Author: Sam Linsen

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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

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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
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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