Global Importance of Antibiotics and Consequences of Antibiotic Overuse – the Role
of the Environment
The introduction of antibiotics to treat bacterial infections is one of the single most
important advancements in human medicine. From the treatment of pneumonia and blood
infections to prevention and treatment of infections related to major invasive surgery,
antibiotics have become indispensable. Unfortunately, the growing phenomenon of
bacterial antibiotic resistance (ABR), the ability of bacteria to survive the harmful action of
an antibiotic, is now threatening to leave us without effective treatment of bacterial
infections.
Resistance has already reached crisis point for some major infections and the
consequences can be seen worldwide. ABR is especially having a devastating impact on the
poor living in low and medium income countries, where for example treatment failure in
pneumonia or sepsis among children results in large number of deaths. Data on the actual
health and economic burden of ABR is severely lacking. Some of the more reliable data
available is discouraging and importantly, only include select ABR bacteria:
 Thailand: >38,000 deaths; Societal costs US$ ~140 million direct, >1.3 billion indirect1
 USA: 23,000 deaths; Societal costs US$ ~20 billion direct, >1.3 billion indirect2
 EU: 25,000 deaths; Societal costs US$ ~1.5 billion3
Bacteria are found in practically all environments. Most are harmless or beneficial to us,
while a few can cause disease. Importantly, bacteria in any environment can become
resistant; either by chance changes in specific genes or by picking up existing ABRmechanisms from bacteria nearby. In the presence of an antibiotic, resistant bacteria are
better off than non-resistant ones and can increase in prevalence. Today, resistance to
different antibiotics as well as heavy metals like copper and silver are commonly found
together on genetic elements that can easily spread between bacteria. This means that
bacteria can become resistant to multiple antibiotics at once. One of these antibiotics (or
metals) is then enough to select for and thus maintain all the other ABR mechanisms.
Long before the introduction of antibiotics as medicines, ABR-mechanisms could be found
in environmental bacteria and as protective measures in antibiotic producing microbes,
but were not common in pathogenic bacteria. During the seventy or so years that humans
have used antibiotics, ABR has become prevalent in pathogenic and environmental
bacteria alike. All resistance genes in the environment can be regarded as a big “pool” of
resistance genes (a “resistome”) that can potentially transfer to pathogenic bacteria.
There are two potential distinct threats where the environmental contamination with
antibiotics and resistance elements becomes a real problem in human health: Spread of
resistant bacteria and emergence of new MDR bacteria.
As just one example of spread, there were recently several reports from Denmark of
“swine-MRSA” infecting swine-farmers and their families. A study of the origin of the
specific bacterial strain indicate that it originally spread from humans to pigs, then
acquired resistance in the antibiotic-rich swine-farming environment and now this
resistant (but less virulent) MRSA is infecting humans.4
So then, from where do these resistant and multidrug-resistant (MDR) bacteria emerge?
More and more scientific evidence suggests that antibiotics in the environment play a
crucial role both in emergence and spread. Waste from large-scale animal farms, use in
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aquaculture and wastewater from antibiotic manufacturing, hospitals and municipalities
are major sources of ABR genes and antibiotic pollution in the environment. Below, a small
selection of studies confirming that antibiotics are accumulating in the environment and
that resistant bacteria are thriving under those conditions are highlighted.
A study of ABR-genes at three high-production swine farms in China found increased
concentrations of antibiotics in both manure and soil, and three times as many unique
ABR-genes as compared to in control manure/soil.5 63 ABR-genes were enriched, some as
much as 28000-fold, as well as genes needed for mobilization of ABR-genes. The authors
estimated that the most abundant resistance gene on average would be found in nearly
every second bacteria in that setting.
Concentrations of antibiotics in effluents from antibiotic-manufacturing sites can reach
extremely high levels. At one wastewater plant in India receiving waste from ~90 drug
manufacturers, 45 kg (99 lbs.) of ciprofloxacin were released into the nearby river each
day.6 Resistance genes were enriched in river sediments and MDR bacteria were prevalent
in the treatment plant.7,8
As antibiotics are transported with water and through the sediments and soil, gradients of
different antibiotic concentrations will form. Even very low antibiotic concentrations may
be enough to select for highly resistant bacteria.9 The probability that resistance
mechanisms in environmental bacteria are transferred to and maintained by pathogenic
bacteria may be rare. However, as the types and abundance of ABR-genes in the
environment increases, so does the risk that it will happen. Wastewater treatment plants
may contribute in this process as high numbers of bacteria from the environment meet
human pathogenic and commensal bacteria here.
Bacteria know no boundaries, and activities such as travel and trade allow them to easily
spread around the world, making this a global problem. International travellers are for
example often colonized with resistant bacteria upon their return home.10 NDM-1
producing Klebsiella, that originated in India but is now a major problem in all corners of
the world, is a striking example.11
So, in summary, antibiotics in the environment have severe consequences. Humans may
become directly sick or colonized by ABR bacteria when consuming contaminated food or
water or through direct contact with animals. In addition, antibiotics also provide a
selection pressure for environmental bacteria to maintain ABR mechanisms and may also
increase the risk that novel resistant bacteria arise and spread.
It is crucial to understand that it is all use of antibiotics, whether appropriate or not, that is
the cause of increased prevalence and rapid spread of ABR as well as the emergence of
new, MDR pathogens that are threatening our entire health systems.
References:
Phumart P, Phodha T, Thamlikitkul V, et al. Health and Economic Impacts of Antimicrobial Resistant
Infections in Thailand: A Preliminary Study. J. of Health Systems Research. 2012; 6(3).
1
US Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013.
(2013). http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf
2
ECDC/EMEA. Technical Report. The bacterial challenge: time to react. (Sept 2009).
http://www.ecdc.europa.eu/en/publications/Publications/0909_TER_The_Bacterial_Challenge_Time_to_Rea
ct.pdf
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2
Price LB, Stegger M, Hasma H et al. Staphylococcus aureus CC398: Host adaptation and emergence of
methicillin resistance in livestock. MBio. (2012); 3(1).
4
Zhu YG, Johnson TA, Su JQ et al. Diverse and abundant antibiotic resistance genes in Chinese swine farms.
Proc Natl Acad Sci U S A. (2013); 110(9).
5
Larsson DG, de Pedro C, Paxeus N. Effluent from drug manufactures contains extremely high levels of
pharmaceuticals. J Hazard Mater. (2007); 148(3).
6
Kristiansson E, Fick J, Janzon A. Pyrosequencing of antibiotic-contaminated river sediments reveals high
levels of resistance and gene transfer elements. PLoS One. (2011); 6(2).
7
Marathe NP, Regina VR, Walujkar SA et al. A treatment plant receiving waste water from multiple bulk drug
manufacturers is a reservoir for highly multi-drug resistant integron-bearing bacteria. PLoS One. (2013);
8(10).
8
Gullberg E, Cao S, Berg OG et al. Selection of resistant bacteria at very low antibiotic concentrations. PLoS
Pathog. (2011); 7(7).
9
von Wintersdorff CJ, Penders J, Stobberingh EE et al. High rates of antimicrobial drug resistance gene
acquisition after international travel, The Netherlands. Emerg Infect Dis. (2014); 20(4).
10
Walsh TR. Emerging carbapenemases: a global perspective. Int J Antimicrob Agents. (2010); 36 Suppl 3:S814.
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