Antibiotic of the week: Sulfadimidine or Sulfamethazine

Antibiotic Pollution Index: 296 (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. It is a broad spectrum, synthetic antibacterial drug.

Who gets it
Sulfadimidine or Sulfamethazine (both refer to the same antibiotic) is often fed to or mixed in drinking water of pigs, cattle, poultry and fish, to prevent disease in crowded farms and fisheries. This drug is also used as a growth promotor in the meat production. However, for sulfadimidine, no lab-based evidence for growth promotion has been found, with the exception of one organ: the thyroid gland. This gland produces a hormone that regulates growth. But a bigger gland does not necessarily lead to a hormone boost. In fact, pigs and rats that get high sulfadimidine dosages are more lean. Even worse, enlargement of the thyroid gland has been described as an oncogenic effect of the drug. In earlier days, sulfadimidine was also approved for medical use, but this has been discontinued in most countries.

Where may it be produced?
US, China, Czech Republic, the Netherlands, Poland.

And, SquaredAnt, does it pollute?
Sulfadimidine or Sulfamethazine is produced in enormous amounts: in China, one factory alone claims a production capacity of 1000 metric tons a month. This would yearly amount to ~12% of the lower estimate of the annual worldwide use of all antibiotics combined (100.000-200.000 metric tons). Pollution has been observed in China, Thailand, Canada and the US, with highest concentrations in agriculture soil and agriculture waste water.

Warning lights
Sulfadimidine pollution has not only sparked antibiotic resistance, but even more so, some bacteria have adopted this antibiotic as a nutrient source. In soy crop fields in Canada, where high dosages of sulfadimidine were put into the soil to study the effect of antibiotic residue in fertilizer, a microbacterium bacteria species started to use sulfadimidine as a carbon source. Translated to humans: they got shot at, warded off the bullets, and built a steel mill with it. We created a monster…. today in your fields, tomorrow in your guts.

Any common sense in this antibiotic?
Concerns related to sulfadimidine use in agriculture have already been raised many years ago. Reasons were potential health risks and the high number of non-compliant farms. In 1989, sulfadimidine was almost withdrawn from the US industry. The New York Times News Service reported that “The long regulatory history of sulfamethazine is the latest illustration of the difficulty federal agencies are having in untangling the web of scientific, political and economic issues before toxic substances can be eliminated from the food supply.” The withdrawal never took place. Non-compliance and conflicts of interests continue until today, throughout the world. Common sense is hard to find.

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Antibiotic of the week: Norfloxacin

Antibiotic Pollution Index: 273 ( 29 September 2017)
What is the Antibiotic Pollution Index?

What it does
Bacterial cell division is an important feature of developing, or maintaining, an (infectious) bacterial population. Norfloxacin binds the bacterial DNA replication machinery and thereby prevents cell division. This leads to cell death in many different types of bacteria, as it is a broad-spectrum antibiotic.

Who gets it
Norfloxacin is used to treat urinary tract, prostate and kidney infections, infections of the gastrointestinal tract, as well as some sexual transmitted diseases. The clinical usage is becoming more restricted because of better alternatives. Namely, norfloxacin has rare but serious side effects such as rupture of the tendons and secondary infections, such as C. difficile, causing a high-risk bowel disease.

Where may it be produced?
India, Italy, Slovenia, Japan, Spain, China, USA.

And, SquaredAnt, does it pollute?
For a not-so-popular drug in the medical domain, norfloxacin pollution is suspiciously widespread. SquaredAnt found reports of norfloxacin pollution in China, UK, Spain, Poland, Japan, Canada, Australia and India. Norfloxacin has also been reported in food. In in Brazil, 15% of milk samples carry residues of this antibiotic (2017). One Nigerian study showed average of 0.173 microgram per gram beef – a nearly therapeutic concentration (2015). In Saudi Arabia, levels 1 microgram per gram in Chicken meat and liver have been reported (2000).

Warning lights
Most reports on norfloxacin date from the beginning of this century, when high resistance rates in Campylobacter and Escherichia coli bacteria became apparent. Merck, the sole producer of medical norfloxacin tablets, seized its production in 2014. In summary, we could conclude that phasing out this drug from the medical domain is already under way.

Any common sense in this antibiotic?
Has the medical field lost interest in this drug, and has this provided veterinarians with a carte blanche for norfloxacin use? The widespread pollution could point into this direction. Furthermore, for the publicly available Maximum Residue Level (MRL) lists that SquaredAnt could locate, none of these includes norfloxacin (an MRL would invoke a systematic monitoring of norfloxacin in food products of animal origin). Separating the medical applications from other usages is wishful thinking. For instance, E. coli that are resistant to norfloxacin often are resistant to related antibiotics as well. In other words, resistance caused by norfloxacin pollution could affect the medical domain indirectly. It would make sense to restrict the pollution of norfloxacin in order to prevent these and other toxicological consequences.

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Antibiotic of the week: Metronidazole

Antibiotics Pollution Index: 400 (11 September 2017)
What is the Antibiotics Pollution Index?

What it does
Metronidazole gets activated in cells that live in oxygen-low environments, known as anaerobic cells. It is effective against many anaerobic organisms, which include bacteria and parasites. It binds DNA, and causes breaks which cells do not survive.
Due to activation in an oxygen-low environment, this drug separates anaerobic cells from the patient’s own aerobic (oxygen-breathing) cells. Metronidazole use, however, increases the risk for cancer, which may be the result of activation in human cells, too. When received in high doses, this drug can also be neurotoxic.

Who gets it
An infamous target for metronidazole is Clostridium difficile, a typical landmark for bad hygiene and incorrect antibiotic use, leading to diarrhea, colon perforation, with a potential fatal outcome. It is also administered to prevent surgery-related infections and sexually transmitted diseases. Not only people are treated. This carcinogenic antibiotic is a frequently used drug in animal husbandry and aquaculture. It has been banned in the USA and Europe for food-producing animals, but big and small pets (such as horses, dogs, ornamental fish and reptiles) still receive it. Outside the EU and USA, you may find your metronidazole in your food, too: it is given to poultry, pigs, and fish. In all animals studied, this antibiotic remains detectable in many organs up to 2-3 weeks after the last dosage. This is 2 weeks short of the complete life of your average meat-chick.

Where may it be produced?
Poland, India, Italy, Portugal, China, Mexico, USA, France.

And, SquaredAnt, does it pollute?
We found evidence for pollution in WWT effluent, hospital effluent and river water. The concentration in WWT effluents is around 0.1 ng/ml. 500 million liters of waste water would give you approximately one dosage of metronidazole, of which you’d probably need 4 in a day. Spectacular enough, this low concentration could trigger resistance against metronidazole. Given the usage in farms, hospitals and pets throughout the world, there are probably quite a few places oxygen-low places -such as sewage systems and lagoons -where metronidazole pollution stimulates resistance on the long term.

Warning lights
The high cost of appropriate tests for infections and the seriousness of anaerobic infections has lead to an overuse of usage and an under-reporting of resistance against metronidazole.  But let’s give patients and doctors the benefit of the doubt. A more worrying signal is our finding that the on-line demand of this drug is very high. For those who ignore resistance, oncogenic and neurotoxic risks, metronidazole may seem like a wonder drug that can compensate bad hygiene and poor maintenance in stables, ponds, terrariums, etc.

Any common sense in this antibiotic?
Since 2 decades, metronidazole has been banned from food producing animals in the USA (1994) and the EU (1998). From 2017, authorities in China have introduced a standard to test for metronidazole in food. This indicates at the very least that metronidazole pollution is on the radar in China.

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Antibiotic of the week: Cefotaxime

Antibiotic pollution index: 236 (11 September 2017)
What is the Antibiotic Pollution Index?

What it does
The cell wall separates the bacterial cell from its surroundings, gives it strength and protection. With cefotaxime, cell walls break and bacteria die.

Who gets it
Cefotaxime is used to treat a wide range of infections, such as pneumonia, meningitis, abdominal infections and joint infections. It is a typical broad spectrum antibiotic: many bacteria dislike it. Veterinarians, however, do like it. Cefotaxime is used to treat pets and small farm animals worldwide, and cattle and pigs in a number of countries.

Where may it be produced?
India, China, Korea, USA, Italy, Germany.

And, SquaredAnt, does it pollute?
It may very well be. We found evidence for pollution in Spain and the United Kingdom, from hospital waste, waste water treatment effluents, and river water. All concentrations lie around 0.1 ng/ml. This means: if a course of cefotaxime would be be 2 gram per day, you would have to drink 20,000,000 liter if you’d like to recycle from river water directly. A daunting task, but hey, what doesn’t kill you makes you stronger!

Warning lights
If antibiotics concentrations are too low to kill bacteria, bacteria may start to allow this antibiotic in their daily lives at higher concentrations. What doesn’t kill them, makes them stronger… we call this “Antibiotic Resistance”, but the term could be “Antibiotic Ignorance” too. Resistance gives the impression of combat, that bacteria struggle to survive, that some day, resistance may be broken. But in many cases, bacteria don’t fight. For resistant bacteria, the antibiotic has become one of the many chemicals they simply deal with. From their perspective, the antibiotic is not even an antibiotic any more. They changed the lock, got a new key, end of story.
Antibiotic resistance (or should I say “ignorance”) against cefotaxime is on the rise everywhere. Portuguese rivers, American fruits an Indian dairy, they all contain bacteria that are perfectly fine to be exposed to cefotaxime.

Any common sense in this antibiotic?
No. Cefotaxime is a very powerful antibiotic to treat serious human diseases. But for now, treating pets, poultry, pigs and other animals with cefotaxime, which leads to a noticeable release into the environment as well as a rise in antibiotic resistance, is incompatible with a common sense strategy that reserves this drug for patients in need.

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Antibiotic of the week: Sulfadimethoxine

Antibiotics Pollution Index: 73 (11 September 2017)
What is the Antibiotics Pollution Index?

What it does
It prevents bacteria to form folic acid. Folic acid is crucial for cell division of bacteria; without folic acid, a bacterium cannot multiply and thereby spread the infection. It does not kill the bacteria directly.

Who gets it
Pets, cattle, poultry and fish. It is given to treat skin infections, urinary tract infections, respiratory infections and even parasitic (non-bacterial) infections. It is also used to treat “Bovine Respiratory Disease”, in cows. This disease  is caused by a combination stress, a mix of infections, and other unknown triggers. This disease is costing the USA alone USD 500 million/year.

Where may it be produced?
China, Japan, Poland, Switzerland.

And, SquaredAnt, does it pollute?
Yes, it does. We found publications about sulfadimethoxine in rivers in across the USA, and in waste-water and soil around farms in the USA and China. Around farms, the concentrations lie around 1 nanogram per gram. For a small farm, this is sufficient for 10 dosages for an animal that weighs 800 kg (see table below).

Farm size 100,000 square meter
Top soil mass 1000 kg/ cubic meter
Penetration of antibiotic (estimation) 0.1 meter
Concentration 0.000001 gram / kg
Product by multiplication 10 gram
(Equals to ~10 dosages for a cow)

Conservative estimation of Sulfadimethoxine pollution on a polluted farm

Warning lights
In 2015, the article “The Ocean as a Global Reservoir of Antibiotic Resistance Genes” described a number of lagoons and bays, where scientists found bacteria that were resistant against sulfadimethoxine. This is remarkable, as sulfadimethoxine is not produced in nature: it is a synthetic molecule. Apparently, some marine bacteria carry resistance against this non-natural antibiotic – in vast amounts, as the ocean harbors so many bacteria.
Coastal waters are increasingly put to use for humans. Creating a meeting point for resistant bacteria from the sea (via seafood, recreation, shipping, or desalination) and sulfadimethoxine residue (via meat, vegetables, pet excretion and surface waters) gives microbes a dream start to spread resistance among each other and should be avoided.

Any common sense in this antibiotic?
It is hopeful that as of 2017, sulfadimethoxine has changed status from OTC to prescription drug for veterinarian use in the USA. Before, gallon-sized bottles were available for anyone. When these are disposed of, and the residue has run off the land, then the pollution level may decrease.

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