Stella Kyriakides

Photo by Aurore Martignoni/European Commission

The creation in the European Union of a list of antimicrobial drugs reserved for human use only is a "landmark worldwide" and a major step in curbing antimicrobial resistance, said Stella Kyriakides, EU Commissioner for Health and Food Safety.

After months of political wrangling, a push in Europe to expand a list of drugs that would be banned for use in veterinary medicine has failed narrowly.

An original list that more closely resembles the status quo in regards to what drugs practitioners can use is now expected to be finalized this month, to the relief of many in the profession.

In an effort to combat resistance to antibiotics and other antimicrobials, the European Union last year proposed the creation of a list of drugs that would be reserved for human patients only.

Overuse of drugs can contribute to antimicrobial resistance, or AMR, which occurs when pathogenic microbes evolve to withstand treatments meant to kill them. Scientists consider AMR to be a major threat to humankind.

The formulation of the European list is being watched closely around the world, not only because it could influence regulators in other countries but because food products from animals treated with any of the banned drugs won't be legally exportable to the EU.

When the proposed list was revealed in February, some anti-AMR campaigners were disappointed. The list, in its current form, specifies antimicrobials that aren't approved for veterinary use in the EU anyway — and, barring a few exceptions, elsewhere, either. Consequently, drugs on the list might seem unfamiliar to many practitioners. They include carboxypenicillins, ureidopenicillins, ceftobiprole, monobactams, oxazolidinones, penems and siderophore cephalosporins.

Moves to expand the list to include drugs more commonly used in veterinary medicine gained traction last month, when the European Parliament's Health Committee allowed an objection raised by dissenting lawmakers. The objection argued the blacklist should more closely resemble the World Health Organization's list of highest-priority critically important antimicrobials for human medicine. Those include third-, fourth- and fifth-generation cephalosporins, fluro- and other quinolones, glycopeptides, ketolides and polymyxins.

The Federation of Veterinarians of Europe (FVE), an umbrella group of veterinary associations in 38 European countries, campaigned against the idea. Banning the antimicrobials listed by the WHO would be "completely unworkable in the veterinary field," Dr. Nancy De Briyne, executive director of the FVE, said in an interview. "We'd have nothing to treat multidrug-resistant gram-negative infections anymore, neither in companion animals, nor in livestock."

Gram-negative bacteria, such as Escherichia coli, can be harder to kill than gram-positive bacteria, due to differences in the structures of their cell walls.

The FVE welcomed news that the objection was voted down in the European Parliament on June 23 — with 280 votes against, 269 in favor and 46 abstaining.

Last week, all 27 EU member states endorsed the list, which the European Commission said in a statement would be formally adopted "in the coming weeks," with the rules coming into effect six months after the list's publication.

"The list voted today, the first of its kind in the EU, and a landmark worldwide, is a major step forward in our One Health policy approach to curb antimicrobial resistance," Stella Kyriakides, the EU Commissioner for Health and Food Safety, said.

Still, the fact that the rejection was voted down by a slim margin shows how precarious veterinary usage of many antibiotics has become.

Debate centers on the antibiotic colistin

Although some campaigners would like to see a variety of antimicrobials taken out of veterinarians' hands, they were most disappointed that colistin, a polymyxin also known as polymyxin-e, didn't make the list.

Polymyxins are used as a last-resort drug to treat certain stubborn infections. Of concern, though, pathogens that are resistant to colistin have been identified in humans and other animals. Fears intensified in 2015, when researchers in China discovered colistin resistance had occurred via horizontal gene transfer, whereby resistance can jump from one organism to another, without the need for reproduction.

In agriculture, the drug typically is used to treat E. Coli infections, including colibacillosis, in baby animals. Usage is most common in piglets; chicks, calves and other livestock also are treated with the drug.

Geographically, colistin use in livestock varies substantially. The drug, usually administered orally, is popular in some European countries, such as Germany, Poland and Portugal, and some Asian countries, such as China. But it is not marketed for agricultural use in countries such as the United States.

The only colistin product authorized for use in food animals there has never been actively marketed in the country, a spokesperson for the U.S. Food and Drug Administration confirmed to the VIN News Service. (Some topical solutions containing another polymyxin — polymyxin-b — are marketed in the U.S. to treat ear infections in food animals and companion animals alike).

For its part, the FVE maintains that colistin, when used sparingly, is important for maintaining animal health and welfare. "For colibacillosis, there are no good alternatives for treating multidrug-resistant pathogens in livestock," FVE policy officer Dr. Wiebke Jansen said.

Colistin, Jansen said, isn't absorbed in the gut, giving it an advantage over other antimicrobials because it can linger in the intestines to attack bacteria.

Overall, sales of polymyxins in the EU sank 77% between 2011 and 2020 due to more judicious usage throughout the bloc. In 2016, the European Medicines Agency concluded that while colistin shouldn't be banned, usage should come with restrictions, including that sensitivity testing to other antimicrobials first be performed on sick animals and that treatment be limited to seven days.

Although colistin-resistant pathogens have been identified in nonhuman animals, the FVE notes that in some European countries, resistance to date has been found to be much lower than the levels of resistance found in humans, with the possible exception of turkeys.

The transmissibility of colistin resistance from animals to people also appears to be limited, even among people who work closely with animals, according to the results of a Dutch study published in April.

'As little as possible, but as much as necessary'

One country that has seen a recent, dramatic fall in the veterinary use of colistin is the United Kingdom. Just 500 grams of the drug were used to treat livestock there in 2020, according to the latest annual antibiotic sales report issued by the U.K. Veterinary Medicines Directorate. That's down from 900 kilograms in 2015.

The sharp drop was driven, in part, by fears that Pseudomonas aeruginosa, which often is responsible for killing children with cystic fibrosis, would develop a resistance to colistin.

"Colistin usage was beginning to pick up a little here, but it turns out the incidence of cystic fibrosis is worse the further west you go in Europe," said Dr. Paul Thompson, a veterinarian who practices in Driffield, York. "So there were some niche circumstances around why the U.K. was so alarmed about colistin."

Indeed, fears about colistin resistance in the U.K. were so acute, colistin manufacturers have stopped freely distributing the product there. Now, although it is still legal to use in agriculture, colistin can be imported into the U.K. only under a special license.

Thompson, a past president of the Pig Veterinary Society, a professional association for swine specialists, no longer uses the drug. Like many colleagues in the U.K., he makes do with aminogyclosides, another class of antibiotics, as a treatment of last resort — especially now that the government has withdrawn marketing authorization for another alternative, zinc oxide, due to concerns it will contaminate the environment.

Preventive measures, too, Thompson said, can be highly effective at stopping animals from becoming infected in the first place. These might include making sure pigs are fed the right diet, drink clean water and are kept in disinfected, comfortable environments.

At the same time, Thompson questions whether colistin should be banned from use in veterinary medicine altogether, noting that it has been very effective in treating E. Coli infections post-weaning.

"In a broader veterinary context, we would be concerned if we lost the facility to prescribe a whole group of antibiotics responsibly," Thompson said. "We've got to look after the welfare of the animals under our care — and there is nothing more deleterious to welfare than disease."

Dr. Gemma Thwaites, who is the Pig Veterinary Society president and works in the same practice as Thompson, agrees, putting it this way: "We encourage responsible use ... based on the overall principle that use should be as little as possible, but as much as necessary."

Still, Thompson welcomes the EU's blacklist. "I can see where some people might feel it didn't go far enough, but it's a good starting point to put some ground rules in to say, 'These will never be veterinary drugs.'"

The FVE notes that usage of all antimicrobials has fallen substantially worldwide in recent years, typically without the need for bans.

"The focus is much on colistin, but we believe that it should be more on prudent and responsible use in all sectors — in the animal sector and in the human sector — of all critically important antimicrobials," De Briyne said. "Some politicians, they want to oversimplify things and they want to find a miracle solution against antimicrobial resistance, but I'm afraid that doesn't exist. We just have to keep on working to prevent diseases and reduce our use."