Age and the risk of resistant pathogens

Starting to read the February Antimicrobial Resistance Benchmark (https://accesstomedicinefoundation.org/publications/2019-methodology-for-the-2020-antimicrobial-resistance-benchmark) the following citation directly hits me:

In recent decades, AMR has become widespread, irrespective of national income levels. In Europe, drug-resistant bacteria are responsible for more than 670,000 infections and 33,000 deaths annually, costing EUR 1 billion in annual healthcare expenditure. Each year in the US, at least 2 million people get an antibacterial-resistant infection leading to at least 23,000 deaths. This costs over USD 20 billion in direct health care costs and as much as USD 35 billion in lost productivity.”

We could conclude that the number of infections with resistant pathogens in Europe is much lower, while the risk to die of it is much higher, compared to the USA. However, different healthcare systems, patient definitions and calculation models make it difficult to compare two different studies. Real world facts are never black and white. So, does such a conclusion hold?

Let’s look at who is at risk. The European study shows that disease risk is regional and demographic. Regions such as Italy, Greece, Romania and Portugal have a lot of work to do to reduce the infectious disease burden. Striking as well is that risk is related to age. Newborns are at risk, and after that, the risk steeply increases from an age of 50 and onward.

Age demographics in America look solid: age groups are evenly spread, meaning that there is a large proportion of younger generations. Whatever burden a society needs to bear, a steady flow of new generations surely helps to deal with it. The age demographics of the EU, on the other hand, looks terrifying. It looks like an obese person ready to collapse under its own weight. The largest age group is around 50 years old, floating into the net that resistant pathogens spun for them (ironically with support of humankind that created these pathogens).

from: https://www.indexmundi.com/european_union/age_structure.html
https://www.indexmundi.com/united_states/age_structure.html

So, in my view, the increased risk to die of resistant pathogens in Europe has to be taken seriously. Age demographics provide an important incentive why Europe must make increased efforts to combat antibiotic resistance.

Check out more demographic graphs on https://www.indexmundi.com/ and ask yourself how else demographics impact your society.

Maximum Residue Levels in times of Antibiotic Resistance

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.

Out of Africa, out of this world: the miraculous story of E.bugandensis

What does a Space-X or Soyuz capsule carry as cargo to and from the International Space Station (ISS)? In 2015 and 2016, among the freeze-dried apple slices, it included kits to collect bacteria and send them back to Earth. The goal was to study which bacteria inhabit ISS, on the dining table, hygiene compartment, the permanent multipurpose module, and other places. And to uncover their antibiotic resistance patterns. Nearly 60 strains of microbes where identified. Antibiotic resistance was found against penicillin (92 %), oxacillin (68%), rifampin (66 %), erythromycin (64%), cefoxitin (49%), cefazolin (29%), tobramycin (19% ), and gentamicin and ciprofloxacin (14%) (these were all the drugs tested). The most resistant species was the bacterium E. bugandensis: with the exception of 2 strains sensitive to tobramycin, all six isolates from ISS were resistant to all 9 antibiotics.

This is an intriguing story, but even more so since E.bugandensis showed up. E.bugandensis was discovered in 2010, in a pediatric ward of the Bugando Medical Centre in Mwanza, Tanzania. A place in all aspects at the very opposite of ISS. Child mortality is high in Tanzania, and out of the children that die before the age of 5, 32 % passes away in the first 28 days, of which bacterial infections are a common cause of death. Scientists who identified E. bugandensis in children that suffered from neonatal septicemia found resistance against many antibiotics: ampicillin, amoxicillin/clavulanic acid, piperacillin/sulbactam, piperacillin-tazobactam, cefa-lotin, cefuroxime, cefuroxime-Axetil, cefoxitin, cefpodoxim, cefotaxim, ceftazidim, gentamicin, tobramicin, ciprofloxacin, norfloxacin, tetracyclin and trimethoprim/sulphamethoxazol.

The team in Tanzania discovered that the resistance was caused by the IncH12 plasmid. A plasmid is a circular piece of DNA that can carries genes, and mechanisms exist to transfer a plasmid from one to another bacterial cell. IncH12 is also known to cause resistance against metals. And, 408 km in orbit, the most advanced collaborative masterpiece of humanity flies over, home to the same bacterial species, resistant to many antibiotics… and guess what? Most of these resistance genes are actually metal resistance genes.

The relation between metal resistance and antibiotic resistance genes is not new. That a new species is identified in Africa, then found in space, and has never been observed without a broad antibiotic resistance phenotype that associates with metal resistance, well… that is striking.

There are many question to be addressed, before we draw conclusions that (heavy) metals cause resistance and childhood mortality in Tanzania. The underlying reasons for the antibiotic resistance on ISS have not been elucidated yet. Space is a harsh environment, and many triggers have to be considered. But if we put our both feet on the ground, we could suggest that at least sometimes, antibiotic resistance may be the result of events that are not related to antibiotics. The gold fever that brought industrial mining -and heavy metal pollution- to Tanzania many decades ago could have provided the suitable trigger for the resistant-greedy E.bugandensis. And if resistance against metals, like resistance against antibiotics, is accelerated by low concentrations, then E.bugandensis is a clear warning light, bright as a star, urging us to look over our horizon and take action accordingly.

References
https://www.nature.com/articles/s41598-017-18506-4#Bib1
http://www.microbiologyresearch.org/docserver/fulltext/ijsem/66/2/968_ijsem000821.pdf
https://www.jamiiforums.com/threads/tanzanian-scientists-discover-dangerous-bacteria-in-mwanza.986562/
https://www.nature.com/articles/srep25312
http://adsabs.harvard.edu/abs/1996ScTEn.191…59I