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The classification of antimicrobials – a clash of views

Over recent years there has been a divergence in views between the World Health Organisation (WHO) and thankfully, the European Medicines Agency (EMA) over the classification of antimicrobials and their use in human and veterinary medicine.

When it comes to the use of antimicrobials in animals, the European Union is in a very different position to many countries around the World. We banned the use of antimicrobials for growth promotion in 2006, nearly 10 years ago. These were compounds that were included in feed by the feed compounders and were free of veterinary prescription and control. All other veterinary medicinal use of antimicrobial drugs is meant to be under veterinary control or prescription.

US taking action to control antimicrobials use in livestock

The United States are now in the process of withdrawing the claims for growth promotion and also of putting antimicrobial use under veterinary control, over the next few years. They will have claims for treatment, control and prevention. In the EU, we are unfortunately likely to lose prevention claims but will have treatment and metaphylaxis (control) still. We have also set up bodies for the Responsible use of Medicines (EPRUMA) and are starting to record antimicrobial use in animals via the EMA (ESVAC). We have two major regions of the world at different levels of antimicrobial control and usage and possibly the new EMA view is more relevant to our situation.

Reclassification of antimicrobials by WHO

The WHO (2011) revised their list of antimicrobials resulting in:

- 15 families of antimicrobial being termed Critically Important Antimicrobials (CIAs) for human medicine,

- 13 were Highly Important Antimicrobials (HIAs) and

- 4 were Important Antimicrobials (IAs).

Reading through these lists, 3 of the 4 IAs were already banned from veterinary use in the EU, e.g. furazolidone, metronidazole/dimetridazole and bacitracin (a former growth promoter) and only the aminocyclitol, spectinomycin, remains.

Most of the antimicrobial products we use routinely in pig medicine are lumped in the CIAs or HIAs.

Interestingly, one family which has been downgraded to HIA is the streptogramins or virginiamycin, which was also a former growth promoter, now banned in the EU. The others in the HIA group, which will be well recognised, are the tetracyclines, sulphonamides, florfenicol, lincomycin and tiamulin. First and second generation cephalosporins and anti-staphylococcal penicillins, like cloxacillin and oxacillin, used for mastitis in dairy cows are also in the HIA group but not methicillin, a related compound. We expect battles over the CIAs between human and veterinary medicines, such as the third and fourth generation cephalosporins and the fluoroquinolones but there is a surprisingly large number of compounds classed as CIAs by WHO, which from our perspective, would consider much less important to human and veterinary medicine, like the macrolide family, e.g. tylosin, tylvalosin and tilmicosin, the natural penicillins (penicillin G and V) and the aminopenicillins, ampicillin and amoxicillin, some of our frontline pig medicines.

EMA list of antibiotics used by vets and the public health risk

The EMA (2014) responded to a question from the European Commission regarding categorisation of antimicrobial families used in veterinary medicine and what was the risk to public health. They produced a much more rational list (see Tables 1a-1c).




EMA Category 1 – Antimicrobials used in veterinary medicine where the risk to public health is currently estimated low or limited;
Category 2 - Antimicrobials used in veterinary medicine where the risk to public health is currently estimated higher;
Category 3 – Antimicrobials currently not approved for use in veterinary medicine.
WHO classification based on selective criteria –
Criterion 1: An antimicrobial agent which is the sole, or one of limited available therapy to treat serious human disease
Criterion 2: Antimicrobial agent is used to treat diseases caused by either: 1. organisms that may be transmitted to humans from non-human sources or 2. Human diseases caused by organisms that may acquire resistance genes from non-human sources.
CIA – Critically important antimicrobials – both criteria;
HIA – Highly important antimicrobials – single criterion;
IA – neither criterion.

The EMA Category 1 includes Macrolides and Natural penicillins (penicillin G and V) as well as penicillinase resistant penicillins, such as oxacillin but where does methicillin sit (of MRSA fame)? In the WHO list, it is a CIA, along with the natural penicillins, whereas the others are HIA. It begs the question whether ampicillin and amoxicillin, which are also penicillinase sensitive, should be separated out from the beta-lactamase inhibitors such as clavulanic acid into Category 1, rather than Category 2? They hardly rank with the 3rd and 4th generation cephalosporins on their own and are more susceptible to beta lactamases than 1st and 2nd generation cephalosporins, for example, which are HIAs. Additionally, there are more and more EU papers (Wu et al, 2013; de Been et al, 2013; Jacobsen et al, 2015) showing there is no real link between human and animal E. coli or ESBLs, using advanced genetic techniques. Colistin and the tetracyclines (e.g. chlortetracycline, oxytetracycline and doxycycline) are in Category 1 as well, which is fortunate, as in most countries the tetracyclines are the most widely used antibiotic in veterinary medicine but much less so in human medicine.

So if the penicillins and cephalosporins can be broken down into different sub-groups, (see article Bacteria and antimicrobials – a concise compendium) why can't we break down other important families like the macrolides into their sub-families, some of which are more important in human medicine and others are more important in veterinary medicine.

Table 2 - Macrolide differentiation based on lactone ring structure (based on Giguere, 2013)
13C 14C 15C 16C
Semisynthetic Natural Semisynthetic (Advanced) Semisynthetic (Advanced) Natural Semisynthetic
Erythromycin* Clarithromycin
Azalides Spiramycin* Tilmicosin*
Oleandomycin Roxithromycin Azithromycin
Tylosin* Tildipirosin*
Dirithromycin Gamithromycin* Josamycin* Tylvalosin*
Triamilide Fluorithromycin Triamilide Kitasamycin* Miokamycin
Tulathromycin (10%)* Ketolides Tulathromycin (90%)* Midecamycin Rokitamycin
*Veterinary use; Azalide – Azithromycin also active against Salmonella and Shigella; Ketolides – overcome some MLS & cross resistance; Advanced generations – have improvements in activity, pharmacokinetics and reduced adverse reactions.

It would appear that there could be additional sub-divisions of groups amongst the macrolides so that the more Advanced generations, Ketolides (reduced cross-resistance), Azalides (broader spectrum of activity) and Triamilides, could be separated from the older, more basic macrolides, if necessary, rather than lumping them altogether. Even WHO refers to Macrolides and Ketolides but lumped together.

One feels that the WHO classification of CIAs is almost over-inclusive of all of the most important families of antibiotics for human health with limited differentiation and consideration for veterinary antimicrobial use and for animal health and welfare. This is why the EMA's list is so welcome, as it appears to be more balanced and pragmatic. There is still a lot of work to do but this is a positive first step forward, especially in the light of the increased current pressure being put on animal producers by food-producing groups and supermarkets, apparently, trying to use the banning of veterinary antimicrobial drugs to improve their market share. What is going to be the cost to animal health and welfare?


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