Table of Contents
Overview
Definition of Antimicrobial Resistance
Antimicrobial resistance (AMR) is defined as the phenomenon where microorganisms, including bacteria, viruses, fungi, and parasites, develop the ability to withstand the effects of antimicrobial medicines that were previously effective against them. This resistance leads to the ineffectiveness of antibiotics and other antimicrobial agents, resulting in infections that are increasingly difficult or impossible to treat, thereby heightening the risk of disease spread, severe illness, disability, and death.[2.1] Antimicrobial resistance (AMR) refers to the phenomenon where microorganisms, including bacteria, viruses, fungi, and parasites, no longer respond to antimicrobial medicines such as antibiotics. This resistance occurs naturally over time due to genetic changes in these microorganisms.[2.1] However, the emergence and spread of AMR are significantly accelerated by human activities, particularly the misuse and overuse of antimicrobial agents in various contexts, including healthcare, agriculture, and livestock production.[2.1] As a result of this resistance, infections become increasingly difficult or even impossible to treat, leading to a heightened risk of disease spread, severe illness, disability, and death.[2.1] AMR is recognized as one of the top global public health threats, with bacterial resistance alone being directly responsible for an estimated 1.27 million deaths worldwide in 2019.[2.1] Mechanisms of resistance can vary among different types of bacteria and include alterations in the structure or number of penicillin-binding proteins (PBPs), the presence of efflux pumps that expel drugs, and the production of enzymes such as β-lactamases that hydrolyze antibiotics.[29.1] Additionally, bacteria can acquire resistance genes from other bacteria through processes such as transformation, conjugation, or transduction, allowing for rapid adaptation to new antimicrobial pressures.[30.1]Global Impact on Public Health
Antimicrobial resistance (AMR) poses a significant global health threat, with its implications extending across various sectors, including agriculture, healthcare, and the environment. The overuse and imprudent application of antibiotics in these areas have been identified as primary drivers of the increasing prevalence of resistant bacteria and their associated resistance genes (ARGs).[11.1] Specifically, the use of antibiotics in livestock and agriculture contributes to environmental contamination, which in turn fosters the emergence and spread of AMR.[12.1] Residual antibiotics from animal products can remain harmful even after cooking, leading to health risks such as yellowing of teeth and other adverse effects.[5.1] The U.S. Government has recognized AMR as a national public health priority and has initiated a comprehensive strategy to combat this issue. The National Strategy for Combating Antibiotic-Resistant Bacteria (CARB) outlines five key goals aimed at reducing the incidence and impact of antibiotic-resistant infections.[16.1] This strategy is supported by various public health initiatives, including the CDC's Antimicrobial Resistance Solutions Initiative, which focuses on enhancing national infrastructure to detect and respond to resistant infections.[17.1] Globally, the World Health Organization (WHO) has also developed a core package of interventions to guide countries in prioritizing their national action plans on AMR. These interventions emphasize a people-centered approach to ensure equitable access to quality health services, which is crucial for the prevention, diagnosis, and treatment of drug-resistant infections.[20.1] The collective efforts of these organizations aim to address the root causes of AMR, including optimizing antibiotic use in both human and animal health settings, thereby reducing the need for antibiotics and slowing the spread of resistant infections.[19.1]History
Early Discoveries of Antimicrobials
The early discoveries of antimicrobials marked a significant turning point in medical history, particularly during the "Golden Age of Antibiotics," spanning from the early 1940s to the mid-1960s. This era was characterized by the rapid discovery of numerous antibiotics, primarily derived from naturally occurring microorganisms. The isolation of streptomycin in 1944 from Streptomyces griseus initiated a global search for new antibiotic agents, resulting in many effective treatments still in use today.[56.1] The discovery of antibiotics has significantly transformed modern medicine, extending the average human lifespan by 23 years over the past century. However, the effectiveness of these antibiotics has been compromised by the emergence of antimicrobial resistance, contributing to the current crisis. In response, regulatory measures, such as the ban on antibiotics as growth promoters in animal feed in New Zealand, have been implemented to address the implications of antibiotic resistance on public health. Currently, 45 drugs are undergoing clinical trials, including several new classes with novel modes of action in phase 3 trials, indicating ongoing efforts to combat this pressing issue.[58.1] The decline in the discovery rate of new antibiotics has led to a reliance on modifying existing drugs to combat emerging resistance. Current strategies to discover new antimicrobials include exploring ecological niches beyond traditional sources, such as marine environments, and utilizing compounds derived from plants and animals.[59.1] The development of new antibiotics now faces significant economic and regulatory challenges, with the average time required to progress an antibiotic candidate from preclinical to clinical stages estimated at 10-15 years. For antibiotics in existing classes, only about one in fifteen candidates successfully reaches the market, while for new classes, the success rate drops to one in thirty.[77.1]Evolution of Resistance Mechanisms
The evolution of resistance mechanisms in bacteria has been significantly influenced by both natural processes and human activities. Initially, the natural history of antibiotic resistance genes suggests that these genes existed long before the clinical use of antibiotics, indicating a pre-existing capacity for resistance in bacterial populations.[49.1] This historical context is crucial for understanding the ongoing evolution of resistance. As antimicrobial usage increased, the complexity of resistance mechanisms among bacterial pathogens also escalated. Bacteria can acquire resistance through various mechanisms, including the acquisition of genes that encode enzymes capable of inactivating antibiotics, such as β-lactamases.[78.1] Additionally, bacteria may employ strategies such as target modification, altered permeability, and metabolic pathway bypassing to resist antibiotic action.[79.1] These biochemical resistance mechanisms are not only diverse but also readily spread among different bacterial genera, contributing to the rapid evolution of resistance.[78.1] Genetic mutations play a pivotal role in the development of antibiotic resistance. Bacteria can generate spontaneous mutants that confer resistance to virtually any antibiotic, although the frequency of such mutations varies by species and antibiotic.[61.1] Furthermore, horizontal gene transfer (HGT) facilitates the spread of resistance genes among bacterial populations, allowing new resistant variants to emerge without direct mutation.[64.1] This process of HGT is a significant driver of pathogen evolution, as it enables the rapid dissemination of resistance traits across different bacterial strains.[64.1] The inappropriate and irrational use of antibiotics has significantly contributed to the development of antimicrobial resistance (AMR), which poses a global threat to public health.[46.1] In both healthcare and agricultural settings, the widespread use of antimicrobials has created an environment conducive to the emergence of resistant strains.[47.1] To combat this issue, there is a pressing need to shift from antibiotic-reliant practices to more sustainable approaches in livestock management. Implementing holistic strategies that focus on enhanced housing conditions, biosecurity, nutrition, and alternative health management can effectively reduce antibiotic use in livestock farming.[53.1] By prioritizing animal welfare and improving hygiene, farmers can not only boost animal health but also mitigate the impact of AMR on both agricultural and human health.[54.1]In this section:
Recent Advancements
Novel Strategies to Combat Resistance
The emergence of antimicrobial resistance (AMR) has prompted the development of various novel strategies aimed at combating this global health crisis. One significant approach involves innovating financial policies to incentivize the development of new antibiotics, diagnostics, and other technologies that can mitigate AMR. This strategy recognizes that AMR is a complex issue that requires sustained efforts over time, including education and training for future healthcare leaders, prescribers, users, and policymakers to ensure effective management of antimicrobial use.[104.1] In addition to financial incentives, strengthening healthcare systems is crucial for addressing AMR. This includes promoting research collaboration and enhancing regulatory frameworks to ensure the responsible use of antimicrobials. International cooperation is also emphasized as a vital component in combating antibiotic resistance, particularly in low- and middle-income countries (LMICs) where the burden of AMR is disproportionately high.[96.1] The United Nations General Assembly has called for the establishment of a global development and stewardship framework to guide these efforts, highlighting the importance of coordinated international action.[97.1] Furthermore, addressing the misuse of antibiotics, particularly through over-the-counter sales, is essential for reducing resistance. Regulatory reforms and infection prevention and control measures must be tailored to local contexts to ensure successful implementation.[98.1] The Centers for Disease Control and Prevention (CDC) has initiated programs such as the Antimicrobial Resistance Solutions Initiative, which invests in national infrastructure to detect and respond to AMR threats.[105.1] Lastly, the establishment of global goals, such as the commitment to reduce deaths associated with bacterial AMR by 10% by 2030, reflects a concerted effort to tackle this issue on an international scale.[106.1] By optimizing antibiotic use in both human and animal health settings and prioritizing infection prevention, these strategies aim to slow the spread of resistant infections and reduce the overall need for antibiotic use.[19.1]Role of Antimicrobial Stewardship
Awareness of the need to curb antibiotic use is increasing globally, particularly in high-income countries, where policies and actions are more prevalent. However, in low- and middle-income countries (LMICs), rising incomes often correlate with increased antibiotic use, despite significant challenges related to access to these medications.[99.1] This situation underscores the importance of antimicrobial stewardship, which aims to optimize the use of antimicrobials to combat resistance while ensuring effective treatment for infections. Antimicrobial stewardship in livestock farming emphasizes the importance of holistic approaches to enhance animal health and welfare while reducing reliance on antibiotics. This proactive method involves improving housing conditions, management practices, and biosecurity measures, which collectively contribute to better animal health and productivity.[100.1] A comprehensive strategy that integrates hygiene, animal welfare, biosecurity, nutrition, genetic selection, and alternative health practices is essential for effectively reducing antibiotic use in livestock.[100.1] Furthermore, breeding for genetically disease-resistant livestock and utilizing alternative growth promotants, such as cattle anabolics or somatotropins, can also play a significant role in minimizing antibiotic dependence in food animals.[101.1] Ultimately, these strategies not only aim to improve livestock health but also seek to benefit human health by reducing the incidence and severity of diseases.[101.1] Despite these advancements, a lack of knowledge about effective alternatives to antimicrobials hampers the adoption of new farming practices.[102.1] Therefore, ongoing education and research are crucial to identify and validate strategies that can effectively replace antibiotics in livestock production. Community engagement plays a vital role in addressing antimicrobial resistance, particularly in LMICs. Initiatives such as the Community Engagement for Antimicrobial Resistance (CE4AMR) network emphasize participatory and creative approaches to empower local populations in combating AMR.[114.1] Successful examples include community dialogues and arts-based projects that raise awareness and foster understanding of antibiotic resistance.[116.1] These initiatives not only educate communities but also facilitate dialogue between local members and AMR experts, ensuring that strategies remain relevant and effective.[117.1] The urgency of addressing antimicrobial resistance is underscored by alarming statistics, with AMR responsible for an estimated 1.27 million deaths globally in 2019 alone.[119.1] The misuse and overuse of antimicrobials in various sectors, including agriculture, are significant contributors to this crisis.[118.1] Therefore, implementing robust antimicrobial stewardship programs, alongside community engagement and education, is essential for mitigating the impact of AMR and safeguarding public health.In this section:
Mechanisms Of Resistance
Genetic Changes in Pathogens
Genetic changes in pathogens play a crucial role in the development of antimicrobial resistance. These changes can occur through various mechanisms, including genetic mutations, horizontal gene transfer, and the acquisition of mobile genetic elements such as plasmids and transposons. For instance, transposons, often referred to as "jumping genes," can integrate into bacterial genomes or plasmids, facilitating the spread of antimicrobial resistance traits among bacterial populations.[130.1] One significant mechanism of resistance involves the alteration of bacterial proteins that serve as targets for antimicrobial agents. This can occur through genetic mutations that modify the structure or expression of these proteins, thereby preventing the drug from effectively binding.[140.1] Additionally, bacteria can develop resistance through the enzymatic degradation of antibiotics, which is often mediated by genes that encode specific enzymes capable of inactivating the drug.[142.1] Efflux pumps are a significant mechanism by which bacteria develop resistance to antibiotics, actively removing drugs from the bacterial cell and thereby reducing their intracellular concentrations.[134.1] This mechanism is part of a broader array of strategies that bacteria employ to evade antimicrobial agents, which also includes enzymatic degradation of antibiotics, target site modifications, and biofilm formation.[142.1] The presence of mobile genetic elements, such as transposons, facilitates the spread of these resistance traits among bacterial populations, complicating efforts to manage antimicrobial resistance.[130.1] As a result, infections caused by resistant strains can become untreatable and pose serious health risks.[134.1] Antimicrobial resistance (AMR) poses a significant threat to global health, as it diminishes the effectiveness of broad-spectrum antibiotics against common bacterial infections.[131.1] The fundamental mechanisms of antimicrobial resistance can be categorized into three primary strategies: (1) enzymatic degradation of antibacterial drugs, (2) alteration of bacterial proteins that serve as targets for these drugs, and (3) changes in membrane permeability to antibiotics.[140.1] These resistance mechanisms can be either plasmid-mediated or maintained on the bacterial chromosome, complicating treatment options.[140.1] A deeper understanding of these mechanisms is crucial for the development of new antimicrobial agents that can withstand the resistance strategies employed by microorganisms.[129.1] The urgent need for innovative therapeutic solutions is underscored by the presence of resistant bacteria and antibiotic residues in the environment, which necessitates immediate global action to combat AMR.[131.1]Environmental Factors Contributing to Resistance
Environmental factors play a significant role in the emergence and spread of antimicrobial resistance (AMR). One of the primary contributors to this issue is the imprudent and overuse of antibiotics in agriculture, veterinary, and medical sectors, which has led to a global epidemic of AMR.[136.1] Agricultural ecosystems are particularly important in this context, as discharges from agricultural practices are recognized as major sources of antibiotic pollution in the environment. It is estimated that up to 90% of antibiotics used in livestock production ultimately end up in various forms in the environment, intensifying the selection for resistant microorganisms.[138.1] The transmission of antibiotic-resistant bacteria and their associated resistance genes (ARGs) is facilitated by various environmental drivers. These include the release of antibiotic residues from domestic settings and the direct use of antimicrobials in healthcare and agriculture.[136.1] The environment acts as a conduit for the transfer of bacteria and genes between humans, animals, and the ecosystem, complicating efforts to manage and mitigate the resistance crisis.[137.1] Furthermore, increasing temperatures and climate change hazards exacerbate these issues by promoting the development and spread of antimicrobials, thereby enhancing resistance.[135.1] Understanding the pathways and identifying the drivers of environmental evolution and transmission of antibiotic resistance are crucial for addressing this public health challenge. Effective surveillance and monitoring of AMR in foodborne bacteria, which integrates data from humans, animals, and food, are essential for developing strategies to combat the spread of resistance.[156.1] Active surveillance methods, which involve public health staff monitoring target pathogens and collecting incidence data, are also vital for tracking and controlling AMR.[157.1] Regular dissemination of AMR surveillance data can inform policymakers and help revise case management recommendations in healthcare settings, contributing to systematic efforts against AMR.[158.1]Public Health Implications
Impact on Treatment Outcomes
Antimicrobial resistance (AMR) significantly complicates the treatment of bacterial infections, leading to poorer patient outcomes. The emergence of resistant pathogens has been linked to increased mortality rates, with AMR directly responsible for an estimated 1.27 million deaths globally in 2019 and contributing to a total of 4.95 million deaths that year.[165.1] The ability of bacteria to develop resistance mechanisms, such as antibiotic inactivation, target modification, and altered permeability, further exacerbates the challenges faced in clinical settings.[184.1] The impact of antimicrobial resistance on treatment outcomes presents significant challenges in clinical practice. The absence of appropriate therapy for patients infected with resistant bacterial pathogens can lead to confounding factors that obscure the true effects of resistance on patient outcomes.[204.1] Moreover, the potential causes for poor outcomes include the use of inferior antibiotics and delays in effective therapy, which complicate the evaluation of treatment efficacy.[204.1] It is crucial to recognize that the definition of effective therapy may not account for treatments that, while microbiologically effective, could be clinically problematic.[204.1] Thus, understanding these dynamics is essential for improving treatment decisions and patient outcomes in the context of antimicrobial resistance. Antimicrobial resistance (AMR) is a critical global health issue that arises from the misuse and overuse of antibiotics across various sectors, leading to the emergence of resistant microorganisms.[168.1] Bacteria can be intrinsically resistant to one or more classes of antimicrobial agents or may acquire resistance through de novo mutation or by obtaining resistance genes from other organisms.[185.1] These acquired resistance genes can enable bacteria to produce enzymes that destroy antibacterial drugs or to express efflux systems that prevent the drugs from being effective.[185.1] The rise of multidrug-resistant pathogens presents significant challenges to healthcare systems worldwide, complicating treatment strategies and impacting clinical outcomes.[168.1] As AMR continues to evolve, it poses serious implications for both human and animal health, making the management of infections increasingly difficult and potentially leading to longer hospital stays and higher healthcare costs.[168.1]Economic Burden of Antimicrobial Resistance
The economic burden of antimicrobial resistance (AMR) is significant and multifaceted, impacting healthcare systems, economies, and public health outcomes. Public health campaigns play a crucial role in addressing this burden by raising awareness about the dangers of antibiotic overuse and promoting responsible antibiotic use among the general population. These campaigns aim to change public perceptions of antibiotics, which are often viewed as "cure-alls," and emphasize the importance of completing prescribed courses of treatment to prevent resistance.[169.1] Evidence from various campaigns indicates that targeted public health interventions can effectively enhance knowledge and commitment to responsible antibiotic use. For instance, a campaign conducted in the UK in 2014 successfully engaged both the public and healthcare professionals, resulting in increased awareness of antimicrobial resistance and a commitment to responsible antibiotic use among participants.[170.1] Similarly, a community-based educational intervention in Ras Al Khaimah, United Arab Emirates, demonstrated a significant improvement in participants' understanding of AMR, with notable increases in knowledge regarding the necessity of completing antibiotic courses and the ineffectiveness of antibiotics against viral infections.[171.1] Moreover, mass media campaigns, such as the "Keep Antibiotics Working" initiative, have utilized diffusion strategies to effectively spread information and modify antibiotic-seeking behaviors, thereby reducing public demand for unnecessary antibiotics.[172.1] These efforts are essential in mitigating the economic impact of AMR, as reducing inappropriate antibiotic use can lead to lower healthcare costs associated with treating resistant infections. On a broader scale, national action plans, such as the U.S. National Action Plan for Combating Antibiotic-Resistant Bacteria, aim to provide a coordinated response to AMR, which is crucial for improving public health and reducing the economic burden associated with resistant infections.[186.1] However, the effectiveness of these policies is contingent upon strengthening governance and integrating AMR strategies into wider health, agricultural, and environmental initiatives.[188.1] Despite the recognition of AMR as a critical public health issue, many countries have yet to implement effective policies to curb the overuse and misuse of antimicrobials, which exacerbates the economic burden of AMR.[190.1] Research indicates a potential relationship between national policies aimed at limiting over-the-counter antibiotic sales and actual antibiotic usage practices, suggesting that further investigation into policy effectiveness is necessary to understand the true impact of government measures on AMR.[189.1] Thus, addressing the economic burden of AMR requires a multifaceted approach that includes public health campaigns, effective governance, and comprehensive national policies.In this section:
Agricultural Use Of Antimicrobials
Antibiotic Use in Livestock
Antibiotics are extensively utilized in agriculture, particularly within livestock, poultry, fisheries, and animal husbandry. Their primary applications include the prevention and treatment of various diseases in crops, as well as promoting growth and combating infections in livestock.[211.1] However, the use of antibiotics in food-producing animals has raised significant concerns regarding the development of antimicrobial resistance (AMR). This issue is particularly pressing as research indicates that pathogenic organisms, including antibiotic-resistant bacteria and genes, can be transmitted from animals to humans through food, water, and direct contact.[210.1] The American Academy of Microbiology has highlighted the critical need to address the impact of antibiotic resistance stemming from agricultural practices. In a colloquium held in 2001, experts discussed strategies to mitigate this issue, which include categorizing antibiotics based on their importance to human medicine, revising safety assessments for new animal drug applications, and establishing regulatory thresholds for antibiotic use.[210.1] Despite these efforts, there remains a significant debate among stakeholders regarding the extent of agriculture's contribution to AMR and the strength of the scientific evidence linking agricultural practices to this global health threat.[212.1] Globally, the patterns of antimicrobial use in livestock vary significantly, with hotspots of usage predominantly located in Asia, where approximately 67% of global antimicrobial consumption occurs.[221.1] This regional disparity is compounded by a lack of comprehensive data on antimicrobial use, which is often hindered by insufficient surveillance systems and reluctance from producers to disclose usage information.[220.1] The indiscriminate prescribing of antibiotics in both human and animal health sectors is recognized as a key driver of AMR, with projections indicating that the misuse of antibiotics could lead to a "Silent Pandemic" surpassing other mortality causes by 2050.[219.1] To combat these challenges, regulatory measures have been implemented, such as the Federal Food and Drug Administration's veterinary feed directive regulations introduced in 2015, which aim to restrict the use of certain over-the-counter antimicrobial drugs in animal production.[226.1] Furthermore, the United States Department of Agriculture (USDA) has proposed an action plan to gather and disseminate science-based information regarding antibiotic use and its relationship to resistance patterns in livestock management practices.[228.1] Effective implementation of these regulations and strategies is essential for ensuring both agricultural productivity and public health, necessitating collaboration between veterinarians and farmers to promote responsible antimicrobial use.[227.1]Consequences for Human Health
The use of antimicrobials in agricultural practices has significant consequences for human health, particularly through the emergence and spread of antimicrobial resistance (AMR). It is widely recognized that reducing antibiotic use in food-producing animals is essential to mitigate the global spread of AMR.[222.1] The intricate interactions between human activities, environmental factors, and microbial processes contribute to this issue, as direct exposure to antibiotic-resistant bacteria and antibiotic resistance genes (ARGs) in agricultural produce—especially in raw vegetables, salads, herbs, and fruits—can facilitate the transmission of resistance from the environment to humans.[223.1] Research indicates that increasing antibiotic use in factory farming can have a profound impact on human health; for instance, a global increase of 1,000 tons in antibiotic use can lead to a 21% rise in antibiotic resistance among humans.[224.1] This correlation is further exacerbated by economic factors, as higher consumer incomes typically drive increased demand for animal-based foods, which in turn contributes to higher levels of AMR in human populations.[224.1] Foodborne antimicrobial resistance (FAMR) is particularly concerning due to its direct link to human infections caused by resistant bacteria originating from contaminated food sources. The mechanisms of resistance are complex, involving genetic adaptations and environmental influences, as well as cross-species interactions that allow resistant bacteria to persist and spread within food systems.[225.1] The movement of these resistant bacteria is facilitated by environmental conditions that promote their survival and dissemination, highlighting the critical need for addressing agricultural practices to protect public health.[225.1]Research And Development
Challenges in Developing New Antibiotics
The development of new antibiotics faces significant challenges due to antimicrobial resistance (AMR) and the economic landscape of drug development. AMR is a major global public health threat, directly causing an estimated 1.27 million deaths in 2019 and contributing to a total of 4.95 million deaths.[248.1] The misuse and overuse of antimicrobials in healthcare and agriculture have fostered an environment where resistant microorganisms thrive, complicating infection treatment and increasing the risk of severe illness and death.[248.1] This has slowed the discovery of new antibiotics, as pharmaceutical companies encounter diminishing economic returns for developing new anti-infectives. The rise in mortality from chronic conditions like cancer and heart disease further overshadows deaths from infectious diseases.[247.1] The economic model for antibiotic development is strained by high research and development costs and limited revenue potential due to the intended sparing use of antibiotics. This has led to reduced investment in antibiotic R&D, resulting in an insufficient pipeline of new drugs.[261.1] The few antibiotics developed, such as carbapenems and novel beta-lactam/beta-lactamase inhibitor combinations, are often expensive and primarily available in high-resource settings, exacerbating the burden of AMR in low- and middle-income countries.[247.1][247.1] The emergence of multidrug-resistant pathogens poses a critical challenge to healthcare systems globally, with projections suggesting that AMR could surpass other causes of mortality by 2050 if unaddressed.[249.1] The complexity of bacterial resistance mechanisms, including drug target mutations and the acquisition of resistance genes, further complicates the development of effective therapies.[250.1] Addressing these challenges requires a multifaceted approach, including economic incentives and policy changes. Current incentives, such as public support for R&D, regulatory changes, and market exclusivity, are inadequate to stimulate new investments in antibiotic R&D.[260.1] Proposals from groups like Chatham House and the Review on Antimicrobial Resistance emphasize the need for substantial pull incentives to encourage innovative product development.[257.1] A combination of push and pull incentives, along with delinkage strategies, may be necessary to tackle issues in antibiotic research and development comprehensively.[256.1] Advanced Market Commitments (AMCs) have been identified as a promising mechanism to stimulate R&D, drawing lessons from neglected vaccine development.[258.1] There is a growing consensus that fully delinked models may offer a more sustainable solution compared to partially delinked options, as they prevent manufacturers from raising unit prices to maximize sales.[259.1] These strategies aim to create a more conducive economic environment for developing new antibiotics, addressing the pressing public health threat posed by AMR.Innovative Approaches in Antibiotic Discovery
Innovative approaches in antibiotic discovery are crucial in addressing the growing challenge of antimicrobial resistance (AMR). One promising strategy involves the discovery of novel antibiotics through the modification of existing compounds, screening of small-molecule libraries, and exploration of unique environments that may harbor new microbial life.[267.1] Additionally, enhancing the efficacy of current antibiotics can be achieved through metabolic stimulation or by employing more efficient delivery systems.[267.1] Alternatives to traditional antibiotics are also being developed, including bacteriophages, anti-biofilm drugs, probiotics, nanomaterials, vaccines, and antibody therapies.[267.1] These alternatives are essential as they provide new mechanisms to combat resistant bacterial strains. The integration of a "One-Health" approach, which emphasizes the interconnectedness of human, animal, and environmental health, is vital for strengthening surveillance and control of antibiotic resistance.[268.1] Understanding the mechanisms of bacterial evolution and resistance is critical for informing these innovative strategies. Bacteria can develop resistance through gene transfer, mutation, and adaptation, which allows for rapid dissemination of resistance traits across populations.[269.1] The interactions within microbial communities also play a significant role in how bacteria respond to antibiotic treatments, suggesting that resistance should be viewed as an emergent property of these communities rather than solely a characteristic of individual species.[270.1] Recent advancements in antibiotic development include the emergence of immuno-antibiotics and targeting biochemical pathways associated with resistance, such as the SOS response and hydrogen sulfide production.[277.1] These new classes of antibiotics aim to disrupt the mechanisms that bacteria use to evade treatment. For instance, darobactin has been identified as a promising candidate due to its unique mechanism of action and broad spectrum of activity.[279.1] The urgency for novel antibiotics is underscored by alarming statistics, with bacterial pathogens responsible for millions of deaths annually, and antibiotic resistance contributing significantly to this toll.[276.1] The World Health Organization has identified several superbugs as priorities for research and development, highlighting the need for innovative solutions to combat AMR effectively.[278.1] As the landscape of antibiotic resistance evolves, continuous research and development efforts are essential to ensure effective treatment options remain available.Global Initiatives
WHO and CDC Efforts
The World Health Organization (WHO) has been instrumental in addressing antimicrobial resistance (AMR) through the Global Action Plan on Antimicrobial Resistance, which emphasizes the need for all countries to develop or update and implement multisectoral national action plans by 2030. These plans are tailored to each country's specific context and leverage existing healthcare infrastructure and resources. To support this initiative, the WHO Evidence-informed Policy Network (EVIPNet) is collaborating with the International Vaccine Institute’s Regional AMR Data Analysis for Advocacy, Response and Policy (RADAAR) project, focusing on enhancing country capacities to develop evidence-informed policies in four countries: Bhutan, Ghana, Kenya, and the Lao People's Democratic Republic.[301.1] In parallel, the Centers for Disease Control and Prevention (CDC) has established the Global Antimicrobial Resistance Laboratory and Response Network, which includes the Antibiotic Resistance in Communities and Hospitals (ARCH) initiative. This program investigates high-risk, multidrug-resistant organisms (MDROs) across six countries to better understand how these pathogens spread in both community and healthcare settings. By gaining insights into exposure pathways, scientists aim to develop targeted interventions to mitigate the spread of these resistant germs.[292.1] Both organizations face significant challenges in implementing their respective action plans. Systematic analyses indicate that the burden of bacterial AMR may surpass that of major diseases such as HIV and malaria, particularly in sub-Saharan Africa. The implementation of effective global responses is hindered by issues such as resource inequity and gaps in execution.[299.1] Furthermore, evaluations of national action plans reveal that many countries struggle with health system barriers, including inadequate stakeholder collaboration and insufficient situational analyses, which are critical for aligning national strategies with WHO objectives.[302.1]Collaborative International Research Programs
In response to the pressing issue of antimicrobial resistance (AMR), several collaborative international research programs have been established to foster innovation in antibiotic discovery. One notable initiative is the Gram-Negative Antibiotic Discovery Innovator (Gr-ADI), launched by the Gates Foundation, Novo Nordisk Foundation, and Wellcome. This $50 million initiative specifically targets the challenges posed by Gram-negative bacteria, which are responsible for a significant number of global deaths, particularly in low- and middle-income countries.[310.1] The Gr-ADI aims to drive innovation in early drug discovery by focusing on the development of direct-acting small molecule antibiotics with broad-spectrum activity against Enterobacteriaceae, using Klebsiella spp. as a model pathogen.[308.1] The Gr-ADI initiative aims to fuel innovative research and development in antibiotic discovery by providing financial resources and support, which encourages scientists and researchers to explore novel pathways for creating effective treatments against Gram-negative infections.[311.1] This collaborative approach is essential, as antimicrobial resistance (AMR) is a serious global health threat that is directly responsible for an estimated 1.14 million deaths annually and contributes to an additional 4.71 million deaths each year, alongside significant economic costs.[309.1] Discovering new antibiotics and bringing them to market presents formidable challenges that must be addressed to enhance our protection against the growing threat of drug-resistant infections.[312.1] Moreover, the initiative recognizes the complexities involved in discovering new antibiotics, such as overcoming bacterial permeability barriers and efflux pump activity, which can hinder the progression of potential drug candidates.[313.1] By fostering cooperation and innovation, Gr-ADI represents a critical step towards addressing the urgent need for new antibiotics in the face of rising drug-resistant infections.[310.1]References
[2] Antimicrobial resistance - World Health Organization (WHO) — © Credits Antimicrobial resistance 21 November 2023 Key facts Antimicrobial resistance (AMR) is one of the top global public health and development threats. It is estimated that bacterial AMR was directly responsible for 1.27 million global deaths in 2019 and contributed to 4.95 million deaths (1). Antimicrobial Resistance (AMR) occurs when bacteria, viruses, fungi and parasites no longer respond to antimicrobial medicines. As a result of drug resistance, antibiotics and other antimicrobial medicines become ineffective and infections become difficult or impossible to treat, increasing the risk of disease spread, severe illness, disability and death. Its emergence and spread is accelerated by human activity, mainly the misuse and overuse of antimicrobials to treat, prevent or control infections in humans, animals and plants.
[5] Pollution from livestock farming antibiotics an emerging environmental ... — Indeed, residual antibiotics (such as penicillin, tetracycline, and streptomycin, etc.) found in products of animal origin are harmful to human health. These antibiotics still exist even after cooking, with no reduction of their quantities (Javadi, 2011). The harmful effects of these antibiotic residues can be featured in teeth yellowing
[11] Environmental Antibiotic Resistance: Recent Trends, Scope, and ... — Multiple drivers contribute to the dissemination of antibiotic-resistant bacteria (ARB) and their associated antibiotic-resistance genes (ARGs). These drivers include direct factors, e.g., the usage of antimicrobial drugs in healthcare, agriculture, livestock, and the environment.
[12] Environmental Spread of Antibiotic Resistance - PMC — Antibiotic resistance represents a global health concern. Soil, water, livestock and plant foods are directly or indirectly exposed to antibiotics due to their agricultural use or contamination. This selective pressure has acted synergistically to
[16] PDF — The U.S. Government is responding to antibiotic resistance with a comprehensive and coordinated suite of actions implemented by a diverse set of agencies using a One Health approach. The National Strategy for Combating Antibiotic-Resistant Bacteria (CARB) lays out five goals to reduce the incidence and impact of antibiotic-resistant infections:
[17] Antimicrobial Resistance Solutions Initiative — CDC's Antimicrobial Resistance Solutions Initiative invests in national infrastructure to detect, respond, contain and prevent resistant infections. ... U.S. Actions & Events to Combat Antimicrobial Resistance. ... Public Health. CDC and FDA Antimicrobial Resistance Isolate Bank
[19] PDF — to reduce antibiotic resistance, such as optimizing the use of antibiotics in human and animal health settings. This Plan continues to prioritize infection prevention and control to slow the spread of resistant infections and reduce the need for antibiotic use. To ensure that patients receive the right antibiotic care, the Plan
[20] 13 critical interventions that support countries to address ... — It also supports a more programmatic and comprehensive response to AMR at the country level underpinning the importance of equitable and affordable access to quality health services for the prevention, diagnosis and treatment of drug-resistant infections. This practical set of interventions, based on the need for a strong people-centred response in the human health sector, will greatly contribute to One Health actions under the umbrella of multisectoral national action plans on AMR,” said Kitty Van Weezenbeek, Director Surveillance Prevention and Control, WHO AMR Division. Overall, the people-centred approach is designed to ensure equitable, affordable access to good-quality preventive services, timely diagnosis, appropriate treatment and care of (resistant) infections to reduce the impact of AMR on patients in terms of morbidity and mortality, while leaving no one behind and contributing to the attainment of the Sustainable Development Goals.
[29] An overview of the antimicrobial resistance mechanisms of bacteria - PMC — One mechanism of resistance to the β-lactam drugs used almost exclusively by gram positive bacteria is via alterations in the structure and/or number of PBPs (penicillin-binding proteins). Resistance to the β-lactam drugs occurs through three general mechanisms: (1) preventing the interaction between the target PBP and the drug, usually by modifying the ability of the drug to bind to the PBP (this is mediated by alterations to existing PBPs or acquisition of other PBPs; (2) the presence of efflux pumps that can extrude β-lactam drugs; (3) hydrolysis of the drug by β-lactamase enzymes ,. The production of β-lactamases is the most common resistance mechanism used by gram negative bacteria against β-lactam drugs, and the most important resistance mechanism against penicillin and cephalosporin drugs ,.
[30] Mechanisms of Antimicrobial Resistance in Bacteria — Thus, normally susceptible populations of bacteria may become resistant to antimicrobial agents through mutation and selection, or by acquiring from other bacteria the genetic information that encodes resistance. The last event may occur through 1 of several genetic mechanisms, including transformation, conjugation, or transduction.
[46] Infographic depicting a timeline of antibiotic resistance: when ... — Antimicrobial resistance (AMR) is a global threat worldwide. Inappropriate and irrational use of antibiotics are the responsible causes for the development of AMR in the pathogenic microorganisms.
[47] A Brief History of Antimicrobial Resistance — While widespread use of antimicrobials in both health care and agricultural settings created an environment for resistance to flourish, the discovery of new antibiotics slowed.26 Soon enough, antimicrobial drug development began to clash with the realities of an economic system predicated on supply and demand.27 As death rates from cancer and heart disease rose to replace deaths from infectious diseases, pharmaceutical companies faced slimmer economic margins for developing new anti-infectives. The rate of discovery of new antibiotics slowed, and those few specialized drugs that were developed to overcome antimicrobial resistance (eg, carbapenems, lipopeptides, oxazolidinones, novel tetracyclines, and novel beta-lactam/beta-lactamase inhibitor combinations) were expensive to use.28 With the latest antimicrobials often only available in highly resourced settings, low- and middle-income countries (LMICs) face a disproportionate burden of antimicrobial resistance and associated deaths.
[49] A Brief History Of Antibiotic Resistance: How A Medical Miracle Turned ... — "The natural history of antibiotic resistance genes can be revealed through the phylogenetic reconstruction," the authors of one study write, "and this kind of analysis suggests the long-term presence of genes conferring resistance to several classes of antibiotics in nature well before the antibiotic era." In short, bacteria have
[53] Strategies for Reducing Antibiotic Use in Livestock — Shifting from antibiotic-reliant feed to holistic approaches focused on enhanced housing conditions and management practices offers a powerful way to reduce antibiotic use in livestock farming. By concentrating on key areas such as hygiene, welfare, biosecurity, nutrition, genetics, and alternative health management, farmers can boost animal
[54] Sustainable Livestock Practices for Minimizing Antibiotic Use — Sustainable Livestock Practices for Minimizing Antibiotic Use Home Sustainable Livestock Practices for Minimizing Antibiotic Use Sustainable Livestock Practices for Minimizing Antibiotic Use They help reduce the reliance on antibiotics and improve animal health. Future livestock practices must focus on sustainability and health. Sustainable livestock farming prioritizes animal welfare. Feeding practices directly impact livestock health and antibiotic use. This approach promotes animal health while reducing reliance on antibiotics. Nutritional Strategies for Improving Livestock Immunity and Reducing Dependency on Antibiotics The Role of Animal Welfare in Sustainable Farming Practices Animal welfare plays a vital role in sustainable farming practices. Green Valley Farms successfully reduced antibiotic use by adopting rotational grazing. Future Trends: Innovations in Sustainable Livestock Practices and Antibiotic Alternatives Pasture Rotation Strategies for Sustainable Livestock Farming
[56] Antibiotics: from prehistory to the present day | Journal of ... — The Golden Age. After this kick-start, the following 20 years became the 'Golden Age' of antibiotic discovery. Initially, the best source of new agents was from other naturally occurring microorganisms and after streptomycin 11 was isolated in 1944 from Streptomyces griseus (an organism found in soil), a worldwide search began. Every effort
[58] Antibiotics: past, present and future - ScienceDirect — In just over 100 years antibiotics have drastically changed modern medicine and extended the average human lifespan by 23 years. Since then, a gradual decline in antibiotic discovery and development and the evolution of drug resistance in many human pathogens has led to the current antimicrobial resistance crisis. Here we give an overview of the history of antibiotic discovery, the major classes of antibiotics and where they come from. We also report on the current state of antibiotic development, with 45 drugs currently going through the clinical trials pipeline, including several new classes with novel modes of action that are in phase 3 clinical trials.
[59] A Brief History of the Antibiotic Era: Lessons Learned and Challenges ... — Therefore, with the decline of the discovery rate, the mainstream approach for the development of new drugs to combat emerging and re-emerging resistance of pathogens to antibiotics has been the modification of existing antibiotics (Chopra et al., 2002). Some possible approaches to tap the novel antimicrobial diversity is the exploration of ecological niches other than soil, such as the marine environment (Hughes and Fenical, 2010; Rahman et al., 2010), borrowing antimicrobial peptides and compounds from animals and plants (Hancock and Sahl, 2006), mimicking the natural lipopeptides of bacteria and fungi (Makovitzki et al., 2006), accessing the uncultivated portion of microbiota through the metagenomic approach (MacNeil et al., 2001), and, finally, the use of the complete synthetic route pioneered during the early years of the antibiotic era.
[61] The emergence of antibiotic resistance by mutation — It is possible to generate spontaneous mutants in vitro that confer resistance to virtually any antibiotic, although frequencies vary dramatically according to the bacterial species and the agent tested (with most frequencies typically ≤ 10 -6).Bacteria carrying resistance mutations may be 'less fit' initially than wild-type organisms, but this is often a temporary phenomenon, and
[64] Horizontal Gene Transfer | Evolution, Medicine, and Public Health ... — Horizontal gene transfer (HGT) is the movement of genetic information between organisms, a process that includes the spread of antibiotic resistance genes among bacteria (except for those from parent to offspring), fueling pathogen evolution.
[77] Lack of innovation set to undermine antibiotic performance and health gains — It currently takes approximately 10-15 years to progress an antibiotic candidate from the preclinical to the clinical stages. For antibiotics in existing classes, on average, only one of every 15 drugs in preclinical development will reach patients. For new classes of antibiotics, only one in 30 candidates will reach patients.
[78] Mechanisms of Antimicrobial Resistance in Bacteria — As antimicrobial usage increased, so did the level and complexity of the resistance mechanisms exhibited by bacterial pathogens. ... Several mechanisms of antimicrobial resistance are readily spread to a variety of bacterial genera. First, the organism may acquire genes encoding enzymes, such as β-lactamases, that destroy the antibacterial
[79] Action and resistance mechanisms of antibiotics: A guide for clinicians ... — Action and resistance mechanisms of antibiotics: A guide for clinicians - PMC Action and resistance mechanisms of antibiotics: A guide for clinicians The biochemical resistance mechanisms used by bacteria include the following: antibiotic inactivation, target modification, altered permeability, and “bypass” of metabolic pathway. Keywords: Antibiotics, antimicrobial resistance, bacterial cell wall, mechanism of action For this purpose, we need to know the basic anatomy of bacterial cell, classification of antibiotics based on their mechanism of action, mechanisms of antibiotic resistance, and individual antibiotics with their common mechanism of resistance. The following biochemical types of resistance mechanisms are used by bacteria: Antibiotic inactivation, target modification, altered permeability, and “bypass” metabolic pathway. Antibiotic resistance mechanisms of clinically important bacteria.
[96] Antibiotics Resistant in the Developing Countries — Recommendations include strengthening healthcare systems, promoting research collaboration, enhancing regulatory frameworks, and fostering international cooperation. By implementing these strategies, developing countries can combat antibiotic resistance effectively, protect public health, and ensure the continued effectiveness of antibiotics.
[97] Global Framework for Development and Stewardship to Combat ... — In September 2016, the United Nations General Assembly in its 'Political declaration of the high-level meeting of the General Assembly on antimicrobial resistance' called upon the WHO, together with the Food and Agriculture Organization of the United Nations (FAO) and the World Organisation for Animal Health (OIE), to finalize a global development and stewardship framework.
[98] Antibiotic Resistance in Developing Countries: Emerging Threats and ... — For example, over-the-counter antibiotic sales exacerbate misuse and resistance while highlighting gaps in regulatory frameworks [15, 22, 28, 45-63]. Efforts to address these drivers, such as ASPs, regulatory reforms, and IPC measures, must consider local contexts for successful implementation.
[99] Policies to Address Antibiotic Resistance in Low- and Middle-Income ... — Awareness of the need to curb antibiotic use is on the rise globally, but policies and actions are more prevalent in high-income countries. As incomes in low- and middle-income countries rise, antibiotic use increases, but there are still significant problems concerning lack of access to antibiotics in such place.
[100] Strategies for Reducing Antibiotic Use in Livestock — This proactive method boosts animal health and welfare while lessening our dependence on antibiotics for managing diseases. Shifting from antibiotic-reliant feed to holistic approaches focused on enhanced housing conditions and management practices offers a powerful way to reduce antibiotic use in livestock farming. By concentrating on key areas such as hygiene, welfare, biosecurity, nutrition, genetics, and alternative health management, farmers can boost animal health and productivity while combating the threat of antibiotic resistance. Reducing antibiotic use in livestock demands a comprehensive approach that blends improved hygiene, animal welfare, biosecurity, nutrition, genetic selection, and alternative health practices. Biosecurity measures are essential for preventing diseases from infiltrating and spreading among livestock populations, improving animal health, productivity, and public health.
[101] Approaches to Minimizing Antibiotic Use in Food-Animal Production — Reducing the use of antibiotics in food animals must benefit human and animal health in reducing the incidence and severity of disease. ... breeding for genetically disease-resistant livestock (Axford and Owen 1991); and (5) in some instances, using alternative growth promotants such as cattle anabolics (Rumsey 1988) or somatotropins (NRC 1994
[102] Strategies to reduce antimicrobials in livestock and ... - PubMed — A lack of knowledge about alternatives to replace antimicrobials, and their effectiveness under field conditions, hampers changes in farming practices. This work aimed to understand the impact of strategies to reduce antimicrobial usage (AMU) in livestock and aquaculture, under field conditions, using a structured scoping literature review.
[104] 3 steps LifeArc is taking to tackle antimicrobial resistance before it ... — Innovating financial policies to incentivise the development of new antibiotics, diagnostics, and other technologies to reduce antimicrobial resistance. AMR isn't going to be a quick fix and so education, and the training of future healthcare leaders, prescribers, users, and policymakers, will also be vital in the effective management and
[105] Antimicrobial Resistance Solutions Initiative — CDC's Antimicrobial Resistance Solutions Initiative invests in national infrastructure to detect, re... July 16, 2024. Antimicrobial Resistance Investment Map and Funding. Map showcases CDC investments in the nation to protect Americans from antimicrobial resistance. May 22, 2024.
[106] U.S. Actions & Events to Combat Antimicrobial Resistance — UN General Assembly held second high-level meeting on antimicrobial resistance and adopted a political declaration [PDF - 15 Pages], which established global goals, commitments, and targets for combating antimicrobial resistance, including a goal to reduce global deaths associated with bacterial antimicrobial resistance by 10% by 2030.
[114] About | Community Engagement for Anti-microbial Resistance — CE4AMR is a network which champions the use of community engagement, participatory and creative approaches to tackle Antimicrobial Resistance (AMR) in low and middle income countries. ... them as integral to meeting global recommendations on tackling AMR as stipulated by the World Health Organisation and country-specific AMR action plans.
[116] Community Engagement • Antimicrobial Resistance (AMR) — It is a collaborative, open-access knowledge hub where community engagement practitioners, researchers, health workers and others can network, share resources, and discuss good practices.Access resources and project reports on AMR, including:A puppet show to engage the community addressing antimicrobial resistance and research with children in ThailandPublic Engagement with Microbial Resistance through Drama in Karnataka, IndiaSuperheroes Against Superbugs: a public engagement project that aims to raise public awareness and improve public understanding of antibiotic resistant-infections in India, and to build a society of smart antibiotic usersAn animation produced by the Vietnamese Platform for Antimicrobial Reductions in Chicken production (ViParc) to encourage local farmers to reduce use of antimicrobials in chicken rearing, that was part of a wider community dialogue project to understand why farmers use antibiotics for livestock.
[117] Engaging Local Communities in The Fight Against Antimicrobial ... — ENGAGING LOCAL COMMUNITIES IN THE FIGHT AGAINST ANTIMICROBIAL RESISTANCE: A CALL FOR INCLUSIVE ACTION - One Health and Development Initiative (OHDI) Antimicrobial resistance (AMR) is a top global threat to human and animal health, the environment, food and nutrition, economic development and social equity. The misuse and overuse of antimicrobials by the local communities in human, animal and plant health are the main drivers in the development of drug-resistant pathogens. These policies can involve resource provision for local projects like the establishment of community health programs aimed at monitoring the usage of antimicrobials and the creation of platforms that encourage dialogue between local community members and AMR experts, ensuring the continued relevance and effectiveness of implemented AMR strategies. https://www.unep.org/topics/chemicals-and-pollution-action/pollution-and-health/antimicrobial-resistance-global-threat
[118] Antimicrobial Resistance (AMR) - PubMed — Antimicrobial resistance (AMR) has now emerged as a chronic public health problem globally, with the forecast of 10 million deaths per year globally by 2050. ... 2023 Jun 28:80:11387. doi: 10.3389/bjbs.2023.11387. eCollection 2023. ... The prominent cause contributing to the current crisis remains to be the overuse and misuse of antimicrobials
[119] Antimicrobial resistance - World Health Organization (WHO) — © Credits Antimicrobial resistance 21 November 2023 Key facts Antimicrobial resistance (AMR) is one of the top global public health and development threats. It is estimated that bacterial AMR was directly responsible for 1.27 million global deaths in 2019 and contributed to 4.95 million deaths (1). Antimicrobial Resistance (AMR) occurs when bacteria, viruses, fungi and parasites no longer respond to antimicrobial medicines. As a result of drug resistance, antibiotics and other antimicrobial medicines become ineffective and infections become difficult or impossible to treat, increasing the risk of disease spread, severe illness, disability and death. Its emergence and spread is accelerated by human activity, mainly the misuse and overuse of antimicrobials to treat, prevent or control infections in humans, animals and plants.
[129] An overview of the antimicrobial resistance mechanisms of bacteria — An overview of the antimicrobial resistance mechanisms of bacteria - PubMed Search in PubMed doi: 10.3934/microbiol.2018.3.482. An overview of the antimicrobial resistance mechanisms of bacteria DOI: 10.3934/microbiol.2018.3.482 An overview of the antimicrobial resistance mechanisms of bacteria Search in PubMed doi: 10.3934/microbiol.2018.3.482. DOI: 10.3934/microbiol.2018.3.482 Understanding more about these mechanisms should hopefully lead to better treatment options for infective diseases, and development of antimicrobial drugs that can withstand the microorganisms attempts to become resistant. There may be cells present that are resistant to the antimicrobial agent (A). General antimicrobial resistance mechanisms. General antimicrobial resistance mechanisms. General antimicrobial resistance mechanisms. Efflux as a mechanism of antimicrobial drug resistance in clinical relevant microorganisms: the role of efflux inhibitors. doi: 10.1080/14728222.2017.1265105. doi: 10.2174/1871526520999201116201911. Search in PubMed
[130] FAMR: Key Factors in Antimicrobial Resistance Mechanisms — FAMR: Key Factors in Antimicrobial Resistance Mechanisms - BiologyInsights FAMR: Key Factors in Antimicrobial Resistance Mechanisms Explore the key factors shaping antimicrobial resistance mechanisms, from genetic adaptations to environmental influences and cross-species interactions. Foodborne antimicrobial resistance (FAMR) is particularly concerning due to its impact on human infections linked to resistant bacteria from contaminated food. Transposons, or “jumping genes,” are mobile genetic elements that integrate into bacterial genomes or plasmids, spreading antimicrobial resistance. The movement of antimicrobial-resistant bacteria through food systems is influenced by environmental conditions that facilitate persistence and dissemination. The movement of antimicrobial resistance across species boundaries is a key factor in the persistence of resistant bacteria in food systems.
[131] Overview of antimicrobial resistance and mechanisms: The relative ... — Overview of antimicrobial resistance and mechanisms: The relative status of the past and current - ScienceDirect Overview of antimicrobial resistance and mechanisms: The relative status of the past and current open access The global development of antibiotic resistance is a serious threat, reducing the effectiveness of broad-spectrum antibiotics against common bacterial illnesses. Antibiotic development is not new to the medical community, but the emergence of antibiotic resistance has become the most serious threat to global health and food security. The presence of resistant bacteria and antibiotic residues in the environment requires urgent global action to combat antimicrobial resistance (AMR). Next article in issue Antimicrobial resistance Recommended articles No articles found. For all open access content, the relevant licensing terms apply.
[134] Antibiotic resistance | Definition, Mechanisms, Examples, & Facts ... — When a resistant strain of bacteria is the dominant strain in an infection, the infection may be untreatable and life-threatening. Mechanisms of resistance mechanisms of antibiotic resistance in bacteriaThere are multiple mechanisms by which bacteria can develop resistance to antibiotics. Examples include the activation of drug efflux pumps that actively remove a drug from the cell, the inactivation of a drug by bacterial enzymes, the alteration of bacterial cell drug targets, and the inhibition of drug uptake into the cell. Examples of biochemical modifications that lead to resistance include the production of enzymes that inactivate the drug; the alteration of the protein, enzyme, or receptor targeted by the drug; the activation of drug efflux pumps that deliberately remove the drug from the cell; and the alteration of cell-wall proteins that inhibit drug uptake.
[135] Antimicrobial Resistance and the Environment — These factors have an important environmental dimension as waterways, air and soil act as means of transmission and increasing temperatures and hazards associated with climate change contribute to greater development and the spread of antimicrobials and consequently increase resistance to their effectiveness.
[136] Environmental antimicrobial resistance and its drivers: a potential ... — Environmental antimicrobial resistance and its drivers: a potential threat to public health - ScienceDirect Environmental antimicrobial resistance and its drivers: a potential threat to public health Imprudent and overuse of clinically relevant antibiotics in agriculture, veterinary and medical sectors contribute to the global epidemic increase in antimicrobial resistance (AMR). Various drivers are contributing factors to the spread of antibiotic-resistant bacteria and their ARGs either directly through antimicrobial drug use in health care, agriculture/livestock and the environment or antibiotic residues released from various domestic settings. This review provides a brief description of AMR as a global concern and the possible contribution of different environmental drivers to the transmission of antibiotic-resistant bacteria or ARGs through various mechanisms. For all open access content, the relevant licensing terms apply.
[137] Antibiotic resistance in the environment - Nature — Advertisement View all journals Search Log in Explore content About the journal Publish with us Subscribe Sign up for alerts RSS feed nature nature reviews microbiology review articles article Review Article Published: 04 November 2021 Antibiotic resistance in the environment D. G. Joakim Larsson ORCID: orcid.org/0000-0002-5496-03281,2 & Carl-Fredrik Flach ORCID: orcid.org/0000-0002-4101-50951,2 Nature Reviews Microbiology volume 20, pages 257–269 (2022)Cite this article 195k Accesses 261 Altmetric Metrics details Subjects Antimicrobial resistance Bacterial infection Microbial ecology Abstract Antibiotic resistance is a global health challenge, involving the transfer of bacteria and genes between humans, animals and the environment. Although multiple barriers restrict the flow of both bacteria and genes, pathogens recurrently acquire new resistance factors from other species, thereby reducing our ability to prevent and treat bacterial infections. Quantifying the pathways and identifying the drivers of and bottlenecks for environmental evolution and transmission of antibiotic resistance are key components to understand and manage the resistance crisis as a whole. In this Review, we present our current understanding of the roles of the environment, including antibiotic pollution, in resistance evolution, in transmission and as a mere reflection of the regional antibiotic resistance situation in the clinic.
[138] Antibiotic Resistance in the Farming Environment - MDPI — Agricultural ecosystems are an important area of the spread of antibiotic resistance [].Discharges from agricultural practices are now seen as one of the major sources of antibiotic pollution in the environment [].Up to 90% of antibiotics used in livestock production ultimately end up in various forms in the environment, resulting in intensified selection for resistant microorganisms .
[140] Mechanisms of Bacterial Resistance to Antibiotics - JAMA Network — The three fundamental mechanisms of antimicrobial resistance are (1) enzymatic degradation of antibacterial drugs, (2) alteration of bacterial proteins that are antimicrobial targets, and (3) changes in membrane permeability to antibiotics. Antibiotic resistance can be either plasmid mediated or maintained on the bacterial chromosome.
[142] Exploring molecular mechanisms of drug resistance in bacteria and ... — Antibiotic resistance in bacteria is a critical global health challenge, driven by molecular mechanisms such as genetic mutations, efflux pumps, enzymatic degradation of antibiotics, target site modifications, and biofilm formation. 52.Blair J.M., Webber M.A., Baylay A.J., Ogbolu D.O., Piddock L.J. Molecular mechanisms of antibiotic resistance. 53.Munita J.M., Arias C.A. Mechanisms of antibiotic resistance. 54.Diene S.M., Rolain J.M. Mechanisms of bacterial resistance: focus on efflux pumps, drug permeability, and target modification. 59.Blair J.M., Webber M.A., Baylay A.J., Ogbolu D.O., Piddock L.J. Molecular mechanisms of antibiotic resistance. 66.Munita J.M., Arias C.A. Mechanisms of antibiotic resistance. 68.Perry J.A., Wright G.D. The antibiotic resistance "mobilome": searching for the link between environment and clinic. 69.Culyba M.J., Mo C.Y., Kohli R.M. Targets for combating the evolution of acquired antibiotic resistance.
[156] Evidence needed for antimicrobial resistance surveillance systems — In the Advisory Group on Integrated Surveillance of Antimicrobial Resistance report, integrated surveillance of antimicrobial resistance in foodborne bacteria is defined as “the collection, validation, analyses and reporting of relevant microbiological and epidemiological data on antimicrobial resistance in foodborne bacteria from humans, animals, and food, and on relevant antimicrobial use in humans and animals.”8 This definition tends to reduce the concept of One Health to integration of data sets from different sources: humans, animals and food. The surveillance evaluation frameworks in both the public and animal health sectors propose groups of attributes that can be assessed as indicators of the effectiveness of a surveillance system, such as acceptability, data quality, data sensitivity, timeliness and cost–effectiveness.19–21 In line with these frameworks, researchers have used economic analysis to estimate the added value of One Health surveillance, although not to examine integrated surveillance of antimicrobial resistance.22–25
[157] Strengthening Surveillance — In the context of antimicrobial resistance, active surveillance can involve the deployment of public health staff to monitor a target pathogen by actively contacting institutions and collecting information about the incidence of infections caused by that pathogen. Across settings, the most effective surveillance for antimicrobial resistance needs to integrate confidential patient data with information from other sources, making an agreement for data management and confidentially of paramount importance (Seale et al., 2017). The Tripartite surveillance system is one of the four global projects supported by the United Nations (UN) AMR Multi-Partner Trust Fund, a pooled funding compact established in 2019 to support the Tripartite’s joint One Health effort to combat antimicrobial resistance (FAO et al., 2020; UN MPTF Office, 2020). n.d.c. https://www.ncbi.nlm.nih.gov/pathogens/antimicrobial-resistance .
[158] PDF — Justification for surveillance of antimicrobial resistance AMR surveillance data help monitor susceptibility patterns of microorganisms to antimicrobial agents. Regular dissemination of data can help policy-makers to revise the recommendations for case management in health facilities and contribute to systematic combating of AMR. In
[165] Antimicrobial resistance - World Health Organization (WHO) — © Credits Antimicrobial resistance 21 November 2023 Key facts Antimicrobial resistance (AMR) is one of the top global public health and development threats. It is estimated that bacterial AMR was directly responsible for 1.27 million global deaths in 2019 and contributed to 4.95 million deaths (1). Antimicrobial Resistance (AMR) occurs when bacteria, viruses, fungi and parasites no longer respond to antimicrobial medicines. As a result of drug resistance, antibiotics and other antimicrobial medicines become ineffective and infections become difficult or impossible to treat, increasing the risk of disease spread, severe illness, disability and death. Its emergence and spread is accelerated by human activity, mainly the misuse and overuse of antimicrobials to treat, prevent or control infections in humans, animals and plants.
[168] Antimicrobial resistance: Impacts, challenges, and future prospects — Antimicrobial resistance: Impacts, challenges, and future prospects - ScienceDirect Antimicrobial resistance (AMR) is a critical global health issue driven by antibiotic misuse and overuse in various sectors, leading to the emergence of resistant microorganisms. The history of AMR dates back to the discovery of penicillin, with the rise of multidrug-resistant pathogens posing significant challenges to healthcare systems worldwide. The misuse of antibiotics in human and animal health, as well as in agriculture, contributes to the spread of resistance genes, creating a "Silent Pandemic" that could surpass other causes of mortality by 2050. AMR affects both humans and animals, with resistant pathogens posing challenges in treating infections. Antibiotic resistance For all open access content, the relevant licensing terms apply.
[169] Antibiotic Resistance in Developing Countries: Emerging Threats and ... — Public health campaigns can complement ASPs by raising awareness among the general population about the dangers of antibiotic overuse. These campaigns should focus on changing public perceptions of ABX as "cure-alls" and emphasize the importance of completing prescribed courses of treatment to prevent resistance [28, 53, 56-59].
[170] Effectiveness of interventions to improve the public's antimicrobial ... — One such campaign, conducted in the UK in 2014, simultaneously targeted members of the public and healthcare professionals who pledged as Antibiotic Guardians and showed an increase in AMR knowledge and commitment to pledge behaviour in both surveyed sub-populations. 34 Another antibiotic awareness campaign, conducted in Hong Kong, targeted the
[171] Public Health Interventions to Improve Antimicrobial Resistance ... — Public Health Interventions to Improve Antimicrobial Resistance Awareness and Behavioural Change Associated with Antimicrobial Use: A Systematic Review Exploring the Use of Social Media - PMC Keywords: antimicrobial resistance, public health intervention, antibiotics, social media, educational campaign, gamification, knowledge and awareness | Impact of community-based educational intervention on antibiotic use and resistance awareness among the people living in Ras Al Khaimah, United Arab Emirates | Educational | After the intervention, participants’ knowledge regarding AMR significantly improved—full course of antibiotics should be taken (% change: 50%, p < 0.00l), infections from resistant bacteria are difficult to treat (% change: 38%, p < 0.001), antibiotics are of no use in viral infections (% change: 72%, p < 0.001).
[172] PDF — the expectations for antibiotics by the public. Antibiotic demand can be reduced due to modifying antibiotic-seeking behaviours, which improves public health outcomes. Also, the 'Keep Antibiotics Working' campaign TV commercial was featured in a larger mass media campaign that used a diffusion strategy to spread information .
[184] Action and resistance mechanisms of antibiotics: A guide for clinicians ... — Action and resistance mechanisms of antibiotics: A guide for clinicians - PMC Action and resistance mechanisms of antibiotics: A guide for clinicians The biochemical resistance mechanisms used by bacteria include the following: antibiotic inactivation, target modification, altered permeability, and “bypass” of metabolic pathway. Keywords: Antibiotics, antimicrobial resistance, bacterial cell wall, mechanism of action For this purpose, we need to know the basic anatomy of bacterial cell, classification of antibiotics based on their mechanism of action, mechanisms of antibiotic resistance, and individual antibiotics with their common mechanism of resistance. The following biochemical types of resistance mechanisms are used by bacteria: Antibiotic inactivation, target modification, altered permeability, and “bypass” metabolic pathway. Antibiotic resistance mechanisms of clinically important bacteria.
[185] Mechanisms of antimicrobial resistance in bacteria - PubMed — Bacteria may be intrinsically resistant to > or =1 class of antimicrobial agents, or may acquire resistance by de novo mutation or via the acquisition of resistance genes from other organisms. Acquired resistance genes may enable a bacterium to produce enzymes that destroy the antibacterial drug, to express efflux systems that prevent the drug
[186] U.S. Actions & Events to Combat Antimicrobial Resistance — The U.S. National Action Plan for Combating Antibiotic-Resistant Bacteria (referred to as National Action Plan or CARB) presents coordinated, strategic goals to accelerate the U.S. Government's response to antimicrobial resistance and improve the health of all Americans.
[188] PDF — AMR action is much more likely to be extended and sustained if it is mainstreamed into broader health, agricultural and environmental projects. In the long term, mainstreaming AMR means that governments will have to resource implementation of their NAPs, building it into national and local budgets and planning cycles to ensure sustainability.
[189] Assessing the impact of antimicrobial resistance policies on antibiotic ... — Conclusion: The results presented here suggest that there is some evidence of an empirical relationship between national policies aimed at limiting over-the-counter antibiotic sales and actual antibiotic usage practices. Further policy effectiveness research will be needed to better understand the true impact of government measures.
[190] Government policy interventions to reduce human antimicrobial use: A ... — Despite global commitments to reduce antimicrobial resistance and protect the effectiveness of antimicrobials, most countries have not yet started implementing government policies to reduce their overuse and misuse of antimicrobials. ... Behdinan A, Hoffman SJ, Pearcey M. Some Global policies for antibiotic resistance depend on legally binding
[204] The effect of antimicrobial resistance on patient outcomes: importance ... — The effect of antimicrobial resistance on patient outcomes: importance of proper evaluation of appropriate therapy - PMC In the absence of these data, the effect of delay or absence of appropriate therapy in patients infected with resistant bacterial pathogens is subject to confounding, and the true effect of resistance on outcomes may be obscured. Regarding the potential therapy-related causes for poor outcomes – inferior antibiotics and delay in effective therapy – here too Depuydt and colleagues' study does not allow for comparison, because its definition of effective therapy does not account for treatment that is microbiologically effective but clinically problematic.
[210] The Role of Antibiotics in Agriculture - NCBI Bookshelf — To specifically address the impact of antibiotic resistance resulting from the use of antibiotics in agriculture, the American Academy of Microbiology convened a colloquium, “Antibiotic Resistance and the Role of Antimicrobials in Agriculture: A Critical Scientific Assessment,” in Santa Fe, New Mexico, November 2–4, 2001. Research studies have shown the transmission of pathogenic organisms and possibly antibiotic resistant bacteria/genes from animals through food, water, and by direct contact to humans. Strategies include (1) categorization of antibioitics based on their importance in human medicine; (2) revision of the pre-approval safety assessments for new animal drug applications to assess microbial safety; (3) post-approval monitoring for resistance development; (4) collection of food animal antibiotic use data; and (5) establishment of regulatory thresholds.
[211] Antibiotics Misuse and Antimicrobial Resistance Development in ... — Antibiotics find extensive application across agriculture, encompassing livestock, poultry, fisheries, and animal husbandry. In the agricultural sector, they serve to prevent and treat a multitude of crop diseases, while in livestock and animal husbandry, their primary role often lies in promoting growth and combating infections.
[212] PDF — Another reason for resistance can be the use of antimicrobials or, more specifically, antibiotics, in food-producing animals. However, stakeholders disagree on the extent of agriculture's contribution to the problem and on the strength of scientific evidence of such a linkage.
[219] Antimicrobial resistance: Impacts, challenges, and future prospects — Antimicrobial resistance: Impacts, challenges, and future prospects - ScienceDirect Antimicrobial resistance (AMR) is a critical global health issue driven by antibiotic misuse and overuse in various sectors, leading to the emergence of resistant microorganisms. The history of AMR dates back to the discovery of penicillin, with the rise of multidrug-resistant pathogens posing significant challenges to healthcare systems worldwide. The misuse of antibiotics in human and animal health, as well as in agriculture, contributes to the spread of resistance genes, creating a "Silent Pandemic" that could surpass other causes of mortality by 2050. AMR affects both humans and animals, with resistant pathogens posing challenges in treating infections. Antibiotic resistance For all open access content, the relevant licensing terms apply.
[220] Global trends in antimicrobial use in food animals - PMC — Data on antimicrobial use in livestock are scarce, stemming from both the lack of publicly funded surveillance systems and the reluctance of food animal producers, animal feed producers, and veterinary pharmaceutical companies to provide comprehensive reports of antimicrobial consumption or sales. ... Recent studies in various regions of India
[221] Global trends in antimicrobial use in food-producing animals: 2020 to ... — Hotspots of antimicrobial use were overwhelmingly in Asia (67%), while <1% were in Africa. Findings indicate higher global antimicrobial usage in 2030 compared to prior projections that used data from 2017; this is likely associated with an upward revision of antimicrobial use in Asia/Oceania (~6,000 tonnes) and the Americas (~4,000 tonnes).
[222] (PDF) Quantifying the Relationship between Antibiotic Use in Food ... — It is commonly asserted that agricultural production systems must use fewer antibiotics in food-producing animals in order to mitigate the global spread of antimicrobial resistance (AMR).
[223] Intrinsic and Acquired Antimicrobial Resistomes in Plant Microbiomes ... — It involves intricate interactions between human activities, environmental factors and microbial processes. Direct exposure to antibiotic-resistant bacteria and ARGs in agricultural produce particularly raw eaten vegetables, salad, herbs and fruits may facilitate the spread of resistance between humans and the environment.
[224] Antibiotic Resistance in Humans: An Analysis of Antibiotic Use in ... — Based on the results, increasing antibiotic use in factory farming by 1,000 tons (at the global level) can increase antibiotic resistance in humans by 21%. The GDP per Capita based on PPP assumes that increasing consumer income leads to higher demand of animal-based foods, which in turn results in increased AMR in humans.
[225] FAMR: Key Factors in Antimicrobial Resistance Mechanisms — FAMR: Key Factors in Antimicrobial Resistance Mechanisms - BiologyInsights FAMR: Key Factors in Antimicrobial Resistance Mechanisms Explore the key factors shaping antimicrobial resistance mechanisms, from genetic adaptations to environmental influences and cross-species interactions. Foodborne antimicrobial resistance (FAMR) is particularly concerning due to its impact on human infections linked to resistant bacteria from contaminated food. Transposons, or “jumping genes,” are mobile genetic elements that integrate into bacterial genomes or plasmids, spreading antimicrobial resistance. The movement of antimicrobial-resistant bacteria through food systems is influenced by environmental conditions that facilitate persistence and dissemination. The movement of antimicrobial resistance across species boundaries is a key factor in the persistence of resistant bacteria in food systems.
[226] Recent government regulations in the United States seek to ensure the ... — To address agriculture's contribution to the emergence of resistant bacteria, the Federal Food and Drug Administration (FDA) issued veterinary feed directive (VFD) regulations in 2015. These regulations alter the classification of selected over-the-counter antimicrobial drugs and prohibit animal production uses of VFD drugs (CFR (Code of Federal Regulations), 2015, FDA, 2015). Under US federal
[227] Antimicrobial use in agriculture: critical review of the factors ... — However, they indicated that this was dependent on how the farmer perceived the effectiveness and expense of the approach.63,64,72,95,97 Dutch studies recognized that vet encouragement and support are fundamentally important, as they can influence farmers’ perceptions, resulting in the successful implementation of antimicrobial stewardship strategies i.e. selective dry cow therapy.68,73 Furthermore, increased vet farm visits facilitated communication and promoted collaboration; this in turn enhanced farmer knowledge and awareness of responsible AMU and AMR and improved compliance with recommended AMU reduction strategies.17,36,38,40,41,44,97 Interestingly, Norwegian farmers did not consider vets as primary discussion partners in relation to homeopathic treatments, instead only seeking veterinarian consultation if homeopathic approaches were unsuccessful or the disease was considered severe.55 Vets in France, the UK and the Netherlands indicated that in addition to their therapeutic role, vets are increasingly focusing on providing farmers with pragmatic advice promoting antimicrobial stewardship; thus promoting disease prevention without adversely affecting production.17,68,72,101,106,107 Conversely, in India, vets were unaware that the provision of advice to use good farm management practices was an integral part of their role, rarely discussing previous experiences with clients.65 Overall, numerous studies indicated that strategies focused on this important stakeholder relationship between the vet and farmer are fundamentally important to facilitate change and improve herd health, as farmers sought veterinary guidance and support to motivate change.17,76,96,97
[228] PDF — The action plan describes how the USDA proposes to obtain and disseminate science-based, actionable, information about antibiotic drug use, its potential role in the development of antibiotic resistance in food-producing animals, and the relationship of drug use and resistance patterns to livestock management practices. This action plan describes how USDA proposes to obtain and disseminate science-based, actionable, quantitative antibiotic drug use information coupled with the development of re sistance in food-producing animals and to relate this to livestock management practices. This action plan outlines USDA’s current activities and proposes a voluntary comprehensive, integrated approach for future surveillance; research and development; and education, exten sion, and outreach activities that span three objectives: Objective 1: Determine and/or model patterns, purposes, and impacts of antibiotic use in food-producing animals.
[247] A Brief History of Antimicrobial Resistance — While widespread use of antimicrobials in both health care and agricultural settings created an environment for resistance to flourish, the discovery of new antibiotics slowed.26 Soon enough, antimicrobial drug development began to clash with the realities of an economic system predicated on supply and demand.27 As death rates from cancer and heart disease rose to replace deaths from infectious diseases, pharmaceutical companies faced slimmer economic margins for developing new anti-infectives. The rate of discovery of new antibiotics slowed, and those few specialized drugs that were developed to overcome antimicrobial resistance (eg, carbapenems, lipopeptides, oxazolidinones, novel tetracyclines, and novel beta-lactam/beta-lactamase inhibitor combinations) were expensive to use.28 With the latest antimicrobials often only available in highly resourced settings, low- and middle-income countries (LMICs) face a disproportionate burden of antimicrobial resistance and associated deaths.
[248] Antimicrobial resistance - World Health Organization (WHO) — © Credits Antimicrobial resistance 21 November 2023 Key facts Antimicrobial resistance (AMR) is one of the top global public health and development threats. It is estimated that bacterial AMR was directly responsible for 1.27 million global deaths in 2019 and contributed to 4.95 million deaths (1). Antimicrobial Resistance (AMR) occurs when bacteria, viruses, fungi and parasites no longer respond to antimicrobial medicines. As a result of drug resistance, antibiotics and other antimicrobial medicines become ineffective and infections become difficult or impossible to treat, increasing the risk of disease spread, severe illness, disability and death. Its emergence and spread is accelerated by human activity, mainly the misuse and overuse of antimicrobials to treat, prevent or control infections in humans, animals and plants.
[249] Antimicrobial resistance: Impacts, challenges, and future prospects — Antimicrobial resistance: Impacts, challenges, and future prospects - ScienceDirect Antimicrobial resistance (AMR) is a critical global health issue driven by antibiotic misuse and overuse in various sectors, leading to the emergence of resistant microorganisms. The history of AMR dates back to the discovery of penicillin, with the rise of multidrug-resistant pathogens posing significant challenges to healthcare systems worldwide. The misuse of antibiotics in human and animal health, as well as in agriculture, contributes to the spread of resistance genes, creating a "Silent Pandemic" that could surpass other causes of mortality by 2050. AMR affects both humans and animals, with resistant pathogens posing challenges in treating infections. Antibiotic resistance For all open access content, the relevant licensing terms apply.
[250] Antibiotic resistance: The challenges and some emerging strategies for ... — Antibiotic resistance is currently the most serious global threat to the effective treatment of bacterial infections. A new class of antibiotics referred to as immuno‐antibiotics and the targeting of some biochemical resistance pathway components including inhibition of SOS response and hydrogen sulfide as biochemical underlying networks of bacteria can be considered as new emerging strategies to combat antibiotic resistance in bacteria. 28 , 40 Bacteria, on the contrary, can develop drug resistance by mutating the bacterial targets that these antibiotics are aimed at, inactivating or pumping out the drugs, or even acquiring resistant genes. As additional targets in the development of alternative antibiotic therapy, two major uniting targets will be considered: the SOS response and the role of hydrogen sulfide in generalized antibiotic resistance in bacteria.
[256] Economic Incentives for Antibacterial Drug Development: Literature ... — Based on the strengths and weaknesses with push, pull, de-linkage, and conservation incentives, a mixture of various incentives may be necessary to broadly address antibiotic research and development. The incentive package should be applicable to academics and multiple companies, including small, medium, and large enterprises.
[257] PDF — development, while groups in Europe, such as Chatham House, the Review on Antimicrobial Resistance, and DRIVE-AB, have released proposals that aim to provide sufficient push and pull economic incentives to stimulate R&D and reward development of innovative products. A common thread in these proposals is the need for substantial pull incentives that
[258] Incentives for new antibiotics: the Options Market for Antibiotics (OMA ... — Recent research from the field of neglected vaccine development provides two promising and novel mechanisms to stimulate R&D, both of which hold lessons for the field of antibiotic development. The first of these mechanisms is the idea of an Advanced Market Commitment (AMC) for vaccines [ 27 ], while the second is the Call Options for Vaccines
[259] Encouraging the Development of New Antibiotics: Are Financial ... — On the other hand, two articles disagreed that a partially delinked option represents the optimal MER model, advocating for a fully delinked MER incentive instead.38,56 These articles argued that the advantages of fully delinked models pertaining to ensuring long-term sustainable use trump the benefits of partially delinked models, as the former ensure that manufacturers no longer have incentive to increase unit prices to maximize sales whereas the latter do not.38 Although Morel and Edwards38 did not provide suggestions pertaining to how such models should be implemented, Rex and Outterson56 recommended that these awards should be paid out to manufactures annually for a period of five years, with payment values being higher for antibiotics meeting one or more of the following criteria: a novel mechanism of action, addressing unmet clinical needs, targeting high-priority pathogens, and/or providing a cost-advantage over existing agents.
[260] Time for a change in how new antibiotics are reimbursed: Development of ... — The current set of incentives of public support for R&D, with regulatory change, and market exclusivity are not sufficient to stimulate new investment in antibiotic R&D. Appropriate reimbursement mechanisms for future antibiotics that are founded on a policy of reducing market uncertainty are needed to drive re-investment in new antibiotics to
[261] PDF — since antibiotics are intended to be used sparingly. The high development costs and reduced possibility of revenue generation have deterred investors from financing antibiotic R&D, which has led to an insufficient pipeline. A balance of different financial incentives to encourage investment is needed across the R&D
[267] Current Promising Strategies against Antibiotic-Resistant Bacterial ... — These strategies include the following: (i) discovery of novel antibiotics by modification of existing antibiotics, screening of small-molecule libraries, or exploration of peculiar places; (ii) improvement in the efficacy of existing antibiotics through metabolic stimulation or by loading a novel, more efficient delivery systems; (iii) development of alternatives to conventional antibiotics such as bacteriophages and their encoded endolysins, anti-biofilm drugs, probiotics, nanomaterials, vaccines, and antibody therapies. 36.Urfer M., Bogdanovic J., Lo Monte F., Moehle K., Zerbe K., Omasits U., Ahrens C.H., Pessi G., Eberl L., Robinson J.A. A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli. 73.Turos E., Shim J.-Y., Wang Y., Greenhalgh K., Reddy G.S.K., Dickey S., Lim D.V. Antibiotic-conjugated polyacrylate nanoparticles: New opportunities for development of anti-MRSA agents.
[268] PDF — 2. Strengthen National One-Health Surveillance Efforts to Combat Resistance. Antibiotic resistance can arise in bacterial pathogens affecting humans, animals, and the environment. Strengthening detection and control of resistance requires the adoption of a "One-Health" approach that promotes integration of public health and veterinary
[269] Mechanisms of Bacterial Evolution and Antibiotic Resistance — Mechanisms of Bacterial Evolution and Antibiotic Resistance - BiologyInsights Mechanisms of Bacterial Evolution and Antibiotic Resistance Explore how bacteria evolve and develop antibiotic resistance through gene transfer, mutation, and adaptation. By examining processes such as gene transfer, mutation, and speciation, we can better understand the genetic basis of resistance and inform future research efforts. This process is significant in the spread of antibiotic resistance genes, allowing rapid dissemination of resistance traits across bacterial populations. The spread of resistance genes is facilitated by genetic transfer mechanisms, which are instrumental in disseminating resistance within and between bacterial populations. These genetic tools enable bacteria to rapidly adapt to antibiotic challenges, complicating efforts to control resistant infections.
[270] Ecology and evolution of antimicrobial resistance in bacterial ... — Advertisement View all journals Search Log in Explore content About the journal RSS feed nature the isme journal perspectives article Ecology and evolution of antimicrobial resistance in bacterial communities Download PDF Download PDF Perspective Open access Published: 20 November 2020 Ecology and evolution of antimicrobial resistance in bacterial communities Michael J. Bottery ORCID: orcid.org/0000-0001-5790-17561, Jonathan W. Pitchford1,2 & Ville-Petri Friman ORCID: orcid.org/0000-0002-1592-157X1 The ISME Journal volume 15, pages 939–948 (2021)Cite this article 40k Accesses 166 Citations 55 Altmetric Metrics details Subjects Antibiotics Bacterial evolution Microbial ecology Abstract Accumulating evidence suggests that the response of bacteria to antibiotics is significantly affected by the presence of other interacting microbes. In this perspective, we argue that resistance and evolutionary responses to antibiotic treatments should not be considered only a trait of an individual bacteria species but also an emergent property of the microbial community in which pathogens are embedded. We outline how interspecies interactions can affect the responses of individual species and communities to antibiotic treatment, and how these responses could affect the strength of selection, potentially changing the trajectory of resistance evolution. In order to effectively tackle the spread of antimicrobial resistance (AMR) through antimicrobial stewardship or development of novel antimicrobial compounds, understanding how bacteria adapt and evolve to survive antibiotic treatments is crucial.
[276] The antibiotic resistance crisis and the development of new antibiotics ... — Bacterial pathogens accounted for 7.7 million deaths and deaths attributable to bacterial antibiotic resistance amounted to 1.3 million, describing a clear demand for novel antibiotics. In a follow‐up study, the GBD 2019 consortium analysed 343 million individual records for deaths in which infection played a role, specifically for deaths attributable to a given infectious syndrome or for deaths attributable to 33 bacterial pathogens across 204 countries (GBD 2019 Diseases and Injuries Collaborators, 2022). In a next step, the GBD 2019 consortium estimated the number of deaths associated with or attributed to antibiotic resistance analysing 88 bacterial pathogen–drug combinations (Antimicrobial Resistance Collaborators, 2022). With respect to both DALY and deaths, the leading AMR pathogens were third‐generation (3G) cephalosporin‐resistant E.
[277] Antibiotic resistance: The challenges and some emerging strategies for ... — Antibiotic resistance is currently the most serious global threat to the effective treatment of bacterial infections. A new class of antibiotics referred to as immuno‐antibiotics and the targeting of some biochemical resistance pathway components including inhibition of SOS response and hydrogen sulfide as biochemical underlying networks of bacteria can be considered as new emerging strategies to combat antibiotic resistance in bacteria. 28 , 40 Bacteria, on the contrary, can develop drug resistance by mutating the bacterial targets that these antibiotics are aimed at, inactivating or pumping out the drugs, or even acquiring resistant genes. As additional targets in the development of alternative antibiotic therapy, two major uniting targets will be considered: the SOS response and the role of hydrogen sulfide in generalized antibiotic resistance in bacteria.
[278] Antimicrobial resistance: Current challenges and future directions — The rise of superbugs and AMR is a critical global health concern, with three superbugs–Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii–identified as a priority by the World Health Organization (WHO).5 It is estimated that superbugs could cause 10 million deaths by 2050, necessitating new classes of antimicrobial agents due to the rapid dissemination of AMR and the emergence of multidrug-resistant (MDR) pathogens.6 AMR is considered a significant threat to human and animal health, with resistance detected to all antibiotics, including those that form the last line of defense against MDR infections.7 India's ‘National One Health Mission’ aims to facilitate better management of diseases affecting humans, animals, and the environment.8 Promotion of intensive poultry production may also increase AMR, especially within resource-limited settings due to a lack of effective biosafety and biosecurity measures.9 Microplastics, heavy metals, and antibiotics are potential sources of environmental pollutants.
[279] Study on promising new antibiotic Darobactin reinforces its potential — Saarbrücken, December 20, 2023 - Darobactin is a promising candidate for the development of new, resistance-breaking antibiotics, as it has an exceptional mechanism of action and a broad spectrum of activity.
[292] Global Projects to Detect and Respond to Antimicrobial Resistance — As part of CDC's Global Antimicrobial Resistance Laboratory and Response Network (Global AR Lab & Response Network), the Antibiotic Resistance in Communities and Hospitals (ARCH) partners are investigating high-risk, multidrug-resistant organisms (MDROs) in six countries to increase understanding of how these pathogens (harmful germs) spread in communities and healthcare settings. As part of the ARCH work, scientists are gaining a foundational understanding of how individuals become exposed to MDROs. By understanding this exposure, scientists can then work to better target interventions to reduce the spread of these germs. By contributing to the global understanding of high-risk MDROs in hospitals and communities, this work will help identify new targets on which to focus to prevent MDRO colonization and the spread of antimicrobial resistance.
[299] An analysis of existing national action plans for antimicrobial ... — Systematic analysis has estimated the current burden of bacterial antimicrobial resistance (AMR) to be potentially larger than many major diseases (eg, HIV and malaria), with highest rates expected in sub-Saharan Africa. 1 Formulating and sustaining an effective global response to this AMR pandemic has substantial challenges, including resource inequity, implementation gaps and failures, and
[301] Strengthening antimicrobial resistance national action plans through ... — To advance this agenda, the declaration includes a commitment to “ensure, by 2030, that all countries have developed or updated and are implementing multisectoral national action plans on antimicrobial resistance”.These plans, aligned with the WHO Global Action Plan on AMR, are tailored to each country's specific context, leveraging existing health-care infrastructure and resources. To support the development, revision and implementation of national action plans (NAPs), the WHO Evidence-informed Policy Network (EVIPNet) is implementing a project in partnership with the International Vaccine Institute’s Regional AMR Data Analysis for Advocacy, Response and Policy (RADAAR). Funded by the UK Aid’s Fleming Fund, the EVIPNet RADAAR project aims to promote country capacities to develop evidence-informed policies, with a focus on four countries: Bhutan, Ghana, Kenya and the Lao People’s Democratic Republic.
[302] A review of national action plans on antimicrobial resistance ... — We reviewed: actors—which sectors (human health, veterinary health, agriculture) were involved in the development of the NAP and if names and substantive positions of contributing individuals were included; context—whether a SWOT (strengths, weaknesses, opportunities and threats) analysis or situation analysis was conducted; and content—if the NAPs addressed the objectives and provided strategies in alignment with those provided in the WHO GAP and if a national antimicrobial surveillance system was in place. South Africa, Belgium, FYRoM, Netherlands, China received a score of zero, with all countries from WHO approved NAPs. A total of nine (13%) approved countries (Ghana, Liberia, Mauritius, Nigeria, United Republic of Tanzania, Jordan, Lebanon, Thailand, Lao PDR received a score of 10 for both alignment with WHO GAP strategic objectives and including information regarding stakeholder collaboration, contributors and SWOT analysis.
[308] Gates/Novo Nordisk/Wellcome Grand Challenge: Gr-ADI, the Gram-Negative ... — I am going to quote liberally from their materials:Responding to the problem of AMR, “… the Novo Nordisk Foundation (NNF), Wellcome, and the Gates Foundation (GF) are jointly launching a new initiative, Gram-Negative Antibiotic Discovery Innovator (Gr-ADI), to drive innovation in early drug discovery for Gram-negative pathogens. The consortium will be formed through this Grand Challenges request for proposals (RFP), with a focus on the discovery of direct-acting small molecule antibiotics with broad-spectrum activity against Enterobacteriaceae, using Klebsiella spp. as the pathogen to initiate a discovery program.”Announced today is an initial Grand Challenges RFP that will be a first step to build a collaborative portfolio of Gr-ADI projects across multiple sectors, all working towards a common goal and unifying efforts of early antibiotic discovery by fostering cooperation and synergy among researchers.
[309] Philanthropic Partnership Launches New Initiative Tackling ... — Our best chance is to collaborate on innovative new approaches to antibiotic development." AMR is a serious global health threat that is directly responsible for an estimated 1.14 million deaths a year, contributes to an additional 4.71 million deaths annually, and results in significant economic costs.
[310] Gram-Negative Antibiotic Discovery Innovator Initiative to Drive Global ... — The Gates Foundation, Novo Nordisk Foundation, and Wellcome have launched the Gram-Negative Antibiotic Discovery Innovator (Gr-ADI), a $50 million initiative designed to address antimicrobial resistance (AMR) caused by Gram-negative bacteria, which significantly contributes to global deaths, particularly in low- and middle-income countries, including infectious diseases and climate-related issues.
[311] Introducing a $50M Initiative to Combat Antimicrobial Resistance — The Gr-ADI initiative aims to fuel innovative research and development in antibiotic discovery. By providing financial resources and support, the program encourages scientists and researchers to explore novel pathways for creating effective treatments against Gram-negative infections. The investment will enable collaborative efforts and foster
[312] Why is it so hard to develop new antibiotics? - News | Wellcome — Discovering new antibiotics and bringing them to market is a formidable challenge - but one we need to solve if we want to enhance our protection against the growing threat of drug-resistant infections. Here's why we need to tackle this challenge head-on and what it takes to develop new antibiotics.
[313] Brief Overview of Approaches and Challenges in New Antibiotic ... — Target-based screening can produce many ‘hits.’ However, if these compounds cannot overcome the permeability barriers and tendencies for efflux pump activity in bacteria, then none of them, not one single hit, will progress to a lead compound (Livermore and British Society for Antimicrobial Chemotherapy Working Party on The Urgent Need: Regenerating Antibacterial Drug D, Development, 2011; Aminov, 2017; Lewis, 2017; Moffat et al., 2017; Singh et al., 2017). In an effort to improve regulatory processes for drug approvals, the FDA developed four expedited drug review pathways ( Table 3 ) for the treatment of life-threatening/serious or rare conditions: i) accelerated approval, ii) priority review, iii) fast track, and iv) breakthrough therapy (Guidance for industry: expedited programs for serious conditions – drugs and biologics, 2014; Hwang et al., 2017).