antibiotic pollution from manufacturing - europe · antibiotic pollution from manufacturing johan...

ANTIBIOTIC POLLUTION FROM MANUFACTURING

JOHAN BENGTSSON-PALME

JOHAN BENGTSSON-PALME HTTP://MICROBIOLOGY.SE

Patancheru, India


Patancheru*


Larsson DGJ, de Pedro C, Paxeus N. 2007. Effluent from drug manufactures contains extremely high levels of pharmaceuticals. J Haz Mat. 148 (3), 751-755

Active ingredient Type of drug Range (µg/L) Ciprofloxacin antibiotic-fluoroquinolone 28,000-31,000 Losartan angiotensin II receptor antagonist 2,400-2,500 Cetirizine H1-receptor antagonist 1,300-1,400 Metoprolol b1-adrenoreceptor antagonist 800-950 Enrofloxacin antibiotic-fluoroquinolone 780-900 Citalopram serotonin reuptake inhibitor 770-840 Norfloxacin antibiotic-fluoroquinolone 390-420 Lomefloxacin antibiotic-fluoroquinolone 150-300 Enoxacin antibiotic-fluoroquinolone 150-300 Ofloxacin antibiotic-fluoroquinolone 150-160 Ranitidin H2-receptor antagonist 90-160

Based on LC-MS/MS, ESI+, 3-point standard addition, no preconcentration of samples

44 kg ciprofloxacin in one day!

Sweden’s daily consumption = 9kg!

1 g/kg in river sediment!

Larsson DGJ, de Pedro C, Paxeus N. 2007. Effluent from drug manufactures contains extremely high levels of pharmaceuticals. J Haz Mat. 148 (3), 751-755


Surface, ground and drinking water highly contaminated with antibiotics and other drugs


Fick J, Söderström H, Lindberg RH, Chau DNP, Tysklind M, Larsson DGJ. 2009. Contamination of surface, ground, and drinking water from pharmaceutical production. Environmental Toxicology & Chemistry 28:2522–2527

IS THE RELEASE OF ANTIBIOTICS INTO THE ENVIRONMENT A PROBLEM?

Development of Antibiotic Resistance

• Mutations in the existing DNA •  Uptake of entirely new genes from other bacteria

•  Bacteria are promiscuous, particularly when stressed!

•  Resistance genes present everywhere, in harmless bugs


Resistant bacteria outcompete sensitive ones


Resistant bacteria outcompete sensitive ones


…which means they can spread and increase in numbers

Highly multi-resistant bacteria within the treatment plant!

Marathe NP, Regina VR, Walujkar SA, Charan SS, Moore ERB, Charan SS, Moore ERB, Larsson DGJ, Shouche YS. 2013. A Treatment Plant Receiving Waste Water from Multiple Bulk Drug Manufacturers Is a Reservoir for Highly Multi-Drug Resistant Integron-Bearing Bacteria. PLoS ONE 8(10): e77310

Johnning A, Moore ERB, Svensson-Stadler L, Shouche YS, Larsson DGJ, Kristiansson E. 2013. The acquired genetic mechanisms of a multi-resistant bacterium isolated from a treatment plant receiving wastewater from antibiotic production. Appl. Environ. Microbiol., 79(23):7256

Resistant bacteria thrive in Indian lakes subjected to dumping of pharmaceutical waste


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CIP"2"µg/mL"

SMX"100"µg/mL"

Flach CF, Johnning A, Nilsson I, Smalla K, Kristiansson E, Larsson DGJ. 2015. Isolation of novel IncA/C and IncN fluoroquinolone resistance plasmids from an antibiotic-polluted lake. Journal of Antimicrobial Chemotherapy, 70, 2709–2717.

High levels of resistance genes in the polluted river sediments


Rela1v

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nce*(%

)*

River*Downstream**Treatment*plant*

River*Upstream**Treatment*plant*

Sulphonamide resistance Aminoglycoside resistance

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)*

River*Upstream**Treatment*plant*

River*Downstream*Treatment*plant*

Kristiansson E, Fick J, Janzon A, Grabic R, Rutgersson C, Weijdegård B, Söderström H, Larsson DGJ. 2011. Pyrosequencing of antibiotic-contaminated river sediments reveals high levels of resistance and gene transfer elements. PLoS ONE. 6:e17038.

Huge resistance diversity in polluted lake JOHAN BENGTSSON-PALME

HTTP://MICROBIOLOGY.SE

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aac(3)-IIa/IIc aac(6')-Ib aac(6')-If ant(2'')-Ia ant(3'')-Ia ant(6)-Ia aph(3'')-Ib aph(6)-Id ACT CAR CFE CM

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PER TEM

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catA1 catA16 catB2/catB3/catB10 catB9 cm

lA dfrA1/dfrA15 dfrA12/dfrA13/dfrA21/dfrA22/dfrA33 dfrA23 dfrA27/dfrA28 dfrA3 dfrA5/dfrA14/dfrA25/dfrA30 dfrA6/dfrA31 dfrB1/dfrB5/dfrB6/dfrB8 dfrB2/drfB3/dfrB7 dfrC ere(A)/ere(C) ere(B) floR qnrA qnrB qnrC qnrD

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Swedish Lake Indian Lake

Aminoglycoside Beta-lactam Chloramphenicol Trimethoprim

Erythromycin

Fluoroquinolone Macrolide

Streptogramin

Sulfonamide Tetracycline Vancomycin

100

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Bengtsson-Palme J, Boulund F, Fick J, Kristiansson E, Larsson DGJ. 2014. Shotgun metagenomics reveals a wide array of antibiotic resistance genes and mobile elements in a polluted lake in India. Front Microbiol. 5:648.

...along with dramatically higher abundance of genes facilitating transfer of resistance


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Number of known plasmids

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Indian lake

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Bengtsson-Palme J, et al. 2014. Front Microbiol. 5:648.

The genes can be transferred to pathogens!


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Sulphamethoxazole"Carbenicillin"Ciprofloxacin"

Flach CF, Johnning A, Nilsson I, Smalla K, Kristiansson E, Larsson DGJ. 2015. Isolation of novel IncA/C and IncN fluoroquinolone resistance plasmids from an antibiotic-polluted lake. Journal of Antimicrobial Chemotherapy, 70, 2709–2717.

And resistance genes also spread by travel


Bengtsson-Palme J, Angelin M, Huss M, Kjellqvist S, Kristiansson E, Palmgren H, Larsson DGJ, Johansson A. 2015. The Human Gut Microbiome as a Transporter of Antibiotic Resistance Genes between Continents. Antimicrob Agents Chemother. 59:6551–60.

Online 27th April 2015

”……we argue that risks are greatest in those cases in which the mobilized resistance gene has not yet been detected in pathogenic bacteria..”

Bengtsson-Palme J, Larsson DGJ. 2015. Antibiotic resistance genes in the environment: prioritizing risks. Nature Reviews Microbiology 13:396.

What actions are needed?

• Consider resistance development in treatment of antibiotic waste

• Disinfection of effluent • Non-toxic effluents • Define discharge limits for antibiotics


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

Industry Roadmap for Progress on Combating Antimicrobial Resistance – September 2016

The Davos Declaration* signed by >100 companies and trade associations in January 2016, called for collective action to create a sustainable and predictable market for antibiotics†, vaccines and diagnostics, that enhances conservation for new and existing treatments. It also called for coordinated action to improve prevention of infections, hygiene, stewardship and conservation measures.

As a group of leading companies supporting the Davos Declaration, we welcome the continued high level political focus on Antimicrobial Resistance (AMR), including discussions at the UN, WHO, G7, G20, the AMR Review team’s Final Report as well as regional and national debate. This work has established an ambitious, comprehensive agenda for the world and challenges each key stakeholder group to act and contribute to managing the threat of resistance.

The pharmaceutical industry recognises our responsibility and remains committed to playing a significant part in this long-term effort. Given the unique scientific, economic, public health and environmental challenges presented by AMR, collaboration between stakeholders is essential to maximise progress. We will continue to engage and partner with governments, global institutions, academia, prescribers and patients at global, regional and national levels. Resolving the complex economic challenges for the development, access and appropriate use of new antibiotics, vaccines and diagnostics remains of critical importance for us. It is necessary to attract sustained investment in developing new technologies to combat AMR.

As signatory companies of the Davos Declaration, we are committed to working to reduce the development of antimicrobial resistance, to invest in R&D and to improve access to high quality antibiotics and vaccines. These are ambitious goals, requiring new ways of working and investments of time, money and skilled people. This paper lays out a Roadmap for four key commitments on which the undersigning companies of this document will deliver, as applicable according to their different businesses and capabilities. Although work is underway on most aspects of the Roadmap, the precise end-points are not yet defined in all cases. These commitments therefore reflect our intent to proactively contribute to the fight against AMR, by developing and implementing solutions that will make a difference. We would welcome similar commitments from, and working collaborations with, other companies involved in combating AMR.

1) We support measures to reduce environmental impact from production of antibiotics, and will:

i. Review our own manufacturing and supply chains to assess good practice in controlling releases of antibiotics into the environment.

ii. Establish a common framework for managing antibiotic discharge, building on existing work such as PSCI ‡, and start to apply it across our own manufacturing and supply chain by 2018.

iii. Work with stakeholders to develop a practical mechanism to transparently demonstrate that our supply chains meet the standards in the framework.

iv. Work with independent technical experts to establish science-driven, risk-based targets for discharge concentrations for antibiotics and good practice methods to reduce environmental impact of manufacturing discharges, by 2020.

* http://amr-review.org/industry-declaration † We use the term antibiotics, recognising that antibacterials represent the top priority for all stakeholders. These principles could subsequently be applied to other types of antimicrobial over time. ‡Pharmaceutical Supply Chain Initiative https://pscinitiative.org/home

Industry Roadmap for Progress on Combating Antimicrobial Resistance – September 2016

The Davos Declaration* signed by >100 companies and trade associations in January 2016, called for collective action to create a sustainable and predictable market for antibiotics†, vaccines and diagnostics, that enhances conservation for new and existing treatments. It also called for coordinated action to improve prevention of infections, hygiene, stewardship and conservation measures.

As a group of leading companies supporting the Davos Declaration, we welcome the continued high level political focus on Antimicrobial Resistance (AMR), including discussions at the UN, WHO, G7, G20, the AMR Review team’s Final Report as well as regional and national debate. This work has established an ambitious, comprehensive agenda for the world and challenges each key stakeholder group to act and contribute to managing the threat of resistance.

The pharmaceutical industry recognises our responsibility and remains committed to playing a significant part in this long-term effort. Given the unique scientific, economic, public health and environmental challenges presented by AMR, collaboration between stakeholders is essential to maximise progress. We will continue to engage and partner with governments, global institutions, academia, prescribers and patients at global, regional and national levels. Resolving the complex economic challenges for the development, access and appropriate use of new antibiotics, vaccines and diagnostics remains of critical importance for us. It is necessary to attract sustained investment in developing new technologies to combat AMR.

As signatory companies of the Davos Declaration, we are committed to working to reduce the development of antimicrobial resistance, to invest in R&D and to improve access to high quality antibiotics and vaccines. These are ambitious goals, requiring new ways of working and investments of time, money and skilled people. This paper lays out a Roadmap for four key commitments on which the undersigning companies of this document will deliver, as applicable according to their different businesses and capabilities. Although work is underway on most aspects of the Roadmap, the precise end-points are not yet defined in all cases. These commitments therefore reflect our intent to proactively contribute to the fight against AMR, by developing and implementing solutions that will make a difference. We would welcome similar commitments from, and working collaborations with, other companies involved in combating AMR.

1) We support measures to reduce environmental impact from production of antibiotics, and will:

i. Review our own manufacturing and supply chains to assess good practice in controlling releases of antibiotics into the environment.

ii. Establish a common framework for managing antibiotic discharge, building on existing work such as PSCI ‡, and start to apply it across our own manufacturing and supply chain by 2018.

iii. Work with stakeholders to develop a practical mechanism to transparently demonstrate that our supply chains meet the standards in the framework.

iv. Work with independent technical experts to establish science-driven, risk-based targets for discharge concentrations for antibiotics and good practice methods to reduce environmental impact of manufacturing discharges, by 2020.

* http://amr-review.org/industry-declaration † We use the term antibiotics, recognising that antibacterials represent the top priority for all stakeholders. These principles could subsequently be applied to other types of antimicrobial over time. ‡Pharmaceutical Supply Chain Initiative https://pscinitiative.org/home

on work started in Europe and US with the goal of improving the speed and efficiency of conducting clinical trials.

iv. Engage with stakeholders, including the new GARDP** initiative, to facilitate data exchange on old antibiotics to try and fill specific gaps in the global pipeline.

Finally, we reiterate our support for a comprehensive multi-sectoral approach to addressing the other factors contributing to, and impacted by AMR, as defined by the WHO Global Action Plan, the AMR Review and the UN AMR High Level Meeting declaration, including reducing inappropriate antibiotic use in humans and animals, improving surveillance and infection control measures and commitments to develop and adopt advanced diagnostics. We support calls for the establishment of a high-level coordinating mechanism to provide global leadership, mobilise resources, set goals and measure progress towards them.

Signatory Companies

Allergan

AstraZeneca

Cipla

DSM Sinochem Pharmaceuticals

F. Hoffman-La Roche Ltd., Switzerland

GSK

Johnson & Johnson

Merck & Co., Inc., Kenilworth, New Jersey, U.S.A.

Novartis

Pfizer

Sanofi

Shionogi & Co., Ltd.

Wockhardt

** Global Antibiotic Research and Development Partnership http://www.dndi.org/2016/media-centre/press-releases/gard-garners-key-support-for-launch/

Can we create incentives to improve environmental standards of production? • Procurement of medicines • Pricing and reimbursement • Good Manufacturing Practice (GMP)


Bengtsson-Palme J, Larsson DGJ. 2016. Time to regulate antibiotic pollution. The Medicine Maker. Apr:17–8.

The Vision of CARe is to, through research, limit mortality, morbidity and socioeconomic costs related to antibiotic resistance on a global scale.

Centre for Antibiotic Resistance Research at University of Gothenburg

Acknowledgements

•  Prof. Joakim Larsson

•  Current and former members of his research group

•  Funding for the work presented in this presentation has been provided by FORMAS, MistraPharma, The Swedish Research Council, SciLifeLab, KA Wallenberg Foundation and the University of Gothenburg Center for Antibiotic Resistance Research (CARe)


JOHAN BENGTSSON-PALME http://microbiology.se

[email protected]

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