Significance of antibiotics in the environment

K. Kümmerer*

Institute of Environmental Medicine and Hospital Epidemiology, Freiburg University Hospital, Hugstetter Straße 55, D-79106 Freiburg, Germany

Keywords: antibiotics, environment


    Background
 Top
 Background
 Use of antibiotics and...
 Fate in the environment
 Effects
 Risk: assessment and management
 Conclusions
 References
 
Pharmaceuticals are designed to stimulate a physiological response in humans, animals, bacteria or other organisms. During the past decade, concern has grown about the adverse effects the use and disposal of pharmaceuticals might potentially have on human and ecological health. Research has shown that after passing through wastewater treatment, pharmaceuticals, amongst other compounds, are released directly into the environment.1

The selection and development of antibiotic-resistant bacteria is one of the greatest concerns with regard to the use of antimicrobials.25 In a report by the House of Lords, it is stated that: ‘resistance to antibiotics and other anti-infective agents constitutes a major threat to public health and ought to be recognized as such more widely than it is at present’.4 Therefore, the European Union (EU) recommends the prudent use of antimicrobial agents in human medicine.2 With respect to the causes of resistance, the focus is on the use of antimicrobials in hospitals, by medical practitioners, i.e. in prescriptions2 and in animal husbandry. ‘...Coordination between human, veterinary and environment sectors should be ensured and the magnitude of the relationship between the occurrence of antimicrobial resistant pathogens in humans, animals and the environment should be further clarified...’.2 However, very little is known about their contribution to the level of bacterial resistance in the environment and its significance. Also, surprisingly, little is known about the extent of environmental occurrence, transport, and ultimate fate and effects of pharmaceuticals in general, as well as of antibiotics in particular.1


    Use of antibiotics and input into the environment
 Top
 Background
 Use of antibiotics and...
 Fate in the environment
 Effects
 Risk: assessment and management
 Conclusions
 References
 
In 1996, about 10 200 tons of antibiotics were used in the EU, of which approximately 50% was applied in veterinary medicine and as growth promoters.6 According to data supplied by the European Federation of Animal Health (FEDESA),7 in 1999, 13 288 tons of antibiotics were used in the EU and Switzerland, of which 65% was used in human medicine; 29% was used in the veterinary field and 6% as growth promoters.7 Since most growth promoters have now been banned within the EU, only four compounds remain in this group of feed additives. This may explain the decline in the use of antibiotics in animal husbandry compared with human medicine. In the USA, ~16 200 tons were produced in 20008 of which 70% was used in livestock farming. This is eight times the amount used in human medicine.

Wise estimated total antibiotic market consumption world-wide to lie between 100 000 and 200 000 tons.9

Unused therapeutic drugs are sometimes disposed of into the sewage system. If the drugs are not degraded or eliminated during sewage treatment, in soil or in other environmental compartments, they will reach surface water and ground water, and, potentially, drinking water. Unmetabolized antibiotic substances are often passed into the aquatic environment in wastewater. Antibiotics used for veterinary purposes or as growth promoters are excreted by the animals and end up in manure. Manure is used as an agricultural fertilizer; thus, the antibiotics seep through the soil and enter ground water (Figure 1). However, very little is known about the occurrence, fate and risks associated with antibiotics entering the environment after being used in human and veterinary medicine and as growth promoters; 95% community use is reported for the UK.4 The figure for the USA is 75%.9 In Germany, ~75% of antimicrobials are used in the community and 25% in hospitals.



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Figure 1. Sources and distribution of pharmaceuticals in the environment1 (STP: sewage treatment plant).

 
Ciprofloxacin, for example, was found in concentrations of between 0.7 and 124.5 µg/L in hospital effluent.10 Ampicillin was found in concentrations of between 20 and 80 µg/L in the effluent of a large German hospital.11 Antibiotic concentrations calculated and measured in hospital effluents are of the same order of magnitude as the minimum inhibitory concentrations for susceptible pathogenic bacteria.12 The dilution of hospital effluents by municipal sewage will lower the concentration of antibiotics only moderately, because municipal waste water also contains antibiotic substances and disinfectants from households, veterinary sources and to a minor extent from livestock. Antibiotics have been detected in the µg/L range in municipal sewage, in the effluent of sewage treatment plants (STPs), in surface water and in ground water.1316 These included quinolones such as ciprofloxacin, sulphonamides, roxythromycin, dehydrated erythromycin and others. If antibiotics are used in animal husbandry, they pass into the soil from manure. Tetracyclines have been detected in concentrations of up to 0.2 µg per kg in soil17 whereas others have been found in the sediment under fish farms.


    Fate in the environment
 Top
 Background
 Use of antibiotics and...
 Fate in the environment
 Effects
 Risk: assessment and management
 Conclusions
 References
 
Only a few of the compounds were partially biodegraded under test conditions in aquatic systems.18,19 Most were persistent. The genotoxicity of compounds such as quinolones or metronidazole was not removed during these tests.18 Quinolones, for example, adsorb strongly onto sewage sludge, soils and sediments and were not biodegraded in tests with sediments. Less than 1% of sarafloxacin, a fluoroquinolone approved for the prevention of poultry diseases, was eliminated from different soils within 80 days, probably because of its high ability to bind to soil.20 Virginiamycin, an antibiotic food additive administered orally as a growth promoter in farm animals, was found to biodegrade in different soils, but only with a long half-life.21 Cyclosporin A was shown to degrade only after some months in samples of wet garden soil, despite the fact that several degrading strains have been isolated from soil. These findings indicate that biodegradation of antibiotics in STPs and other environmental compartments may not be an option for the reliable removal of antibiotic substances and this needs more detailed investigation. Furthermore, future measures aimed at saving water will cause a drop in the volume of effluent. The consumption of antimicrobials will, however, almost certainly continue to grow. The resultant higher concentration of antibiotics in urban waste water will, on the basis of present knowledge, have a substantial impact on bacteria in the aquatic environment.


    Effects
 Top
 Background
 Use of antibiotics and...
 Fate in the environment
 Effects
 Risk: assessment and management
 Conclusions
 References
 
Antimicrobials may have qualitative and quantitative effects upon the resident microbial community of sediments, as summarized by Nygaard et al.22 Resistant bacteria may be selected by antibiotic substances in hospital effluent, municipal sewage, aeration tanks, the anaerobic digestion process of STPs or in soil. Furthermore, resistant bacteria are excreted and discharged into sewage or soil and other environmental compartments. Resistant and even multi-resistant pathogenic bacteria have been detected in wastewater and STPs, as well as in other environmental compartments.2325 Furthermore, in arid regions, wastewater containing resistant bacteria and antibiotics is used for irrigation, and sewage sludge serves as a fertilizer. This allows resistant bacteria to enter the food chain directly.

Concentrations below therapeutic levels may play a role in the selection of resistance and its genetic transfer in certain bacteria. Exposure of bacteria to sub-therapeutic antimicrobial concentrations is thought to increase the speed at which resistant strains of bacteria are selected. Resistance can be transferred to other bacteria living in other environments such as ground water or drinking water. In general, knowledge of subinhibitory concentrations and their effects against environmental bacteria is poor, especially with respect to resistance. There are a number of recent and older publications about the mechanisms of very low antibiotic concentrations on the expression of bacterial virulence factors. As for the fate and effects of antibiotics against bacteria and other organisms in the environment, it is not clear whether the standardized tests used for risk assessment of chemicals are appropriate for antibiotics and other pharmaceuticals. Studies using test systems indicate that various antibiotics remain active against different groups of bacteria present in waste water.11,12 Effects against algae and daphnids have been reported at surprisingly low concentrations (5–100 µg/L).2628


    Risk: assessment and management
 Top
 Background
 Use of antibiotics and...
 Fate in the environment
 Effects
 Risk: assessment and management
 Conclusions
 References
 
Most compounds or at least most groups of compounds acting via the same mechanisms are found in hospital effluent and in some cases even in municipal sewage in concentrations that are high enough to warrant further risk assessment and risk management. It is imperative that we obtain a better database of the sources, fate and effects of both antibiotics and resistant bacteria in the environment. This information is necessary if appropriate and, in the long run, successful measures for sound risk assessment and proper risk management are to be taken.

The emission of antibiotics into the environment should be reduced as an important part of the risk management. For this reason, unused therapeutic drugs should not be flushed down the drain and physicians must be made aware that antibiotics are not completely metabolized by patients. On the contrary, antibiotics and other pharmaceuticals are often excreted largely unchanged, i.e. as active compounds. Doctors and patients as well as pharmacists play an important role in reducing the release of antibiotics, other pharmaceuticals, and disinfectants into the environment. The environmental significance of therapeutic drugs, disinfectants and diagnostics should be included in the undergraduate curricula of medical students and pharmacists. Patients should be made aware that antibiotics help against bacterial diseases but not against the common cold, which is caused by viruses. These issues should be addressed as part of a sustainable development in medicine and for the environment. This holds also for the agricultural use of antibiotics as well as their use in fish farming and elsewhere, e.g. as pesticides or for pets.

Because of the timescales involved in acquiring the necessary knowledge, in the reaction times of ecological systems,29 in getting people to react, and also the socio-economic timescales involved we have to act now—at least for precautionary reasons and sustainable development. This is especially important in respect of the effects of antibiotics, i.e. the promotion of resistance.


    Conclusions
 Top
 Background
 Use of antibiotics and...
 Fate in the environment
 Effects
 Risk: assessment and management
 Conclusions
 References
 
Only little is known about the occurrence, fate, effects and risks associated with the release of antibiotics and other drugs into the environment. There is still a lack of fundamental data on the occurrence, fate and effects of antimicrobials in the environment needed for proper risk assessment and risk management both for humans and the environment. Hospitals are one, albeit not the only, source of antibiotic input into the environment. Although antibiotics are used by patients outside hospitals, in livestock and for pets, attention should also be paid to their use in hospitals.


    Footnotes
 
* Tel: +49-761-270-5464; Fax: +49-761-270-5440; E-mail: k.kuemmerer{at}iuk3.ukl.uni-freiburg.de Back


    References
 Top
 Background
 Use of antibiotics and...
 Fate in the environment
 Effects
 Risk: assessment and management
 Conclusions
 References
 
1 . Kümmerer, K. (Ed.). (2001). Pharmaceuticals in the Environment. Sources, Fate, Effects and Risks. Springer, Heidelberg, Germany.

2 . The Council of the European Union. (2002). Council Recommendation of 15 November 2001 on the Prudent Use of Antimicrobial Agents in Human Medicine (Text with EEA relevance). 2002/77/EC. 5 February, Brussels, Belgium.

3 . Wise, R., Hart, T., Cars, O. et al. (1998). Antimicrobial resistance is a major threat to public health. British Medical Journal 317, 609–10.[Free Full Text]

4 . House of Lords Select Committee on Science and Technology. (1998). 7th Report. The Stationery Office, London, UK.

5 . Morris, A. K. & Masterton, R. G. (2002). Antibiotic resistance surveillance: action for international studies. Journal of Antimicrobial Chemotherapy 49, 7–10.[Abstract/Free Full Text]

6 . European Federation of Animal Health (FEDESA). (1997). Antibiotics and Animals. FEDESA/FEFANA Press release. 8 September. Brussels, Belgium.

7 . European Federation of Animal Health (FEDESA). (2001). Antibiotic Use in Farm Animals does not threaten Human Health. FEDESA/FEFANA Press release. 13 July. Brussels, Belgium.

8 . Union of Concerned Scientists. (2001). 70 Percent of All Antibiotics Given to Healthy Livestock. Press release. 8 January. Cambridge, MA, USA.

9 . Wise, R. (2002). Antimicrobial resistance: priorities for action. Journal of Antimicrobial Chemotherapy 49, 585–6.[Free Full Text]

10 . Hartmann, A., Golet, E. M., Gartiser, S. et al. (1999). Primary DNA damage but not mutagenicity correlates with ciprofloxacin concentrations in German hospital waste waters. Archives of Environmental Contamination and Toxicology 36, 115–9.[CrossRef][ISI][Medline]

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12 . Kümmerer, K. & Henninger, A. (2003). Promoting resistance by the emission of antibiotics from hospitals and households into effluents. Clinical Microbiology and Infection, in press.

13 . Zuccato, E., Calamari, D., Natangelo, M. et al. (2000). Presence of therapeutic drugs in the environment. Lancet 335, 1789–90.

14 . Golet, E. M., Alder, A. C., Hartmann, A. et al. (2001). Trace determination of fluoroquinolone antibacterial agents in urban wastewater by solid-phase extraction and liquid chromatography with fluorescence detection. Analytical Chemistry 73, 3632–8.[CrossRef][ISI][Medline]

15 . Sacher, F., Brauch, H.-J., Lange, F. T. et al. (2001). Occurrence of antibiotics in groundwater in Baden-Württemberg, Germany—results of a comprehensive monitoring program. In Abstracts of the 11th Annual Meeting of SETAC Europe (Society of Environmental Toxicology and Chemistry), Madrid, Spain, 2001. Abstract M/EH056, p. 112. SETAC Europe, Brussels, Belgium.

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17 . Hamscher, G., Sczesny, S., Höper, H. et al. (2002). Determination of persistent tetracycline residues in soil fertilized with liquid manure by high-performance liquid chromatography with electrospray ionization tandem mass spectrometry. Analytical Chemistry 74, 1509–18.[CrossRef][ISI][Medline]

18 . Kümmerer, K., Al-Ahmad, A. & Mersch-Sundermann, V. (2000). Biodegradability of some antibiotics, elimination of the genotoxicity and affection of wastewater bacteria in a simple test. Chemosphere 40, 701–10.[CrossRef][ISI][Medline]

19 . Al-Ahmad, A., Daschner, F. D. & Kümmerer, K. (1999). Biodegradability of cefotiam, ciprofloxacin, meropenem, penicillin G, and sulfamethoxazole and inhibition of waste water bacteria. Archives of Environmental Contamination and Toxicology 37, 158–63.[CrossRef][ISI][Medline]

20 . Marengo, J. R., Kok, R. A., Velagaleti, R. et al. (1997). Aerobic degradation of 14C-sarafloxacin hydrochloride in soil. Environmental Toxicology and Chemistry 16, 462–71.[ISI]

21 . Weerasinghe, C. A. & Towner, D. (1997). Aerobic biodegradation of virginiamycin in soil. Environmental Toxicology and Chemistry 16, 1873–6.[ISI]

22 . Nygaard, K., Lunestad, B. T., Hektoern, H. et al. (1992). Resistance to oxytetracycline, oxolinic acid and furazolidone in bacteria from marine sediments. Aquaculture 104, 21–36.

23 . Guardabassi, L., Petersen, A., Olsen, J. E. et al. (1998). Antibiotic resistance in Acinetobacter spp. isolated from sewers receiving waste effluent from a hospital and a pharmaceutical plant. Applied and Environmental Microbiology 64, 3499–502.[Abstract/Free Full Text]

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26 . Holten-Lützhøft, H.-C., Halling-Sørensen, B. & Jörgensen, S. E. (1999). Algae toxicity of antibacterial agents applied in Danish fish farming. Archives of Environmental Contamination and Toxicology 36, 1–6.[CrossRef][ISI][Medline]

27 . Wollenberger, L., Halling-Sørensen, B. & Kusk, K. O. (2000). Acute and chronic toxicity of veterinary antibiotics to Daphnia magna. Chemosphere 40, 723–30.[CrossRef][ISI][Medline]

28 . Macri, A., Stazi, V. & Dojmi di Delupis, G. (1988). Acute toxicity of furazolidone on Artemia salina, Daphnia magna, and Culex pipiens molestus larvae. Ecotoxicology and Environmental Safety 16, 90–4.[ISI][Medline]

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