International Manufacturing and Trade in Colistin, its Implications in Polymyxin Resistance and One-Health Global Policies: A Microbiological, Economic and Anthropological Study

Background: The emergence of colistin-resistant Enterobacterales (ColRE) is a global public health concern, yet colistin is still widely used in food animals as treatment, metaphylaxis, prophylaxis, and growth promotion. Herein, we investigated the impact of ColRE in Pakistan, global trade of colistin and relevant socio-economic factors.Methods: A total of 1131 samples including chicken cloacal, chicken meat, flies, cattle rectal, cattle meat, human rectal, wild birds and sewage water were collected between 2018-2019 from Faisalabad, Pakistan for mcr-1 positive Escherichia coli (MCRPEC). Colistin trade between 2017-20 including importation, manufacturing, and usage were accessed in Pakistan, Bangladesh, and Nigeria. International manufacturing, export, value analysis, and trade routes of colistin pharmaceutical raw material (PRM), feed additive (FA), and finished pharmaceutical products (FPP) were accessed from 2018-21 export data sets.Findings: A total of 75/1129 (6.9%) isolates were MCRPEC including wild birds (25%; 25/100), chicken meat (13%; n=13/100), chicken cloacal (8.91%; n=17/202), poultry flies (8%; n=8/100), and sewage water (6.7% n=6/90). Between 2017-20, Pakistan imported 275.5 tonnes of colistin as PRM, all sourced from China, 701.94 tonnes of FAs from China and Vietnam, and 62.99 tonnes as FPPs from different countries in Asia and Europe. For Bangladesh and Nigeria colistin PRM and FPPs were imported from China and Europe. Colistin knowledge and usage practices in Pakistan and Nigeria were found below par­, the data is not reported from Bangladesh. China is the major manufacturer of PRM and FA colistin and exported 2664.88 tonnes of PRM and 2570.2 tonnes of FA in 1331 shipments during 2018-21 to 23 countries. Export value of colistin PRM and FA were found to be 10.24 and 2.62 USD/kg, respectively. Vietnam is a major importer of colistin PRM and FA and exports colistin products to various countries in Asia, Middle East, and Africa whereas Indian imports include colistin PRM and FA and exports mainly human colistin FPPs to Asia, Middle East, Africa, and Latin America. China directly exports colistin FPPs and FAs to various countries in Asia, Middle East, Europe, Africa, and America; however, we identified at least 21 European trading companies supplying colistin PRM sourced from China to numerous regions including low-middle income countries (LMICS).Interpretation: Regardless of 193 countries signing the UN agreement to tackle antimicrobial resistance, trading of colistin as PRM, FPP and FA/GP in LMICs continues unabated. Robust national and international laws are urgently required to mitigate the international trade of a WHO reserved human medicine.Funding Information: MU was funded by the Punjab Educational Endowment Fund – Chief Minister Merit Scholarship (PEEF–CMMS). BH was funded by the UK Medical Research Council (project DETER-XDR-China-HUB, grant number MR/S013768/1). RF was funded by the Wellcome Trust (project COVID-19/DRI). TRW and KS were funded by the INEOS Oxford Institute for Antimicrobial Research. The project was sponsored by the Global Challenges Research Fund (GCRF), Agricultural Innovation Program / International Maize and Wheat Improvement Center (AIP/CIMMYT) – Pakistan Agricultural Research Council (PARC) (Grant No. AS04), and INEOS Oxford Institute for Antimicrobial Research (IOI–AMR).Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: Ethical approval was obtained from the Institutional Bioethics/Biosafety Committee of the University of Agriculture, Faisalabad (D. No. 109/ORIC dated 05-01-2018) and consent was taken from human subjects.