Elsevier

Environmental Pollution

Volume 157, Issue 11, November 2009, Pages 2893-2902
Environmental Pollution

Review
Environmental pollution by antibiotics and by antibiotic resistance determinants

https://doi.org/10.1016/j.envpol.2009.05.051Get rights and content

Abstract

Antibiotics are among the most successful drugs used for human therapy. However, since they can challenge microbial populations, they must be considered as important pollutants as well. Besides being used for human therapy, antibiotics are extensively used for animal farming and for agricultural purposes. Residues from human environments and from farms may contain antibiotics and antibiotic resistance genes that can contaminate natural environments. The clearest consequence of antibiotic release in natural environments is the selection of resistant bacteria. The same resistance genes found at clinical settings are currently disseminated among pristine ecosystems without any record of antibiotic contamination. Nevertheless, the effect of antibiotics on the biosphere is wider than this and can impact the structure and activity of environmental microbiota. Along the article, we review the impact that pollution by antibiotics or by antibiotic resistance genes may have for both human health and for the evolution of environmental microbial populations.

Introduction

Antibiotics are probably the most successful family of drugs so far developed for improving human health. Besides this fundamental application, antibiotics (antimicrobials at large) have also been used for preventing and treating animals and plants infections as well as for promoting growth in animal farming (McManus et al., 2002, Smith et al., 2002, Singer et al., 2003, Cabello, 2006). All these applications made antibiotics to be released in large amounts in natural ecosystems. Little is known on the overall effects of antibiotics on the population dynamics of the microbiosphere (Sarmah et al., 2006). However, the effect of antibiotics used for treating infections or for farming purposes in the selection of antibiotic-resistant microorganisms, which can impact human health has been studied in more detail (Witte, 1998, Ferber, 2003, Singer et al., 2003). As stated by the World Health Organization, the increasing emergence of antibiotic resistance in human pathogens is a special concern, not only for treating infectious disease, but also for other pathologies in which antibiotic prophylaxis is needed for avoiding associated infections. In this regard, the spread of antibiotic-resistant bacteria “…means that commonplace medical procedures once previously taken for granted could be conceivably consigned to medical limbo. The repercussions are almost unimaginable” (WHO, 2000).

It is important to remark that several antibiotics are produced by environmental microorganisms (Waksman and Woodruff, 1940). Conversely, antibiotic resistance genes, acquired by pathogenic bacteria trough Horizontal Gene Transfer (HGT) have been originated as well in environmental bacteria (Davies, 1997), although they can evolve later on under strong antibiotic selective pressure during the treatment of infections (Martinez and Baquero, 2000, Martinez et al., 2007). To understand in full the development of resistance, we will thus need to address the study of antibiotics and their resistance genes, not just in clinics but in natural non-clinical environments also (Martinez, 2008). The situation concerning antibiotics and their resistances resembles in some aspects to heavy metal contamination. Like antibiotics, heavy metals are natural compounds present in different ecosystems. However, their utilization by humans has increased their bioavailability, leading to dramatic changes in polluted ecosystems. Differing to heavy metals that challenge all forms of life, antimicrobials mainly alter the microbiosphere and probably because of this, the consequences of antibiotic pollution on the biodiversity have received less attention.

Understanding heavy metal resistance in natural ecosystems may help as well to understand antibiotic resistance in the environment. The elements involved in the resistance to heavy metals are encoded in the chromosomes of bacteria like Ralstonia metallidurans (Mergeay et al., 2003), which are well adapted for surviving in naturally heavy metals-rich habitats (e.g. volcanic soils). However, strong selective pressure due to anthropogenic pollution has made that these chromosomally-encoded determinants are now present in gene-transfer units, so that they can efficiently spread among bacterial populations (Silver and Phung, 1996, Silver and Phung, 2005, Nies, 2003). Similarly, antibiotic resistance genes that were naturally present in the chromosomes of environmental bacteria (D'Acosta et al., 2006, Wright, 2007, Fajardo et al., 2008) are now present in plasmids that can be transferred to human pathogens. It has been highlighted that the contact of bacteria from human-associated microbiota with environmental microorganisms in sewage plants or in natural ecosystems is an important feature to understand the emergence of novel mechanisms of resistance in human pathogens (Baquero et al., 2008). A key issue for this emergence will be the integration of antibiotic resistance genes in gene-transfer elements (e.g. plasmids), a feature that is favoured by the release of antibiotics in natural ecosystems (Cattoir et al., 2008).

Section snippets

Functional role of antibiotics and antibiotic resistance elements in bacterial natural ecosystems

Since antibiotics are efficient inhibitors of bacterial growth produced by environmental microorganisms, it has been widely accepted that their role in nature will be to inhibit microbial competitors. Conversely, antibiotic resistance determinants should serve to avoid the activity of antibiotics, in such a way that they would be a good example of the Darwinian struggle for life. Although this can be true in some occasions, an alternative hypothesis stating that antibiotics could be signal

Different consequences of antibiotic pollution and antibiotic resistance pollution

Antibiotic utilization for clinical or farming purposes selects resistant microorganisms (Teuber, 2001, Livermore, 2005). It is thus predictable that residues from hospitals or farms will contain both types of pollutants: antibiotics and resistance genes. Nevertheless, the fate of both types of pollutants is likely different. Several antibiotics are natural compounds that have been in contact with environmental microbiota for millions of years and are thus biodegradable, an even serve as a food

Release, behaviour and effects of antibiotics in natural ecosystems

Most antibiotics used for preventing or treating infections in humans or animals as well as for promoting faster growth of livestock are only partially metabolized and are then discharged along the excreta, either to sewage treatment plants or straightforward in waters or soils (Dolliver and Gupta, 2008). Besides, antimicrobial compounds used in intensive fish farming are added directly to the water rendering high local concentrations both in water and in adjoining sediments (Cabello, 2006). In

When an antibiotic resistance gene is a pollutant

Several works highlight the presence of antibiotic resistance genes in pristine, isolated or extreme environments that are unlikely contaminated with antibiotics used by humans. These include the deep terrestrial subsurface (Brown and Balkwill, 2009), non-contaminated Antarctic waters (De Souza et al., 2006) or deep Greenland ice core (Miteva et al., 2004) among others. These works constitute a good example of the ubiquity of genes that might confer resistance upon expression in a heterologous

Mechanisms for the maintenance of antibiotic resistance genes

A key issue for predicting the fate of antibiotic resistance genes in natural environments is the understanding of their effects on bacterial physiology. It has been assumed that antibiotic resistance confers a metabolic burden for the resistant bacteria so that they will be out-competed by their wild-type counterparts in the absence of antibiotic selective pressure (Andersson and Levin, 1999, Andersson, 2006). Although in some occasions this is likely true, some examples demonstrate that

Consequences of pollution by antibiotic resistance genes

Pollution by antibiotic resistance genes can increase the chances of human pathogens for acquiring resistance. The release of residues containing human microbiota into environments containing bacteria enriched in resistance elements increases the possibility of acquiring novel resistance determinants by human-linked bacteria. For this reason, it has been proposed that the release of residues from hospitals that contain human commensal and infective bacteria (resistant and susceptible) as well

Concluding remarks

The release of high concentrations of antibiotics and resistance genes in natural ecosystems is a recent event in evolutionary terms. Nevertheless, both types of pollution can impact the structure and the activity of environmental microbial populations. Given that environmental microorganisms are the original source of resistance genes acquired through HGT by human pathogens (Davies, 1997), these changes are relevant for the future of human health. It has been reported that the same antibiotic

Acknowledgements

Author's laboratory is supported by grants BIO2005-04278 and BIO2008-00090 from the Spanish Ministerio de Ciencia e Innovación, and LSHM-CT-2005-518152 and LSHM-CT-2005-018705 from European Union. Thanks are given to Helen Green for language editing.

References (132)

  • J. Davies et al.

    The world of subinhibitory antibiotic concentrations

    Curr. Opin. Microbiol.

    (2006)
  • M.C. Dodd et al.

    Aqueous chlorination of the antibacterial agent trimethoprim: reaction kinetics and pathways

    Water Res.

    (2007)
  • V.I. Enne et al.

    Persistence of sulphonamide resistance in Escherichia coli in the UK despite national prescribing restriction

    Lancet

    (2001)
  • A. Fajardo et al.

    Antibiotics as signals that trigger specific bacterial responses

    Curr. Opin. Microbiol.

    (2008)
  • C. Garofalo et al.

    Direct detection of antibiotic resistance genes in specimens of chicken and pork meat

    Int. J. Food Microbiol.

    (2007)
  • M.P. Gonzalo et al.

    Sewage dilution and loss of antibiotic resistance and virulence determinants in E. coli

    FEMS Microbiol. Lett.

    (1989)
  • A. Gulkowska et al.

    Removal of antibiotics from wastewater by sewage treatment facilities in Hong Kong and Shenzhen, China

    Water Res.

    (2008)
  • B. Halling-Sorensen et al.

    Occurrence, fate and effects of pharmaceutical substances in the environment – a review

    Chemosphere

    (1998)
  • R. Hirsch et al.

    Occurrence of antibiotics in the aquatic environment

    Sci. Total Environ.

    (1999)
  • D.C. Hooper

    Mechanisms of fluoroquinolone resistance

    Drug Resist. Updat.

    (1999)
  • P.K. Jjemba

    The potential impact of veterinary and human therapeutic agents in manure and biosolids of plants grown on arable land: a review

    Agric., Ecosyst. Environ.

    (2002)
  • W.D. Kong et al.

    The veterinary antibiotic oxytetracycline and Cu influence functional diversity of the soil microbial community

    Environ. Pollut.

    (2006)
  • A. Kotzerke et al.

    Alterations in soil microbial activity and N-transformation processes due to sulfadiazine loads in pig-manure

    Environ. Pollut.

    (2008)
  • D. Li et al.

    Determination of penicillin G and its degradation products in a penicillin production wastewater treatment plant and the receiving river

    Water Res.

    (2008)
  • R.H. Lindberg et al.

    Environmental risk assessment of antibiotics in the Swedish environment with emphasis on sewage treatment plants

    Water Res.

    (2007)
  • D.M. Livermore

    Minimising antibiotic resistance

    Lancet Infect. Dis.

    (2005)
  • S. Lofmark et al.

    Restored fitness leads to long-term persistence of resistant Bacteroides strains in the human intestine

    Anaerobe

    (2008)
  • J.L. Martinez et al.

    Incidence of aerobactin production in Gram-negative hospital isolates

    FEMS Microbiol. Lett.

    (1987)
  • J.L. Martinez et al.

    Cloning of the determinants for microcin D93 production and analysis of three different D-type microcin plasmids

    Plasmid

    (1990)
  • E. Martinez-Carballo et al.

    Environmental monitoring study of selected veterinary antibiotics in animal manure and soils in Austria

    Environ. Pollut.

    (2007)
  • M. Mergeay et al.

    Ralstonia metallidurans, a bacterium specifically adapted to toxic metals: towards a catalogue of metal-responsive genes

    FEMS Microbiol. Rev.

    (2003)
  • D.H. Nies

    Efflux-mediated heavy metal resistance in prokaryotes

    FEMS Microbiol. Rev.

    (2003)
  • R. Pei et al.

    Effect of river landscape on the sediment concentrations of antibiotics and corresponding antibiotic resistance genes (ARG)

    Water Res.

    (2006)
  • M.T. Roe et al.

    Class 1 and class 2 integrons in poultry carcasses from broiler house and poultry processing environments

    J. Food Prot.

    (2003)
  • F.M. Aarestrup et al.

    Effect of abolishment of the use of antimicrobial agents for growth promotion on occurrence of antimicrobial resistance in fecal enterococci from food animals in Denmark

    Antimicrob. Agents Chemother.

    (2001)
  • S.D. Alcaine et al.

    Ceftiofur-resistant Salmonella strains isolated from dairy farms represent multiple widely distributed subtypes that evolved by independent horizontal gene transfer

    Antimicrob. Agents Chemother.

    (2005)
  • A. Alonso et al.

    Environmental selection of antibiotic resistance genes

    Environ. Microbiol.

    (2001)
  • A. Alonso et al.

    Overexpression of the multidrug efflux pump SmeDEF impairs Stenotrophomonas maltophilia physiology

    J. Antimicrob. Chemother.

    (2004)
  • A. Alonso et al.

    Cloning and characterization of SmeDEF, a novel multidrug efflux pump from Stenotrophomonas maltophilia

    Antimicrob. Agents Chemother.

    (2000)
  • F.J. Angulo et al.

    Evidence of an association between use of anti-microbial agents in food animals and anti-microbial resistance among bacteria isolated from humans and the human health consequences of such resistance

    J. Vet. Med. B Infect. Dis. Vet. Public Health

    (2004)
  • L. Balsalobre et al.

    Fitness of Streptococcus pneumoniae fluoroquinolone-resistant strains with topoisomerase IV recombinant genes

    Antimicrob. Agents Chemother.

    (2008)
  • R.S. Barlow et al.

    A comparison of antibiotic resistance integrons in cattle from separate beef meat production systems at slaughter

    J. Appl. Microbiol.

    (2008)
  • P.T. Biyela et al.

    The role of aquatic ecosystems as reservoirs of antibiotic resistant bacteria and antibiotic resistance genes

    Water Sci. Technol.

    (2004)
  • J. Bjorkman et al.

    Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistance

    Science

    (2000)
  • T. Brody et al.

    Horizontal gene transfers link a human MRSA pathogen to contagious bovine mastitis bacteria

    PLoS ONE

    (2008)
  • M.G. Brown et al.

    Antibiotic resistance in bacteria isolated from the deep terrestrial subsurface

    Microb. Ecol.

    (2009)
  • F.C. Cabello

    Heavy use of prophylactic antibiotics in aquaculture: a growing problem for human and animal health and for the environment

    Environ. Microbiol.

    (2006)
  • Calabrese, E.J., 2004. Hormesis: a revolution in toxicology, risk assessment and medicine. EMBO Rep 5 Spec No,...
  • E.J. Calabrese

    Paradigm lost, paradigm found: the re-emergence of hormesis as a fundamental dose response model in the toxicological sciences

    Environ. Pollut.

    (2005)
  • V. Cattoir et al.

    Unexpected occurrence of plasmid-mediated quinolone resistance determinants in environmental Aeromonas spp

    Emerg. Infect. Dis.

    (2008)
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