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Underappreciated Role of Regionally Poor Water Quality on Globally Increasing Antibiotic Resistance David W. Graham,*,† Peter Collignon,‡ Julian Davies,§ D. G. Joakim Larsson,∥ and Jason Snape⊥ †
School of Civil Engineering & Geosciences, Newcastle University, Newcastle upon Tyne NE1 7RU, U.K. Australian National University and Canberra Hospital, Canberra 2605, Australia § Department of Microbiology and Immunology, University of British Columbia, Vancouver V6T 1Z4, Canada ∥ Institute for Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden ⊥ AstraZeneca U.K., Global Safety, Health and Environment, Alderley Park, Macclesfield, U.K. pollutants (e.g., antibiotics, biocides, heavy metals) select andor coselect for AR, although until recently, no global mechanistic explanation has existed. Some mobile genetic elements that carry AR genes also carry heavy metal resistance genes, but this only explains some environmental AR scenarios. However, Gillings2 recently provided a general explanation for how pollution might impact AR transmission based on the activation of integrons during bacterial stress. Simplistically, antibiotics and other pollutants stress microorganisms, even at low concentrations. Stress induces cellular gene rearrangement processes, which increase the chance of any cell acquiring and activating AR genes, even if no antibiotics are present. Pollutant stress increases AR potential in bacteria; therefore, locations with high levels of pollution also have elevated potential for AR transmission. This is most apparent with domestic sewage releases. It has been long known that inadequately treated sewage allows the dissemination of bacterial pathogens, both resistant and nonresistant. However, in developed countries, effective wastewater and water treatment infrastructures have produced a false sense of security among decision-makers with respect to waterborne pathogen dissemination. The marked reduction of he widespread use of antibiotics over the last 60 years has epidemic disease since Victorian times almost exactly improved the treatment and prevention of bacterial corresponds to the implementation of effective domestic infections, saving millions of lives and alleviating much waste treatment and increased awareness of water as a vector human misery. However, increased exposure to mass produced for infectious disease. Unfortunately, water quality in many antibiotics has eroded the efficacy of many antibiotics to a point parts of the world has declined since Queen Victoria due to where many drugs have been compromised and multi antibiotic overpopulation, increased urbanization and greater pollution on resistant (AR) pathogens are common.1 This AR burden is wide scales. The impact of poor water quality is most profound placing a huge cost on society with an estimated >200 000 lives in emerging countries where increasing personal wealth permits lost annually in the United States, China and Europe alone. greater purchase and use of antibiotics in medical and Most believe increasing AR has resulted from antibiotic overuse agriculture sectors, often by self-prescription. However, waste management in emerging countries has not kept up with in medicine and agriculture, providing selective pressure that economic growth and contaminated water may dominate AR drives AR strains to emerge and spread. However, we feel this dissemination in such locations. explanation is too simplistic and does not consider environThree main pathways exist by which AR disease might be mental influences that fuel global AR dissemination, especially gained in the gut of an individual (Figure 1): AR (1) selected inadequate sanitation and poor water quality in over 80% of the due to antibiotic use itself, (2) disseminated via exposed food, world. and-or (3) by water consumption. In developed countries, We contend the only way of curbing increasing AR water has become a minor vector for AR transmission because worldwide is by recognizing AR is not solely an issue of wastewater treatment restricts recycling of AR potential to inappropriate antibiotic use, but is also rooted in how we previously unexposed individuals. However, if one removes manage our wastes. The key role of pollution in the emergence of mobile resistance factors in medically important strains has become apparent,1 including horizontal gene transfer of AR Received: July 24, 2014 genes from environmental bacteria to pathogens. Further, many Published: October 1, 2014 ‡
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© 2014 American Chemical Society
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dx.doi.org/10.1021/es504206x | Environ. Sci. Technol. 2014, 48, 11746−11747
Environmental Science & Technology
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decision-makers, critically important antibiotics will continue to fail and AR will increase. We suggest “One Health”, a growing perspective in medicine, be adopted worldwide; however, such a holistic health strategy must include environmental quality to be successful. Unless such a perspective is adopted, we will almost certainly enter a “post-antibiotic age” that many doomsayers are predicting.
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AUTHOR INFORMATION
Corresponding Author
*Phone: (44)-0-191-222-7930; fax: (44)-0-191-222-6502; email:
[email protected]. Notes
The authors declare no competing financial interest.
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Figure 1. Major exposure pathways to humans for antibiotic resistance (AR) genes and bacteria. Antibiotic use fuels the “AR pump“. However, without adequate water and waste treatment, the AR pump is readily primed by contaminated food and water, amplifying AR potential on much broader scales (red plus brown vs. brown lines).
REFERENCES
(1) Wellington, E. M. H.; Boxall, A. B. A.; Cross, P.; Feil, E. J.; Gaze, W. H.; Hawkey, P. M.; Johnson-Rollings, A. S.; Jones, D. L.; Lee, N. M.; Otten, W.; Thomas, C. M.; Williams, A. P. The role of the natural environment in the emergence of antibiotic resistance in gram-negative bacteria. Lancet Infect Dis. 2013, 13, 155−165. (2) Gillings, M. R. Integrons: Past, present, and future. Microbiol. Mol. Biol. Rev. 2014, 78, 257−277. (3) Ahammad, Z. S.; Sreekrishnan, T. R.; Hands, C. L.; Knapp, C. W.; Graham, D. W. Increased waterborne blaNDM-1 resistance gene abundances associated with seasonal human pilgrimages to the Upper Ganges River. Environ. Sci. Technol. 2014, 48, 3014−3020. (4) Kennedy, K.; Collignon, P. Colonisation with Escherichia coli resistant to “critically important” antibiotics: A high risk for international travellers. Eur. J. Clin. Microbiol. Infect. Dis. 2010, 29, 1501−1506. (5) Science and Technology Committee (UK). Ensuring access to working antimicrobials. http://www.publications.parliament.uk/pa/ cm201415/cmselect/cmsctech/509/50902.htm (accessed July 18, 2014).
waste treatment from the exposure matrix (see figure), polluted water becomes a major AR exposure pathway, both via consumed water and exposed food. Therefore, although antibiotic use fuels the “AR pump”, inadequate waste treatment and clean water amplifies the impact of inappropriate use, dramatically increasing AR transmission. This is most apparent in recent data from the emerging world,3 especially the potential for multi-AR pathogens being transmitted through contaminated water. Bacteria, such as Vibrio cholera, Salmonella, and E. coli, are all transmitted via water or water-exposed food; strains with particularly increasing rates of occurrence of AR.2 One might cynically argue these are local issues in emerging countries; however, international travel and increased human mobility has changed the epidemiology of disease.4 Individuals can now obtain the genetic potential for multi AR in their guts in one part of the world and then carry latent AR potential anywhere through travel. Further, global travel is growing as local wealth increases, often to and from countries with poor water quality. Therefore, once a novel resistant determinant emerges, travel habits allow it to spread widely, only becoming evident again when the next antibiotic treatment fails; maybe in a hospital very disconnected from the original cause. As such, the impact of poor water quality is often vailed, but may be as important as how antibiotics are used in many parts of the world. We contend improving how we use antibiotics is only one part of the solution; promoting cleaner water is also essential. While altruistic reasons exist for improving water quality on large scales, addressing this issue also is in everyone’s selfinterest. Unfortunately, urgency for improving global water quality problem does not seem to prevail among many decision-makers, especially in the developed world. Recent public hearings in the United Kingdom aimed at developing strategies for reducing antimicrobial resistance did not include oral witnesses specializing in wastewater treatment. Therefore, it is not surprising that waste management and water quality are only incidentally mentioned in the final report.5 Further, although clean water is included in the recent WHO statement aimed at reducing AR, it only was provided as a secondary topic, implying it is still not perceived to be central to globally increasing AR. The economic drive for new antibiotic development has almost gone and, unless perceptions change quickly among 11747
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