Defining the AMR Burden of Antimicrobial Manufacturing Waste in Puducherry and Chennai

Pharmaceutical manufacturing waste is an important and neglected source of antimicrobial contamination in the environment that can result in expansion of antimicrobially-resistant microbes. Countries such as India, one of the world's main producers of Active Pharmaceutical Ingredients (APIs) including antibiotics are at particular risk. Studies indicate that pharmaceutical effluent waste in specific areas of India are associated with excessively high concentrations of antimicrobials in the surrounding environment and to increased frequency of antimicrobial resistance (AMR) in environmental water. The impact of such waste in other areas is unknown. There are currently no international standards to limit antimicrobials in antimicrobial manufacturing waste (AMW). Such pollution from manufacturing therefore creates environments that are spawning grounds for antimicrobial resistance in environmental bacteria; new genetic resistance factors can evolve through mutation, and, together with already-existing resistance traits will be enriched by selection. Due to the ability of bacterial to transfer genetic material on mobile genetic elements, AMR genetic traits may be transferred from environmental bacteria to harmful bacteria (pathogens), either within the environment, or within animals and humans, with potential harmful health consequences for everyone, regardless of where the pollution occurred.

Focusing on Chennai and Puducherry, we will investigate the link between antibiotics manufactured by different methods, contamination levels in manufacturing wastes and downstream locations, where we will sample for antibiotics and antimicrobial resistance in waters, sediments, animals, and humans, contrasting our findings with control upstream environments. These two regions in India have a significant number of pharmaceutical companies (both active pharmaceutical ingredient manufacturers and formulation companies) producing a range of products including amoxicillin, cephalosporins, macrolides, tetracyclines, and fluroquinolones. We will validate techniques to detect and measure different antibiotics in environmental samples, and undertake state of the art bacterial, genomic and metagenomic studies on the same samples to identify AMR bacteria and the genetic elements conferring resistance, providing a library of AMR risk in this region of India. AMR data will be integrated with locations of sampling and levels of antibiotic contamination to determine the degree of association between these factors.

Armed with this information, our work will provide a platform to advise on the risk posed by antimicrobial manufacturing waste and ultimately identify the need for risk-reducing investments by industry to deal with the proliferation of AMR. The project will develop novel analytical methods for the quantification of active pharmaceutical ingredients related to antibiotic manufacturing and novel approaches to quantify and characterise the penetration of AMR into the environment and animal and human microbiota. We will deliver mass balance methods and risk assessment tools that predict concentrations and risk based on production loads of antimicrobials, and policy recommendations for international environmental standards for antimicrobials in manufacturing effluents and receiving environments. Global implications of this work relate to larger pharma who purchase antibiotic ingredients, as well as medical professionals and patients; there may be a need to consider that the low cost of antibiotics should be balanced by a need to maintain environmental performance and sustainability of their manufacturing methods. Given the significant industrial emissions of antibiotics repeatedly documented in India, our work will encourage and support the Indian government in its determination to monitor and regulate antibiotic discharges from manufacturing, whilst supporting global efforts for tackling AMR.

The immediate impacts from this work relate to the advancement of scientific knowledge for addressing antimicrobial resistance in the environment and the development of skills, capacity and capability. In the longer term, this research has the potential to impact on diverse areas of human, animal and environmental health. The proposed research will combine the latest genomics technologies to detect and critically develop novel approaches for the quantification of active pharmaceutical ingredients related to antibiotic manufacturing.

Armed with this information, our work will provide a platform to advise on the risk posed by antimicrobial manufacturing waste and ultimately identify the need for risk-reducing investments by industry to deal with the proliferation of AMR. Beneficiaries beyond academia (see 'academic beneficiaries' above) are the wider public and the pharmaceutical sector.

Global implications of this work relate to larger pharma who purchase antibiotic ingredients, as well as medical professionals and patients; there may be a need to consider that the low cost of antibiotics should be balanced by a need to maintain environmental performance and sustainability of their manufacturing methods.

Although the discharge of active pharmaceutical ingredients and pharmaceutical waste is currently not fully regulated in India, it is likely that regulation will eventually be put in place. Project outputs will contribute to India's strategic priority under the National Action Plan for Antimicrobial Resistance, in "defining the standards for antibiotic residues in industrial effluents" and to recent initiatives from the pharmaceuticals industry (AMR Road map) including their commitment 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".

Given the significant industrial emissions of antibiotics repeatedly documented in India, our work will encourage and support the Indian government in its determination to monitor and regulate antibiotic discharges from manufacturing, whilst supporting global efforts for tackling AMR. Ultimately, the general public may thus benefit from our fundamental contribution to the understanding of AMR that will guide and empower research in understanding further the human health and environmental risk of the discharge flow. This in turn will help to develop preventative measures against amplification of AMR.