Food for Thought, Sprinkled With Small Amounts of Antibiotic Residues

Tramates versicolor

80% of antibiotics worldwide are used in veterinary medicine. With only a minor fraction metabolized to inactive compounds, there are plenty of antibiotics excreted by farm animals in unchanged active form. These antibiotic residues are found in manure, in the soil onto which manure is sprayed, tilled in, or in the wastewater and creeks that drain the pastures.  We rely on UV light and soil microbes to further degrade the antibiotic load; indeed, many drugs are broken up and inactivated in soil by the combined action of pH, fungi/molds, sun rays and adsorption processes.

A problem arises with drugs that are super-inert to degradation, that lack a chromophore that could be targeted by UV light for breakdown, and when there are no soil microbes to inactivate the antibiotic.  Even worse, waste water and sewage treatment plants depend on a sessile microflora to help with the clean-up process.  If we flush active antibiotics into our sewage plants, the local microbiome will be killed making the entire system so much less efficient [1].

Does anybody care about the antibiotic residues in soil and water?  The European Medicines Agency (EMA) requires that companies provide an Environmental Risk Assessment (ERA) for every submission.  There are also some good folks out there who dutifully check environmental samples and report back on antibiotic levels in various places and ask some very pertinent questions, like:

  • What actually is the half-life of veterinary and medicinal antibiotics in nature?
  • What concentrations of antibiotics can be found in the rivers and streams, in the hospital effluent, in the farming communities or downstream from antibiotic manufacturing plants?
  • What concentration of drug is found in wildlife that grazes on land laced with a hefty dose of antibiotics? Is there accumulation of antibiotics in meat and organs as we go higher up the food chain?
  • What consequences are there for resistance development when our environment is contaminated with low but measurable levels of antibiotics from many classes?
  • Has there ever been regulatory action because of an unfavorable ERA rating?
  • Is the public being informed about any incidents / accidents related to antibiotic spillage into waters causing significant contamination?

Here just some facts – call it: food for thought:

  • 75-80% of antibiotics used in veterinary medicine are excreted by animals in active form [2]
  • Fluoroquinolone (FQ) concentrations as high as 321 ng/mL were found in waste water near swine feedlots in China [3]
  • Urine from ceftiofur-treated cattle drives selection for cephalosporin resistant Escherichia coli in soil. Ceftiofur is a 3rd generation cephalosporine; its long-acting metabolite has antibiotic properties as well.[4]
  • Quinolones and tetracyclines have half-lives in nature approaching 100 days or perhaps longer [3].
  • Tetracycline concentrations as high as 199 μg/kg, were detected in agricultural soil fertilized with liquid manure in Germany due to accumulation over time [5].
  • The fluorinated ring system of FQ is not found in nature – no wonder, there are few organisms that can biodegrade it. Only Trametes versicolor, a tree fungus, and a few basidiomycetes (eg,  Gloeophyllum striatum) have the capability to inactivate ciprofloxacin [6].
  • Close to Haiderabad neither Trametes nor Gloeophyllum seem to be particularly prevalent; waste waters from bulk drug manufacturers’ effluent, from the waste water facility itself, and from nearby lakes and wells contained antibiotics at concentrations up to and exceeding fully therapeutic levels. Ciprofloxacin levels as high as 14 mg/L were measured [7].

If you think that “what happens in India, stays in India”, I have news for you.  Bengtsson-Palme just reported on the new resistance genes acquired by Swedish exchange students after returning from India (sulfonamides, B-lactams, trimethoprim, ESBL) [8].   Well, if the outside environment provides higher, more diverse exposure to antibiotics than our hospitals, we can give ourselves a pat on the back for a job well done, right?

With colistin resistance reported from China as we speak, ESBLs on the rise, and carbapenem resistance increasing, It almost seems like the battle is over.  The genie is out of the bottle, and no scientist or politician can put it back in again…even for the unlikely event that they wanted to.

References:
[1] Prieto, A. Degradation of the antibiotics norfloxacin and ciprofloxacin by a white-rot fungus and identification of degradation products.  Bioresource Technology 102:10987, 2011
[2] K.-R. Kim, G. Owens, S.-I. Kwon, K.-H. So, D.-B. Lee, and Y. S. Ok, “Occurrence and environmental fate of veterinary antibiotics in the terrestrial environment,” Water, Air, & Soil Pollution, vol. 214, no. 1–4, pp. 163–174, 2011
[3] Li, J.  Plasmid-Mediated Quinolone Resistance Genes and Antibiotic Residues in Wastewater and Soil Adjacent to Swine Feedlots: Potential Transfer to Agricultural Lands 120: 1144, 2012
[4] Call, D. Do antibiotic residues in soils play a role in amplification and transmission of antibiotic resistant bacteria in cattle populations?  Front Microbiol. 4: 193, 2013
[5] Hamscher, G.  Determination of persistent tetracycline residues in soil fertilized with liquid manure by high-performance liquid chromatography with electrospray ionization tandem mass spectrometry.  Anal Chem. 74: 1509, 2002
[6] Wetzstein, H.  Degradation of ciprofloxacin by basidiomycetes and identification of metabolites generated by the brown rot fungus Gloeophyllum striatum. Appl. Environ. Microbiol. 65:1556,1999
[7] Fick, J. Contamination of surface, ground, and drinking water from pharmaceutical production. Environmental Toxicology and Chemistry, 28: 2522, 2009
[8] Bengtsson-Palme, M. The human gut microbiome as a transporter of antibiotic resistance genes between continents.  AAC Online (ahead of print 10 Aug 2015)

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