The Scourge of Antibiotic Resistance: The Important Role of the Environment
TL;DR: The rapid evolution and spread of "new" antibiotic resistance genes has been enhanced by modern human activity and its influence on the environmental resistome, which highlights the importance of including the role of the environmental vectors, such as bacterial genetic diversity within soil and water, in resistance risk management.
Abstract: Antibiotic resistance and associated genes are ubiquitous and ancient, with most genes that encode resistance in human pathogens having originated in bacteria from the natural environment (eg, β-lactamases and fluoroquinolones resistance genes, such as qnr). The rapid evolution and spread of "new" antibiotic resistance genes has been enhanced by modern human activity and its influence on the environmental resistome. This highlights the importance of including the role of the environmental vectors, such as bacterial genetic diversity within soil and water, in resistance risk management. We need to take more steps to decrease the spread of resistance genes in environmental bacteria into human pathogens, to decrease the spread of resistant bacteria to people and animals via foodstuffs, wastes and water, and to minimize the levels of antibiotics and antibiotic-resistant bacteria introduced into the environment. Reducing this risk must include improved management of waste containing antibiotic residues and antibiotic-resistant microorganisms.
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TL;DR: The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large as discussed by the authors, and the evolution and widespread distribution of antibiotic-resistant elements in bacterial pathogens has made diseases that were once easily treatable deadly again.
Abstract: The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large. The evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens has made diseases that were once easily treatable deadly again. Unfortunately, accompanying the rise in global resistance is a failure in antibacterial drug discovery. Lessons from the history of antibiotic discovery and fresh understanding of antibiotic action and the cell biology of microorganisms have the potential to deliver twenty-first century medicines that are able to control infection in the resistance era.
1,481 citations
TL;DR: This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps, with particular focus on AcrAB-TolC and Mex pumps.
Abstract: The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.
1,016 citations
University of Barcelona1, Hacettepe University2, Cajal Institute3, European Medicines Agency4, University of Antwerp5, Brighton and Sussex Medical School6, GlaxoSmithKline7, Radboud University Nijmegen8, European Centre for Disease Prevention and Control9, Center for Disease Dynamics, Economics & Policy10, European Food Safety Authority11, University of Seville12, Southmead Hospital13, University College Dublin14, Aix-Marseille University15, Carlos III Health Institute16, University of Tübingen17, University of Warwick18
TL;DR: The views of the B-Debate participants regarding the current situation of antimicrobial resistance in animals and the food chain, within the community and the healthcare setting as well as the role of the environment and the development of novel diagnostic and therapeutic strategies are summarized, providing expert recommendations to tackle the global threat of antimacterial resistance.
Abstract: In the last decade we have witnessed a dramatic increase in the proportion and absolute number of bacterial pathogens resistant to multiple antibacterial agents. Multidrug-resistant bacteria are currently considered as an emergent global disease and a major public health problem. The B-Debate meeting brought together renowned experts representing the main stakeholders (i.e. policy makers, public health authorities, regulatory agencies, pharmaceutical companies and the scientific community at large) to review the global threat of antibiotic resistance and come up with a coordinated set of strategies to fight antimicrobial resistance in a multifaceted approach. We summarize the views of the B-Debate participants regarding the current situation of antimicrobial resistance in animals and the food chain, within the community and the healthcare setting as well as the role of the environment and the development of novel diagnostic and therapeutic strategies, providing expert recommendations to tackle the global threat of antimicrobial resistance.
803 citations
Cites background from "The Scourge of Antibiotic Resistanc..."
...Antibacterial agents have several routes of entry into the environment, such as sewage from the community or hospitals through manure and water bodies [17,18]....
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TL;DR: Rules are proposed for estimating the risks associated with genes that are present in environmental resistomes by evaluating the likelihood of their introduction into human pathogens, and the consequences of such events for the treatment of infections.
Abstract: In this Opinion article, Baquero and colleagues propose a hierarchical system for estimating the risks associated with genes present in environmental resistomes, by evaluating the likelihood of their introduction into human pathogens, and the consequences of such introduction events for the treatment of bacterial infections.
679 citations
TL;DR: Joint collaboration across the world with international bodies is needed to assist the developing countries to implement good surveillance of antibiotic use and antibiotic resistance, and strengthening of regulations that direct antibiotic manufacture, distribution, dispensing, and prescription is needed, hence fostering antibiotic stewardship.
Abstract: Due to the increased demand of animal protein in developing countries, intensive farming is instigated, which results in antibiotic residues in animal-derived products, and eventually, antibiotic resistance. Antibiotic resistance is of great public health concern because the antibiotic-resistant bacteria associated with the animals may be pathogenic to humans, easily transmitted to humans via food chains, and widely disseminated in the environment via animal wastes. These may cause complicated, untreatable, and prolonged infections in humans, leading to higher healthcare cost and sometimes death. In the said countries, antibiotic resistance is so complex and difficult, due to irrational use of antibiotics both in the clinical and agriculture settings, low socioeconomic status, poor sanitation and hygienic status, as well as that zoonotic bacterial pathogens are not regularly cultured, and their resistance to commonly used antibiotics are scarcely investigated (poor surveillance systems). The challenges that follow are of local, national, regional, and international dimensions, as there are no geographic boundaries to impede the spread of antibiotic resistance. In addition, the information assembled in this study through a thorough review of published findings, emphasized the presence of antibiotics in animal-derived products and the phenomenon of multidrug resistance in environmental samples. This therefore calls for strengthening of regulations that direct antibiotic manufacture, distribution, dispensing, and prescription, hence fostering antibiotic stewardship. Joint collaboration across the world with international bodies is needed to assist the developing countries to implement good surveillance of antibiotic use and antibiotic resistance.
670 citations
Cites background from "The Scourge of Antibiotic Resistanc..."
...Microorganisms (specifically, bacteria) do not live in isolation [4], but are found in milieu/medium (humans, air, water, plants, and soil) known as their habitat (aquatic ecosystem), which offers them with the appropriate nutritional and growth requirements necessary for survival....
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...It is somewhat obvious that the abundance and the mobility of antibiotic-resistant bacteria and resistance determinants in the soil can be greatly influenced by the application of manure (containing antibiotic residues, antibiotic-resistant bacteria, and their resistance genes on mobile elements) during fertilization of the soil, the use of wastewater (black or grey water) for the irrigation of agricultural lands, and the use of antibiotics to treat crop diseases [4,223]....
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...Human activities in response to industrialization drastically heightened the availability of antibiotic residues in food and the environment, and the development and distribution of antibiotic resistant bacteria along with their resistance genes, thus causing an increase in the abundance of resistant bacteria and genes [4]....
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References
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Tufts Medical Center1, University of California, San Diego2, Boston Children's Hospital3, University of California, Los Angeles4, Los Angeles Biomedical Research Institute5, Providence Portland Medical Center6, Case Western Reserve University7, United States Department of Veterans Affairs8, University of Virginia9, Johns Hopkins University School of Medicine10
TL;DR: An update on potentially effective antibacterial drugs in the late-stage development pipeline is provided, in the hope of encouraging collaboration between industry, academia, the National Institutes of Health, the Food and Drug Administration, and the Centers for Disease Control and Prevention work productively together.
Abstract: The Infectious Diseases Society of America (IDSA) continues to view with concern the lean pipeline for novel therapeutics to treat drug-resistant infections, especially those caused by gram-negative pathogens. Infections now occur that are resistant to all current antibacterial options. Although the IDSA is encouraged by the prospect of success for some agents currently in preclinical development, there is an urgent, immediate need for new agents with activity against these panresistant organisms. There is no evidence that this need will be met in the foreseeable future. Furthermore, we remain concerned that the infrastructure for discovering and developing new antibacterials continues to stagnate, thereby risking the future pipeline of antibacterial drugs. The IDSA proposed solutions in its 2004 policy report, “Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, a Public Health Crisis Brews,” and recently issued a “Call to Action” to provide an update on the scope of the problem and the proposed solutions. A primary objective of these periodic reports is to encourage a community and legislative response to establish greater financial parity between the antimicrobial development and the development of other drugs. Although recent actions of the Food and Drug Administration and the 110th US Congress present a glimmer of hope, significant uncertainly remains. Now, more than ever, it is essential to create a robust and sustainable antibacterial research and development infrastructure—one that can respond to current antibacterial resistance now and anticipate evolving resistance. This challenge requires that industry, academia, the National Institutes of Health, the Food and Drug Administration, the Centers for Disease Control and Prevention, the US Department of Defense, and the new Biomedical Advanced Research and Development Authority at the Department of Health and Human Services work productively together. This report provides an update on potentially effective antibacterial drugs in the late-stage development pipeline, in the hope of encouraging such collaborative action.
4,256 citations
TL;DR: This review brings up important questions that are still open, and addresses some significant issues which must be tackled in the future for a better understanding of the behavior of antibiotics in the environment, as well as the risks associated with their occurrence.
3,620 citations
TL;DR: Target metagenomic analyses of rigorously authenticated ancient DNA from 30,000-year-old Beringian permafrost sediments are reported and show conclusively that antibiotic resistance is a natural phenomenon that predates the modern selective pressure of clinical antibiotic use.
Abstract: The discovery of antibiotics more than 70 years ago initiated a period of drug innovation and implementation in human and animal health and agriculture. These discoveries were tempered in all cases by the emergence of resistant microbes. This history has been interpreted to mean that antibiotic resistance in pathogenic bacteria is a modern phenomenon; this view is reinforced by the fact that collections of microbes that predate the antibiotic era are highly susceptible to antibiotics. Here we report targeted metagenomic analyses of rigorously authenticated ancient DNA from 30,000-year-old Beringian permafrost sediments and the identification of a highly diverse collection of genes encoding resistance to β-lactam, tetracycline and glycopeptide antibiotics. Structure and function studies on the complete vancomycin resistance element VanA confirmed its similarity to modern variants. These results show conclusively that antibiotic resistance is a natural phenomenon that predates the modern selective pressure of clinical antibiotic use.
1,973 citations
"The Scourge of Antibiotic Resistanc..." refers background in this paper
...dates antibiotic use in medicine and agriculture [10]....
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TL;DR: Molden et al. as discussed by the authors presented a comprehensive assessment of water management in agriculture, focusing on water for food, water for life, and water for the future of agriculture.
Abstract: In Molden, David (Ed.). Water for food, water for life: a Comprehensive Assessment of Water Management in Agriculture. London, UK: Earthscan; Colombo, Sri Lanka: International Water Management Institute (IWMI).
1,931 citations
TL;DR: Methods to reduce resistant bacterial load in wastewaters, and the amount of antimicrobial agents, in most cases originated in hospitals and farms, include optimization of disinfection procedures and management of wastewater and manure.
1,755 citations
"The Scourge of Antibiotic Resistanc..." refers background in this paper
...well as the reverse; that is, emergence of novel mechanisms of acquired resistance in pathogens, genes that originally were present in harmless bacteria [51]....
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