Codex Alimentarius Discussion Paper on Antimicrobial Resistance

Comments submitted by COMISA (IFAH)

March 2001

The Global Animal Health Industry Association (COMISA) to be known in future as the International federation for Animal Health (IFAH) requested comments from its members to assist the drafting of a discussion paper on antimicrobial resistance. The Animal Health Institute in the US has prepared a series of suggestions and these are re-stated here as the position that COMISA (IFAH) supports.

BACKGROUND

At its Twelfth Session held 28-31 March 2000, CCRVDF requested the Delegation of the United States to draft a discussion paper on antimicrobial resistance. Australia, Brazil, Canada, Costa Rica, Denmark, Finland, Germany, New Zealand, Thailand, United Kingdom, OIE, WHO, European Union, COMISA, and Consumers International all expressed interest in being part of the drafting group. The US Delegation was requested to:

1. consider all aspects of antimicrobial resistance relevant to the work of CCRVDF,
2. identify specific areas for further action, as required, and
3. develop a code of practice for the containment of antimicrobial resistance.

We believe that CCRVDF should recommend that a draft paper is not necessary for the following reasons:

1. Antimicrobial resistance in food-borne pathogens is not a problem that has been attributed to antibiotic residues;
2. MRL’s are currently recommended with consideration given to effects of residues on normal gut flora, including resistance;
3. concerns regarding antimicrobial resistance from the use of a product are outside the specific remit of CCRVDF;
4. and the Codex code of practice for use of veterinary drugs already has wording regarding containment of antimicrobial resistance that provides sovereign nations sufficient guidance to generate their own guidelines.

However, in the event that Codex will do something regarding this issue; CCRVDF may be the best-placed Codex committee to do so. AHI supports CCRVDF involvement if Codex does, in fact, develop further guidelines in this area. If that is the case, we suggest the first two items be handled by amending the OIE document on antimicrobial resistance and the third item be handled with existing language from the Codex code of practice.

THE OIE DOCUMENT

We suggest a good starting place to fill the request of CCRVDF is the document produced by the OIE ad hoc group on antimicrobial resistance titled: "Guideline For The Responsible And Prudent Use Of Antimicrobial Agents In Veterinary Medicine". We suggest it be used with the following changes:

A. AIMS AND OBJECTIVES

We have no comments on this section.

B. RESPONSIBILITIES OF THE REGULATORY AUTHORITIES

Risk Assessment

Because of the importance of risk assessment in guiding regulatory decisions there should be a discussion of how known information can be utilized in a risk assessment methodology (and identification of knowledge gaps and uncertainties. Codex uses risk assessment as part of its guiding principles; WHO Principles mention risk assessment, and so does OIE, so this commonality should be amplified into a practical application as defined below:

1. Identify and define the hazard of concern

• Source, target population, adverse health effect
• Causal mechanism(s) for exposure-response

1. Identify a set of alternative risk management acts to be evaluated
2. Quantify the probable exposure and health consequences of each alternative act

• Estimate population frequency distribution of exposures (microbial loads ingested or exposed)
• Estimate population frequency distribution of illness-days for excess illnesses caused by the exposures
• Discrete-event simulation framework supports both

1. Characterize uncertainties about the probable health consequences of each act

• Uncertainty and sensitivity analyses
• Data, model, and construct uncertainties

1. Choose the risk management act (from among those evaluated) having the most preferred probable frequency distribution of health impacts (and uncertainties).

A variety of risk assessment models can be offered, for example, that of Cox Associates for fluoroquinolone-resistant campylobacter in chickens (available from the Animal Health Institute or Tony Cox). The HAN foundation report may suffice for antimicrobial growth promoters http://www.euronet.nl/~ssf/hanagp1.html

Particular emphasis should be given regarding the conformity of remaining growth promoters in Europe to the Swann principles and WHO prudent use guidelines. As well, discussion on the public health improvements (at the expense of animal health) since the implementation of the European withdrawal of growth promoter registrations is needed. This discussion thread should support the contention that there in fact has been no reduction in antimicrobial resistant human pathogens from clinical cases, such as VRE, in Europe. Had an appropriate risk assessment been completed, the risk management option of product withdrawals would have predicted this outcome.

In fact, a predictive modeling tool is essential to determine the effectiveness of any recommended code of practice that is designed to contain antimicrobial resistant microorganisms. Once the various options are evaluated the best risk management action(s) can be confidently selected for implementation. A variety of recommendations have been put forward in the WHO and OIE recommendations, however, there is no scientific basis that these actions or restrictions of antimicrobial use will in fact achieve the objective of minimizing or containing antimicrobial resistant food-borne bacteria. It is critical that some assurance be provided that these actions will achieve the hoped for objectives. Additionally, these recommendations specifically excluded any intervention steps post-slaughter/processing, and these are known to be particularly effective, and should be included in the discussion

B.2.1 Preclinical trials

Methods are not available to "assess the ability of the antimicrobial agent to select for resistant bacteria". Nor do we know how to find a dosage regimen that ensures therapeutic efficacy and limits selection of resistant bacteria, short-term or long-term. We suggest these references be deleted.

We would remove the emphasis on pharmacokinetic (PK) work to establish activity at the site of infection. No matter what such preclinical work shows, clinical efficacy decisions will be based on the clinical trials. For example, if PK results predict efficacy, but the clinical trial does not, efficacy is not established; conversely, if the PK work predicts no efficacy, but the drug is effective in the clinical trial, efficacy is established.

B.3 Assessment of the potential to select for resistant bacteria

This section recommends several types of studies that are not interpretable. OIE recognizes this, (see the 2^nd an d 3^rd paragraphs of this section) but continues to press for the studies. The items listed in the bullet points are probably all do-able, but generation of such data without knowing how to interpret it will not facilitate the regulatory decision process. We suggest this section be deleted or modified to suggest further related research.

B.6 Establishment of a summary of product characteristics

We suggest caution in using language that disqualifies a compound (or especially a class of compounds) used in human medicine from use in animal medicine. Such generalizations may eliminate valuable antimicrobials from animal use without any benefit to human medicine. The first group eliminated would be the old established drugs whose resistance development effect has long since occurred. This would force veterinarians to use other drugs and could result in a net increase in resistance development. Globally, the definition of "critical disease" and the determination that "alternatives are unavailable or inappropriate" will vary among countries and regions. A disease that is "critical" in one area may be easily controlled by education and lifestyle or may not even exist in another area. An alternative drug may be "unavailable or inappropriate" because it is too expensive in some economies, because it has not been approved in a particular country, or because herd management makes use impractical in some areas. We suggest local monitoring programs on an individual drug basis be used to help mitigate resistance and to determine if use practices need to be modified.

We do not believe the caution in the last paragraph of section B.6 (which discourages use of oral medication) is justified. In many cases the safest and most effective route is oral administration. Oftentimes whole-herd medication is necessary and cannot practically be administered except orally. If enteric diseases are effectively treated, the medication enters the gut -- whether the administration is oral or parenteral. Oral medication does not always stay in the gut; parenteral medication often enters the gut. Oral medication should not be singled out for any particular caution. It has been an effective, convenient, and safe tool in human and animal medicine.

B.7 Post-marketing antimicrobial surveillance

There are several items in this section that will increase the cost of food production without a resulting benefit.

We suggest surveillance not include reporting of "lack of efficacy related to antimicrobial resistance". Such a determination, if it can be done, is expensive. It requires establishment of a baseline, sacrifice and posting of animals, careful culture, and accurate interpretation of results. This is a lot to expect for any given producer every time lack of efficacy is suspected. "Lack of efficacy" is not a simple determination in situations where "successful" treatment in the supporting pivotal clinical trials, sometimes resulted in death loss of 10% or more. Also, in intractable cases, the veterinarian will often have treated the animals with several antibiotics, complicating any determination of resistance development. Effective surveillance can be based on less expensive, more objective criteria than determination of "lack of efficacy related to antimicrobial resistance".

We do not agree there is value in evaluating resistance in commensals. It is not at all clear which commensals should be evaluated -- partly because it is not at all clear how such information would be interpreted or if it is relevant to human health. We suggest reference to commensals be deleted.

We suggest deleting the language about providing a "continuous survey on the amounts of antimicrobial agents used by veterinarian and other authorized users". Most products have multiple claims in multiple species and dosage is dependent on body weight and severity of disease. Such data could not be interpreted in any meaningful way and could be easily misinterpreted

B.8 INTERVENTION STATEGIES TO CONTROL FOODBORNE PATHOGENS

Because of important hygienic measures that should be taken by all national authorities in regulating the production of meat and poultry, there should be a discussion of how foods of animal origin are contaminated with bacteria and key steps at which intervention actions can be taken to minimize or contain such contamination (food processing system overview). A global perspective is necessary for chicken, swine, beef, sheep and dairy production sectors

C. RESPONSIBILITIES OF THE VETERINARY PHARMACEUTICAL INDUSTRY

C.2 Marketing and export of veterinary medicinal products

We suggest deleting the restriction that "only veterinary medicinal products authorized by the (exporting) country . . . should be exported". This will conflict with specific laws established by some countries permitting the export of certain "unauthorized" animal drugs, as long as there is an authorization in the importing country.

There are also numerous examples of products for species and claims that are unique to certain regions of the world. There is not a scientific reason why such products must be produced only in the region where they are used.

C.3 Advertising

We disagree that there is benefit in ensuring that disseminated information "reaches only those authorized professionals involved in the prescription and distribution of the products." The more we can inform and educate about the appropriate use of antimicrobials, the better. We suggest this wording be deleted.

D. RESPONSIBILITIES OF PHARMACISTS

We have no comments on this section.

E. RESPONSIBILITIES OF VETERINARIANS

We suggest veterinary professional organizations not be asked to "develop for their members species-specific clinical practice guidelines on the responsible use of antimicrobials, with particular reference to the choice of product . . ." This would require professional organizations comparative statements about products governments have approved for use. To have a basis for such comparisons the professional organizations would need to establish an evaluation process comparable to that of government agencies.

We suggest including a discussion of the applications of antimicrobial agents within these various food animal production sectors on a global basis; including Judicious Use Guidelines from AVMA, Prudent Use Guidelines from COMISA, OIE, WHO, etc. Emphasis on maintaining animal health and welfare should not be forgotten, as the paper will seek to focus on safeguarding public health.

E.1 Use of antimicrobial agents when necessary

There is not enough value in diagnostic procedures to recommend them for general use. Generally they are used for exceptional situations and we suggest that approach be indicated here. Similar to what is done in human medicine, the veterinarian uses his knowledge, the history of the farm, and his experience with the disease to select a particular antibiotic in a given situation. That choice is usually effective and the antibiotic is administered in a more timely manner than if the culture had been done -- probably using less antibiotic than if the veterinarian had run the culture and treated later. We suggest recommendations for using diagnostic procedures is for exceptional situations, not for routine use.

E.2 Determination of the choice of an antimicrobial by:

E.2.1 Again the use of diagnostic procedure is over-emphasized. We suggest this emphasis be omitted. See our comments on E.1 above.

E.2.2 Please refer to the first paragraph of our comments on B.6 above.

E.2.3 This section does not provide any useful guidance on the use of combinations. We suggest it be deleted.

E.4 Recording

Again we doubt that "lack of response due to antimicrobial resistance" can be determined. See our comments under B.F.RESPONSIBILITIES OF THE PRODUCERS

We have no comments on this section.

CODE OF PRACTICE

Codex Alimentarius has published a "Recommended International Code of Practice for Control of the Use of Veterinary Drugs" (CAC/RCP 38-1993). This document provides general guidelines for responsible use of drugs in animal medicine, including the statement in paragraph 7 that alludes to the control of resistance. However, we propose to revise this statement as follows to take into account the use of antimicrobials used in the production of animals, since the Codex Alimentarius Commission Procedural manual defines the term veterinary drug to include, therapeutic, prophylactic diagnostic, and modification of physiological functions or behavior

This statement clearly defines the areas of concern and establishes who is responsible, then leaves to national governments the details of implementation. Therefore, we propose that this is the proper amount of direction from Codex on prudent use of antibiotics and can continue to serve as the Codex code of practice.

CONCLUSION

It is our hope that you will find these comments useful in developing a position regarding a draft discussion paper on antimicrobial resistance. We are willing to continue to work with you in this effort.