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

Antibiotic of the week: Chloramphenicol

Antibiotic Pollution Index: 731 (19 November 2017)
What is the Antibiotic Pollution Index?

What it does
Chloramphenicol blocks the production of proteins in bacteria. When protein production is delayed, the bacterial cell stops to grow.

Who gets it
Chloramphenicol is a broad-spectrum antibiotic that is used to treat a large number of infectious diseases. Given a number of serious side effects, most physicians look for alternatives first before prescribing this drug, and in some countries it has been banned from the clinic. For instance, this drug has been linked to bone marrow damage, leading to anemia and potentially childhood leukemia. When risk groups are avoided or when the disease is life threatening, chloramphenicol is, however, an important drug: in regions with less sophisticated healthcare systems, it is used to treat meningitis, typhoid fever, plague and cholera.

The drug, although practically banned from medical use and meat production in many countries, is not reserved for people in need alone. It is still used for non-food producing animals around the world, and seafood production in Asia has become notorious for chloramphenicol pollution. Recently, this drug was seen in pharmacies that sell to fish and shrimp farms in Vietnam; and  Chinese authorities found chemical traces in 9% of seafood found in restaurants in some major cities, including chloramphenicol.

Production and trade
It may be produced in India, Hungary, China, Japan, USA, Spain, Italy.
In 2016, Top-3 importers were Venezuela, Chile and the Netherlands; exporters were China, the Netherlands and India.

And, SquaredAnt, does it pollute?
18 Sites with environmental chloramphenicol residue in our database reside in Nigeria (waste water, river water and sludge) and Tianjin, China (agriculture soil). Especially in Nigeria, the concentrations are fairly high, up to ~100 ng/ml in sludge. Probably, this is due to a combination of medical and veterinary use, too: for instance, observations in 2012 showed that chloramphenicol has been routinely used in poultry farming in Nigeria.
The bacterium that produces chloramphenicol can be present in soil. Therefore it may be not as straightforward as it seems to distinguish polluting from naturally occurring trace amounts. A broad evaluation of historical land usage, irrigation sources and agricultural practices is crucial to rule out chemical pollution or its consequences (e.g. soil enrichment for chloramphenicol-producing bacteria).

Warning lights
Chloramphenicol was no popular drug, given a number of potentially serious toxic side effects. Whenever alternatives have become available, this drug has been phased out. In the recent years, it may have become more poplar, as a replacement for other antibiotics against which resistance has been developed. This is a warning light – not so much for chloramphenicol, but for the gravity of the overall AMR challenge. Increased usage of this antibiotic is probably an unsustainable solution in the longer term: chloramphenicol resistance genes have been detected on farms, and historical data shows that chloramphenicol resistance is common in places where it is used – and can extend to resistance against other antibiotics, too.

Any common sense in this antibiotic?
Chloramphenicol remains essential for treatment of life-threatening meningitis, typhoid fever, and other infections in developing countries. Chloramphenicol is slowly becoming a last resort drug, as a replacement for other, originally safer, and more effective antibiotics that are now phased out due to antibiotic resistance. The importance of this drug will therefore grow, therefore tighter restrictions on its usage in food production are needed.

Sources

Antibiotic of the week: Clarithromycin

Antibiotic Pollution Index: 203 (19 November 2017)
What is the Antibiotic Pollution Index?

What it does
Clarithromycin inhibits the synthesis of proteins in many different types of bacterial pathogens. It does so in some parasites as well, such the one responsible for toxoplasmosis.

Who gets it
Clarithromycin is used to treat lung, stomach and throat infections, and other infections of the gastrointestinal tract, respiratory tract, or skin. In case of pregnancy, this drug should be taken only when absolutely necessary, as it slightly increases the risk for a miscarriage. When it entered the market, its efficacy against Mycobacterium Avium Complex (MAC), a lethal lung infection in patients with a defect immune system, had a great impact among carriers of HIV – not the least because the industry delayed market entrance in the US for economic reasons. It is a popular drug: it is highly consumed, for instance, in Canada it ranked second after amoxicillin in 2014. Resistance level are, however, fairly high as well. In Asia, resistance levels in S.pneumonia   reached 80% in the beginning of this century. In Canada, 22% was resistant in 2014, the highest rate of all antibiotics in this pathogen. Worldwide, it may be used in food animals, but clarithromycin’s ancestor, tetracycline, is more abundantly used. There seems nevertheless a noticeable interest of pet-owners to purchase this drug on-line.

Where may it be produced?
India, Japan, USA, Saudi Arabia, Spain, Mexico, China, Germany, Malaysia, Israel.

And, SquaredAnt, does it pollute?
There is evidence for trace amounts in the environment in Germany, the UK, and Canada; in Spain, the concentration tends to be substantial, up to 1 ng/ml in hospital waste water and o.5 ng/ml in Waste Water Treatment effluents. Such values are well above  the predicted concentration that leads to resistance, which is 0.25 ng/ml.

Warning lights
Anno 2017, a clear warning light comes from the Helicobacter pylori community, that has to deal with a bacterium that infects half of the worlds population, causes ulcers in 10% of these carriers and is strongly linked to cancer in the stomach (1-3% of people infected develop stomach cancer, a disease that causes 700.000 deaths per year worldwide). Whereas billions of people are only carriers, the infection can become symptomatic with grave consequences when left untreated. H.pylori infections are often treated with a cocktail of drugs, and clarithromycin is usually among these. Despite a sharp increase in resistance rates in H.pylori (from 5% to 50% from 1993 to 2013), there is no alternative for clarithromycin in the drug cocktail. This leads to desperation, as reflected by the following quote: “The problem with this critical role [of Clarithromycin] is that antimicrobial resistance to this drug is sharply increasing and our hopes to have successful eradication regimens (i.e., consistent treatment success > 90%) including the clarithromycin is unfortunately falling.”

Any common sense in this antibiotic?
Clarithromycin is an essential drug according to the WHO and indispensable for H.pylori treatment. Furthermore, this drug is popular and used for many other infections too, for human disease and in animals as well. Resistance against this drug is increasing. Once resistance occurs to clarithromycin, resistance to other important antibiotics such as erythromycin occurs as well, and vice versa. More restricted use of clarithromycin and its related drugs, especially in the veterinarian domain, could safeguard its efficacy in human disease.

Sources

Antibiotic of the week: Nalidixic acid

Antibiotic Pollution Index: 129 (19 November 2017)
What is the Antibiotic Pollution Index?

What it does
Nalidixic acid was discovered in 1962 and became the first antibiotic of the quinolone family. This family targets DNA synthesis in bacteria that leads to their death. Nalidixic acid mainly affects gram negative bacteria. Its successors, quinolones and fluoroquinolones drugs (such as norfloxacin), are less toxic and more effective against a broader spectrum of bacteria.

Who gets it
Nalidixic acid was commonly used to treat urinary tract infections, as it is rapidly secreted via the kidney and therefore reaches the urinary tract in a straightforward manner, both in humans as animals. These and other infections may be caused by food-borne pathogens such as Shigella, Salmonella and E. coli. Otherwise healthy individuals would be able to restore their own health, but dehydrated and/or undernourished children, elderly, and patients with a weak immune system, need medical treatment. In advanced healthcare systems, better alternatives are now available and this drug may be over its peak.

Where may it be produced?
Italy, India.

And, SquaredAnt, does it pollute?
We find minimal evidence for pollution of surface waters and waste effluents in Spain and in Australia. Concentrations tend to be low: the highest concentration is 0.06 ng/ml from a waste water treatment effluent in Spain. Or,  from 17 billion liters of water you can harvest one dosage of 1 gram. The environmental concerns related to this drug, so far, seem to be limited.

Warning lights
Many -but not all- types of resistance in the quinolone family include nalidixic acid resistance. As such, resistance against nalidixic acid may not be caused by nalidixic acid per se, and vice versa, resistance to other quinolone drugs may be caused by inadequate use of nalidixic acid. This is of importance when looking at resistance against this drug, which rose quickly after the turn of this century. In those years, in Germany, France, Spain, UK and Taiwan, an increase in the incidence of Salmonella strains that are resistant to nalidixic acid rose from ~5% to ~50% in humans and pigs. This occurred after the licensing of veterinary use of enrofloxacin and danloxacin, which belong to the same family as nalidixic acid. In 2004, resistance of Campylobacter bacteria against nalidixic acid in chicken and/or cattle throughout Europe reached 100%. An Australian study traced the origin of resistance against nalidixic acid in bacteria that cause enteric fever (Salmonella Typhi and Paratyphi). There, the share of resistant strains rose 70% in from 2009 to 2010. Most of these isolates came from India. Studies in the Shigella pathogens showed similar trends for Asian and African isolates. Summarized: nalidixic acid resistance itself is a warning light, very much a global phenomenon, and related to food production and food safety.

Any common sense in this antibiotic?
Nalidixic acid resistance is likely a result of the overuse of its family members. The sudden global rise in resistance has had a great impact on the interest from the academic community. Since 2000, resistance started to dominate the publications on nalidixic acid. In essence, nalidixic acid is a poster case for antibiotic resistance. In the past it was a popular drug, but now it mainly returns on resistance charts. Intriguing for scientists and a challenge for public health. If we learn from this pitfall, we may avoid others.

 

Academic publications on nalidixic acid. Blue: articles that mention resistance. Red: all others. Resistance becomes dominant after 2000. Source: https://www.ncbi.nlm.nih.gov/pubmed

Sources

 

Antibiotic of the week: Cephalexin

Antibiotic Pollution Index: 230 (19 November 2017)
What is the Antibiotic Pollution Index?

What it does
Cephalexin kills bacteria by disrupting molecules (peptidoglycan) in their outer layer. It is mainly effective against gram-positive bacteria, such as streptococci, staphylococci and bacilli. In these bacteria, this outer layer is unprotected, while in gram-negatives, this layer is thinner and protected by a membrane structure.

Who gets it
Cephalexin is widely used against ear, bone, joint, skin and urinary tract infections. It ranks around the 100th mostly used drug in the USA, with over 7.5 million prescriptions annually. It is also used in companion animals. In the USA, cephalexin is generally prohibited for food-producing animals, while in Europe, it is allowed: Maximum Residue Levels (MRLs) have been established up to between 100 micrograms and 1 mg/kg of cattle-derived meat and milk. This antibiotic is nevertheless not common in the European meat industry. For instance, in 2014, the class to which cephalexin belongs (1st and 2nd generation cephalosporins) made up 7 out of the total 9000 metric tonnes of antibiotics used in the 29 European countries. Globally, there is hardly any evidence for large-scale use of this drug in the food sector.

Where may it be produced?
Japan, USA, India, China, Israel, France, Brazil.

And, SquaredAnt, does it pollute?
Cephalexin has been detected in Australia, Vietnam and Saoudi Arabia, in concentrations between 0.1 – 0.3 ng/ml (rivers, aquaculture, WWT effluent) and 4 ng/ml (Hospital effluent). In large reservoirs such as rivers, those concentrations may be low, but do point towards a substantial spoilage of the drug into the environment and thereby indicate the presence of hotspots where resistance may occur. Indeed, a study from 2006 showed that over 40% of bacterial isolates from aquacultures in Australia carried resistance genes against cephalexin.

Warning lights
Cephalexin as an isolated case is a popular drug that does not ring alarm bells. However, cephalexin resistance is associated to two major forms of multi-resistance: extended spectrum beta-lactamase (ESBL) pathogens and methicillin-resistant Staphylococcus Aureus (MRSA). Companion animals are seen as potential sources for the so-called EBSL bacteria, especially E. coli and Salmonella strains. This may be related to the frequent use of cephalexin in companion animals: an estimated 40 percent of all dogs in the USA (roughly 35 million of them) receive at least one treatment of cephalexin each year. Because of its link to both MRSA and ESBL, cephalexin use and resistance may have to be observed in a broader context, where overuse of one antibiotic may accelerate resistance against the other.

Any common sense in this antibiotic?
Yes and no. The usage in food animals is restricted, but it is a poplar drug for pets, and patients. This may have played a role in some of the problems we face with resistance. For so far, the searchlights have not focused on cephalexin yet. As an example, ESBL is mainly seen as a consequence of more recently developed, broader spectrum family members of cephalexin. This may have lead to an underestimation of the role that cephalexin usage could play in this type of resistance. A more inclusive and systematic approach to antibiotic resistance may be needed.

Sources

  1. production locations
  2. general information
  3. general information
  4. Resistance genes in Australian aquaculture
  5. Maximum residue limits in Europe
  6. sales of antimicrobial drugs in 29 European countries in 2014
  7. cephalexin use in dogs
  8. companion animals as source for ESBL
  9. cross-resistance in MRSA
  10. number of pets in the USA

Antibiotic of the week: Spiramycin

Antibiotic Pollution Index: 37 (12 October 2017)
What is the Antibiotic Pollution Index?

What it does
Spiramycin belongs to a family that inhibits protein synthesis. Protein synthesis is an essential process. Proteins digest, transport, arrange and manipulate all sorts of cell components. In low dosages, spiramycin stops bacterial cell growth; in high dosages, it may kill the bacteria.
In the body, spiramycin is metabolized to neo-spiramycin, which is also an antibiotic agent. Ignoring this metabolic step may lead to an underestimation of antibiotic residue after spiramycin consumption.

Who gets it
Spiramycin is available in the EU and many other regions, but not in the USA. It is effective against a number of bacterial infections (such as Streptococcal, Legionella, Chlamydia, Mycoplasma) and is also used to treat toxoplasmosis, a parasitic infection. Veterinary use often targets respiratory infections. Spiramycin tends to bind to and accumulate in specific tissues, such as tonsils, bronchi, and (after injection) muscle around the injection site. This has advantages to target infections in those tissues, but its mixed accumulation in different organs challenges its use in the veterinary sector. Withdrawal periods -depending on the animal- up to 52 days have been recommended for this drug. Consumers may be exposed to spiramycin if withdrawal periods are not obeyed. For instance, micrograms per chicken egg can still be detected up to 10 days after treatment.

Where may it be produced?
France, China.

And, SquaredAnt, does it pollute?
For now, SquaredAnt only found one report of spiramycin in an environmental sample.

Warning lights
In France, resistance levels to spiramycin are high in some bacteria in pigs: up to 77% of Streptococcus suis is resistant against this drug. This particular pathogen has many resistance phenotypes. In Brazil, for instance, 99.61% of Strep. suis in healthy pigs is multi-drug resistant against at least 3 out of 16 antibiotics (spiramycin was not included in this analysis). This indicates that gradually, options to control Strep. suis infections are getting less. Strep. suis can infect humans, too. Alltogether, advancing resistance in this pathogen potentially has public health consequences.

Any common sense in this antibiotic?
The Antibiotic Pollution Index for this antibiotic is relatively low. This is likely the result of a limited usage of this drug on a global scale and its absence on the US market. The Strep. suis example shows us, however, that one day this drug may replace antibiotics that have been phased out due to antibiotic resistance. It will then be important to strictly control the use, as spiramycin resistance is related to its usage. Avoiding additional resistance phenotypes should be prioritized.

Sources

Antibiotic of the week: Amoxicillin

Antibiotic Pollution Index: 411 (12 October 2017)
What is the Antibiotic Pollution Index?

What it does
Amoxicillin works against gram-positive bacteria (bacteria with only one cell membrane). Few gram-negatives (which have two membranes) are also sensitive to it. This drug blocks the formation of the cell wall and kills the bacterial cell. It is often administered in combination with clavulanic acid, which, in essence, protects amoxicillin to be broken down by the bacteria it targets.

Who gets it
Amoxicillin is prescribed against throat, ear, lung, urinary or skin infections (often in children), and to treat Helicobacter pylori infections of the stomach. It is also used in farm and pet animals. In fact, amoxicillin is a commonly used “top critically important” antibiotic (as described in the UN List of Essential Medicines) in a number of pork farms in Europe. In Spain, one study found that 90 percent of pigs in so-called “finisher farms” was on antibiotics, where amoxicillin (51%) ranked only after colistin (61%) and doxycycline (62%) (please note that these 3 already sum up to more than 100%). Amoxicillin is used in some countries in aquaculture, too.

Where may it be produced?
Spain, Italy, India, China, Korea, Netherlands, Singapore, United Kingdom, Germany, Israel.

And, SquaredAnt, does it pollute?
Amoxicillin has been found in surface waters and waste-water effluents, generally in concentrations below 0.2 ng per ml. Sludge of from waste-water plants, on the contrary, may reach 79 ng/g. Such concentrations lie well above the predicted concentration of selection for resistant bacteria, which is estimated to be 0.25 ng/ml.

Warning lights
Health care systems fear a number of major resistance phenotypes, 3 of which (methicillin-resistant Staphylococcus aureus, vancomycin resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis) include amoxicillin resistance. Amoxicillin resistance in Helicobacter Pylori is also quite common in some regions worldwide, up to 50% in China.

Any common sense in this antibiotic?
Amoxicillin being pumped into pigs in the EU, as part of a cocktail of antibiotics, is indicative for quite a few shortcomings in pig breeding, health management, the meat industry and its underlying business model. Such overuse may be indicative for many regions in the world. In the USA, 19 out of 55 reported outbreaks of resistant food-borne pathogens were amoxicillin-resistant bacteria (mainly Salmonella). And, when a Jordan research group analyzed seafood imported from India, Egypt and Yemen, practically everything carried Salmonella and Shigella species that were antibiotic resistant… the majority of which against amoxicillin. Knowing that amoxicillin accumulates in sludge, it would make sense to approach the resistance in the context of fisheries and farms, and the link to human health via food, with more care.

Sources

Antibiotic of the week: Trimethoprim

Antibiotic Pollution Index: 471 (12 October 2017)
What is the Antibiotic Pollution Index?

What it does
This drug blocks the propagation of bacteria, by interfering with folic acid synthesis. Folic acid is important for a number of processes, one of which is building up DNA. With trimethoprim, the bacterial cell number cannot increase, because DNA cannot be synthesized. It is often given in combination with a sulfonamide drug, acting jointly on the same pathway and leading to death of the bacteria.

Who gets it
Trimethoprim is used clinically to treat many infections in the urinary tract, skin, gastrointestinal tract, ear and respiratory tract. It is also used in the meat and fish industries: in 2008, more than 10 metric tons per year in the UK alone, accounting for over 80% of the total trimethoprim usage there. In Europe, it is used to treat and prevent respiratory infections after a disease has been diagnosed in a herd (pigs) or flock (poultry). It is used to treat big and small pets as well. Treated chickens accumulate high amounts in eggs (up to thousands of ng/g), which only diminshes after 10-20 days. It seems unlikely that such a long withdrawal time is respected in the present-day bio-industry, where, if a disease occurs, whole flocks are treated via drinking water. If this is indeed the case, poultry treatment could lead to residue in eggs, each egg containing ~1/1000 of a typical patient dosage. And cooking won’t help: trimethoprim is stable up to 200 degrees Celsius.

Where may it be produced?
Cyprus, Republic of Korea, Italy, Brazil, China, India, Spain, USA, Israel, Germany.

And, SquaredAnt, does it pollute?
We found evidence for pollution on 25 places around the world, including Europe, the USA, Asia, and Australia, in different types of waste and surface water. Concentrations are generally less then 0.1 ng/ml, with few exceptions. Even in possibly the global antibiotic pollution hotspot -Hyderabad, India-, the pollution does not exceed 4.4 ng/ml – quite a difference from the 14000 ng/ml that was reported there for ciprofloxacin. But don’t get your vision blurred by rankings: polluting less doesn’t mean that you don’t pollute. The predicted concentration for selecting resistant bacteria is 0.5 ng/ml. A wide-spread pollution in water may indicate that there are many sources, with potentially higher concentrations.

Warning lights
Overuse quickly leads to antibiotic resistance against trimethoprim, and this resistance is there to stay. For instance, already in the 1970s, up to 40% of inpatients carried resistance against trimethoprim in Turku, Finland. Elsewhere, resistance levels up to 65% are reported. And there is no quick fix. When Kronoberg County, Sweden, intervened to drastically reduce the local clinical trimethoprim usage for 2 years, resistance levels reduced only marginally, and returned to baseline level shortly after the intervention.

Any common sense in this antibiotic?
At least, in Europe and the USA, the veterinary use of trimethoprim has been restricted to animals in a herd or flock where a disease has occurred. Furthermore, health systems sometimes interfere to reduce trimethoprim usage. However, most measures to reduce trimethoprim usage are local, theoretical, or lead to compensation (=overuse) of another antibiotic. If no-one is connecting the dots, the world may lose this essential drug.

Sources