Many food animals cope with overcrowding, transport, disease, lack of exercise, aka stress 1 2 , while farmers aim to maximize food production for an ever demanding market. To bring out the best of both worlds, the food animal industry’s medical cabinet contains a wide range of anti-infectious agents, antibiotics, anti-parasitics, tranquillizers, psychotic drugs, corticoides, and fertility regulators.

Residues of these pharmaceutical compounds are a potential threat for public health. Many markets therefore work with Maximum Residue Level (MRLs) regulations. MRLs indicate how much of each pharmaceutical compound may be present in the food at the moment the consumer buys it. The regulation for “pharmacologically active substances and their classification regarding maximum residue limits in foodstuffs of animal origin” of the EU includes over 600 compounds, fifty-seven of which are antibiotic agents 3.

The production of foodstuffs of animal origin (meat, diary, eggs, fish, etc) is one of the core pillars on which the antibiotic market thrives: in the biggest markets (China and the US), it reportedly accounts for up to 80% of the total antibiotic consumption 5. Due to the systematic use of antibiotics in animals and their accumulation in agricultural soil through manure-based fertilizers, bacteria in and around farms are constantly exposed to antibiotics. This, in turn, accelerates antibiotic resistance in bacteria.

In fact, twenty-three of the 57 antibiotics in the EU MRL list (40%) can be found in the SquaredAnt’s Antibiotic Pollution Index 4. This index takes antibiotics that have been found in the environment and gives an estimate which of these are used inappropriately, thereby causing antibiotic resistance, and gradually losing effectiveness. An overlap with the EU MRL list indicates that indeed sources of pollution exist for many of these pharmaceutical agents.

Antibiotic resistant bacteria can thrive in high dosages of antibiotics. Resistance against one antibiotic often implies resistance against other antibiotics (cross resistance), which may jump from one pathogen to the other (resistance spreading). One such example is apramycin. In many cases, its resistance is encoded on a piece of DNA that is called AAC(3)-IV which encodes for resistance against many other antibiotics as well. For instance, apramycin resistance spread from Escherichia coli to Salmonella typhimurium when given to calves in 1999 6; treatment of calves increased resistance against apramycin as well as tobramycin, gentomycin, tetratcycline and streptomycin in 2004 7; and after treating chicken, resistance developed against ampicillin, piperacillin, cefazolin, cefotaxime, amoxicillin, ampicillin, doxycycline, and many more, in both chicken as houseflies in 2018 8. Such a snowball-effect is observed more often 9, but still very much underappreciated in the efforts to control the usage of antibiotic agents in food production.

At present, avoiding a direct health risk for consumers is the only objective of MRL regulation. With the current antibiotic resistance challenge, this does not make sense. In fact, to calculate the MRL, resistance would actually lead to higher values. In theory, on the day your intestinal flora tolerates more antibiotics due to antibiotic resistance, the current formula to calculate MRL will lead to a higher outcome and resistance will be reinforced.

Back to apramycin. In a steak sold in the EU, the MRL is 1 microgram/gram. This concentration is actually growth-inhibiting to some but not all, intestinal E. coli strains 9 and therefore selects for antibiotic resistance per definition, where it be in the cow or in the consumer. The current MRL system does not take this into account.

But this is not all. Perhaps more striking than the absence of antibiotic resistance in the equation to calculate MRLs, is the fact that MRL regulations do not consider accumulating concentrations of different pharmaceuticals together. For instance, whereas your glass of milk may contain at most 100 microgram/liter chlortetracycline in the EU, the accumulated amount of antibiotics may in theory reach up to 4868 microgram/liter, and the accumulated amount of all pharmaceutical agents even much more. Is the effect on public health of consuming one drug in a safe dosage (say, 1 x s) the same as consuming many drugs in their respective safe dosages (N x s)? This cannot be just taken as a given.

For antibiotic resistance, at least, 1 x s may not be N x s. If resistance against one antibiotic agent implies resistance against others, it may be that multiple drugs together jointly select for one resistance mechanism.

Theoretically, in times of Antibiotic Resistance, Maximum Residue Levels provide a powerful framework to control the (mis)use the use of pharmaceuticals in food animals. They may have to be re-evaluated in order to maximize their potential to curb antibiotic resistance, thereby serving public health and food production goals on the long term.

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