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Drugs and Health Products

Categorization of Antimicrobial Drugs Based on Importance in Human Medicine

(Version - April, 2009)

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 limit the development of antimicrobial resistance and 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.

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.

Purpose

The purpose of this document is to assist the microbiological safety assessment of pre- and post-market evaluation of veterinary antimicrobials. This also provides a rationale for priority setting and identifying the level of detail required for risk assessments related to antimicrobial resistance.

As this categorization system serves as part of a guide for the evaluation of new veterinary antimicrobial drug submissions, sponsors are requested to take it into consideration when preparing their submissions. It is considered that resistance to drugs of higher importance may be expected to have greater adverse consequences to human health than resistance to drugs of lesser importance, and may require more detailed assessment/data related to their microbiological safety.

Role of the Categorization in the Risk Analysis of Antimicrobial Resistance

This document can be used for priority setting in antimicrobial resistance risk analysis. As antimicrobial drug categories also reflect severity of adverse human health consequences in case of resistance development, the categories could be used to represent the part of consequence assessment in risk assessment. However, the categorization itself is not a risk assessment. Therefore, overall risks to human health related to the particular antimicrobial agents need to be assessed separately in considering the specific application of each antimicrobial during the pre-market or post-market evaluation. The risk analysis or assessment is expected to include drug categorization and other relevant information.

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. For the sake of transparency of the categorization process, 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, the availability of new drugs in the market, or due to identification of a new indication. Therefore, this categorization will be periodically (e.g., in 2-3 years) reviewed and, if necessary, revised on the basis of new scientific evidence or emerging information on changing patterns of antimicrobial use and/or resistance trends.

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 is not considered during this categorization, but would be part of a separate human health risk assessment process. The extent of use in human medicine is also not considered in this document, but could be applicable to prioritizing antimicrobials within a category or during a 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. The antimicrobial agents are grouped into four categories.

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.

It is noted that 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.

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   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   Streptogramins
  • 2.9   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