Categorization of Antimicrobial Drugs Based on Importance in Human Medicine

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(Version - November 30, 2006)

Preamble

Antimicrobial drugs are used primarily in human and veterinary medicine for the treatment, control and prevention of bacterial diseases. In addition, some of these drugs are used for the purpose of growth promotion and improvement of feed efficiency in the agri-food industry. It is well recognized that many of the chemical classes of antimicrobial drugs used in animals are also used in humans. Some of these antimicrobials are essential for treatment of serious life-threatening infections in humans. If these drugs become ineffective due to the development of bacterial resistance, alternative antimicrobials may not be available to treat infections caused by resistant bacteria. Therefore, it is imperative to develop measures to mitigate the loss of effectiveness of these life-saving drugs. In this context, careful attention needs to be directed on how these drugs are used both in humans and animals, and on how to facilitate their prudent and judicious use.

Health Canada recognizes that all available antimicrobial drugs are important. However, some drugs are considered more important than others in the treatment of serious bacterial infections, and resistance development against those antimicrobials might have more serious consequences in human health. This document uses pre-defined criteria to group antimicrobials into different categories based on the implications of resistance to these drugs to human medicine. This categorization is expected to assist the regulatory risk assessment process during pre- and post-market evaluation of veterinary antimicrobials.

For the sake of simplicity, antimicrobial drugs have been ranked according to their chemical class and have been placed in a category where the majority of the drugs within the class may fall. It is understood that some of the individual drugs in a particular class may not fall in the same category as other drugs of the same class and such exceptions will be treated on a case-by-case basis.

As this categorization system serves as a guide for the evaluation of veterinary new antimicrobial drug submissions, sponsors are encouraged to take it into consideration when preparing their submissions. 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 antimicrobial resistance-related issues, compared to the drug of a less important category. However, overall risks to human health will be assessed separately considering the specific application of each antimicrobial during the pre-market evaluation. This risk assessment will include drug categorization and other relevant information.

Currently this document focuses on the antibacterial drug products. Other antimicrobials, e.g., antifungal or antiviral drugs which are less frequently used in animals, are not included in this document, but may be considered in future.

Complexity and dynamics of antimicrobial categorization

It is understood that antimicrobial categorization is a complex issue influenced by multiple factors related not only to the characteristics of an antimicrobial agent but also to the variability in existing medical practice and guidelines in antimicrobial chemotherapy. In an attempt to make this categorization process transparent, predefined criteria, based on consultation with experts, are applied to rank antimicrobial drugs. It is also recognized that the categorization scheme presented here is part of a dynamic process. The relative importance of a drug and its use pattern may be altered over time due to changes in factors that determine the drug efficacy, e.g., emergence of resistance or the availability of new drugs in the market, or due to identification of a new indication. Therefore, this categorization will be periodically updated on the basis of new scientific evidence or emerging information on resistance trends and/or changing patterns of antimicrobial use.

Criteria for categorization

The principal criteria for this categorization are the indication and the availability of alternative antimicrobials for the treatment of infections in human medicine. The use of antimicrobials in veterinary medicine and the impact of such use on human medicine are not considered during this categorization. Such considerations would be part of a separate human health risk assessment process.

The two major categorization criteria are briefly described below:

Indication : This includes the use of drugs in human medicine and the spectrum of activity as well as the efficacy of drugs. A drug which is preferred for treatment of serious bacterial infections will be considered more important than those that are not used for this purpose. It is noted that development and increased occurrence of antimicrobial resistance, including cross- and co-resistance to other classes of antimicrobials, can alter the usefulness and hence the indications of a drug.

Availability of alternative antimicrobial drugs: Drugs with limited or no alternatives for treatment of infections, or where alternatives available are within the same class, will be considered more important than others. A drug used generally as a last resort treatment will be considered more important. Acquired resistance, including multidrug resistance, may make a drug ineffective and limit the availability of effective alternative antimicrobials.

The following table provides general application of criteria for antimicrobial categorization in an attempt to make the process transparent.

Table. Application of criteria for antimicrobial categorization

Category	Preferred option for treatment of serious human infections*	No or limited alternatives available
I - Very High Importance	Yes	Yes
II - High Importance	Yes	No
III - Medium Importance	No	No/Yes
IV - Low Importance	Not applicable	Not applicable

*Serious infections are considered those which if left untreated would lead to significant morbidity requiring emergency care including hospitalization and/or mortality.

1. Category I: Very High Importance

These antimicrobials are considered of very high importance in human medicine as they meet the criteria of being essential for the treatment of serious bacterial infections and limited or no availability of alternative antimicrobials for effective treatment in case of emergence of resistance to these agents. Examples include:

1.1 Carbapenems
1.2 Cephalosporins - the third and fourth generations
1.3 Fluoroquinolones
1.4 Glycopeptides
1.5 Glycylcyclines
1.6 Ketolides
1.7 Lipopeptides
1.8 Monobactams
1.9 Nitroimidazoles (metronidazole)
1.10 Oxazolidinones
1.11 Penicillin- β -lactamase inhibitor combinations
1.12 Polymyxins (colistin)
1.13 Streptogramins
1.14 Therapeutic agents for tuberculosis (e.g., ethambutol, isoniazid, pyrazinamide and rifampin)

2. Category II: High Importance

Antimicrobials in this category consist of those that can be used to treat a variety of infections including serious infections and for which alternatives are generally available. Bacteria resistant to drugs of this category are generally susceptible to Category I drugs which could be used as the alternatives. Examples include:

2.1 Aminoglycosides (except topical agents)
2.2 Cephalosporins - the first and second generations (including cephamycins)
2.3 Fusidic acid
2.4 Lincosamides
2.5 Macrolides
2.6 Penicillins
2.7 Quinolones (except fluoroquinolones)
2.8 Trimethoprim/sulfamethoxazole

3. Category III: Medium Importance

Antimicrobials in this category are used for treatment of bacterial infections for which alternatives are generally available. Infections caused by bacteria resistant to these drugs can, in general, be treated by Category II or I antimicrobials. Examples include:

3.1 Aminocyclitols
3.2 Aminoglycosides (topical agents)
3.3 Bacitracins
3.4 Fosfomycin
3.5 Nitrofurans
3.6 Phenicols
3.7 Sulphonamides
3.8 Tetracyclines
3.9 Trimethoprim

4. Category IV: Low Importance

Antimicrobials in this category are currently not used in human medicine. Examples include:

4.1 Flavophospholipols
4.2 Ionophores