November 18, 2016 by Becky Brown


Global concerns regarding antimicrobial resistance (AMR) and the growing risk that antibiotics will no longer be able to treat infectious diseases is high on the political agenda. At a major United Nations (UN) meeting in September all 193 member states signed a declaration which insisted upon tackling the spread of AMR1. The pharmaceutical industry has a major role to play in limiting the impacts of AMR, both in managing the use of existing antibiotics and in developing a new generation of drugs. There has also been criticism of the pharmaceutical industry and the discharge of antibiotics into the environment via manufacturing discharges from production plants in developing countries such as China and India 2 3. Ahead of the UN meeting on AMR the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) published an industry roadmap pledging its efforts for combating AMR4. The United Nations General Assembly (UNGA) agreement was signed by 13 major pharmaceutical companies and agrees to:

1.Reduce the environmental impact from the production of antibiotics,

2.Help ensure antibiotics are used only by patients who need them,

3.Improve access to current and future antibiotics, vaccines, and diagnostics,

4.Explore new opportunities for open collaborations between industry and the public sector to address challenges in the research and development of new antibiotics.

In order to limit the environmental impacts of antibiotics, there needs to be refined environmental risk assessments (ERA) for these substances which take into consideration the risks to microbial communities and for promoting AMR. The current European Medicines Agency (EMA) risk assessment for antibiotics is based on effects to single species, which includes a cyanobacteria, Daphnia and fish5. There is also an evaluation for microbial communities which is based on effects on respiration or enzymatic activity in activated sludge (OECD 209)6 or soil (OECD 216)7, respectively. Following a review of the scientific literature, Brandt et al. (2015)8 made recommendations for improving the ERA of antibiotics, which includes the development of new tests that improve the understanding of the effects of antibiotics on microbial diversity (“species” richness) and also to develop tests based on more sensitive endpoints than respiration, such as growth. In the short term risk assessments should make better use of currently available standard test methods by testing a larger number of microbial endpoints (to account for differences in species and community sensitivities) and by taking into account the mode of action of the antibiotic.

Bengtsson-Palme and Larsson (2016)9 have also proposed an approach to take into consideration the effects of antibiotics on AMR (i.e. to derive a Predicted No Effect Concentration (PNEC) for resistance). Ideally a PNECresistance would be based on the concentrations of an antibiotic, which are known to “select” for AMR or the minimum selective concentration (MSC); however, this information is not available for many antibiotics. Bengtsson-Palme and Larsson (2016) instead used readily available minimum inhibitory concentrations (MICs) data for effects of antibiotics to clinically relevant bacteria (CRB). An assessment factor of 10 was then applied to account for the difference in the MSC compared with the MIC. The authors found that the PNECresistance was more sensitive than a PNEC derived based on ecotoxicological effects.

In summary, manufacturers of antibiotics have pledged to reduce the environmental impacts of their drugs. To do this risk assessment for antibiotics must take into account recent developments in scientific understanding of the effects of antibiotics on microbial communities and on the selection for AMR, to ensure discharge levels for antibiotics are protective of the environment.

References

1 General Assembly of the United Nations. 2016. At UN, global leaders commit to act on antimicrobial resistance: Collective effort to address a challenge to health, food security, and development. Press Release High-Level Meeting on Antimicrobial Resistance 21st September 2016.

2 Changing Markets. 2016. Superbugs in the Supply Chain: How pollution from antibiotics factories in India and China is fuelling the global rise of drug-resistant infections.

3 InPharma Technologist. 2016. Pharma pollution an 'ignored' cause of antibiotic resistance. Article by Taylor P, 24th Aug 2016

4 The International Federation of Pharmaceutical Manufacturers & Associations (IFPMA). 2016. Leading Pharmaceutical Companies Present Industry Roadmap to Combat Antimicrobial Resistance. Press release 20th September 2016.

5 EMA. 2006.Guideline on the environmental risk assessment of medicinal products for human use. Committee for Medicinal Products for Human Use (CHMP), European Medicines Agency (EMEA), London, UK. EMEA/CHMP/SWP/4447/00. 1 June 2006.

6 OECD 209. 2010. Activated sludge, respiration inhibition test. Guidelines for the Testing of Chemicals. Effects on biotic systems.

7 OECD 216. 2000. Soil microorganisms: nitrogen transformation test. Guidelines for the Testing of Chemicals. Effects on biotic systems.

8 Brandt KK, Amézquita A, Backhaus T, Boxall A, Coors A, Heberer T, John R. Lawrence JR, Lazorchak J, Schönfeld J, Snape JR, Zhu YG, Topp E. 2015. Ecotoxicological assessment of antibiotics: A call for improved consideration of microorganisms. Environment International 85:189-205.

9 Bengtsson-Palme J, Larsson JDG. 2016. Concentrations of antibiotics predicted to select for resistant bacteria: Proposed limits for environmental regulation. Environment International 86:140-149.