J. Antimicrob. Chemother.-2003-Kümmerer-5-7.pdf

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Journal of Antimicrobial Chemotherapy (2003) 52 , 5–7DOI: 10.1093/jac/dkg293Advance Access publication 12 June 2003

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© 2003 The British Society for Antimicrobial Chemotherapy

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

Pharmaceuticals are designed to stimulate a physiological responsein humans, animals, bacteria or other organisms. During the pastdecade, concern has grown about the adverse effects the use anddisposal of pharmaceuticals might potentially have on human andecological health. Research has shown that after passing throughwastewater treatment, pharmaceuticals, amongst other compounds,are released directly into the environment. 1

The selection and development of antibiotic-resistant bacteria isone of the greatest concerns with regard to the use of antimicrobials. 2–5

In a report by the House of Lords, it is stated that: ‘resistance toantibiotics and other anti-infective agents constitutes a major threatto public health and ought to be recognized as such more widely thanit is at present ’.4 Therefore, the European Union (EU) recommendsthe prudent use of antimicrobial agents in human medicine. 2 Withrespect to the causes of resistance, the focus is on the use of antimicro-bials in hospitals, by medical practitioners, i.e. in prescriptions 2 andin animal husbandry. ‘…Coordination between human, veterinaryand environment sectors should be ensured and the magnitude of therelationship between the occurrence of antimicrobial resistantpathogens in humans, animals and the environment should be furtherclarified …’.2 However, very little is known about their contributionto the level of bacterial resistance in the environment and itssignificance. 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

In 1996, about 10200 tons of antibiotics were used in the EU, of which approximately 50% was applied in veterinary medicine andas growth promoters. 6 According to data supplied by the EuropeanFederation of Animal Health (FEDESA), 7 in 1999, 13288 tons of antibiotics were used in the EU and Switzerland, of which 65% wasused in human medicine; 29% was used in the veterinary field and 6%as growth promoters. 7 Since most growth promoters have now beenbanned within the EU, only four compounds remain in this group of feed additives. This may explain the decline in the use of antibioticsin animal husbandry compared with human medicine. In the USA,

∼16 200 tons were produced in 2000 8 of which 70% was used in live-

stock farming. This is eight times the amount used in human medi-cine.

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

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

Ciprofloxacin, for example, was found in concentrations of between 0.7 and 124.5 µ g/L in hospital effluent. 10 Ampicillin wasfound in concentrations of between 20 and 80 µ g/L in the effluent of a large German hospital. 11 Antibiotic concentrations calculated andmeasured in hospital effluents are of the same order of magnitude asthe minimum inhibitory concentrations for susceptible pathogenic

bacteria.12

The dilution of hospital effluents by municipal sewagewill lower the concentration of antibiotics only moderately, becausemunicipal waste water also contains antibiotic substances and disin-fectants from households, veterinary sources and to a minor extentfrom livestock. Antibiotics have been detected in the µ g/L range inmunicipal sewage, in the effluent of sewage treatment plants (STPs),in surface water and in ground water. 13–16 These included quinolonessuch as ciprofloxacin, sulphonamides, roxythromycin, dehydratederythromycin and others. If antibiotics are used in animal husbandry,they pass into the soil from manure. Tetracyclines have been detectedin concentrations of up to 0.2 µ g per kg in soil 17 whereas others havebeen found in the sediment under fish farms.

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*Tel: +49-761-270-5464; Fax: +49-761-270-5440; E-mail: [email protected]

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Fate in the environment

Only a few of the compounds were partially biodegraded under testconditions in aquatic systems. 18,19 Most were persistent. The geno-toxicity of compounds such as quinolones or metronidazole was notremoved during these tests. 18 Quinolones, for example, adsorbstrongly onto sewage sludge, soils and sediments and were not bio-degraded in tests with sediments. Less than 1% of sarafloxacin, a fluoro-quinolone approved for the prevention of poultry diseases, waseliminated from different soils within 80 days, probably because of its high ability to bind to soil. 20 Virginiamycin, an antibiotic foodadditive 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 insamples of wet garden soil, despite the fact that several degradingstrains have been isolated from soil. These findings indicate that bio-degradation of antibiotics in STPs and other environmental compart-ments may not be an option for the reliable removal of antibioticsubstances and this needs more detailed investigation. Furthermore,future measures aimed at saving water will cause a drop in the volumeof effluent. The consumption of antimicrobials will, however, almostcertainly continue to grow. The resultant higher concentration of antibiotics in urban waste water will, on the basis of present know-ledge, have a substantial impact on bacteria in the aquatic environ-

ment.

Effects

Antimicrobials may have qualitative and quantitative effects uponthe resident microbial community of sediments, as summarized byNygaard et al. 22 Resistant bacteria may be selected by antibioticsubstances in hospital effluent, municipal sewage, aeration tanks, theanaerobic digestion process of STPs or in soil. Furthermore, resistantbacteria are excreted and discharged into sewage or soil and otherenvironmental compartments. Resistant and even multi-resistantpathogenic bacteria have been detected in wastewater and STPs, aswell as in other environmental compartments. 23–25 Furthermore, in

arid regions, wastewater containing resistant bacteria and antibiotics

is used for irrigation, and sewage sludge serves as a fertilizer. Thisallows resistant bacteria to enter the food chain directly.

Concentrations below therapeutic levels may play a role in theselection of resistance and its genetic transfer in certain bacteria.Exposure of bacteria to sub-therapeutic antimicrobial concentrationsis thought to increase the speed at which resistant strains of bacteria

are selected. Resistance can be transferred to other bacteria livingin other environments such as ground water or drinking water. Ingeneral, knowledge of subinhibitory concentrations and their effectsagainst environmental bacteria is poor, especially with respect toresistance. There are a number of recent and older publications aboutthe mechanisms of very low antibiotic concentrations on the expres-sion of bacterial virulence factors. As for the fate and effects of antibiotics against bacteria and other organisms in the environment, itis 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 remainactive against different groups of bacteria present in waste water. 11,12

Effects against algae and daphnids have been reported at surprisinglylow concentrations (5 –100 µ g/L). 26–28

Risk: assessment and management

Most compounds or at least most groups of compounds acting via thesame mechanisms are found in hospital effluent and in some caseseven in municipal sewage in concentrations that are high enough towarrant further risk assessment and risk management. It is imperativethat we obtain a better database of the sources, fate and effects of bothantibiotics and resistant bacteria in the environment. This infor-mation is necessary if appropriate and, in the long run, successfulmeasures for sound risk assessment and proper risk management areto 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 andphysicians must be made aware that antibiotics are not completelymetabolized by patients. On the contrary, antibiotics and otherpharmaceuticals are often excreted largely unchanged, i.e. as activecompounds. Doctors and patients as well as pharmacists play animportant role in reducing the release of antibiotics, other pharma-ceuticals, and disinfectants into the environment. The environmentalsignificance of therapeutic drugs, disinfectants and diagnosticsshould be included in the undergraduate curricula of medical studentsand pharmacists. Patients should be made aware that antibiotics helpagainst bacterial diseases but not against the common cold, which iscaused by viruses. These issues should be addressed as part of asustainable development in medicine and for the environment. Thisholds also for the agricultural use of antibiotics as well as their use infish farming and elsewhere, e.g. as pesticides or for pets.

Because of the timescales involved in acquiring the necessaryknowledge, in the reaction times of ecological systems, 29 in gettingpeople to react, and also the socio-economic timescales involved wehave to act now —at least for precautionary reasons and sustainabledevelopment. This is especially important in respect of the effects of antibiotics, i.e. the promotion of resistance.

Conclusions

Only little is known about the occurrence, fate, effects and risksassociated with the release of antibiotics and other drugs into the

environment. There is still a lack of fundamental data on the occur-

Figure 1. Sources and distribution of pharmaceuticals in the environment 1

(STP: sewage treatment plant).

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rence, fate and effects of antimicrobials in the environment neededfor proper risk assessment and risk management both for humansand the environment. Hospitals are one, albeit not the only, source of antibiotic input into the environment. Although antibiotics are usedby patients outside hospitals, in livestock and for pets, attentionshould also be paid to their use in hospitals.

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 Recommen- dation 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 resistanceis a major threat to public health. British Medical Journal 317 , 609 –10.

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 resistancesurveillance: action for international studies. Journal of Antimicrobial Chemotherapy 49 , 7 –10.

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

7. European Federation of Animal Health (FEDESA). (2001). Anti- biotic 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 Anti- biotics 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.

10. Hartmann, A., Golet, E. M., Gartiser, S. et al. (1999). Primary DNAdamage but not mutagenicity correlates with ciprofloxacin concentrations

in German hospital waste waters. Archives of Environmental Contamina- tion and Toxicology 36 , 115 –9.

11. Kümmerer, K. (2001). Drugs in the environment: emission ofdrugs, diagnostic aids and disinfectants into wastewater by hospitals inrelation to other sources —a review. Chemosphere 45 , 957 –69.

12. Kümmerer, K. & Henninger, A. (2003). Promoting resistance bythe 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 oftherapeutic drugs in the environment. Lancet 335 , 1789 –90.

14. Golet, E. M., Alder, A. C., Hartmann, A. et al. (2001). Trace deter-mination of fluoroquinolone antibacterial agents in urban wastewater bysolid-phase extraction and liquid chromatography with fluorescence detec-tion. Analytical Chemistry 73 , 3632 –8.

15. Sacher, F., Brauch, H.-J., Lange, F. T. et al. (2001). Occurrence ofantibiotics in groundwater in Baden-W ürttemberg, Germany —results of acomprehensive 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. SETACEurope, Brussels, Belgium.

16. Kolpin, D., Furlong, E. T., Meyer, M. T. et al. (2002). Pharma-

ceuticals, hormones, and other organic wastewater contaminants in U.S.streams, 1999 –2000: a national reconnaissance. Environmental Science and Technology 36 , 1202 –11.

17. Hamscher, G., Sczesny, S., H öper, H. et al. (2002). Determinationof persistent tetracycline residues in soil fertilized with liquid manure byhigh-performance liquid chromatography with electrospray ionizationtandem mass spectrometry. Analytical Chemistry 74 , 1509 –18.

18. Kümmerer, K., Al-Ahmad, A. & Mersch-Sundermann, V. (2000).Biodegradability of some antibiotics, elimination of the genotoxicityand affection of wastewater bacteria in a s imple test. Chemosphere 40 ,701 –10.

19. Al-Ahmad, A., Daschner, F. D. & K ümmerer, K. (1999). Biodegrad-ability of cefotiam, ciprofloxacin, meropenem, penicillin G, and sulfa-methoxazole and inhibition of waste water bacteria. Archives of Environmental Contamination and Toxicology 37 , 158 –63.

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

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

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

23. Guardabassi, L., Petersen, A., Olsen, J. E. et al. (1998). Antibioticresistance in Acinetobacter spp. isolated from sewers receiving wasteeffluent from a hospital and a pharmaceutical plant. Applied and Environ- mental Microbiology 64 , 3499 –502.

24. Witte, W. (1998). Medical consequences of antibiotic use in agri-culture. Science 279 , 996 –7.

25. Feuerpfeil, I., Lopez-Pila, J., Schmidt, R. et al. (1999). Antibiotikaresistente Bakterien und Antibiotika in der Umwelt. Bundesgesundheits- blatt Gesundheitsforschung Gesundheitsschutz 42 , 37 –50.

26. Holten-L ützh ø ft, H.-C., Halling-S ø rensen, B. & J örgensen, S. E.(1999). Algae toxicity of antibacterial agents applied in Danish fish farm-ing. Archives of Environmental Contamination and Toxicology 36 , 1 –6.

27. Wollenberger, L., Halling-S ø rensen, B. & Kusk, K. O. (2000).Acute and chronic toxicity of veterinary antibiotics to Daphnia magna .Chemosphere 40 , 723 –30.

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

29. Kümmerer, K. (1996). The ecological impact of time. Time and Society 5 , 219 –25.

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