Hot off the press (at long last), here is the latest version of the World Health Organization’s Medically Important Antimicrobial List.

What is the WHO Medically Important Antimicrobial List?

It’s a document that categorizes all the classes of antimicrobials that are used in people and/or animals by how important they are to human medicine, and assesses the human health risks associated with use of these drugs in animals.

How’s is the list made?

The process is driven by an expert panel that includes people with a wide range of expertise from across the world. I was Chair of this revision, and it was a great group. Discussions weren’t always easy (which is often a good sign), but they were productive.

Please note that the comments below are my personal opinions, not necessarily those of the working group.

What is this list meant to achieve?

The document’s subtitle is “A risk management tool for mitigating antimicrobial resistance due to non-human use.” That’s a bit overstated, as we didn’t assess risks of antimicrobial use in plants or crops (but hopefully that will be rolled into future revisions), but it does highlight the overall goal: to assess the risks posed by antimicrobial use in animals, and use this as the basis for thinking about how we use and monitor antimicrobial use in animals.

The assessment is based on a few things, including the human diseases different drugs are used to treat, and any evidence of use in animals leading to increased antimicrobial resistance in human infections.

A brief description of the process for creating the list:

Step 1 was sorting out which drug classes are used in humans only, animals only, or both (something that takes a surprising amount of work and digging).

Step 2 was assessing each drug class through the appropriate pathway in the figure below:

The criteria for each of the boxes in the diagram are explained below:

C1: The antimicrobial class is the sole, or one of limited available therapies, to treat serious bacterial infections in people.

 C2: The antimicrobial class is used to treat infections caused by bacteria 1) possibly transmitted from non-human sources, or 2) with resistance genes from non-human sources.

Prioritization factor 1 (PF1): The class contains at least one antimicrobial that is BOTH on the WHO Essential Medicines List  and is classified as Watch or Reserve list of the AWaRe classification of antibiotics.

Prioritization factor 2 (PF2): The antimicrobial class is used to treat infections in people for which there is already extensive evidence of transmission of resistant bacteria (e.g., non-typhoidal Salmonella spp.) or resistance genes (e.g., E. coli, Klebsiella spp., S. aureus and Enterococcus spp.) for the particular antimicrobial class from non-human sources, and these infections are frequent causes of invasive and life-threatening infections in people.

Ultimately, each antimicrobial class ends up in one of six categories:

Medically important (in descending level of importance)

  • Authorized for use in humans only
  • Highest priority critically important antimicrobials (HPCIA)
  • Critically important antimicrobials (CIA)
  • Highly important antimicrobials (HIA)
  • Important antimicrobials (IA)

Not medically important

  • Drugs that are authorized for use in animals only and which have no evidence of cross-resistance or co-selection of resistance with medically important antimicrobials.

There’s a section in the document that outlines the changes from the previous version of the list. I’ve listed the changes here:

  • Addition of new categories for human only and animal only antimicrobials (details above).
  • Changes to PF1 and PF2 (details below).
  • Downgrading macrolides from HPCIA to CIA.
  • Downgrading aminopenicillins from CIA to HIA.
  • Upgrading phosphonic acid derivatives (fosfomycin) to HPCIA.
  • Upgrading nitroimidazoles from IA to HIA.
  • Separation of ketolides from macrolides, and separation of fidaxomicin from other macrolides, since they’re so different.
  • Separation of eravacycline and omadacycline from the tetracycline class, since there are major differences in resistance mechanisms and concerns with these drugs.
  • Separation of plazomycin from aminoglycosides for similar reasons.

A few questions commonly come up about the revision:

Why create the human use only category?

This was required to ensure that important, new human drugs are appropriately categorized. Part of the prioritization process is looking at the evidence that use in animals contributes to resistance in people (PF2). If we have new drugs that are not used in animals, there’s no way new drugs could hit that bar. So, a precautionary approach is needed.

  • If the drug class is not licensed in animals, it gets in its own category, with the implication that it’s importance is at or above that of the HPCIA group. If we didn’t do that, important drug classes like carbapenems (that are used in critically ill humans) wouldn’t be able to hit the bar to be “highest priority” unless we started using them a lot in animals and found a resistance link… at which point we’re already too late. We need to be proactive and protect these important drugs, so they got a new category.

Why create the animal use only category?

In the past, there was an Annex to the list that listed animal-only drug classes, but they didn’t undergo a formal review and the list was incomplete. While drug classes not used in humans are reasonably considered not to be medically important, bacteria don’t read guideline documents, so it’s still important to properly assess these drugs. The new process built in an assessment of the animal-only antimicrobials to see if there was any real or plausible evidence that their use could co-select for resistance to medically important drugs (e.g. could resistance to the animal only drug also confer resistance to a drug used in people).

Why change the prioritization factors?

There were two prioritization factors in the previous version, but there was a lot of overlap between them and a lot of confusion about what they meant. There was also a need for a bit more specificity.

  • PF1 was changed to incorporate the newer WHO AWaRe document, that categorizes antimicrobials in humans into Access, Watch and Reserve. Since there was a rigourous process used to determine how important a drug is for humans for that list, it made sense to build that into this assessment too.
  • PF2 was tinkered to add in consideration of the severity of human disease. Resistance to any bacterium that causes disease in people is a concern, but the concern is greatest for diseases that are common and severe.

Why downgrade some drugs, even when they’re used a lot in people?

Downgrading the category of certain drug class doesn’t mean “go ahead and use it at will.” It means they are less of a concern than drugs in the higher categories. We have concerns about all medically important drugs, but we can’t just put them all in the same high category. If we did that, there’d be no guidance and we’d be saying “we don’t care if you use a new fluoroquinolone versus an old penicillin” – but we most certainly do care about a decision like that. There needs to be separation of categories for this document to be useful in risk assessment, surveillance and guideline development.

  • For example, macrolides were controversial as HPCIAs in the last version of the list. On one hand, they hit the criteria to be an HPCIA at the time. On the other, I’d much rather use a macrolide in an animal than HPCIA drugs like 3rd generation cephalosporins and fluoroquinolones. By having them all as HPCIAs, it basically says the risk of use is comparable and it doesn’t matter which one we use. I think most people in antimicrobial stewardship circles would agree that we’re much less concerned about macrolide use and resistance compared to those other classes.
  • The downgrading came as a result on the new PF2, which incorporates severity of disease into the evaluation. While macrolides are important for treating campylobacteriosis in people (the main driver for the “yes” for PF2 previously), most cases of this disease are self-limiting, antimicrobial therapy is not usually required, and Campylobacter spp. are infrequent causes of invasive, life-threatening human disease.

A document like this isn’t meant to be the final word on how we use antimicrobials in animals, but it’s an important part of the equation. We need to consider this list along with other things like the WHO Essential Medicines List, various treatment guidelines, and drug accessibility. This list is a foundational document for considering how we use and monitor antimicrobial use in animals.