ARCHIVED - Memo - Considerations for Pesticidal Uses of Antimicrobial Drugs

11 September 2009

1.0 Purpose

This memo clarifies Health Canada Pest Management Regulatory Agency (PMRA)'s considerations when reviewing applications for pesticidal uses of antimicrobial drugs. This document provides clarifications to stakeholders on how PMRA determines acceptability of such submissions.

2.0 Background

Antimicrobial resistance (AMR) occurs when bacteria change in a way that reduces or eliminates the effectiveness of antimicrobial drugs. A bacterium can acquire resistance when a genetic mutation occurs within the organism and this resistance can be passed vertically to daughter cells. Alternatively, resistance genes may reside on plasmids that can be passed by horizontal transfer to other bacteria including human pathogens. When selective pressure, such as the presence of an antimicrobial drug, is applied, these resistant bacteria survive and multiply to emerge from the general population leading to more virulent human and animal pathogens that cannot be treated with the standard microbial drugs. The ability to combat human and animal diseases is threatened posing potentially serious public health consequences in the form of limited and expensive drug choices and adverse health outcomes.

Antimicrobial resistance has been observed as a result of veterinary drug use. The low level but prolonged exposure to antimicrobial drugs employed for the purpose of growth promotion presents the ideal conditions for the development of antimicrobial resistance. Curative uses typically require high doses for short periods that are less likely to result in the emergence of resistant populations.

Although resistance is virtually inevitable whenever antimicrobial drugs are used, prudent and managed use of antimicrobial drugs and better infection control slows its development.

Streptomycin 17, containing the active ingredient streptomycin sulphate, is currently the only antimicrobial drug registered for pesticidal purposes in Canada. It is intended for use on apple and pear trees for control of fireblight. A re-evaluation decision on Streptomycin noted that although the limited uses under consideration posed an acceptable risk from an AMR perspective, potential for AMR would be considered for any future actions such as registration renewals or approvals of new uses.

The 2008 Agriculture and Agri-Food Canada (AAFC) Minor Use Pesticide Priority-Setting Workshop identified several potential label expansions for Streptomycin 17 that PMRA agreed to consider on a "case-by-case" basis.

The PMRA identified the need to clarify the term "case-by-case" as it relates to the regulation of antimicrobial drugs for pesticidal uses. The PMRA's current approach and thinking when assessing pesticidal uses of antimicrobial drugs are summarized below. When drafting this approach, the PMRA consulted with the Veterinary Drugs Directorate (VDD), the Health Canada working group lead on risk assessment for the Codex Alimentarius Task Force on Antimicrobial Resistance, and considered the risk factors identified by the Fungicide Resistance Action Committee.

3.0 Regulation of Pesticidal Uses of Antimicrobial Drugs in Canada

Antimicrobial agents are used in human medicine, veterinary medicine, animal husbandry, plant agriculture, aquaculture and consumer products. Health Canada, through the VDD of the Health Products and Food Branch (HPFB) is working internationally on AMR through the Codex Alimentarius Task Force. Although the objective of the task force is to provide guidance on the use of antimicrobial drugs in food and feed production, the main emphasis has been on veterinary drug uses.

The PMRA has concerns with regards to agricultural uses of antimicrobial drugs and expansions of such uses due to the potential for development of AMR. Pesticidal uses of antimicrobial agents present unique issues for consideration such as occupational and environmental exposure. The PMRA is working with VDD, as part of the Codex work, in formulating a policy on the regulation of pesticidal uses of antimicrobial drugs. In the interim, guidance for PMRA stakeholders is required.

Currently, the PMRA adopts a weight of evidence approach to assessing pesticidal uses of antimicrobial drugs. A number of factors are considered (see Section 4.0) and the applicant should build a scientific rationale based on these factors in order to support its application for registration.

4.0 Considerations

4.1 Health and Environmental Considerations

1. Clinical importance of the antimicrobial drug in human medicine: As a general rule, resistance to drugs of higher importance may be expected to have greater consequences to human health than resistance to drugs of lesser importance. Therefore, drugs of higher importance will receive more rigorous scrutiny for microbiological safety assessment, such as AMR-related issues, compared to drugs of a less important category. A ranking of antimicrobial drugs, based on clinical importance, has been compiled by the Food and Agriculture Organization of the United Nations/World Health Organization/World Organization for Animal Health.¹
2. Extent and frequency of use: The use pattern (for example,  greenhouse vs. outdoor applications, number of applications, preventative vs. curative uses, crop production cycle/crop turnover, pervasiveness of use, etc.) determines the level of occupational and environmental exposure and, indirectly, the potential for development of AMR. Uses that are long in duration and low in dose, particularly in an enclosed setting, are considered less desirable as they are more conducive to the development of resistance.
3. Potential for cross resistance: Cross-resistance to an antimicrobial drug may develop when bacteria treated with one drug, develop resistance to other drugs of the same or different family (for example, multiple-resistant Staphylococcus aureus is resistant to a number of beta-lactam antibiotics including methicillin, dicloxacillin, nafcillin, and oxacillin). Cross-resistance is the result of a single biochemical mechanism (for example, a drug efflux mechanism of resistance often confers resistance to several antimicrobial drugs). Antimicrobial drugs that select for resistance mechanisms associated with cross-resistance pose a greater concern.
4. Potential for co-resistance: Genes encoding resistance to multiple antimicrobial drugs are often linked together (for example, beta-lactamase genes and aminoglycoside resistance genes have been commonly found to co-exist on the same plasmid). Co-resistance may be the result of several different biochemical mechanisms of resistance (for example, inactivating enzymes and altered drug binding sites). Use of one antimicrobial drug can, therefore, select for resistance to a completely unrelated antimicrobial drug. Antimicrobial drugs that select for linked resistance genes pose a greater risk.
5. Genetic transferability of resistance: Resistance genes can be transferred to other bacteria. Where the resistance genes reside (i.e. chromosome, plasmid, transposon) determines how readily transfer of resistance can occur.
6. Environmental exposure: Interaction in the environment between resistant bacteria and human bacterial pathogens provides an opportunity for transfer of resistance.
7. Manufacturing process: In the case of industrial uses of antimicrobial drugs (for example, production of ethanol from distiller's grain), full details of the manufacturing process must be included. Manufacturing processes that include procedures to degrade/inactivate or remove/filter the antimicrobial drug and any microorganisms are considered more favourably.

4.2 Value and Sustainability Considerations

Registration of antimicrobial drugs to control bacterial diseases on plants must be considered from a value as well as a human health perspective. From a value and sustainability perspective, factors that influence the development of antimicrobial resistance fall into three categories: antimicrobial drug-associated risks, pathogen-associated risks, and use pattern-associated risks. Refer to the Fungicide Resistance Action Committee for detailed information on these risk factors. The Fungicide Resistance Action Committee is a Specialist Technical Group of CropLife International whose purpose is to provide fungicide resistance management guidelines to prolong the effectiveness of "at risk" fungicides and to limit crop losses should resistance occur. These guidelines are widely accepted internationally.

The following are positive indications of the risk of developing antimicrobial resistance:

A) Antimicrobial Drug-Associated Risk Factors

Mode of action

An antimicrobial drug with a single-site mode of action on the target pest has a greater risk of resistance development because a single mutation (monogenic, or single step, resistance) is more likely to occur than a simultaneous development of mutations in several genes (polygenic, or multi-step, resistance)

Cross-resistance

A pathogen that becomes resistant to one antimicrobial drug may exhibit lowered sensitivity to other antimicrobial drugs affected by the same gene mutation.

B) Pathogen-Associated Risk Factors

Generation time

Rapid multiplication of the pathogen and the presence of large populations provide greater opportunities for mutations. Shorter generation time requires more frequent exposure to the antimicrobial drug, which increases the speed of resistance build-up.

Pathogen dispersal

Pathogens that move readily between plants, crops, or regions result in more rapid spread of resistance from its site of origin.

History of resistance

Reports of confirmed cases of field resistance and/or laboratory-induced resistance in the pathogen is a significant concern.

Fitness of resistant strains

Resistant strains able to compete well with sensitive strains increase the possibility that resistance will be maintained even when the active ingredient is no longer in use.

Ability to infect at multiple crop stages

Infection throughout the life of the plant requires repeated application, which drives resistance development.

C) Use Pattern-Associated Risk Factors

Sequential applications

Repeated applications of the antimicrobial drug to the pathogen population favour the selection of resistant strains.

Reliance on antimicrobial drugs as a sole treatment option

The use of antimicrobial drugs as an exclusive treatment favours resistance development. A rotation scheme involving use of registered alternatives with different modes of action reduces this risk.

Absence of complementary control measures

Non-chemical strategies for disease prevention or reduction, such as crop rotation, use of resistant varieties, thresholds, forecasting programs, and hygienic precautions, contribute to the delay of pathogen resistance development. If these measures are not available or are not being adopted, the risk of resistance development is greater.

Geographical isolation of plant pathogens

A greenhouse environment isolates the bacterial population and prevents the re-entry of sensitive forms, allowing the resistant population to increase more rapidly.

Crop area to be treated

Larger cropping areas provide more opportunities for selection. The greater the area to be treated, the more widespread the selection and build-up of resistant individuals.

Use of susceptible cultivars

Susceptible cultivars encourage the growth of a larger pathogen population that requires more frequent spraying. Repeated application of the antimicrobial drug promotes the development of resistance.

Routine preventative applications

Preventativeapplication of an at-risk antimicrobial drug without the use of a forecasting system that predicts primary infection events increases the risk of resistance development.

Multiple crop cycles

Several crop cycles in a greenhouse that require treatment with an antimicrobial drug exposes the pathogen population to the antimicrobial drug with greater frequency.

Lack of a resistance management plan

The use of the antimicrobial drug without a clearly defined, feasible resistance management plan increases the risk of resistance development.

5.0 Implications for Applicants Making a Submission

Applicants are strongly encouraged to request a pre-submission consultation with the PMRA in order to receive more product-specific guidance. When preparing a proposal to use an antimicrobial drug as a pesticide, the health and value related risk factors that apply to the proposed use should be identified. Measures to mitigate these risks should be considered whenever possible. The proposal would then be assessed using a "weight of evidence" approach to determine if it can be supported. Furthermore, if required, assessments will be made in consultation with other national and international bodies.

6.0 Future Work

The PMRA will continue to work with its departmental and international partners in developing a policy on AMR.

7.0 Implementation

This memo documents and clarifies the PMRA's current practices regarding requirements for pesticidal uses of antimicrobial drugs and is effective as of the date of publication.

8.0 Questions

Questions concerning this memo should be directed to the PMRA's Pest Management Information Service.