes JD, Stefanova R, Cave MD (1999). The home environment and salmonellosis in children. Pediatrics 103: E1.
  • Scott GM, Thomson R, Malone-Lee J, Ridgway GJ (1988). Cross infection between animals and man: possible transmission of Staphylococcus aureus infection in humans? J Hosp Infect 12: 29 –34.
  • Weese JS, Archambault M, Willey BM, Dick H, Hearn P, Kreiswirth BN, Said-Salim B, McGeer A, Likhoshvay Y, Prescott JF, Low DE. (2005). Methicillin-resistant Staphylococcus aureus in horses and horse personnel, 2000–2002. Emerg Infect Dis 11: 430–435

REVISION HISTORY

Revision Date Description of Revision
1 July 2005

First edition

  • first MORAG edition—unchanged from the original Vet Requirements Series.

1 October 2005

Second edition

  • no changes.

1 April 2006

Third edition

  • correlation of data requirements with EMEA VICH guideline #27
  • revised introduction, objectives and scope
  • added references to FDA and EMEA guidelines
  • more detail provided for risk assessments in non-food-producing animals.
1 July 2007

Fourth edition·

  • minor layout change.