Public health disaster on the cards if pharmaceutical pollution is left unchecked

Dear
Mr Timmermans,

We write in relation to the risks to human health and the environment posed by releases of pharmaceuticals into the environment. In particular, we are very concerned about how these releases affect ecosystems and are contributing to the development of antimicrobial resistance (AMR), one of the major threats to human health today. We would like to discuss with you the opportunities that the Commission has in the coming months to spearhead action against the global rise of drug resistance, including within the framework of its Proposal for a Regulation on veterinary medicinal products and its upcoming Strategic Approach to Pharmaceuticals in the Environment.

In its report on Frontiers 2017: Emerging Issues of Environmental Concern, UN Environment identifies growing AMR linked to the discharge of drugs and particular chemicals into the environment as one of the most worrying health threats today. Indeed, experts view the promotion of antibiotic resistant bacteria as “by far the greatest human health risk” posed by the presence of pharmaceutical residues in the environment and note that, in addition to fostering the spread of resistant pathogens, antibiotic residues can also turn harmless environmental bacteria into carriers of resistance.

Europe’s AMR burden in terms of lives lost, morbidity, healthcare costs and productivity losses is much greater than currently available statistics suggest. Recent projections estimate a 15-fold increase in morbidity in Europe due to AMR by 2050, with 390,000 deaths every year as a result of drug-resistant infections. The use of antibiotics in intensive livestock farming promotes the development of resistant bacterial strains and the environment plays not only an important role in the spread of those, but also wildlife organisms and ecosystem services are at risk.

We are concerned that the pharmaceutical industry is currently excluded from any kind of environmental legislation, which is untenable in the light of the risk that pharmaceutical pollution poses to the environment and to human health. We expect legislative action from the Commission to tackle this issue, similar to the regulation of the chemical industry through REACH.

Since AMR is a quintessential cross-border issue, it is important that the EU-One Health Action Plan against AMR is supported by policy measures and legislation in other areas, along the lines with those proposed in our recent briefing on policy options to be considered in the context of the Strategic Approach to Pharmaceuticals in the Environment and the proposal for a Regulation on veterinary medicinal products to ensure that we tackle the problem in a comprehensive way.

We would therefore like to request a meeting with you to discuss the main policy measures available to successfully tackle this problem.

References

• European Environmental Bureau, joint letter, 10 April 2018.
  Public health disaster on the cards if pharmaceutical pollution left unchecked say campaigners, metamag, 12 Apr 2018.
• Policy options for regulating pharmaceuticals in the environment, eeb, Feb 2018.
• Prevention is better than cure: Europe’s chance to act on AMR is now, epha, May 8, 2017.
• Ecological Impacts of Veterinary Pharmaceuticals: More Transparency-Better Protection of the Environment, pan-germany.
• Antibiotics in Livestock Farming. What can be done to reduce environmental threats and avoid the development of antibiotic
  resistance? pan-germany.
• Antimicrobial resistance from environmental pollution among biggest emerging health threats, says UN Environment, unenvironment, dec 2017.
  Improving environmental risk assessment of human pharmaceutical, American Chemical Society, 2015.
• Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations, amr-review, 2014.
• Image credit oceancrusaders.

Antibiotic resistance genes traced from manure to soil and water on Finnish farms

A recent study has investigated the movement of antibiotic resistance genes between farm animals, soil and water in Finland. The results show that many of these genes are spread from animals to the soil through manure application; however, these genes do not appear to persist in soil. The study suggests that practices that minimise the use of antibiotics, as used in Finland, may lead to lower levels of clinically relevant resistance genes in agricultural soils.

2017 Study Abstract

The co-occurrence of antibiotic-resistance genes (ARGs) and mobile genetic elements (MGEs) in farm environments can potentially foster the development of antibiotic-resistant pathogens. We studied the resistome of Finnish dairy and swine farms where use of antibiotics is limited to treating bacterial infections and manure is only applied from April to September. The resistome of manure, soil, and tile drainage water from the ditch was investigated from the beginning of the growing season until forage harvest. The relative ARG and MGE abundance was measured using a qPCR array with 363 primer pairs. Manure samples had the highest abundance of ARGs and MGEs, which increased during storage. Immediately following land application, the ARGs abundant in manure were detected in soil, but their abundance decreased over time with many becoming undetectable. This suggests that increases in ARG abundances after fertilizing are temporary and occur annually under agricultural practices that restrict antibiotic use. A few of the ARGs were detected in the ditch water, but most of them were undetected in the manure. Our results document the dissipation and dissemination off farm of ARGs under Finnish limited antibiotic use and suggest that such practices could help reduce the load of antibiotic-resistance genes in the environment.

Sources

• Antibiotic resistance genes traced from manure to soil and water on Finnish farms, ec.europa.eu, 08 February 2018.
• Influence of Manure Application on the Environmental Resistome under Finnish Agricultural Practice with Restricted Antibiotic Use, Environmental Science & Technology, April 28, 2017.

The world is running out of antibiotics, WHO report confirms

A new report, Antibacterial agents in clinical development – an analysis of the antibacterial clinical development pipeline, including tuberculosis, launched this week by WHO shows a serious lack of new antibiotics under development to combat the growing threat of antimicrobial resistance.

Most of the drugs currently in the clinical pipeline are modifications of existing classes of antibiotics and are only short-term solutions. The report found very few potential treatment options for those antibiotic-resistant infections identified by WHO as posing the greatest threat to health, including drug-resistant tuberculosis which kills around 250 000 people each year.

“Antimicrobial resistance is a global health emergency that will seriously jeopardize progress in modern medicine,”
“There is an urgent need for more investment in research and development for antibiotic-resistant infections including TB, otherwise we will be forced back to a time when people feared common infections and risked their lives from minor surgery.”

says Dr Tedros Adhanom Ghebreyesus, Director-General of WHO.

In addition to multidrug-resistant tuberculosis, WHO has identified 12 classes of priority pathogens – some of them causing common infections such as pneumonia or urinary tract infections – that are increasingly resistant to existing antibiotics and urgently in need of new treatments.

The report identifies 51 new antibiotics and biologicals in clinical development to treat priority antibiotic-resistant pathogens, as well as tuberculosis and the sometimes deadly diarrhoeal infection Clostridium difficile.

Among all these candidate medicines, however, only 8 are classed by WHO as innovative treatments that will add value to the current antibiotic treatment arsenal.

There is a serious lack of treatment options for multidrug- and extensively drug-resistant M. tuberculosis and gram-negative pathogens, including Acinetobacter and Enterobacteriaceae (such as Klebsiella and E.coli) which can cause severe and often deadly infections that pose a particular threat in hospitals and nursing homes.

There are also very few oral antibiotics in the pipeline, yet these are essential formulations for treating infections outside hospitals or in resource-limited settings.

“Pharmaceutical companies and researchers must urgently focus on new antibiotics against certain types of extremely serious infections that can kill patients in a matter of days because we have no line of defence,”

says Dr Suzanne Hill, Director of the Department of Essential Medicines at WHO.

To counter this threat, WHO and the Drugs for Neglected Diseases Initiative (DNDi) set up the Global Antibiotic Research and Development Partnership (known as GARDP). On 4 September 2017, Germany, Luxembourg, the Netherlands, South Africa, Switzerland and the United Kingdom of Great Britain and Northern Ireland and the Wellcome Trust pledged more than €56 million for this work.

“Research for tuberculosis is seriously underfunded, with only two new antibiotics for treatment of drug-resistant tuberculosis having reached the market in over 70 years,”
“If we are to end tuberculosis, more than US$ 800 million per year is urgently needed to fund research for new antituberculosis medicines”.

says Dr Mario Raviglione, Director of the WHO Global Tuberculosis Programme.

New treatments alone, however, will not be sufficient to combat the threat of antimicrobial resistance. WHO works with countries and partners to improve infection prevention and control and to foster appropriate use of existing and future antibiotics. WHO is also developing guidance for the responsible use of antibiotics in the human, animal and agricultural sectors.

Why Our Misuse of Antibiotics Could Mean the End of Modern Medicine

Adam Conover starts explaining that the reckless prescription of antibiotics is making them worthless – abstract from Adam Ruins The Hospital.

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Drivers, dynamics and epidemiology of antimicrobial resistance in animal production

The widespread use of antibiotics through food chains is thus becoming catastrophic. A review by the Food & Agriculture Organization of the United Nations explains how antibiotic-resistant bacteria in animals are infecting humans, through direct contact with animals or indirect transmission through the food we eat.

Executive Summary

It is now accepted that increased antimicrobial resistance (AMR) in bacteria affecting humans and animals in recent decades is primarily influenced by an increase in usage of antimicrobials for a variety of purposes, including therapeutic and non-therapeutic uses in animal production. Antimicrobial resistance is an ancient and naturally occurring phenomenon in bacteria. But the use of antimicrobial drugs – in health care, agriculture or industrial settings – exerts a selection pressure which can favour the survival of resistant strains (or genes) over susceptible ones, leading to a relative increase in resistant bacteria within microbial communities. It has been observed that, in countries where use of particular substances (e.g. fluoroquinolones) is banned in animal production, there are low levels of resistance to these antimicrobials in livestock populations. The rate of AMR emergence in ecosystems such as the human or animal gut is likely to be highly dependent on the quantity of antimicrobials used, along with the duration and frequency of exposure. In animal production, the prolonged use of antimicrobial growth promoters (AGPs) at subtherapeutic levels in large groups of livestock is known to encourage resistance emergence, and is still common practice in many countries today. Due to the interdependence and interconnectedness of epidemiological pathways between humans, animals and the environment, determining the relative importance of factors influencing AMR emergence and spread in animal production is a significant challenge, and is likely to remain one for some time.

In intensive livestock production systems, resistant bacteria can spread easily between animals and this can be exacerbated if biosecurity is inadequate. While some studies have shown reduced levels of AMR on organic farms, a high prevalence of multidrug-resistant (MDR) Campylobacter strains has been detected in organic pig farms in the United States even in the absence of antimicrobial usage (AMU).

In aquaculture, AMR can develop in aquatic and fish gut bacteria as a result of antimicrobial therapy or contamination of the aquatic environment with human or animal waste. The extent and persistence of antimicrobial residues in aquatic systems is unknown and current evidence is conflicting. Furthermore, no international guidelines currently exist for maximum antimicrobial residue limits in water. Water is an important vehicle for the spread of both antimicrobial residues and resistance determinants, since contaminated water can be consumed directly by humans and livestock and used to irrigate crops.

Food is likely to be quantitatively the most important potential transmission pathway from livestock to humans, although direct evidence linking AMR emergence in humans to food consumption is lacking. There is a theoretical risk of widespread dissemination of AMR due to the increasingly global nature of food trade and human travel. This would mean that strains of resistant bacteria could now very quickly reach parts of the world where they had previously not been present. Agricultural systems in emerging economies such as China and India have changed radically in recent years, becoming increasingly intensive in order to meet growing domestic and global demands for animal protein. This is likely to heighten the occurrence and spread of infectious diseases in these systems, thereby leading to increased AMU and therefore resistance.

If the selection pressure resulting from AMU in animals and humans were to be removed, this would still not completely halt the emergence and global spread of AMR due to the ability of AMR genes to move between bacteria, hosts and environments, and the occurrence of spontaneous mutations.

However, the release of large quantities of antimicrobials or resistant bacteria into the environment is still thought to be an important point for control, and therefore measures which encourage the prudent use of antimicrobials are likely to be extremely useful in reducing the emergence and spread of AMR. Future development of quickly biodegradable antimicrobials could help to reduce environmental contamination, and pharmacodynamic studies in livestock can be used to inform the optimization of AMU. Improved hygiene and biosecurity should be a major focus for all types of animal production systems so that the risks of introducing pathogens and resistance genes – and the spread of these within animal populations – can be reduced. Detailed, specific recommendations for countries to move towards more prudent AMU in different agricultural settings are, however, beyond the scope of this paper.

An improved understanding of the epidemiology of AMR emergence and spread in animal production will provide an essential foundation for successful mitigation strategies. There are still considerable gaps in our understanding of the complex mechanisms that lead to the emergence of AMR in bacteria, and the interactions that take place within microbial ecosystems enabling the transfer of resistance between bacteria. There are insufficient data at present to determine quantitatively how important the selection pressure of AMU is for the emergence of AMR in bacteria. Evidence regarding AMR transmission pathways between food animals and humans is lacking, especially from low- and middle-income countries (LMICs).

Such pathways are likely to be highly complex and multi-directional, especially in LMICs, but are still largely unknown. There remains little doubt, however, that the most significant factor in AMR emergence in humans is AMU for human treatment and prevention. It is clear that both human and animal AMU can contribute to environmental contamination, although collection of meaningful data is challenging. The relationships between different types of farming systems and both AMU and the emergence and spread of AMR are discussed in this paper, including extensive and organic systems, but there is still a notable lack of knowledge on the role that sustainable agriculture systems can play in combatting AMR. Most importantly, future research needs to involve an interdisciplinary (e.g. One Health) approach, integrating agricultural, medical, environmental and social sciences, and especially recognizing the importance of human behaviour. A set of specific recommendations to fill current knowledge gaps is presented in the final section of this technical paper.

• Drivers, dynamics and epidemiology of antimicrobial resistance in animal production, FAO Newsroom, 2016.
• Excessive Use of Antibiotics Turns Food Into Catastrophic Threat, truth-out, April 12, 2017.

Wastewater treatment plant discharges can promote the development of antibiotic resistance genes in streams

Widespread use of antibiotics has led to pollution of waterways, potentially creating resistance among freshwater bacterial communities. A new study looked for antibiotic resistance genes in a river basin in Spain, revealing that wastewater discharges can promote the spread of antibiotic resistance in streams and small rivers.

Abstract

Occurrence and persistence of antibiotic resistance genes in river biofilms after wastewater inputs in small rivers, ScienceDirect, Environmental Pollution, Volume 210, March 2016, Pages 121–128.

The extensive use of antibiotics in human and veterinary medicine and their subsequent release into the environment may have direct consequences for autochthonous bacterial communities, especially in freshwater ecosystems. In small streams and rivers, local inputs of wastewater treatment plants (WWTPs) may become important sources of organic matter, nutrients and emerging pollutants, such as antibiotic resistance genes (ARGs).

In this study, we evaluated the effect of WWTP effluents as a source of ARGs in river biofilms. The prevalence of genes conferring resistance to main antibiotic families, such as beta-lactams (bla_CTX-M), fluoroquinolones (qnrS), sulfonamides (sul I), and macrolides (ermB), was determined using quantitative PCR (qPCR) in biofilm samples collected upstream and downstream WWTPs discharge points in four low-order streams. Our results showed that the WWTP effluents strongly modified the hydrology, physico-chemistry and biological characteristics of the receiving streams and favoured the persistence and spread of antibiotic resistance in microbial benthic communities. It was also shown that the magnitude of effects depended on the relative contribution of each WWTP to the receiving system. Specifically, low concentrations of ARGs were detected at sites located upstream of the WWTPs, while a significant increase of their concentrations was observed in biofilms collected downstream of the WWTP discharge points (particularly ermB and sul I genes). These findings suggest that WWTP discharges may favour the increase and spread of antibiotic resistance among streambed biofilms. The present study also showed that the presence of ARGs in biofilms was noticeable far downstream of the WWTP discharge (up to 1 km).

It is therefore reasonable to assume that biofilms may represent an ideal setting for the acquisition and spread of antibiotic resistance determinants and thus be considered suitable biological indicators of anthropogenic pollution by active pharmaceutical compounds.

Drug-resistant bacteria found in streams and small rivers near wastewater discharges

Antibiotics are a cornerstone of modern medicine and have saved millions of lives. However, their extensive use has led to the development of widespread resistance, rendering them ineffective against some infections. Microorganisms resistant to commonly prescribed antibiotics are increasingly being found, leading the World Health Organization to declare antibiotic resistance a ‘major threat to public health’. Already, approximately 25 000 European citizens die every year from infections caused by bacteria resistant to antibiotics.

Wastewater treatment plant discharges can promote the development of antibiotic resistance in streams, Science for Environment Policy News Alert, 08 April 2016.

Although some bacteria are intrinsically resistant to antibiotics, and resistant strains evolve naturally, the overuse of antibiotics accelerates this process. Drug-resistant bacteria can pass on resistance to other bacteria, via a process called ‘horizontal gene transfer’, which is thought to be the major cause of the spread of resistance among bacteria.

While the clinical side of this problem has been studied extensively, there is a less-studied environmental aspect. Antibiotics are not fully metabolised by animals (including humans), which means that residues can enter the aquatic environment via wastewater discharges. Recent studies have shown that concentrations of antibiotics found in aquatic environments could aid selection of resistant bacteria. Inputs from urban wastewater treatment plants (WWTPs) can also include antibiotic-resistant bacteria and resistance genes.

Occurrence and persistence of antibiotic resistance genes in river biofilms after wastewater inputs in small rivers, ScienceDirect, Environmental Pollution, Volume 210, March 2016, Pages 121–128.

This study is one of very few to assess antibiotic resistance in river biofilms: the layer of slime composed of microbial organisms that is found on rocks, plants and other surfaces in rivers. Antibiotic-resistant bacteria can integrate into these biofilms, which may provide an optimal environment for the exchange of genetic material, including genes encoding resistance to antibiotics.

The researchers, who were part-funded by the European Regional Development Fund, evaluated the abundance of antibiotic resistance genes in the Tordera River Basin in northern Spain, which receives input from domestic WWTPs. They looked for genes conferring resistance to major families of antibiotics in biofilm samples collected upstream and downstream of WWTP discharge points in four streams.

The monitored genes confer resistance to antibiotics commonly used in hospitals and communities (such as fluoroquinolones, macrolides and sulfonamides). Previous studies have shown a high prevalence of these genes in water samples collected from Mediterranean rivers.

WWTPs are necessary to minimise, inter alia, organic pollution from wastewater generated by human settlements, which would otherwise affect water bodies and the wider environment. Despite the overall positive role of WWTPs, the results of the study showed that WWTP discharges can strongly affect the hydrology and physical, chemical and biological characteristics of receiving streams.

In the study, WWTPs increased stream flow, water conductivity and nitrogen/phosphorus content. They also significantly increased the abundance of antibiotic resistance genes downstream. For example, the ermB gene (which confers resistance to erythromycin, an antibiotic used to treat respiratory infections) occurred four times more frequently in biofilms collected downstream of WWTPs than in those collected upstream. The extent of the changes was influenced by the relative contribution of each WWTP. The authors say their findings suggest WWTP discharges support the spread of antibiotic resistance in streams.

The researchers found antibiotic resistance genes as far as 1 km downstream of the WWTPs, which suggests resistance genes can persist in the environment even in the absence of an additional pollution source, perhaps due to the ‘drift’ of antibiotic-resistant bacteria or resistance genes in the water flow. Alternatively, resistant bacteria or resistance genes could have entered the river from unknown sources located between the WWTP discharge site and the site 1 km downstream.

The authors say further studies are needed to determine the reason for the increase in antibiotic resistance in biofilms downstream of the WWTPs. It could have resulted from the release of resistant bacteria from the WWTPs, or from indigenous bacteria becoming resistant in response to the presence of antibiotic residues discharged into the streams. Overall, the researchers say river biofilms could be useful as indicators of anthropogenic pollution with pharmaceutical residues.

If wastewater discharges negatively affect the quality of a water body, for example by increasing the level of an antibiotic above an established environmental quality standard (EQS), measures must be taken by Member States to improve the water quality. At present, EQS for pollutants are set in relation to their toxic (or similar) effects on organisms. For antibiotics, account may also need to be taken of their role in triggering the development of resistance in bacteria, and of the significance of that resistance.

Unnecessary antibiotics prescriptions reduced in British trial

Writing to GPs about use of antibiotics changes their prescribing patterns. Sheep purple.

Provision of social norm feedback to high prescribers of antibiotics in general practice: a pragmatic national randomised controlled trial, thelancet, doi.org/10.1016/S0140-6736(16)00215-4, 18 February 2016.

A trial involving over 1,500 GP practices found that writing to GPs about their antibiotics prescribing resulted in 73,000 fewer prescriptions (a 3.3% reduction) over 6 months. This equates to direct savings of over £92,000 in prescription costs.

This is part of the government’s plans to slow the growth of antimicrobial resistance. Increasing resistance to antibiotics and a lack of new drugs means there is a greater risk of infections that cannot be treated.

The trial was a collaboration between Chief Medical Officer Dame Sally Davies, Public Health England, and the Behavioural Insights Team.

We know that drug resistant infections are one of the biggest health threats we face. This innovative trial has shown effective and low cost ways to reduce unnecessary prescribing of antibiotics which is essential if we are to preserve these precious medicines and help to save modern medicine as we know it.

Professor Dame Sally Davies said.

There were 2 groups involved in the trial, GPs and patients. GPs were sent a letter saying ‘80% of practices in your local area prescribe fewer antibiotics per head than yours’, and were provided with 3 ways to make sure any antibiotics prescriptions were necessary.

Patients were targeted with leaflets and posters about why reducing the use of antibiotics is important.

GPs who received the letter reduced their rate of antibiotic prescriptions to 127 per 1,000 compared to 131 per 1,000 by GPs who did not receive the letter. There was no significant difference in the rate of antibiotics prescriptions in the patient targeted group.

Global impact of antibiotic resistance

TARGET stands for: Treat Antibiotics Responsibly, Guidance, Education, Tools.

The TARGET Antibiotics Toolkit aims to help influence prescribers’ and patients’ personal attitudes, social norms and perceived barriers to optimal antibiotic prescribing. It includes a range of resources that can each be used to support prescribers’ and patients’ responsible antibiotic use, helping to fulfil CPD and revalidation requirements.

Health posters

• Image sources: Royal College of General Practitioners, December 9, 2015.
• Enjoy our health posters album on Flickr.

Related posts

• Antimicrobial resistance strategy: will the U.K. be ready on time in case of superbug outbreak?.
• Ten reasons you should be worried about the antibiotic resistance increase.
• Our posts tagged antibiotic resistance and our medical research video playlist.

Antibiotic discovery and resistance timeline

TARGET stands for: Treat Antibiotics Responsibly, Guidance, Education, Tools.

The TARGET Antibiotics Toolkit aims to help influence prescribers’ and patients’ personal attitudes, social norms and perceived barriers to optimal antibiotic prescribing. It includes a range of resources that can each be used to support prescribers’ and patients’ responsible antibiotic use, helping to fulfil CPD and revalidation requirements.

Health posters

• Image sources: Royal College of General Practitioners, December 9, 2015.
• Enjoy our health posters album on Flickr.

Related posts

• Antimicrobial resistance strategy: will the U.K. be ready on time in case of superbug outbreak?.
• Ten reasons you should be worried about the antibiotic resistance increase.
• Our posts tagged antibiotic resistance and our medical research video playlist.