Background: Antimicrobial resistance (AMR) in gram-negative bacteria represents a growing global health threat, increasingly fueled by environmental factors. Wastewater, agricultural runoff, aquaculture, and pharmaceutical discharge contribute to the release of antibiotic residues, resistant bacteria, and resistance genes into ecosystems. Objective: This literature review explores the environmental persistence and dissemination of antibiotic resistance, focusing on the mechanisms by which multidrug-resistant (MDR) genes are maintained and transferred—particularly through water sources—and highlights emerging mitigation strategies and regulatory challenges. Key Findings: Gram-negative bacteria such as Salmonella enterica and ESKAPE pathogens exhibit intrinsic and acquired resistance mechanisms, including efflux pumps and mobile genetic elements. Environmental reservoirs, especially wastewater treatment plants, facilitate horizontal gene transfer between pathogenic and non-pathogenic bacteria. Agricultural practices, antibiotic overuse, and inadequate waste management further exacerbate the spread. While ozone treatment, membrane bioreactor systems, bacteriophage therapy, and efflux pump inhibitors show promise in reducing AMR load, widespread implementation remains limited. Policy efforts—at federal, state, and international levels—lack consistency and enforcement, particularly regarding environmental discharge and regulation of antibiotic residues. Conclusion: Environmental AMR, particularly via water systems, poses a substantial public health risk. A coordinated One Health approach, incorporating policy reform, technological advancements, and cross-sector collaboration, is essential to address AMR at its environmental source and mitigate its global spread.
KeywordsAntimicrobial ResistanceGram-Negative BacteriaWastewater TreatmentMultidrug ResistanceEnvironmental HealthSalmonella entericaHorizontal Gene Transfer
World Health Organization (2021) Antimicrobial Resistance. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance
Agyeman, W.Y., Bisht, A., Gopinath, A., Cheema, A.H., Chaludiya, K., Khalid, M., et al. (2022) A Systematic Review of Antibiotic Resistance Trends and Treatment Options for Hospital-Acquired Multidrug-Resistant Infections. Cureus , 14, e29956. https://doi.org/10.7759/cureus.29956
Aljeldah, M.M. (2022) Antimicrobial Resistance and Its Spread Is a Global Threat. Antibiotics , 11, Article 1082. https://doi.org/10.3390/antibiotics11081082
Ventola, C.L. (2015) The Antibiotic Resistance Crisis. P& T , 40, 277-283.
Zaman, S.B., Hussain, M.A., Nye, R., Mehta, V., Mamun, K.T. and Hossain, N. (2017) A Review on Antibiotic Resistance: Alarm Bells Are Ringing. Cureus , 9, e1403. https://doi.org/10.7759/cureus.1403
Nikaido, H. (1998) Antibiotic Resistance Caused by Gram-Negative Multidrug Efflux Pumps. Clinical Infectious Diseases , 27, S32-S41. https://doi.org/10.1086/514920
Centers for Disease Control and Prevention (2024) Antimicrobial Resistance in the Environment and the Food Supply: Causes and How It Spreads. https://www.cdc.gov/antimicrobial-resistance/causes/environmental-food.html?CDC_AAref_Val= https://www.cdc.gov/drugresistance/environment.html
Berglund, F., Ebmeyer, S., Kristiansson, E. and Larsson, D.G.J. (2023) Evidence for Wastewaters as Environments Where Mobile Antibiotic Resistance Genes Emerge. Communications Biology , 6, Article No. 321. https://doi.org/10.1038/s42003-023-04676-7
Nappier, S.P., Liguori, K., Ichida, A.M., Stewart, J.R. and Jones, K.R. (2020) Antibiotic Resistance in Recreational Waters: State of the Science. International Journal of Environmental Research and Public Health , 17, Article 8034. https://doi.org/10.3390/ijerph17218034
Williams, M.R., Stedtfeld, R.D., Guo, X. and Hashsham, S.A. (2016) Antimicrobial Resistance in the Environment. Water Environment Research , 88, 1951-1967. https://doi.org/10.2175/106143016x14696400495974
Han, B., Ma, L., Yu, Q., et al. (2022) The Source, Fate and Prospect of Antibiotic Resistance Genes in Soil: A Review. Frontiers in Microbiology , 13, Article 976657. https://doi.org/10.3389/fmicb.2022.976657
Doğan, S. and Önalan, Ş. (2023) Determination of Antimicrobial Resistance Gene Variations Using Tet and Str Genes in Freshwater Fish Species. Cellular and Molecular Biology , 69, 150-155. https://doi.org/10.14715/cmb/2022.69.1.26
Samreen, Ahmad, I., Malak, H.A. and Abulreesh, H.H. (2021) Environmental Antimicrobial Resistance and Its Drivers: A Potential Threat to Public Health. Journal of Global Antimicrobial Resistance , 27, 101-111. https://doi.org/10.1016/j.jgar.2021.08.001
Smith, R.D. and Coast, J. (2022) The Economic Impact of Antibiotic Resistance: Why It Is a Global Issue. The Lancet Infectious Dis eases , 7, 286-292.
Murray, C.J.L., Ikuta, K.S., Sharara, F., Swetschinski, L., Robles Aguilar, G., Gray, A., et al. (2022) Global Burden of Bacterial Antimicrobial Resistance in 2019: A Systematic Analysis. The Lancet , 399, 629-655. https://doi.org/10.1016/s0140-6736(21)02724-0
World Health Organization (2021) Antimicrobial Resistance: Global Report on Surveillance. https://www.who.int/publications/i/item/9789241564748
Johnson, L., Sabel, A., Burman, W.J., Everhart, R.M., Rome, M., MacKenzie, T.D., et al . (2008) Emergence of Fluoroquinolone Resistance in Outpatient Urinary Escherichia Coli Isolates. The American Journal of Medicine , 121, 876-884. https://doi.org/10.1016/j.amjmed.2008.04.039
Kumarasamy, K.K., Toleman, M.A., Walsh, T.R., et al. (2010) Emergence of a New Antibiotic Resistance Mechanism in India, Pakistan, and the UK: A Molecular, Biological, and Epidemiological Study. The Lancet Infectious Diseases , 10, 597-602.
Abdelbary, M.M.H., Basset, P., Blanc, D.S. and Feil, E.J. (2017) The Evolution and Dynamics of Methicillin-Resistant Staphylococcus Aureus. In: Genetics and Evolution of Infectious Diseases , Elsevier, 553-572. https://doi.org/10.1016/b978-0-12-799942-5.00024-x
Elfadadny, A., Ragab, R.F., AlHarbi, M., Badshah, F., Ibáñez-Arancibia, E., Farag, A., et al . (2024) Antimicrobial Resistance of Pseudomonas Aeruginosa: Navigating Clinical Impacts, Current Resistance Trends, and Innovations in Breaking Therapies. Frontiers in Microbiology , 15. https://doi.org/10.3389/fmicb.2024.1374466
Aleksandrowicz, A., Carolak, E., Dutkiewicz, A., Błachut, A., Waszczuk, W. and Grzymajlo, K. (2023) Better Together— Salmonella Biofilm-Associated Antibiotic Resistance. Gut Microbes , 15, Article ID: 2229937. https://doi.org/10.1080/19490976.2023.2229937
Andino, A. and Hanning, I. (2015) Salmonella enterica : Survival, Colonization, and Virulence Differences among Serovars. The Scientific World Journal , 2015, Article ID: 520179. https://doi.org/10.1155/2015/520179
Giannella, R. (1996) Salmonella. In: Baron, S., Ed., Medical Microbiology , 4th Edition, University of Texas Medical Branch at Galveston.
Robertson, J., Schonfeld, J., Bessonov, K., Bastedo, P. and Nash, J.H.E. (2023) A Global Survey of Salmonella Plasmids and Their Associations with Antimicrobial Resistance. Microbial Genomics , 9, Article ID: 001002. https://doi.org/10.1099/mgen.0.001002
Lehner, R., Wang, X. and Hunziker, P. (2013) Plasmid Linearization Changes Shape and Efficiency of Transfection Complexes. European Journal of Nanomedicine , 5, 205-212. https://doi.org/10.1515/ejnm-2013-0028
Bethke, J.H., Ma, H.R., Tsoi, R., Cheng, L., Xiao, M. and You, L. (2022) Vertical and Horizontal Gene Transfer Tradeoffs Direct Plasmid Fitness. Molecular Systems Biology , 19, e11300. https://doi.org/10.15252/msb.202211300
Mancuso, G., Midiri, A., Gerace, E. and Biondo, C. (2021) Bacterial Antibiotic Resistance: The Most Critical Pathogens. Pathogens , 10, Article 1310. https://doi.org/10.3390/pathogens10101310
Marutescu, L.G., Popa, M., Gheorghe-Barbu, I., Barbu, I.C., Rodríguez-Molina, D., Berglund, F., et al. (2023) Wastewater Treatment Plants, an “Escape Gate” for ESCAPE Pathogens. Frontiers in Microbiology , 14, Article 1193907. https://doi.org/10.3389/fmicb.2023.1193907
Gervasoni, L.F., Peixoto, I.C., Imperador, A.C., De Oliveira, L.B., Correia, L.F., de Oliveira Vieira, K.C., et al. (2023) Relationship between Antibiotic Resistance, Biofilm Formation, Virulence Factors and Source of Origin of Pseudomonas aeruginosa Environmental Isolates with Regard to the Presence of Metallo- β -Lactamase-Encoding Genes. Microbial Pathogenesis , 182, Article ID: 106223. https://doi.org/10.1016/j.micpath.2023.106223
Shobo, C.O., Amoako, D.G., Allam, M., Ismail, A., Essack, S.Y. and Bester, L.A. (2023) A Genomic Snapshot of Antibiotic-Resistantenterococcus Faecalis within Public Hospital Environments in South Africa. Global Health , 2023, Article ID: 6639983. https://doi.org/10.1155/2023/6639983
Iweriebor, B., Gaqavu, S., Obi, L., Nwodo, U. and Okoh, A. (2015) Antibiotic Susceptibilities of Enterococcus Species Isolated from Hospital and Domestic Wastewater Effluents in Alice, Eastern Cape Province of South Africa. International Journal of Environmental Research and Public Health , 12, 4231-4246. https://doi.org/10.3390/ijerph120404231
Zhang, R., Yang, S., An, Y., Wang, Y., Lei, Y. and Song, L. (2022) Antibiotics and Antibiotic Resistance Genes in Landfills: A Review. Science of the Total Environment , 806, Article ID: 150647. https://doi.org/10.1016/j.scitotenv.2021.150647
Zainab, S.M., Junaid, M., Xu, N. and Malik, R.N. (2020) Antibiotics and Antibiotic Resistant Genes (ARGs) in Groundwater: A Global Review on Dissemination, Sources, Interactions, Environmental and Human Health Risks. Water Research , 187, Article ID: 116455. https://doi.org/10.1016/j.watres.2020.116455
Manaia, C.M., Rocha, J., Scaccia, N., Marano, R., Radu, E., Biancullo, F., et al. (2018) Antibiotic Resistance in Wastewater Treatment Plants: Tackling the Black Box. Environment International , 115, 312-324. https://doi.org/10.1016/j.envint.2018.03.044
Kraemer, S.A., Ramachandran, A. and Perron, G.G. (2019) Antibiotic Pollution in the Environment: From Microbial Ecology to Public Policy. Microorganisms , 7, Article 180. https://doi.org/10.3390/microorganisms7060180
Wang, J., Xu, S., Zhao, K., Song, G., Zhao, S. and Liu, R. (2023) Risk Control of Antibiotics, Antibiotic Resistance Genes (ARGs) and Antibiotic Resistant Bacteria (ARB) during Sewage Sludge Treatment and Disposal: A Review. Science of the Total Environment , 877, Article ID: 162772. https://doi.org/10.1016/j.scitotenv.2023.162772
Rizzo, L., Manaia, C., Merlin, C., Schwartz, T., Dagot, C., Ploy, M.C., et al. (2013) Urban Wastewater Treatment Plants as Hotspots for Antibiotic Resistant Bacteria and Genes Spread into the Environment: A Review. Science of the Total Environment , 447, 345-360. https://doi.org/10.1016/j.scitotenv.2013.01.032
Qumsani, A.T. (2023) Role of Nanocarrier Systems in Drug Delivery for Overcoming Multi-Drug Resistance in Bacteria. Pakistan Journal of Biological Sciences , 26, 131-137. https://doi.org/10.3923/pjbs.2023.131.137
Karkman, A., Do, T.T., Walsh, F. and Virta, M.P.J. (2018) Antibiotic-Resistance Genes in Waste Water. Trends in Microbiology , 26, 220-228. https://doi.org/10.1016/j.tim.2017.09.005
Jochum, J.M., Redweik, G.A.J., Ott, L.C. and Mellata, M. (2021) Bacteria Broadly-Resistant to Last Resort Antibiotics Detected in Commercial Chicken Farms. Microorganisms , 9, Article 141. https://doi.org/10.3390/microorganisms9010141
Tuvo, B., Scarpaci, M., Bracaloni, S., Esposito, E., Costa, A.L., Ioppolo, M., et al. (2023) Microplastics and Antibiotic Resistance: The Magnitude of the Problem and the Emerging Role of Hospital Wastewater. International Journal of Environmental Research and Public Health , 20, Article 5868. https://doi.org/10.3390/ijerph20105868
Dionisio, F., Domingues, C.P.F., Rebelo, J.S., Monteiro, F. and Nogueira, T. (2023) The Impact of Non-Pathogenic Bacteria on the Spread of Virulence and Resistance Genes. International Journal of Molecular Sciences , 24, Article 1967. https://doi.org/10.3390/ijms24031967
Martínez, J.L. (2012) Bottlenecks in the Transferability of Antibiotic Resistance from Natural Ecosystems to Human Bacterial Pathogens. Frontiers in Microbiology , 2, Article 265. https://doi.org/10.3389/fmicb.2011.00265
Keelara, S. and Thakur, S. (2014) Dissemination of Plasmid-Encoded AmpC β -Lactamases in Antimicrobial Resistant Salmonella Serotypes Originating from Humans, Pigs and the Swine Environment. Veterinary Microbiology , 173, 76-83. https://doi.org/10.1016/j.vetmic.2014.07.018
Kempf, A.J., Hulsebus, H.J. and Akbar, S. (2016) Multiple Plasmids Contribute to Antibiotic Resistance and Macrophage Survival in Vitro in CMY2-Bearing Salmonella enterica . Foodborne Pathogens and Disease , 13, 398-404. https://doi.org/10.1089/fpd.2015.2067
Castañeda-Barba, S., Top, E.M. and Stalder, T. (2023) Plasmids, a Molecular Cornerstone of Antimicrobial Resistance in the One Health Era. Nature Reviews Microbiology , 22, 18-32. https://doi.org/10.1038/s41579-023-00926-x
Li, L. and Zhang, T. (2023) Plasmid-Mediated Antibiotic Resistance Gene Transfer under Environmental Stresses: Insights from Laboratory-Based Studies. Science of the Total Environment , 887, Article ID: 163870. https://doi.org/10.1016/j.scitotenv.2023.163870
Larsson, D.G.J., Andremont, A., Bengtsson-Palme, J., Brandt, K.K., de Roda Husman, A.M., Fagerstedt, P., et al. (2018) Critical Knowledge Gaps and Research Needs Related to the Environmental Dimensions of Antibiotic Resistance. Environment International , 117, 132-138. https://doi.org/10.1016/j.envint.2018.04.041
Ramanan Laxminarayan, T.V. (2015) The Economic Costs of Withdrawing Anti-Microbial Growth Promoters from the Livestock Sector. OECD Food, Agriculture and Fisheries Papers, 42.
Centers for Disease Control and Prevention (2023) U.S. Antibiotic Resistance (AR) Programs and Activities. Centers for Disease Control and Prevention. https://www.cdc.gov/antimicrobial-resistance/programs/AR-actions-events.html
CDC (2019) Antibiotic Resistance Threats in the United States. U.S. Department of Health and Human Services, 150.
U.S. Department of Health and Human Services (2025) Antimicrobial Resistance. U.S. Department of Health and Human Services. https://www.hhs.gov/about/agencies/oga/global-health-security/antimicrobial-resistance/index.html
Centers for Disease Control and Prevention (2021) The AMR Challenge. Centers for Disease Control and Prevention. https://archive.cdc.gov/www_cdc_gov/drugresistance/us-activities/amr-challenge.html
Antimicrobial Stewardship (2022) Indiana Department of Health. https://www.in.gov/health/idepd/healthcare-associated-infections-and-antimicrobial-resistance-epidemiology/antimicrobial-stewardship/
Indiana Department of Health: Antimicrobial Resistance. Indiana Department of Health. https://www.in.gov/health/idepd/healthcare-associated-infections-and-antimicrobial-resistance-epidemiology/antimicrobial-resistance/
Center for Disease Dynamics, Economics & Policy (CDDEP) (2015) The State of the World’s Antibiotics, 2015. https://cddep.org/publications/state_worlds_antibiotics_2015/
Gandra, S., Kotwani, A. and Laxminarayan, R. (2017) Point Prevalence Surveys of Antimicrobial Use among Hospitalized Children in Six Hospitals in India in 2016. WHO South - East Asia Journal of Public Health , 9, 107-115.
Azuma, T., Usui, M. and Hayashi, T. (2022) Inactivation of Antibiotic-Resistant Bacteria in Wastewater by Ozone-Based Advanced Water Treatment Processes. Antibi otics , 11, Article 210. https://doi.org/10.3390/antibiotics11020210
Reisoglu, Ş. and Aydin, S. (2023) Bacteriophages as a Promising Approach for the Biocontrol of Antibiotic Resistant Pathogens and the Reconstruction of Microbial Interaction Networks in Wastewater Treatment Systems: A Review. Science of the Total Environment , 890, Article ID: 164291. https://doi.org/10.1016/j.scitotenv.2023.164291
Iakovides, I.C., Michael-Kordatou, I., Moreira, N.F.F., Ribeiro, A.R., Fernandes, T., Pereira, M.F.R., et al. (2019) Continuous Ozonation of Urban Wastewater: Removal of Antibiotics, Antibiotic-Resistant Escherichia Coli and Antibiotic Resistance Genes and Phytotoxicity. Water Research , 159, 333-347. https://doi.org/10.1016/j.watres.2019.05.025
Le, T., Ng, C., Tran, N.H., Chen, H. and Gin, K.Y. (2018) Removal of Antibiotic Residues, Antibiotic Resistant Bacteria and Antibiotic Resistance Genes in Municipal Wastewater by Membrane Bioreactor Systems. Water Research , 145, 498-508. https://doi.org/10.1016/j.watres.2018.08.060
Price, E.D.J., Dassanayake, R.P. and Bearson, S.M.D. (2023) Increasing Antimicrobial Susceptibility of MDR Salmonella with the Efflux Pump Inhibitor 1-(1-Naphthylmethyl)-Piperazine. Biochemical and Biophysical Research Communications , 668, 49-54. https://doi.org/10.1016/j.bbrc.2023.05.035
Bengtsson-Palme, J., Abramova, A., Berendonk, T.U., Coelho, L.P., Forslund, S.K., Gschwind, R., et al. (2023) Towards Monitoring of Antimicrobial Resistance in the Environment: For What Reasons, How to Implement It, and What Are the Data Needs? Environment International , 178, Article ID: 108089. https://doi.org/10.1016/j.envint.2023.108089
Cristina Zarama: Antimicrobial Resistance & Multidrug Resistant Salmonella. University of Minnesota. https://cahfs.umn.edu/antimicrobial-resistance-multidrug-resistant-salmonella