WHO publishes updated list of medically important antimicrobials

The World Health Organization (WHO) has released its updated list of medically important antimicrobials. Published February 8, the WHO List of Medically Important Antimicrobials adds new categories on the basis of their importance in human medicine, risk of antimicrobial resistance (AMR), and the potential human health implications of inappropriate use in nonhuman sectors, particularly in animal agriculture.

The list is intended to assist policy makers and regulators with risk-based decisions to minimize any adverse impact of antimicrobial use in animals on AMR in humans. The WHO also intends the list to promote antimicrobial stewardship among veterinary professionals and prescribers of antimicrobials, as well as to provide guidance for national AMR steering committees and food animal producers.

"AMR remains one of the top global public health threats facing humanity and was associated with the death of close to 5 million people globally in 2019," the WHO said in a statement. "The WHO MIA List supports the optimized use of antimicrobial medicines in human and animal health."

The WHO list is not without its critics, however. Dr. Patricia Gaunt, chair of the AVMA Committee on Antimicrobials, said the list needed a One Health approach to the judicious use of antimicrobials rather than focusing so much on humans.

"The WHO committee should consider that human health is also dependent upon interaction with animals and the environment, and the focus for all these sectors should be the judicious use of antimicrobials," she said.

Revised antimicrobial categories

In 2005, the WHO began publishing a list of critically important antimicrobials, previously known as the WHO Critically Important Antimicrobial List for Human Medicine. The list has undergone regular revisions over the years, with the last iteration published in 2018.

Three new categories have been added to the list-"authorized for use in humans only," "medically important," and "not medically important"-to provide a more comprehensive pathway for assessing all antimicrobial classes.

The authorized for use in humans only group includes anti-pseudomonal penicillins, carbapanems, and third-, fourth-, and fifth-generation cephalosporins with beta-lactamase inhibitors.

All classes of antimicrobials used in people and animals are categorized in the World Health Organization's List of Medically Important Antimicrobials according to their importance in human medicine. The list is based on an assessment of the human health risks from the potential development of antimicrobial resistance associated with their use in animals.

The medically important antimicrobials group is further divided into "highest priority critically important antimicrobials (HPCIA)," "critically important antimicrobials (CIA)," "highly important antimicrobials," and "important antimicrobials." Antimicrobials in this group were categorized using the WHO Model List of Essential Medicines and its Access, Watch, and Reserve (AWaRe) classification system.

Two criteria used to categorize a drug in the first two medically important antimicrobial categories were whether the antimicrobial class is the sole, or one of limited available therapies, to treat serious bacterial infections in people and whether the antimicrobial class is used to treat infections caused by bacteria possibly transmitted from nonhuman sources or with resistance genes from nonhuman sources.

Among the classes categorized as HPCIA are third- and fourth-generation cephalosporins, quinolones, and polymyxins. The CIA category includes aminoglycosides and macrolides.

Another new category, "authorized for use in animals only," includes antimicrobials for which there is no substantial evidence that their use could result in resistance to medically important antimicrobials.

Antimicrobial classes authorized only for topical use were not considered unless they are frequently used to treat multidrug-resistant pathogens in humans.

The list was developed with the Food and Agriculture Organization (FAO), the United Nations Environmental Programme (UNEP), and the World Organisation for Animal Health (WOAH, founded as the OIE) as a joint effort to harmonize and align related guidance and lists developed by the four organizations.

Further work is ongoing to harmonize guidance on the prudent use of antimicrobials across all four organizations (FAO, UNEP, WHO, and WOAH) along with the WHO antimicrobial list and the WOAH list of antimicrobial agents of veterinary importance.

Implications for veterinary medicine

Although the WHO states that it supports the use of antimicrobials in animal health, there are recommendations in the list that indicate differently, according to Dr. Gaunt, who is an associate professor of aquatic animal health at Mississippi State University College of Veterinary Medicine.

For example, the WHO list opposes the use of novel antibiotics in animal health, stating: "The following best practices statements are aligned with the position of the Quadripartite organizations (FAO, UNEP, WHO, and WOAH) and are critical to preserving the effectiveness of these agents in humans: Any new antimicrobial class that is authorized only in humans will automatically be placed in the authorized for use in humans only category. For implementation purposes, drugs within classes in the group of authorized for use in humans only should not be authorized in the future for use in food-producing animals, crops, or plants."

"If (the Food and Drug Administration) were to adopt the WHO recommendation, newly developed antimicrobials classes not currently authorized in food-producing animals could not be used in the future," she said. "This disincentivizes drug sponsors to develop new drugs for treatment of animal diseases."

Limiting access to novel antimicrobials in veterinary medicine could lead to repeated use of existing antimicrobials, resulting in selection for resistant bacteria to existing antimicrobials, which is counterintuitive to their judicious use, Dr. Gaunt explained. Moreover, as technology evolves and more is learned about bacterial pathways and mechanisms of action of antimicrobials, novel antimicrobials will offer additional prevention, control, and treatment.

"However, none of these tools would be available to veterinarians for use in food animals under the WHO list if regulatory agencies follow this line of thinking," she said.

Dr. Gaunt also criticized the list for not defining the terms "off-label" or "extralabel use."

"Do the terms include only certain classes of (medically important antimicrobials) such as the critically important antimicrobials? Do they apply to nonapproved uses of an antimicrobials already approved in an animal species?" she asked.

Another lingering question is whether the list would affect a U.S. veterinarian's ability to use antimicrobials under the Animal Medicinal Drug Use Clarification Act or Compliance Policy Guide 615.115 (Extralabel Use of Medicated Feeds for Minor Species), which allows veterinarians to use a veterinary feed directive containing an approved antimicrobial in an extralabel fashion in minor species.

Although the WHO list is a nonbinding regulation, it does serve as a reference tool for antimicrobial use by policymakers and regulators.

"Regulation of antimicrobial use should utilize a risk and science-based approach, an approach which is not evident in this document," Dr. Gaunt added. "This list is more likely to have an impact in Europe, but it could influence U.S. regulatory agencies in their antimicrobial rankings, which could restrict veterinarians' access to certain antimicrobials."

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