The human factor


sewage pipes water

There is growing concern over the level of antibiotics and other pharmaceuticals in the environment. Sheshtyn Paola investigates how this can lead to the spread of antimicrobial resistance

In the Piedmont region of Virginia, on the southeast coast of the United States, researchers take samples
of water from 59 headwater-stream sites in the local area. Analysing the samples in a lab, the scientists
find significant concentrations of pharmaceutical medicines.

Metformin is “pervasive”—being present in 89% of the samples and at 97% of sites—while nicotine, acetaminophen, carbamazepine, fexofenadine, lidocaine, pseudoephedrine, sulfamethoxazole and tramadol are also present in significant amounts.1

At least one pharmaceutical was detected at every site, with one site having concentrations of 45 different
drugs present.

Within contaminated waterways across North America, diltiazem concentrations have been found in
the local fish and osprey.2 Researchers found concentrations of diltiazem in fish plasma 21.6 times greater than those in water, and osprey plasma concentrations 4.71 times higher than those of fish.

They have also discovered populations of male fish that have been feminised after being exposed to
effluent containing synthetic oestrogen.

Antidepressants and other psychoactive drugs have made their way into aquatic ecosystems around
the world. For example, elevated concentrations of sertraline and carbamazepine were “ubiquitous”in sewage-contaminated ecosystems in central Texas, US.3

Across the ocean to the Indian subcontinent, nearly an entire population of vultures died of kidney
failure after consuming livestock carcasses medicated with diclofenac.2

Not even Antarctica has escaped contamination from pharmaceuticals substances. A water sample study in the area found concentrations of 16 pharmaceuticals and recreational drugs. The highest concentrations were found for the analgesics acetaminophen, diclofenac and ibuprofen.4

Looking at the research, it seems unlikely that there are places across the world that have been left untouched by our pharmaceutical drug use.

With a burgeoning rise in the use of medication across all populations, humans have certainly left their mark on the planet.

Pharmaceuticals enter the environment through a variety of pathways, but mainly through patient
excretion or the inappropriate disposal of unwanted pharmaceuticals.5

In fact, many medications are excreted from the body virtually unchanged or are only partially metabolised, and are often poorly removed by conventional wastewater treatment technologies.6

For example, the antidepressant fluoxetine is only partially metabolised, incompletely removed by current
wastewater treatment plant processes, and exhibits minimal degradation in sewage or soil over many months.2

“Conventional waste technologies treat pharmaceuticals only incidentally, resulting in ubiquitous release of pharmaceutical contaminants in effluent,” say researchers from the US Geological Survey.1

Antibiotics in the environment

As awareness of antibiotic resistance due to overprescribing and overuse spreads across the world, one has to wonder: how much does the presence of antibiotics in the environment impact on helping to spread resistance?

Are traces of antibiotics in the environment as ubiquitous as other medications?

The answer is a resounding yes.

As with some other medications, many antibiotics are not metabolised, excreted unchanged and are
environmentally persistent.6

While some antibiotics such as penicillins are easily degraded, others are more persistent, including
fluoroquinolones and tetracyclines.7

This allows such antibiotics to “prevail for longer times in the environment, to spread further, and to
accumulate to higher concentrations,” explains Professor Joakim Larsson from the University of Gothenburg in Sweden.

Since industrialisation, millions of tonnes of antibiotics have been released into the environment via wastewater effluents, the use of animal waste on land, treatment of crop diseases, aquaculture and animal production.

Antibiotic use across livestock and aquaculture is also widespread—for example, fish infections are treated through administration of antibiotics directly into the water.

In a 2015 research article, environmental scientists Céline Roose-Amsaleg and Anniet Laverman
said that improved analytical capabilities have led to the detection of antibiotic residues in virtually all
natural habitats.8

Manure excreted by animals treated with antibiotics (for veterinary purposes or as growth promoters) is
used as an agricultural fertiliser, with antibiotics seeping through the soil and entering ground water.

In some areas, wastewater containing resistant bacteria and antibiotics is used for irrigation, and sewage sludge is used as fertiliser, allowing resistant bacteria to enter the food chain directly.9

Large numbers of resistant bacteria that have multiplied in the gastrointestinal tracts of people and
animals treated with antibiotics are also released into the environment, as are active residues of antibiotics.

Antibiotic residues in the environment have been found ranging in concentrations from nanograms per
litre up to low micrograms per litre.

“Although these are well below minimum inhibitory concentrations, even low concentrations provide
selective advantages for certain resistant strains,” says Rita Finley and colleagues from the Public Health
Agency of Canada, Ontario.

Within aquatic systems, antibiotics have been found to be persistent.

For example, quinolones absorb into sewage sludge, soils and sediments and are not biodegraded in tests with sediments.

Discarding unused or unwanted antibiotics unsafely—for example, through the household garbage or down the toilet—is another way they find their way into the environment (see RUM Project breakout).

Resistance on the rise

Scientists say that resistance predates current antibiotic use in medicine and agriculture, with resistance genes existing since ancient times.

However they add that current levels of antibiotic exposure in the environment may be helping to accelerate the evolution of resistance, increasing the abundance and distribution of resistance genes, and increasing the exchange of antibiotic resistance genes between bacteria.6

“The selection and development of antibiotic-resistant bacteria is one of the greatest concerns with regard to the
use of antimicrobials,” says Professor Klaus Kümmerer, from the Institute of Environmental Medicine and Hospital Epidemiology at the Freiburg University Hospital in Germany.9

“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.

“The external environment provides a reservoir or source for resistance genes not yet encountered in pathogens,” Professor Larsson explains.

“Concentrations as low as 100ng/L of ciprofloxacin have been shown to provide a small but measurable selective advantage to the resistant bacterium.

“This corresponds to antibiotic levels found within sewage treatment plants, and thus calls for concern,” he says.

“In principle, the transfer of a novel resistance gene or resistance vector to a pathogen colonising a human being only needs to happen once in one place on our planet, as our heavy use of
antibiotics, lack of sufficient hygiene, and extensive travel habits often take care of the dissemination thereafter.”

Researchers from the University of Gothenburg and the Umea University in Sweden collected river sediment samples collected upstream and downstream from an Indian wastewater treatment plant processing effluent from nearly 100 drug manufacturers.10

They found high levels of several broad spectrum antibiotics, with “extraordinary levels” of
fluoroquinolones and an abundance of ciprofloxacin.

The researchers concluded that their data showed exposure to effluent contaminated with antibiotics promote resistance genes in environmental bacterial communities.

“Our results show that multiple classes of resistance genes are promoted in a highly antibiotic contaminated environment,” they say.

“These results stress the role of the environmental microbial communities, in combination with
unintentional antibiotic release, as potential recruitment pools for human pathogens.

“Further efforts to protect environmental bacteria against antibiotic pollution are therefore
motivated.”

What can pharmacists do to help?

Antibacterial therapy has prevented millions of premature deaths due to bacterial infection, but resistance
threatens to take us back to a time when acquiring a bacterial infection was often fatal.

Australian pharmacy researchers Judith Singleton, Lisa Nissen, Nick Barter and Malcolm McIntosh say pharmacists have a significant role to play in the sustainable use of pharmaceuticals, and environmentally responsible disposal of pharmaceutical waste.

“The role of pharmacists through the quality use of medicines … aims to reduce the amount of unwanted pharmaceuticals in the community,” says Dr Singleton and colleagues.5

This includes being aware of factors that can contribute to accumulation and poor use of these medicines,
including non-adherence to therapy, non-completion of course, and overprescribing.

Pharmacists can also play a very important role in encouraging the environmentally responsible handling of pharmaceutical waste.

“At a national level, the implementation and active promotion of community pharmacy initiatives such as Australia’s RUM Project, which encourages the public to return unwanted medicines to pharmacies for correct disposal, will minimise the negative impact of pharmaceuticals on the environment.

“Also, healthcare organisations need to show leadership by encouraging pharmacists and other medical staff both in the hospital and community pharmacy settings to separate out non-contaminated packaging waste from contaminated waste.”

Pharmacists are the last line of defence in educating patients who may be planning to use antibiotics in an unhelpful way, says Associate Professor Therese Kairuz from the School of Biomedical Sciences and Pharmacy at the University of Newcastle.

A/Prof Kairuz co-authored a study that found nearly one in ten (9%) antibiotics were dispensed from
prescriptions were more than one month old, and more than one in five (22%) were dispensed from a repeat prescription.11

“An important take-home message is that pharmacists should exercise their responsibility as custodians of medicines, as part of the medication counselling service,” she told the AJP.

Luc Besançon, pharmacist and former CEO of the International Pharmaceutical Federation (FIP) agrees that pharmacists worldwide will play a key part in turning the tide against antimicrobial resistance.12

They have a variety of roles to play—from increasing awareness and education in their communities, to
providing vaccination services that reduce the number of infections and, therefore, antibiotic use.

Besançon points out that consumption of antibiotics in Australia is one of the highest among developed
countries and 65% of Australians still believe that antibiotics will help them recover from a cold or  influenza more quickly.

“The link between antibiotic use and resistance has been shown at the individual hospital level. Despite
valuable efforts by a single institution, or even an entire nation, they will not solve this problem,” he says.

“The main role that pharmacists can play is in ensuring the right dose, at the right time, in the right patient. In other words, ensuring the responsible use of medicines. Involving pharmacists in preventing antimicrobial resistance makes the implementation of successful policies more likely.”

His additional advice for healthcare workers is to stay strong and committed in the face of resistance.

“A substantial decline in antimicrobial resistance can take a number of years of sustained change
in prescribing practices. Perseverance is needed to see the results of antimicrobial stewardship.

“We must be careful not to lose momentum.”

REFERENCES

1. Bradley PM, Journey CA, Button DT, Carlisle DM, Clark JM, Mahler BJ, et al. Metformin and other pharmaceuticals widespread in wadeable streams of the Southeastern United States. Environ Sci Technol Lett. 2016;3(6):243-9.

2. Arnold KE, Brown AR, Ankley GT, Sumpter JP. Medicating the environment: assessing risks of pharmaceuticals to wildlife and ecosystems. Philos Trans R Soc Lond B Biol Sci. 2014 Nov
19;369:(1656).

3. Du B, Haddad SP, Luek A, Scott WC, Saari GN, Kristofco LA, et al. Bioaccumulation and trophic dilution of human pharmaceuticals across trophic positions of an effluent-dependent wadeable stream. Philos Trans R Soc Lond B Biol Sci. 2014 Nov 19;369(1656).

4. González-Alonso S, Merino LM, Esteban S, López de Alda M, Barceló D, Durán JJ et al. Occurrence of pharmaceutical, recreational and psychotropic drug residues in surface water on the northern Antarctic Peninsula region. Environ Pollut. 2017 Oct;229:241-254.

5. Singleton JA, Nissen LM, Barter N, McIntosh M. The global public health issue of pharmaceutical waste: what role for pharmacists? J Glob Resp. 2014;5(1):126-37.

6. Finley RL, Collignon P, Larsson DG, McEwen SA, Li XZ, Gaze WH, et al. The scourge of antibiotic resistance: the important role of the environment. Clin Infect Dis. 2013 Sep;57(5):704-10.

7. Larsson DGJ. Antibiotics in the environment. Ups J Med Sci. 2014;119(2):108-12.

8. Roose-Amsaleg C, Laverman AM. Do antibiotics have environmental side-effects? Impact of synthetic antibiotics on biogeochemical processes. Environ Sci Pollut Res Int. 2016 Mar; 23(5):4000–12.

9. Kummerer K. Significance of antibiotics in the environment. J Antimicrob Chemother. 2003 Jul 1;52:5–7.

10. Kristiansson E, Fick J, Janzon A, Grabic R, Rutgersson C, et al. Pyrosequencing of antibiotic-contaminated river sediments reveals high levels of resistance and gene transfer elements. PLoS ONE 2011;6(2): e17038.

11. Fredericks I, Hollingworth S, Pudmenzky A, Rossato L, Kairuz T. ‘Repeat’ prescriptions and antibiotic resistance: findings from Australian community pharmacy. Int J Pharm Pract. 2017 Feb;25(1):50-8.

12. Besançon L. Antimicrobial resistance. What will it take to turn the tide? Pharmacists! J Pharm Pract Res, 2016;46(1): 4-5.

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