Table of Contents
Overview
Definition of Drug Resistance
Drug resistance is defined as the ability of microorganisms, including bacteria, viruses, fungi, and parasites, to withstand the effects of medications that once effectively treated them. This phenomenon occurs when these organisms evolve in response to the selective pressures imposed by drug treatments, leading to a situation where standard therapies become ineffective, thereby complicating treatment options for patients.[4.1] In the context of cancer, drug resistance refers specifically to the insensitivity of tumor cells to antitumor drugs, which significantly contributes to treatment failure and poses a major challenge in oncology.[19.1] The emergence of drug resistance in cancer is a multifaceted challenge influenced by various intrinsic factors. Key mechanisms include pre-existing genetic mutations, tumor heterogeneity, and the activation of intracellular defense pathways, which collectively enable cancer cells to evade the cytotoxic effects of therapies. These mechanisms can lead to alterations in drug targets, desensitization to treatments, enhanced DNA repair capabilities, and the activation of survival pathways.[20.1] Resistance can develop rapidly, sometimes within weeks of initiating treatment, or may take months or even years, often arising from molecular changes in a small group of cells within a tumor that render them insensitive to specific drugs even before treatment begins.[19.1] To combat drug resistance, strategies such as polytherapy, immunotherapy, and targeted therapies are being explored, aiming to optimize treatment sensitivity and improve patient outcomes.[21.1]Types of Drug Resistance
Drug resistance can be categorized based on the mechanisms microorganisms use to evade the effects of antimicrobial agents. One significant mechanism is enzymatic degradation, where bacteria produce enzymes that inactivate antibiotics, rendering them ineffective. This is particularly common among gram-negative bacteria, which often produce β-lactamases that hydrolyze β-lactam antibiotics, such as penicillin and cephalosporins.[18.1] Another prevalent mechanism is the alteration of target sites, where mutations in bacterial proteins prevent antibiotics from binding effectively. For instance, mutations in penicillin-binding proteins (PBPs) can hinder the interaction between β-lactam drugs and their targets, leading to resistance.[18.1] Additionally, changes in membrane permeability can contribute to resistance, as bacteria may modify their cell membranes to limit antibiotic entry.[13.1] Antimicrobial resistance in bacteria represents a critical global health challenge, driven by several biochemical mechanisms that impact treatment options in clinical settings. These include (1) enzymatic degradation of antibacterial drugs, (2) alteration of bacterial proteins that serve as antimicrobial targets, and (3) changes in membrane permeability to antibiotics.[12.1] Additionally, bacteria can employ efflux pumps to actively expel antibiotics, reducing drug effectiveness.[13.1] Genetic mutations also contribute to antibiotic resistance, enabling bacteria to survive antibiotic treatment and proliferate through natural selection.[15.1] This process can increase the population of resistant strains, complicating infection management.[15.1] Overall, these mechanisms underscore the complexity of antibiotic resistance and the challenges it poses to effective treatment.[12.1] In viral infections, resistance mechanisms often involve mutations in viral enzymes targeted by antiviral drugs. For example, mutations in reverse transcriptase in HIV or neuraminidase in influenza can alter drug-binding sites, diminishing the efficacy of these antiviral agents.[11.1]In this section:
History
Evolution of Antibiotic Resistance
The evolution of antibiotic resistance has been a significant concern since the early twentieth century, coinciding with the development of antibiotics. The history of antibiotic resistance began shortly after the introduction of the first clinically used antibiotic, Salvarsan, around 1910, which saw resistance emerge approximately 20 years later. In contrast, resistance to sulfonamides and penicillin developed much more rapidly, within about 12 years.[49.1] This rapid emergence of resistance highlights the evolutionary pressure that pathogens face, which drives the development of drug resistance and poses a major challenge to modern medicine.[47.1] One of the most notable examples of antibiotic resistance is methicillin-resistant Staphylococcus aureus (MRSA), which emerged within a year of methicillin's introduction. MRSA can resist most antibiotics and has become a common cause of infections in hospitals, representing a significant threat as one of the foremost multiple-drug resistant (MDR) bacteria.[48.1] The increasing prevalence of resistance to common antimicrobial drugs has made previously treatable infections increasingly difficult to manage.[46.1] The global health crisis of antibiotic resistance has prompted urgent calls for the development of new classes of antibiotics capable of treating drug-resistant infections.[50.1] However, the decline in antibiotic discovery rates, coupled with the evolution of resistance in many pathogens, has led to a current crisis in antimicrobial resistance.[58.1] As a response, strategies have been implemented to modify existing antibiotics and explore novel antimicrobial sources, such as ecological niches beyond soil and compounds derived from animals and plants.[59.1] Public health policies play a crucial role in addressing antibiotic resistance. Governments worldwide are enacting stricter guidelines on antibiotic use in healthcare and agriculture to curb the spread of resistance.[51.1] Initiatives such as the WHO's Global Action Plan on Antimicrobial Resistance emphasize responsible antibiotic use as a key priority area for intervention, advocating for regulatory measures to optimize prescribing practices.[54.1] Furthermore, antibiotic stewardship programs aim to improve how antibiotics are prescribed and used, thereby enhancing patient safety and treatment outcomes.[56.1]Milestones in Drug Discovery
The history of drug discovery, particularly in the context of antibiotics, is closely tied to the emergence of antibiotic resistance, which began to develop in the early twentieth century. Workshop speaker Julian Davies from the University of British Columbia highlights this historical progression, noting that the initial strategies to combat drug-resistant microbes have involved the discovery or design of new pathogen-targeting drugs.[45.1] This ongoing challenge underscores the importance of continued innovation in drug discovery to address the evolving landscape of microbial resistance. The history of antibiotics is marked by significant developments, particularly in the context of antimicrobial resistance. Infectious diseases have been a persistent challenge throughout human history, with various methods employed to treat infections for millennia. However, the increasing resistance to common antimicrobial drugs has made readily treatable infections increasingly difficult to manage.[46.1] This growing concern highlights the ongoing need for research and innovation in the field of drug discovery to address the challenges posed by resistant pathogens.[46.1] The history of drug resistance is a significant concern in the field of medicine, as resistance to common antimicrobial drugs is increasing, making readily treatable infections increasingly challenging to manage.[46.1] Infectious diseases have been a persistent feature of human life and death throughout history, with humans treating infections for millennia.[46.1] This historical context underscores the importance of understanding the evolution of antimicrobial resistance and its implications for current and future treatment strategies.[46.1]Mechanisms Of Drug Resistance
Genetic Changes and Mutations
Genetic changes and mutations play a crucial role in the development of drug resistance among microorganisms. One significant mechanism of resistance involves alterations in the structure and/or number of penicillin-binding proteins (PBPs), particularly in gram-positive bacteria, which can prevent the effective interaction between β-lactam drugs and their target sites. This alteration can occur through modifications to existing PBPs or the acquisition of new PBPs, thereby reducing the drug's ability to bind effectively.[94.1] Additionally, the production of β-lactamases, enzymes that hydrolyze β-lactam drugs, is a prevalent resistance mechanism employed by gram-negative bacteria. This enzymatic activity is particularly significant against penicillin and cephalosporin drugs, highlighting the genetic adaptations that enable these bacteria to survive despite the presence of antibiotics.[94.1] Moreover, genetic mutations can lead to the emergence of dormant states in some microbes, allowing them to evade the effects of antibiotics. This phenomenon underscores the complexity of microbial resistance and the necessity for innovative approaches to treatment.[124.1] The integration of pharmacogenomics into clinical practice is also transforming the understanding of drug resistance. By employing genetic testing to identify markers that influence individual drug responses, pharmacogenomics facilitates personalized medicine, which can optimize drug efficacy and minimize adverse reactions.[127.1] This approach is particularly relevant in the context of drug-resistant infections, as it allows for tailored therapies based on a patient's unique genetic profile.[126.1]Environmental Factors Influencing Resistance
Bacterial antibiotic resistance is increasingly severe in water environments, where the emergence of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) has attracted significant attention from researchers.[92.1] The role of the environment in the recruitment of ARGs to human pathogens involves four major steps: the emergence of novel resistance factors, their mobilization onto mobile genetic elements, the transfer of these genes to human pathogens, and the subsequent dissemination into the human microbiome.[92.1] Horizontal gene transfer (HGT) is a key process in bacterial evolution, facilitating the exchange of genetic material between organisms without reproduction, which contributes to genetic diversity and rapid adaptation within bacterial populations.[93.1] Understanding these environmental influences is crucial for addressing the development and spread of antibiotic resistance, as they have significant implications for public health and antibiotic stewardship.[92.1] The inappropriate use of antibiotics in healthcare and agriculture has led to their dispersal into the environment, significantly accelerating bacterial resistance through the transfer of genetic elements and antibiotic resistance genes.[103.1] This phenomenon is part of a broader global health challenge, as antibiotic resistance involves the transfer of bacteria and resistance genes between humans, animals, and the environment.[111.1] Environmental factors, including antibiotic pollution, play a crucial role in the evolution and transmission of antibiotic resistance, as they create conditions that facilitate the acquisition of new resistance factors by pathogens.[111.1] Understanding these dynamics is essential for managing the resistance crisis, as they reflect the complex interactions between human health, animal husbandry, and environmental influences.[111.1] Addressing these interactions is vital for developing effective strategies to combat antibiotic-resistant bacteria and mitigate their impact on public health.[103.1] Research indicates that environmental dissemination routes for resistant bacteria are crucial for understanding the broader implications of antibiotic resistance.[110.1] The interaction between human health, animal husbandry, and environmental factors creates a complex web that supports the propagation of resistant organisms.[113.1] Thus, quantifying the pathways and identifying the drivers of environmental evolution and transmission of antibiotic resistance are essential for addressing this global health challenge.[111.1]In this section:
Recent Advancements
Novel Antibiotics and Therapeutics
The development of novel antibiotics and therapeutics is critical in the ongoing battle against antimicrobial resistance (AMR), which poses significant challenges to global public health. The emergence of multidrug-resistant organisms (MDROs) necessitates innovative approaches to drug discovery and development. Recent advancements highlight several strategies aimed at overcoming these challenges. One promising approach is the use of combination therapies, which involve administering multiple drugs that target different bacterial functions or resistance mechanisms. This strategy not only enhances treatment efficacy but also reduces the likelihood of resistance development.[149.1] Additionally, researchers are exploring the repurposing of existing drugs, which allows for the identification of new uses for already approved medications, thereby accelerating the availability of effective treatments.[165.1] The discovery of novel antibiotics is also being pursued through various innovative methods, including the modification of existing antibiotics and the screening of small-molecule libraries. These efforts aim to uncover new antibacterial agents that can effectively combat resistant pathogens.[152.1] Furthermore, the integration of advanced technologies, such as proteomics, enables scientists to screen large numbers of proteins rapidly, facilitating the identification of potential drug targets and biomarkers for multiple diseases.[153.1] Gene editing technologies, particularly CRISPR-Cas, have emerged as a viable method for addressing antibiotic resistance by directly targeting and deactivating genes responsible for resistance. This technique has shown promise in rendering resistant strains, such as Staphylococcus aureus, susceptible to antibiotics once more.[154.1] Moreover, the development of alternatives to conventional antibiotics is gaining traction. These alternatives include bacteriophages, anti-biofilm drugs, probiotics, and vaccines, which offer new avenues for treatment in the face of rising resistance.[152.1]Social, Cultural, And Economic Aspects
Impact of Antibiotic Misuse
Antibiotic misuse is significantly influenced by various social, cultural, and economic factors, which contribute to the development of antimicrobial resistance (AMR). The misuse of antibiotics is often rooted in cultural beliefs and misconceptions regarding their purpose and function, particularly among specific populations such as the Latino community, where these misconceptions play a major role in antibiotic misuse.[213.1] Additionally, the perception of antibiotics as having strong benefits with minimal concerns about potential harm can lead to inappropriate demand and use.[215.1] Social determinants, including health literacy and access to healthcare, also play a critical role in antibiotic misuse. For instance, inadequate health literacy and sub-optimal training of healthcare providers can facilitate the misuse of antibiotics, particularly in underserved communities.[211.1] Furthermore, community-based interventions aimed at improving "antibiotic resistance literacy" among minority and underserved groups have been identified as potentially impactful in addressing these disparities.[204.1] Economic factors further exacerbate the situation, as drug-resistant infections increase healthcare costs, mortality, morbidity, and decrease productivity.[210.1] The economic burden of antibiotic resistance is disproportionately felt by lower-income individuals and communities, who are at higher risk of infections caused by antibiotic-resistant pathogens.[206.1] Addressing these social and economic determinants is crucial for reducing the overall impact of antibiotic resistance on public health.[210.1]Global Strategies for Antimicrobial Stewardship
Global strategies for antimicrobial stewardship are crucial in combating the escalating threat of antimicrobial resistance (AMR) worldwide. A key component of these strategies is enhancing patient education and awareness about the appropriate use of antibiotics. Limited patient knowledge about AMR and their role in stewardship can impede efforts to combat resistance. Therefore, comprehensive education campaigns tailored to specific cultural contexts are essential for improving patient understanding and engagement.[183.1] Healthcare professionals play a pivotal role in promoting responsible antibiotic use through effective communication strategies. For example, a structured communication approach can facilitate discussions about appropriate antibiotic prescribing, especially when a patient's condition changes.[180.1] Additionally, tools like Commitment Posters in healthcare settings publicly affirm a practice's dedication to improving antibiotic care.[181.1] Healthcare organizations can also utilize resources such as Antibiotic Stewardship Resource Bundles to raise awareness during events like U.S. Antibiotic Awareness Week, reinforcing the importance of responsible antibiotic use.[182.1] Addressing the economic implications of AMR is vital, as the economic burden is substantial, with significant costs reported in countries like Thailand and the United States due to drug resistance.[188.1] Economic evaluations of healthcare strategies aimed at reducing antibiotic prescribing should consider their impact on AMR, as many current evaluations overlook these critical costs and outcomes.[187.1] Implementing antibiotic stewardship programs (ASPs) is critical in addressing the global health crisis of AMR, which leads to significant mortality and is projected to worsen by 2050, particularly affecting marginalized populations.[189.1] These communities face socioeconomic, ethnic, and geographic barriers that limit access to effective healthcare, exacerbating the threat of AMR.[189.1] To effectively implement ASPs in underserved areas, it is essential to identify contextual factors influencing their success. A mixed-methods approach, guided by the Consolidated Framework for Implementation Research (CFIR), can be employed to gather data through semi-structured interviews and focus groups, uncovering barriers and facilitators to effective implementation.[190.1]Challenges In Combatting Drug Resistance
Regulatory and Market Barriers
The challenge of drug resistance has historically been recognized, particularly in the context of HIV treatment. Common mechanisms and challenges in combating drug resistance necessitate a united front, emphasizing the need for a collective effort to leverage chemistry. This approach aims to discover robust drugs or drug combinations that can endure and avoid the development of resistance.[217.1] Addressing these challenges requires a comprehensive understanding of the constraints imposed by evolution on drug efficacy and the ongoing need for innovative solutions in the field of antimicrobial resistance. The implementation of robust public health policies is essential in regulating antibiotic prescriptions to mitigate misuse and overuse in both healthcare settings and the community. By addressing these regulatory and market barriers, countries can enhance their capacity to manage antibiotic resistance and safeguard public health.Future Perspectives
Research Directions and Innovations
The ongoing crisis of antimicrobial resistance (AMR) necessitates innovative research directions and strategies to combat the rise of multidrug-resistant (MDR) pathogens. A significant focus is on the development of novel antibiotics, which can be achieved through various approaches such as modifying existing antibiotics, screening small-molecule libraries, and exploring unique environments for new compounds.[277.1] Additionally, enhancing the efficacy of current antibiotics through metabolic stimulation and improved delivery systems is crucial.[277.1] Emerging technologies, particularly artificial intelligence (AI), are playing a transformative role in AMR research. AI-driven models can predict resistance patterns and enhance antibiotic discovery, thereby augmenting the arsenal against resistant pathogens.[279.1] Furthermore, the DARTS initiative, led by Harvard Medical School, aims to leverage AI, high-throughput testing, and robotics to create rapid diagnostic platforms for antibiotic resistance.[278.1] Public-private partnerships (PPPs) are increasingly recognized as a cornerstone of pharmaceutical research, particularly in the development of new antibiotics. These collaborations are essential for advancing drug development and addressing global health challenges, as they offer several advantages over traditional models.[288.1] Substantial economic challenges discourage private investment in antibiotic research and development (R&D), resulting in a decline in the number of companies and researchers engaged in this critical field.[286.1] To improve this dire situation, new models of drug development based on collaborative endeavors are urgently needed.[289.1] The Critical Path Initiative, introduced by the US Food and Drug Administration (FDA) in 2004, exemplifies efforts to modernize drug development through the implementation of PPPs that facilitate the sharing of data and expertise among stakeholders.[289.1] In addition to traditional antibiotics, alternative therapies such as bacteriophages, anti-biofilm drugs, probiotics, and vaccines are being explored as potential solutions to combat AMR.[277.1] The integration of these diverse strategies, alongside the One Health model, which emphasizes collaboration across human, animal, and environmental health sectors, is essential for a comprehensive approach to managing AMR.[256.1]Public Health Implications
One of the most significant public health implications of antimicrobial resistance (AMR) is the urgent need for improved surveillance and data sharing, particularly in low-resource settings. The generation, sharing, systematic analysis, and dissemination of AMR data are critical challenges that must be addressed to enhance global surveillance efforts. Leveraging emerging technologies related to 'Big Data' and artificial intelligence could facilitate more effective mechanisms for AMR data management and sharing.[260.1] The World Health Organization (WHO), along with the Food and Agriculture Organization (FAO), the World Organisation for Animal Health (WOAH), and the United Nations Environment Programme (UNEP), has recognized the importance of collaboration in combating AMR. They have developed a Strategic Framework that promotes a One Health approach to AMR, which integrates human, animal, and environmental health considerations at global, regional, and national levels.[262.1] This collaborative effort is essential for standardizing AMR surveillance, as exemplified by the launch of the Global Antimicrobial Resistance and Use Surveillance System (GLASS) in 2015, which aims to unify AMR monitoring efforts worldwide.[263.1] Furthermore, addressing AMR requires a multisectoral approach that encompasses various initiatives at both national and global levels. The Global Action Plan on AMR emphasizes the need for coordinated actions across different sectors to effectively tackle this growing health crisis.[264.1] In addition to surveillance and collaboration, human behaviors and environmental factors significantly contribute to the acceleration of antibiotic resistance. The overuse of antibiotics, particularly in livestock for growth promotion, has been identified as a major driver of AMR.[272.1] Veterinarians play a crucial role in mitigating these impacts by monitoring antibiotic use in livestock and promoting responsible practices.[270.1] They are also instrumental in advising farmers on preventing antimicrobial-resistant infections tailored to specific farm conditions.[271.1] Moreover, the environmental dimension of AMR cannot be overlooked. The recruitment of antibiotic resistance genes (ARGs) from the environment into human pathogens involves several steps, including the emergence of novel resistance factors and their subsequent transfer to human microbiomes.[269.1] Addressing these environmental factors, alongside human behaviors, is vital for developing comprehensive strategies to combat AMR effectively.[267.1]In this section:
Delivery SystemsArtificial IntelligenceRoboticsPublic-private PartnershipsPharmaceutical Research
References
[4] Drug resistance - Wikipedia — Drug, toxin, or chemical resistance is a consequence of evolution and is a response to pressures imposed on any living organism. Individual organisms vary in their sensitivity to the drug used and some with greater fitness may be capable of surviving drug treatment. Drug-resistant traits are accordingly inherited by subsequent offspring, resulting in a population that is more drug-resistant.
[11] PDF — The mechanisms of antiviral resistance vary depending on the drug and the virus. One common mechanism is the mutation of viral enzymes targeted by the drug, such as reverse transcriptase in HIV or neuraminidase in influenza. These mutations alter the drug-binding site, reducing the drug's ability to inhibit the enzyme's function. Another
[12] Mechanisms of bacterial resistance to antibiotics - PubMed — 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 mai …
[13] 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.
[15] Mutations and selection - Antibiotic resistance - ReAct — Mutations and selection – Antibiotic resistance – ReAct Mutations can result in antibiotic resistance in bacteria. Resistant bacteria survive antibiotic treatment and can increase in numbers by natural selection. Mutations are one way for bacteria to become resistant to antibiotics. Natural selection of antibiotic resistant bacteria. Thus, the antibiotic can select for resistance genes and mechanisms in both pathogenic bacteria and in commensal bacteria living in the body that have nothing to do with the infection in question. | The rise in antibiotic resistance | Animation of selection of resistant bacteria in the body, some resistance mechanisms and how they may spread. | Mutations – selection: the bacteria resist | Video about natural selection of antibiotic resistant bacteria (5 min).
[18] 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 ,.
[19] Why Do Cancer Treatments Stop Working? - NCI - National Cancer Institute — Sometimes resistance develops quickly, within a matter of weeks of starting treatment. In other cases, it develops months, or even years, later. Resistance can occur when cancer cells—even a small group of cells within a tumor—contain molecular changes that make them insensitive to a particular drug before treatment even begins.
[20] Unveiling the mechanisms and challenges of cancer drug resistance — Intrinsic factors include pre-existing genetic mutations, tumor heterogeneity, and activation of intracellular defense pathways, that confer resistance by activating various oncogenic pathways, altering drug targets, desensitization towards therapies, enhancing DNA repair mechanisms, as well as activation of survival pathways, thereby potentiating cancer cells to evade the cytotoxic effects of treatments . Targeting drug-resistant cancer cell-intrinsic and tumor microenvironment components, alone or in combination with anticancer therapies may prove to be a better approach in enhancing the efficacy of cancer treatments and improving patient outcomes. Contrasting features of cancer cells and drug-resistant cells are represented in Fig. 1. These diverse genomic changes contribute to acquiring beneficial properties like drug resistance and tumor recurrence in these selected cancer cells . Drug resistance and Cancer stem cells.
[21] Understanding and targeting resistance mechanisms in cancer — The present article focuses on the different mechanisms of drug resistance in cancer and the corresponding tackling approaches with recent updates. The purpose of overcoming the drug resistance of cancer cells is to optimize the sensitivity of the therapy. This can be achieved by polytherapy using the combination of at least two drugs; immunotherapy using checkpoint inhibitors or monoclonal antibodies; antibody‐drug conjugates improving the selectivity of cancer treatment; gene technology modifying the epigenetic sequence; targeted therapy targeting the overexpression of drug efflux transporter or vital proteins for the cancer cell apoptosis; and nanoparticle delivery system improving the efficacy of the drug and reducing the side effect. Cancer resistance mechanisms, including drug inactivation, insufficient intracellular drug concentration, drug target alterations, compensatory pathways activation, DNA repair enhancement, and tumor plasticity. Nanoparticle‐based combination therapy toward overcoming drug resistance in cancer.
[45] Antibiotic Resistance: Origins and Countermeasures — In the chapter's first paper, workshop speaker Julian Davies, of the University of British Columbia, reviews the history of the development of antibiotic resistance, beginning in the early twentieth century. ... Thus far, the strategy for coping with drug-resistant microbes has been to discover or design new pathogen-targeting drugs, but
[46] Antibiotics and antimicrobial resistance - a timeline — Resistance to common antimicrobial drugs increases, and readily treatable infections are becoming increasingly challenging to manage. ... The history of antibiotics and antimicrobial resistance. Infectious diseases have been a feature of life and death throughout history. Humans have been treating infections for millennia, including use of
[47] Introduction: Drug Resistance - PMC — The evolutionary pressure of survival drives the emergence of drug resistance, and thereby poses a major challenge to modern medicine. Resistance threatens the longevity of drugs and restricts treatment options for patients, with high prevalence in all areas of oncology and infectious diseases. Any biological entity capable of evolving and
[48] A Brief History Of Antibiotic Resistance: How A Medical Miracle Turned ... — But within a year, bacterial strains developed resistance to methicillin too — eventually called MRSA, methicillin-resistant Staphylococcus aureus, or S. aureus. Now, MRSA can resist most antibiotics, and infections are common in hospitals — making it one of the biggest forerunners of multiple-drug resistant (MDR) bacteria.
[49] The history of antimicrobial resistance and the important role ... — Interestingly, resistance to Salvarsan TM (the first clinically used antibiotic ~1910) took approximately 20 years to emerge. 3,4 Resistance to sulfonamides and penicillin occurred much sooner [~12 years], as outlined in the timeline below. 3 Newer antibiotics approved since 2010 are listed in Table 1 and consist of combinations of current
[50] Derivation of a Precise and Consistent Timeline for Antibiotic Development — Antibiotic resistance is a global health crisis. New classes of antibiotics that can treat drug-resistant infections are urgently needed. To communicate this message, researchers have used antibiotic development timelines, but these are often
[51] The Role of Public Health Initiatives in Combating Antibiotic Resistance — Policy and regulation play a significant role in curbing antibiotic resistance. Governments worldwide are implementing stricter guidelines on antibiotic use in healthcare and agriculture. ... What are public health initiatives doing to combat antibiotic resistance? A: Public health initiatives are taking a multi-faceted approach that includes
[54] Impact of national interventions to promote responsible antibiotic use ... — To counter the rise in AMR, the WHO's Global Action Plan on Antimicrobial Resistance (2015) 3 has identified responsible use as one of five key priority areas for urgent intervention, endorsing strategies to reduce both the supply of and demand for antibiotics. These include regulatory measures to reduce and optimize antimicrobial prescribing
[56] Core Elements of Antibiotic Stewardship | Antibiotic Prescribing and ... — Antibiotic stewardship is the effort to measure and improve how antibiotics are prescribed by clinicians and used by patients. CDC's Core Elements of Antibiotic Stewardship offer providers and facilities a set of key principles to guide efforts to improve antibiotic use and, therefore, advance patient safety and improve outcomes.
[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.
[92] An overview of the antimicrobial resistance mechanisms of bacteria — The main mechanisms of resistance are: limiting uptake of a drug, modification of a drug target, inactivation of a drug, and active efflux of a drug. These mechanisms may be native to the microorganisms, or acquired from other microorganisms. Understanding more about these mechanisms should hopefully lead to better treatment options for
[93] Introduction: Drug Resistance - PMC - PubMed Central (PMC) — Common mechanisms and challenges in drug resistance necessitate a united front with a collective effort to leverage chemistry, while considering the constraints of evolution, to discover robust drugs or drug combinations that last and avoid resistance. Historically, the challenge of drug resistance was realized initially in the treatment of HIV
[94] An overview of the antimicrobial resistance mechanisms of bacteria — 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 ,.
[103] Environmental occurrence of antibiotic resistance, control measures and ... — Environmental occurrence of antibiotic resistance, control measures and challenges in finding therapeutic management - ScienceDirect Environmental occurrence of antibiotic resistance, control measures and challenges in finding therapeutic management open access Inappropriate use of antibiotics in healthcare and agriculture contributes to their dispersal into the environment, thereby accelerating bacterial resistance through the transfer of genetic elements and antibiotic resistance genes. In contrast, this extensive state-of-the-art review aspires to furnish an updated synthesis of the distribution of antibiotic resistance, its repercussions on human health and economy, as well as innovative therapeutic strategies that exhibit potential in combating antibiotic-resistant bacteria. Next article in issue Antibiotic resistance Antibiotic resistance genes No articles found. All content on this site: Copyright © 2024 Elsevier B.V., its licensors, and contributors. For all open access content, the Creative Commons licensing terms apply.
[110] Environmental factors influencing the development and spread of ... — Apart from transmission between humans, environmental dissemination routes for resistant bacteria have also been pointed out as potentially important for the spread of antibiotic resistance (Allen et al. For the long-term maintenance of antibiotic resistance genes in bacterial communities, two parallel evolutionary forces are at play: selection promoting resistance phenotypes, and selection leading to reduction of the fitness costs associated with carrying resistance genes (Andersson and Hughes 2010; Baquero, Coque and de la Cruz 2011; Hernando-Amado et al. Risks associated with transfer of novel resistance genes to human pathogens in STPs appear somewhat smaller due to seemingly lacking selection pressures and lower proportions of human-associated bacteria in the effluent (Bengtsson-Palme et al.
[111] 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.
[113] Understanding the contribution of environmental factors in the spread ... — The overuse and abuse of antibiotics have contributed to the global epidemic of antibiotic resistance. Current evidence suggests that widespread dependency on antibiotics and complex interactions between human health, animal husbandry and veterinary medicine, have contributed to the propagation and spread of resistant organisms. The lack of information on pathogens of major public health
[124] Full article: Pharmacogenomic Strategies Against Microbial Resistance ... — Other microbes escape antibiotic impact by turning into dormant states, ... It is very clear that today an innovative systems perspective is apparent for pharmacogenomics treatment of infections. This new view will ultimately treat infections with unprecedented efficiency, personalized and long lasting, based on a fundamental understanding of
[126] Advancements in Personalized Medicine: Integrating Pharmacogenomics ... — The integration of pharmacogenomics into clinical practice is revolutionizing personalized medicine by tailoring drug therapies to an individuals genetic profile. This approach has the potential to optimize drug efficacy, minimize adverse drug reactions, and streamline the drug development process. This review explores recent advancements in pharmacogenomics, including high-throughput genomic
[127] The Future of Antibiotics: Fighting Drug Resistance with Pharmacogenomics — How Fighting Drug Resistance with Pharmacogenomics Works. Fighting drug resistance through pharmacogenomics employs genetic testing to pinpoint genetic markers influencing an individual's drug response. This method facilitates personalized medicine, tailoring treatments to an individual's
[149] Innovative Approaches to Overcoming Antimicrobial Resistance: A ... — Combination therapies represent another innovative approach to overcoming AMR. By using multiple drugs that target different bacterial functions or resistance mechanisms, combination therapies can enhance treatment efficacy and reduce the likelihood of resistance development.
[152] 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.
[153] New strategies to combat drug resistance in bacteria — Recent proteomic technologies enable scientists to screen large numbers of proteins within a time that helps to synthesize biomarkers for multiple diseases, identify, validate, design more drug targets, and to check drug efficacy. ... Apart from EPs key role in combating drug resistance, they are also involved in other physiological processes
[154] New frontiers in CRISPR: Addressing antimicrobial resistance with Cas9 ... — Gene disruption is a viable approach for utilizing CRISPR-Cas technology against antibiotic resistance by directly targeting and deactivating the responsible genes . Studies have successfully illustrated this technique in Staphylococcus aureus , rendering it susceptible once more to antibiotics after gene inhibition.
[165] Brief Overview of Approaches and Challenges in New Antibiotic ... — Drug repurposing, or identifying new uses for existing drugs, has emerged as an alternative to traditional drug discovery processes involving de novo synthesis. Drugs that are currently approved or under development for non-antibiotic indications
[180] PDF — Two scenarios using the communication strategy to decrease unnecessary prescribing for asymptomatic bacteriuria . and respiratory infections are described on the pages that follow. Healthcare professionals can use the 4-part . Communication Strategy. 6. to discuss appropriate antibiotic use when there is a change in the resident's condition
[181] Learn Strategies for Communicating With Colleagues, Patients, and ... — Tools. The five tools below are designed to assist the practice in creating a safety culture that values appropriate antibiotic prescribing. The Commitment Poster (in English and Spanish) can be signed by clinicians and staff, or include pictures of clinicians and staff, and posted to let your patients know that your practice is committed to improving the antibiotic care they receive.
[182] Antibiotic Stewardship Resource Bundles | Antibiotic Prescribing and ... — Healthcare professionals and partner organizations—including health departments and professional societies — can review and share the Antibiotic Stewardship Resource Bundles as part of their organization's U.S. Antibiotic Awareness Week promotion efforts. ... This fact sheet provides four steps for effectively communicating with residents
[183] Participatory antimicrobial stewardship: fostering patient and public ... — Limited patient knowledge and awareness. Limited patient understanding of AMR, appropriate antibiotic use, and their role in stewardship hinders active participation. A potential solution is comprehensive patient education and awareness campaigns . Tailoring these campaigns to specific needs and cultural contexts is essential.
[187] Challenges for Economic Evaluation of Health Care Strategies to Contain ... — Economic evaluation of health care strategies to reduce antibiotic prescribing, for instance, ought to value their impact on antimicrobial resistance. Most economic evaluations in this area, however, fail to consider the costs and outcomes relating to antimicrobial resistance—or where they have, consideration has been restricted to projected
[188] Enumerating the economic cost of antimicrobial resistance per ... — The total economic cost of AMR due to drug resistance in the five pathogens was $0.5 billion and $2.8 billion in Thailand and the United States, respectively. This is disaggregated into direct and the indirect costs for each of the organisms in the two countries in Tables 4 and 5, respectively. As an illustration, the direct and indirect annual
[189] The global antimicrobial resistance response effort must not exclude ... — Antimicrobial resistance (AMR), a rising global health crisis causing about 700,000 deaths annually and potentially 10 million deaths by 2050, disproportionately impacts marginalised populations. Due to socioeconomic, ethnic, geographic, and other barriers, these communities often have restricted healthcare access, compounding the AMR threat. Unequal access to effective antibiotics, inadequate
[190] A Pilot Study on Understanding the Contextual Factors Impacting the ... — Objective: This study aimed to identify contextual factors influencing the implementation of an antibiotic stewardship program (ASP) in a rural primary care center serving underserved communities. Methods: A mixed-methods approach guided by the Consolidated Framework for Implementation Research (CFIR) was employed. Data were collected through semi-structured interviews, focus groups, and
[204] (PDF) 17157 Racial/ethnic disparities in antibiotic-resistant ... — Community-based interventions that seek to address disparities in 'antibiotic resistance literacy' among minority and underserved groups could be particularly impactful. Discover the world's
[206] Antibiotic resistance: a call to action to prevent the next epidemic of ... — This stark imbalance has highlighted the need to examine the role of racial and ethnic disparities in shaping health outcomes. Antibiotic resistance (AR) is widely considered to be the next global pandemic. ... Hispanic and lower-income people are at higher risk of infection with community-acquired antibiotic-resistant pathogens such as
[210] Socioeconomics, antimicrobial use and antimicrobial resistance — Drug-resistant infections also affect patients' social and economic status by increasing healthcare costs, mortality and morbidity, and decreasing productivity. In this article, we review the evidence for socioeconomic effects on antimicrobial use and AMR at global, national, and individual levels.
[211] 'The disease isn't listening to the drug': The socio-cultural context ... — Many socio-cultural factors facilitate antibiotic misuse: patient and provider beliefs about antibiotics, inadequate regulation, poor health literacy, inadequate healthcare provider training, and sub-optimal diagnostic capability. This study investigates the influence of such factors on antibiotic use and community health in rural Uganda.
[213] Are Latino Cultural Beliefs Increasing Antibiotic Resistance in the US ... — Furthermore, cultural beliefs and misconceptions regarding the purpose and function of antibiotics play a major role in their misuse among the Latino population.
[215] Beliefs about antibiotics, perceptions of antimicrobial resistance, and ... — Generally, the public tends to view antibiotics as having strong benefits and have few concerns about their harm, which may have implications for inappropriate use. These initial findings highlight beliefs that could be targeted in messages to reduce inappropriate demand for antibiotics.
[217] Introduction: Drug Resistance - PMC — Common mechanisms and challenges in drug resistance necessitate a united front with a collective effort to leverage chemistry, while considering the constraints of evolution, to discover robust drugs or drug combinations that last and avoid resistance. Historically, the challenge of drug resistance was realized initially in the treatment of HIV
[256] 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.
[260] Harnessing alternative sources of antimicrobial resistance data to ... — One of the most pressing challenges facing the global surveillance of antimicrobial resistance (AMR) is the generation, sharing, systematic analysis and dissemination of data in low-resource settings. ... harnessing emerging technologies relating to 'Big Data' and artificial intelligence could lead to more effective mechanisms of AMR data
[262] Strategic framework for collaboration on antimicrobial resistance — Building on the momentum of increased collaboration, the WHO, FAO, WOAH and UNEP have developed a Strategic Framework for collaboration on antimicrobial resistance (AMR). This Framework reflects the joint work of the four organizations to advance a One Health response to AMR at the global, regional and country level.
[263] Global Antimicrobial Resistance and Use Surveillance System (GLASS) — Importantly, it is the cornerstone for assessing the spread of AMR and to inform and monitor the impact of local, national and global strategies. On 22 October 2015, WHO launched the Global Antimicrobial Resistance and Use Surveillance System (GLASS), the first global collaborative effort to standardize AMR surveillance. Endorsed by the Sixty
[264] [Global and national strategies against antibiotic resistance] — Antimicrobial resistance (AMR) is increasingly perceived as a global health problem. To tackle AMR effectively, a multisectoral one health approach is needed. We present some of the initiatives and activities at the national and global level that target the AMR challenge. The Global Action Plan on A …
[267] The Antimicrobial Resistance Crisis: Causes, Consequences, and ... — The antimicrobial resistance (AMR) crisis is the increasing global incidence of infectious diseases affecting the human population, which are untreatable with any known antimicrobial agent. Three major factors determine this crisis: (1) the increasing frequency of AMR phenotypes among microbes is an evolutionary response to the widespread use of antimicrobials; (2) the large and globally connected human population allows pathogens in any environment access to all of humanity; and (3) the extensive and often unnecessary use of antimicrobials by humanity provides the strong selective pressure that is driving the evolutionary response in the microbial world. Importantly, the demonstrated ability of the microbial adaptive mechanisms to provide effective “answers” to all environmental challenges encountered over the last 3 billion years indicates that resistance to current antimicrobials will continue to occur as long as a strong selective pressure is imposed upon microbial populations.
[269] Environmental factors influencing the development and spread of ... — An overview of the main roles of the external environment in antibiotic resistance development and dissemination. The role of the environment in the recruitment of antibiotic resistance genes (ARGs)… The role of the environment in the recruitment of antibiotic resistance genes (ARGs) to human pathogens includes four major steps: (1) emergence of novel resistance factors in the environment, (2) mobilization onto mobile genetic elements, (3) transfer of ARGs to human pathogens, and (4) dissemination of ARGs into the human microbiome. What Is the Role of the Environment in the Emergence of Novel Antibiotic Resistance Genes? Bengtsson-Palme J, et al. doi: 10.1111/j.1574-6968.2007.00757.x. Epub 2007 May 8. Antibiotic resistance in the environment. . Call of the wild: antibiotic resistance genes in natural environments.
[270] Role of Veterinarians in Livestock Sector - Pashudhan Praharee — Veterinarians contribute to food safety by monitoring antibiotic use in livestock production and promoting responsible practices to combat antibiotic resistance. They also participate in inspections of processing facilities to ensure that meat and dairy products meet safety standards before reaching consumers (NCBI, 2023).
[271] Controlling Antimicrobial Resistance: Livestock and Poultry Producers — Communicate often with your veterinarian, who will decide when antibiotics and antifungals are needed and prescribe the most appropriate drug to treat, control, and/or prevent disease in animals. Ask for advice related to preventing antimicrobial-resistant infections specific to your farm size, animal species and environment.
[272] Antimicrobial Resistance and Food Animals: Influence of Livestock ... — The use of antibiotics in human and veterinary medicine, and especially the use of large quantities of antibiotics in livestock for the purpose of growth promotion of food animals is believed to be contributing to the modern trend of the emergence and spread of bacteria with antibiotic resistant traits.
[277] 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.
[278] Transformative solutions to antibiotic resistance — A step-change technology to diagnose antibiotic resistance. The aim of DARTS is to combine the power of artificial intelligence (AI), high-throughput testing and robotics to develop rapid platforms to test for antibiotic resistance. Led by Harvard Medical School, DARTS brings together more than twenty partners in the United States.
[279] Enhancing antimicrobial resistance strategies: Leveraging artificial ... — Enhancing antimicrobial resistance strategies: Leveraging artificial intelligence for improved outcomes - ScienceDirect This review explores the burgeoning role of artificial intelligence (AI) in revolutionizing AMR strategies, offering a beacon of hope for turning the tide against resistant pathogens. By synthesizing current research and applications, the potential of AI-driven technologies—ranging from machine learning models that predict resistance patterns to algorithms enhancing antibiotic discovery—is illuminated to augment our arsenal against AMR. This review not only highlights AI's potential to enhance AMR management but also calls for a concerted effort to harness its capabilities, thereby safeguarding the efficacy of antimicrobial agents and ensuring a sustainable healthcare future. For all open access content, the Creative Commons licensing terms apply.
[286] Advancing global antibiotic research, development and access — Substantial economic challenges discourage private investment in antibiotic research and development (R&D), with a decline in the number of companies and researchers working in the field.
[288] The Impact of Public-Private Partnerships on Pharma R&D — Aside from the large-scale infrastructure projects they are typically associated with, public-private partnerships (PPPs) are increasingly becoming a cornerstone of pharmaceutical research. These collaborations are crucial to advancing drug development and addressing global health challenges, providing several benefits over conventional models.
[289] Public-private partnerships as driving forces in the quest for ... — New models of drug development based on collaborative endeavours are badly needed to improve this dire situation. Findings. In 2004, the US Food and Drug Administration (FDA) introduced the Critical Path Initiative with the intent of modernizing drug development by implementing public-private partnerships (PPP) to share data, expertise, and