Novel classes of antibiotics or more of the same
TL;DR: It is suggested that, if the world is to return to a situation in which there are enough antibiotics to cope with the inevitable ongoing emergence of bacterial resistance, it needs to recreate the prolific antibiotic discovery period between 1940 and 1962, which produced 20 classes that served the world well for 60 years.
Abstract: The world is running out of antibiotics. Between 1940 and 1962, more than 20 new classes of antibiotics were marketed. Since then, only two new classes have reached the market. Analogue development kept pace with the emergence of resistant bacteria until 10-20 years ago. Now, not enough analogues are reaching the market to stem the tide of antibiotic resistance, particularly among gram-negative bacteria. This review examines the existing systemic antibiotic pipeline in the public domain, and reveals that 27 compounds are in clinical development, of which two are new classes, both of which are in Phase I clinical trials. In view of the high attrition rate of drugs in early clinical development, particularly new classes and the current regulatory hurdles, it does not seem likely that new classes will be marketed soon. This paper suggests that, if the world is to return to a situation in which there are enough antibiotics to cope with the inevitable ongoing emergence of bacterial resistance, we need to recreate the prolific antibiotic discovery period between 1940 and 1962, which produced 20 classes that served the world well for 60 years. If another 20 classes and their analogues, particularly targeting gram-negatives could be produced soon, they might last us for the next 60 years. How can this be achieved? Only a huge effort by governments in the form of finance, legislation and providing industry with real incentives will reverse this. Industry needs to re-enter the market on a much larger scale, and academia should rebuild its antibiotic discovery infrastructure to support this effort. The alternative is Medicine without effective antibiotics.
Citations
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Princeton University1, Public Health Foundation of India2, Center for Disease Dynamics, Economics & Policy3, University of the Witwatersrand4, Aga Khan University5, University of Oxford6, Food and Drug Administration7, Institute of Tropical Medicine Antwerp8, Aberdeen Royal Infirmary9, University of Antwerp10, National Veterinary Institute11, Duke University12, Karolinska Institutet13, St. John's University of Tanzania14, University of Cuenca15, Wellcome Trust16, St George's, University of London17, McMaster University18, Uppsala University19
TL;DR: The global situation of antibiotic resistance, its major causes and consequences, and key areas in which action is urgently needed are described and identified.
Abstract: The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.
3,181 citations
TL;DR: Progressive alternate approaches including probiotics, antibodies, and vaccines have shown promising results in trials that suggest the role of these alternatives as preventive or adjunct therapies in future.
Abstract: The advent of multidrug resistance among pathogenic bacteria is imperiling the worth of antibiotics, which have previously transformed medical sciences. The crisis of antimicrobial resistance has been ascribed to the misuse of these agents and due to unavailability of newer drugs attributable to exigent regulatory requirements and reduced financial inducements. Comprehensive efforts are needed to minimize the pace of resistance by studying emergent microorganisms, resistance mechanisms, and antimicrobial agents. Multidisciplinary approaches are required across health care settings as well as environment and agriculture sectors. Progressive alternate approaches including probiotics, antibodies, and vaccines have shown promising results in trials that suggest the role of these alternatives as preventive or adjunct therapies in future.
1,328 citations
TL;DR: This literature review summarizes the state of knowledge on the occurrence of antibiotics in the different aqueous environmental systems across the Europe, as reported since 2000 and provides an improved understanding on aquatic pollution by antibiotics to outline the European scenario.
789 citations
Cites background from "Novel classes of antibiotics or mor..."
...Ever since, only two new classes of antibiotics have been marketed (Davies, 2006; Coates et al., 2011)....
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TL;DR: In this tutorial review, the application of macromolecular NO therapies for cardiovascular disease, cancer, bacterial infections, and wound healing are reviewed.
Abstract: A wide range of nitric oxide (NO)-releasing materials has emerged as potential therapeutics that exploit NO's vast biological roles. Macromolecular NO-releasing scaffolds are particularly promising due to their ability to store and deliver larger NO payloads in a more controlled and effective manner compared to low molecular weight NO donors. While a variety of scaffolds (e.g., particles, dendrimers, and polymers/films) have been cleverly designed, the ultimate clinical utility of most NO-releasing macromolecules remains unrealized. Although not wholly predictive of clinical success, in vitro and in vivo investigations have enabled a preliminary evaluation of the therapeutic potential of such materials. In this tutorial review, we review the application of macromolecular NO therapies for cardiovascular disease, cancer, bacterial infections, and wound healing.
729 citations
TL;DR: Their added-value in the development of alternative, more effective antibiotics against multi-resistant Gram-negative bacteria has been highlighted and their production methods, physicochemical characterization, and pharmacokinetics are reviewed.
Abstract: Metal-based nanoparticles have been extensively investigated for a set of biomedical applications. According to the World Health Organization, in addition to their reduced size and selectivity for bacteria, metal-based nanoparticles have also proved to be effective against pathogens listed as a priority. Metal-based nanoparticles are known to have non-specific bacterial toxicity mechanisms (they do not bind to a specific receptor in the bacterial cell) which not only makes the development of resistance by bacteria difficult, but also broadens the spectrum of antibacterial activity. As a result, a large majority of metal-based nanoparticles efficacy studies performed so far have shown promising results in both Gram-positive and Gram-negative bacteria. The aim of this review has been a comprehensive discussion of the state of the art on the use of the most relevant types of metal nanoparticles employed as antimicrobial agents. A special emphasis to silver nanoparticles is given, while others (e.g., gold, zinc oxide, copper, and copper oxide nanoparticles) commonly used in antibiotherapy are also reviewed. The novelty of this review relies on the comparative discussion of the different types of metal nanoparticles, their production methods, physicochemical characterization, and pharmacokinetics together with the toxicological risk encountered with the use of different types of nanoparticles as antimicrobial agents. Their added-value in the development of alternative, more effective antibiotics against multi-resistant Gram-negative bacteria has been highlighted.
629 citations
Cites background from "Novel classes of antibiotics or mor..."
...However, a high number of analogues of existing classes and antibiotic combinations has reached the market [2]....
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...More than 20 new classes of antibiotics were produced between 1930 and 1962, but due to the evolution of new resistant bacteria, discovery of new molecules with antibacterial activity has become even more challenging to the pharmaceutical industry [2,3]....
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References
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Tufts Medical Center1, Boston Children's Hospital2, University of California, San Diego3, University of California, Los Angeles4, Los Angeles Biomedical Research Institute5, Providence Portland Medical Center6, United States Department of Veterans Affairs7, Case Western Reserve University8, University of Virginia9, Johns Hopkins University School of Medicine10
TL;DR: An update on potentially effective antibacterial drugs in the late-stage development pipeline is provided, in the hope of encouraging collaboration between industry, academia, the National Institutes of Health, the Food and Drug Administration, and the Centers for Disease Control and Prevention work productively together.
Abstract: The Infectious Diseases Society of America (IDSA) continues to view with concern the lean pipeline for novel therapeutics to treat drug-resistant infections, especially those caused by gram-negative pathogens. Infections now occur that are resistant to all current antibacterial options. Although the IDSA is encouraged by the prospect of success for some agents currently in preclinical development, there is an urgent, immediate need for new agents with activity against these panresistant organisms. There is no evidence that this need will be met in the foreseeable future. Furthermore, we remain concerned that the infrastructure for discovering and developing new antibacterials continues to stagnate, thereby risking the future pipeline of antibacterial drugs. The IDSA proposed solutions in its 2004 policy report, “Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, a Public Health Crisis Brews,” and recently issued a “Call to Action” to provide an update on the scope of the problem and the proposed solutions. A primary objective of these periodic reports is to encourage a community and legislative response to establish greater financial parity between the antimicrobial development and the development of other drugs. Although recent actions of the Food and Drug Administration and the 110th US Congress present a glimmer of hope, significant uncertainly remains. Now, more than ever, it is essential to create a robust and sustainable antibacterial research and development infrastructure—one that can respond to current antibacterial resistance now and anticipate evolving resistance. This challenge requires that industry, academia, the National Institutes of Health, the Food and Drug Administration, the Centers for Disease Control and Prevention, the US Department of Defense, and the new Biomedical Advanced Research and Development Authority at the Department of Health and Human Services work productively together. This report provides an update on potentially effective antibacterial drugs in the late-stage development pipeline, in the hope of encouraging such collaborative action.
4,256 citations
"Novel classes of antibiotics or mor..." refers background in this paper
..., 2010), while others, such as gram-positive Staphylococcal infections like methicillin-resistant Staphylococcus aureus (MRSA) are still susceptible to a range of old and new antibiotics (Boucher et al., 2009; Walkey et al., 2010)....
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...The numbers of major pharmaceutical companies which are engaged in antibiotic discovery decreased substan- tially over the past two to three decades; now, only five remain active in the field (Boucher et al., 2009)....
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...…producing pathogens which neutralize carbapenems (Kumarasamy et al., 2010), while others, such as gram-positive Staphylococcal infections like methicillin-resistant Staphylococcus aureus (MRSA) are still susceptible to a range of old and new antibiotics (Boucher et al., 2009; Walkey et al., 2010)....
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...The numbers of major pharmaceutical companies which are engaged in antibiotic discovery decreased substantially over the past two to three decades; now, only five remain active in the field (Boucher et al., 2009)....
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TL;DR: The optimism of the early period of antimicrobial discovery has been tempered by the emergence of bacterial strains with resistance to these therapeutics, and today, clinically important bacteria are characterized not only by single drug resistance but also by multiple antibiotic resistance.
Abstract: The optimism of the early period of antimicrobial discovery has been tempered by the emergence of bacterial strains with resistance to these therapeutics. Today, clinically important bacteria are characterized not only by single drug resistance but also by multiple antibiotic resistance--the legacy of past decades of antimicrobial use and misuse. Drug resistance presents an ever-increasing global public health threat that involves all major microbial pathogens and antimicrobial drugs.
3,526 citations
"Novel classes of antibiotics or mor..." refers background in this paper
...Meanwhile, multi-drug-resistant bacteria (superbugs) have emerged throughout the world (Levy and Marshall, 2004), and now half the deaths from clinical infection in Europe are associated with multi-drug-resistant bacteria (Watson, 2008)....
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...Meanwhile, multi-drug-resistant bacteria (superbugs) have emerged throughout the world (Levy and Marshall, 2004), and now half the deaths from clinical infection in Europe are associated with multi-drug-resistant bacteria (Watson, 2008)....
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University of Madras1, Cardiff University2, Health Protection Agency3, Karolinska University Hospital4, Aga Khan University5, Amrita Institute of Medical Sciences and Research Centre6, University of Queensland7, Gleneagles Hospital8, Northumbria Healthcare NHS Foundation Trust9, Apollo Hospitals10, Institute of Medical Sciences, Banaras Hindu University11
TL;DR: The prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the UK is investigated, and co-ordinated international surveillance is needed.
Abstract: Summary Background Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1 (NDM-1) are potentially a major global health problem. We investigated the prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the UK. Methods Enterobacteriaceae isolates were studied from two major centres in India—Chennai (south India), Haryana (north India)—and those referred to the UK's national reference laboratory. Antibiotic susceptibilities were assessed, and the presence of the carbapenem resistance gene bla NDM-1 was established by PCR. Isolates were typed by pulsed-field gel electrophoresis of XbaI-restricted genomic DNA. Plasmids were analysed by S1 nuclease digestion and PCR typing. Case data for UK patients were reviewed for evidence of travel and recent admission to hospitals in India or Pakistan. Findings We identified 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan. NDM-1 was mostly found among Escherichia coli (36) and Klebsiella pneumoniae (111), which were highly resistant to all antibiotics except to tigecycline and colistin. K pneumoniae isolates from Haryana were clonal but NDM-1 producers from the UK and Chennai were clonally diverse. Most isolates carried the NDM-1 gene on plasmids: those from UK and Chennai were readily transferable whereas those from Haryana were not conjugative. Many of the UK NDM-1 positive patients had travelled to India or Pakistan within the past year, or had links with these countries. Interpretation The potential of NDM-1 to be a worldwide public health problem is great, and co-ordinated international surveillance is needed. Funding European Union, Wellcome Trust, and Wyeth.
2,680 citations
"Novel classes of antibiotics or mor..." refers background in this paper
...Some bacterial infections, such as gram-negatives, are already very difficult to treat, for example, metallo-b-lactamase producing pathogens which neutralize carbapenems (Kumarasamy et al., 2010), while others, such as gram-positive Staphylococcal infections like methicillin-resistant Staphylococcus aureus (MRSA) are still susceptible to a range of old and new antibiotics (Boucher et al....
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...The neoglycoside from Achaogen is immune to nearly, but not all, the aminoglycoside modifying enzymes found in Enterobacteriaceae but is not active against Pseudomonas aeruginosa....
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...Now Enterobacteriaceae (Kumarasamy et al., 2010), which are resistant to carbapenem conferred by New Delhi metallo-blactamase 1, are being isolated from patients in several countries....
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...…such as gram-negatives, are already very difficult to treat, for example, metallo-b-lactamase producing pathogens which neutralize carbapenems (Kumarasamy et al., 2010), while others, such as gram-positive Staphylococcal infections like methicillin-resistant Staphylococcus aureus (MRSA) are…...
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TL;DR: The experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years is shared, and what is learned is looked at and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.
Abstract: The sequencing of the first complete bacterial genome in 1995 heralded a new era of hope for antibacterial drug discoverers, who now had the tools to search entire genomes for new antibacterial targets. Several companies, including GlaxoSmithKline, moved back into the antibacterials area and embraced a genomics-derived, target-based approach to screen for new classes of drugs with novel modes of action. Here, we share our experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years, and look at what we learned and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.
2,228 citations
"Novel classes of antibiotics or mor..." refers background in this paper
...In addition, the genomics approach (Payne et al., 2007) in which essential enzyme pathways in bacteria are targeted by inhibitors, may provide new classes, although none have been marketed so far....
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TL;DR: The molecular epidemiology of the epidemic waves of peniillin- and methicillin-resistant strains of S. aureus that have occurred since 1940 are reviewed, with a focus on the clinical and molecular epidemiological of CA-MRSA.
Abstract: Staphylococcus aureus is notorious for its ability to become resistant to antibiotics. Infections that are caused by antibiotic-resistant strains often occur in epidemic waves that are initiated by one or a few successful clones. Methicillin-resistant S. aureus (MRSA) features prominently in these epidemics. Historically associated with hospitals and other health care settings, MRSA has now emerged as a widespread cause of community infections. Community or community-associated MRSA (CA-MRSA) can spread rapidly among healthy individuals. Outbreaks of CA-MRSA infections have been reported worldwide, and CA-MRSA strains are now epidemic in the United States. Here, we review the molecular epidemiology of the epidemic waves of penicillin- and methicillin-resistant strains of S. aureus that have occurred since 1940, with a focus on the clinical and molecular epidemiology of CA-MRSA.
2,222 citations
"Novel classes of antibiotics or mor..." refers background in this paper
...…some strains of Neisseria meningitidis (du Plessis et al., 2008) still show only a reduced susceptibility to penicillin, while for S. aureus (Chambers and Deleo, 2009) resistance to penicillin appeared in the early 1940s, shortly after its introduction into the market, and resistance to…...
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