ManishKumar,RahulSilori,PayalMazumder,VikalpShrivastava,FrankLoge,DamiàBarceló,JürgenMahlknecht
Since the development of antibiotics, microorganisms have developed resistance to the germicidal effects. (1,2) In 2019, 1.27 million people died due to antimicrobial resistance (AMR), which ranked higher than the mortality associated with human immunodeficiency virus (HIV) (864 000) and malaria (643 000). If left unchecked, approximately 10 million people could die annually from AMR by 2050. (3) To direct the effects of AMR comprehensively and put policies into place at the national level, in 2016 the United Nations called for coordinated action. (4) AMR Industry Alliance assists the pharmaceutical industries in putting into practice measures to reduce the potential influence of pharmaceutical manufacturing on the spread of AMR via one of its milestones to publish anticipated no-effect concentrations (PNECs) of known antibiotics. (5) Although several novel technologies and approaches have been developed for combating AMR, for example, reverse vaccinology, (6) structural vaccinology, (7) and artificially designed bacterial outer membrane vesicles (OMVs), (8) such developments and progress are moving too slowly to be effective. In this Highlight, we consider the impact of wars and pandemics on AMR and the potential for accelerated antimicrobial resistance development. With the rise of socioeconomic development, nuclear weapons, and technological development, war seems archaic. However, throughout the past several decades, the number of conflicts has increased, regardless of their ferocity, and a majority of them have continued to occur in developing countries. Eight times as many members of the British army perished from sickness during the Napoleonic wars than from wounds received in combat. Two-thirds of the projected military deaths during the American civil conflict were attributed to diseases such as dysentery, pneumonia, malaria, and typhoid, which was termed the third army, which prolonged the war by two years. (9) The disease-related death toll due to typhoid and cholera was 3.8 times greater than war deaths in the Crimean war. (10) Exposure to a war environment, unhygienic conditions [e.g., lice containing Bartonella quintana causing trench fever (11) and typhoid (Salmonella typhi)], war-related stress, and geopolitical consequences of war might impact immune systems leading to more susceptibility to diseases. The longer a war prevails, the more resources, including food, are diverted from the public, elevating health issues and weak immunity. In the Vietnam war (1955–1975), dextroamphetamine use increased from 3.2% to 5.2%. (12) War settings make it difficult or impossible to access medical help due to disrupted transportation networks and the destruction of healthcare facilities, leading to prolonged injuries without treatment that cause infections. Inoperative hospitals, migration to war-safe zones, and discontinuation of medications trigger secondary infection(s) and resistance to drug(s). In addition to the current COVID-19 pandemic, the globe has been struck by four major pandemics since 1900: Spanish Flu (1918), Asian Flu (1957), Hong Kong Flu (1968), and H1N1 Swine Flu (2009). Through wars and pandemics, new types of wounds, infections, and diseases emerge, urgently requiring medicines and treatment procedures, leading to a spike in the consumption and excretion of pharmaceutical products, in particular antibiotics. (13) The demand for pharmaceuticals in Portugal increased by 60% within a week after the World Health Organization declared COVID-19 a pandemic. India witnessed an increase of 38 million doses of azithromycin. In Wuhan, China, 71% of the nonsurvivors were treated with antibiotics. In addition, (i) sulfonamides introduced to treat Neisseria gonorrheae in the 1930s were found to be less effective in soldiers stationed in Italy and Sicily during WW II (1939–1945) and penicillin production increased approximately 325%, leading to subsequent reports of AMR (e.g., penicillin-resistant Escherichia coli in 1940). (ii) Tetracycline and erythromycin, which were extensively used during the Asian flu pandemic (1957–1958), became ineffective against Streptococcus pyogenes discovered in Japan in the mid-1970s. (iii) Ingavirin and oseltamivir, prescribed during the Russian Flu (1977–1979), were gradually found to be ineffective against influenza A virus when by 2007–08 oseltamivir resistance H1N1 was discovered. (iv) In the Syrian (since 2011) and Yemenis conflicts (since 2014), Klebsiella pneumoniae, E. coli, and Pseudomonas aeruginosa developed AMR to ciprofloxacin, gentamycin, tobramycin, and amikacin. (v) During the Iraq war (2003–2011), multidrug resistance Acinetobacter baumannii infection was spread. (vi) During the Ukrainian conflict (2014 to the present), bacteria like Acinetobacter, P. aeruginosa, E. coli, and Staphylococcus aureus acquired resistance to combat antibiotics such as fluoroquinolones, carbapenems, and relevant aminoglycosides. AMR is also fueled by heavy metal exposure from the demolition of the built environment and exudation of antibiotics from treatment plants during the war. This time line of war and discovery of drugs along with the developed resistance microbes, case fatality risk, mortality rate of human diseases, and time required for new drug discovery to clinical approval are summarized in Figure 1. Figure 1. (A) Timeline of war, conflicts, and disease outbreaks along with the occurrence of AMR. (B) Case fatality risk (CFR) (13) of various human diseases and mortality rates of common human pathogenic bacteria. (14) (C) Time line of the drug discovery process (15) (created with BioRender.com). The war in Ukraine is a reminder of the ongoing certainty of future conflict, and the COVID-19 pandemic is a reminder of the rapidity and force of a global disease. Antimicrobial resistance cannot be solved but is only effectively managed. The challenge for the international community is to address the issue of antibiotic resistance as quickly as possible as it occurs, whether through refining protocols of when antibiotics are prescribed, extensive R&D, etc. Novel research must focus on the rapid diagnosis of AMR. While the distribution of medicines and medical facilities should not be disrupted during the war, harmonized and standardized protocols should be formulated and disseminated globally in response to AMR development. Overtaxed hospitals must continue to prioritize hospital sanitation and staff hygiene to minimize the spread of resistant pathogens. In addition, international efforts are required to find alternative advanced treatments to combat new resistance infections. In summary, a rapid international strategy and response are necessary to effectively manage this silent and global AMR pandemic. M.K. conceptualized and visualized the work. R.S. and V.S. wrote the first draft of the manuscript with input from M.K. P.M. made the figure in consultation with M.K, reviewed the manuscript, and gave further input about the manuscript. M.K. then revised the manuscript with input from J.M., F.L., and D.B. Dr. Manish Kumar has been a Professor and Head of the Sustainability Cluster in the School of Engineering at UPES, Dehradun, India, since 2021. He serves as a Distinguished Professor in Water Science in the School of Engineering and Sciences, Tec de Monterrey, Mexico. After completing his Ph.D. from the University of Tokyo, Japan, he served on the faculty at Tezpur University, Assam, and Indian Institute of Technology (IIT) Gandhinagar, Gujarat, India. He worked at the University of Nebraska Lincoln (UNL), United States, as Visiting Faculty. His academic career has included work at Kunsan National University, South Korea; Uppsala University, Sweden; and JNU, New Delhi, India. He was featured in the list of the top 2% of the researchers in the world and is a Fellow of the Royal Society of Chemistry (FRSC). He was on the expert panel for UNEP on antimicrobial resistance. Dr. Kumar's research focuses on ascertaining, broadening, comprehending, and developing various dimensions of the fate, transport, and remediation of geogenic, micro, microbial, and emerging contaminants in freshwater systems. He renders editorial services to journals like Environmental Science & Technology Letters, ACS ES&T Engineering, npj Clean Water, Science of the Total Environment, Current Pollution Report, Groundwater for Sustainable Development, Reviews of Environmental Contamination and Toxicology, and Hydrological Research Letters. The authors are grateful for the support received from the Science and Engineering Research Board (SERB) of the Government of India, Department of Science and Technology, for supporting this ongoing research by a sponsored research project (SERB/CVD/2022/000033, May 2022). The authors also thank Tecnologico de Monterrey for bringing together some of the authors of this work and UPES, Dehradun, for hosting the project. This article references 15 other publications. This article has not yet been cited by other publications. Figure 1. (A) Timeline of war, conflicts, and disease outbreaks along with the occurrence of AMR. (B) Case fatality risk (CFR) (13) of various human diseases and mortality rates of common human pathogenic bacteria. (14) (C) Time line of the drug discovery process (15) (created with BioRender.com). Dr. Manish Kumar has been a Professor and Head of the Sustainability Cluster in the School of Engineering at UPES, Dehradun, India, since 2021. He serves as a Distinguished Professor in Water Science in the School of Engineering and Sciences, Tec de Monterrey, Mexico. After completing his Ph.D. from the University of Tokyo, Japan, he served on the faculty at Tezpur University, Assam, and Indian Institute of Technology (IIT) Gandhinagar, Gujarat, India. He worked at the University of Nebraska Lincoln (UNL), United States, as Visiting Faculty. His academic career has included work at Kunsan National University, South Korea; Uppsala University, Sweden; and JNU, New Delhi, India. He was featured in the list of the top 2% of the researchers in the world and is a Fellow of the Royal Society of Chemistry (FRSC). He was on the expert panel for UNEP on antimicrobial resistance. Dr. Kumar's research focuses on ascertaining, broadening, comprehending, and developing various dimensions of the fate, transport, and remediation of geogenic, micro, microbial, and emerging contaminants in freshwater systems. He renders editorial services to journals like Environmental Science & Technology Letters, ACS ES&T Engineering, npj Clean Water, Science of the Total Environment, Current Pollution Report, Groundwater for Sustainable Development, Reviews of Environmental Contamination and Toxicology, and Hydrological Research Letters. This article references 15 other publications.