Phylogenomics and antimicrobial resistance of the leprosy bacillus Mycobacterium leprae. Benjak Andrej,Avanzi Charlotte,Singh Pushpendra,Loiseau Chloé,Girma Selfu,Busso Philippe,Fontes Amanda N Brum,Miyamoto Yuji,Namisato Masako,Bobosha Kidist,Salgado Claudio G,da Silva Moisés B,Bouth Raquel C,Frade Marco A C,Filho Fred Bernardes,Barreto Josafá G,Nery José A C,Bührer-Sékula Samira,Lupien Andréanne,Al-Samie Abdul R,Al-Qubati Yasin,Alkubati Abdul S,Bretzel Gisela,Vera-Cabrera Lucio,Sakho Fatoumata,Johnson Christian R,Kodio Mamoudou,Fomba Abdoulaye,Sow Samba O,Gado Moussa,Konaté Ousmane,Stefani Mariane M A,Penna Gerson O,Suffys Philip N,Sarno Euzenir Nunes,Moraes Milton O,Rosa Patricia S,Baptista Ida M F Dias,Spencer John S,Aseffa Abraham,Matsuoka Masanori,Kai Masanori,Cole Stewart T Nature communications Leprosy is a chronic human disease caused by the yet-uncultured pathogen Mycobacterium leprae. Although readily curable with multidrug therapy (MDT), over 200,000 new cases are still reported annually. Here, we obtain M. leprae genome sequences from DNA extracted directly from patients' skin biopsies using a customized protocol. Comparative and phylogenetic analysis of 154 genomes from 25 countries provides insight into evolution and antimicrobial resistance, uncovering lineages and phylogeographic trends, with the most ancestral strains linked to the Far East. In addition to known MDT-resistance mutations, we detect other mutations associated with antibiotic resistance, and retrace a potential stepwise emergence of extensive drug resistance in the pre-MDT era. Some of the previously undescribed mutations occur in genes that are apparently subject to positive selection, and two of these (ribD, fadD9) are restricted to drug-resistant strains. Finally, nonsense mutations in the nth excision repair gene are associated with greater sequence diversity and drug resistance. 10.1038/s41467-017-02576-z
    Multidrug-Resistant Enterococcal Infections: New Compounds, Novel Antimicrobial Therapies? van Harten Roel M,Willems Rob J L,Martin Nathaniel I,Hendrickx Antoni P A Trends in microbiology Over the past two decades infections due to antibiotic-resistant bacteria have escalated world-wide, affecting patient morbidity, mortality, and health care costs. Among these bacteria, Enterococcus faecium and Enterococcus faecalis represent opportunistic nosocomial pathogens that cause difficult-to-treat infections because of intrinsic and acquired resistance to a plethora of antibiotics. In recent years, a number of novel antimicrobial compound classes have been discovered and developed that target Gram-positive bacteria, including E. faecium and E. faecalis. These new antibacterial agents include teixobactin (targeting lipid II and lipid III), lipopeptides derived from nisin (targeting lipid II), dimeric vancomycin analogues (targeting lipid II), sortase transpeptidase inhibitors (targeting the sortase enzyme), alanine racemase inhibitors, lipoteichoic acid synthesis inhibitors (targeting LtaS), various oxazolidinones (targeting the bacterial ribosome), and tarocins (interfering with teichoic acid biosynthesis). The targets of these novel compounds and mode of action make them very promising for further antimicrobial drug development and future treatment of Gram-positive bacterial infections. Here we review current knowledge of the most favorable anti-enterococcal compounds along with their implicated modes of action and efficacy in animal models to project their possible future use in the clinical setting. 10.1016/j.tim.2017.01.004
    Addressing Antimicrobial Resistance and Stewardship: The Priority Antimicrobial Value and Entry (PAVE) Award. Daniel Gregory W,Schneider Monika,McClellan Mark B JAMA 10.1001/jama.2017.10164
    Drug repurposing for antimicrobial discovery. Farha Maya A,Brown Eric D Nature microbiology Antimicrobial resistance continues to be a public threat on a global scale. The ongoing need to develop new antimicrobial drugs that are effective against multi-drug-resistant pathogens has spurred the research community to invest in various drug discovery strategies, one of which is drug repurposing-the process of finding new uses for existing drugs. While still nascent in the antimicrobial field, the approach is gaining traction in both the public and private sector. While the approach has particular promise in fast-tracking compounds into clinical studies, it nevertheless has substantial obstacles to success. This Review covers the art of repurposing existing drugs for antimicrobial purposes. We discuss enabling screening platforms for antimicrobial discovery and present encouraging findings of novel antimicrobial therapeutic strategies. Also covered are general advantages of repurposing over de novo drug development and challenges of the strategy, including scientific, intellectual property and regulatory issues. 10.1038/s41564-019-0357-1
    A governance framework for development and assessment of national action plans on antimicrobial resistance. Anderson Michael,Schulze Kai,Cassini Alessandro,Plachouras Diamantis,Mossialos Elias The Lancet. Infectious diseases Strengthening governance is an essential strategy to tackling antimicrobial resistance (AMR) at all levels: global, national, regional, and local. To date, no systematic approach to governance of national action plans on AMR exists. To address this issue, we aimed to develop the first governance framework to offer guidance for both the development and assessment of national action plans on AMR. We reviewed health system governance framework reviews to inform the basic structure of our framework, international guidance documents from WHO, the Food and Agriculture Organization, the World Organisation for Animal Health, and the European Commission, and sought the input of 25 experts from international organisations, government ministries, policy institutes, and academic institutions to develop and refine our framework. The framework consists of 18 domains with 52 indicators that are contained within three governance areas: policy design, implementation tools, and monitoring and evaluation. To consider the dynamic nature of AMR, the framework is conceptualised as a cyclical process, which is responsive to the context and allows for continuous improvement and adaptation of national action plans on AMR. 10.1016/S1473-3099(19)30415-3
    Tackling antimicrobial resistance at global and local scales. Gelband Hellen,Laxminarayan Ramanan Trends in microbiology Antibiotic resistance, similar to climate change, is a shared global problem, but unlike climate change, national and local action produces direct localized benefits in addition to improving the global situation. 10.1016/j.tim.2015.06.005
    Antimicrobial peptide capsids of de novo design. De Santis Emiliana,Alkassem Hasan,Lamarre Baptiste,Faruqui Nilofar,Bella Angelo,Noble James E,Micale Nicola,Ray Santanu,Burns Jonathan R,Yon Alexander R,Hoogenboom Bart W,Ryadnov Maxim G Nature communications The spread of bacterial resistance to antibiotics poses the need for antimicrobial discovery. With traditional search paradigms being exhausted, approaches that are altogether different from antibiotics may offer promising and creative solutions. Here, we introduce a de novo peptide topology that-by emulating the virus architecture-assembles into discrete antimicrobial capsids. Using the combination of high-resolution and real-time imaging, we demonstrate that these artificial capsids assemble as 20-nm hollow shells that attack bacterial membranes and upon landing on phospholipid bilayers instantaneously (seconds) convert into rapidly expanding pores causing membrane lysis (minutes). The designed capsids show broad antimicrobial activities, thus executing one primary function-they destroy bacteria on contact. 10.1038/s41467-017-02475-3
    Out-of-pocket health expenditures and antimicrobial resistance in low-income and middle-income countries: an economic analysis. Alsan Marcella,Schoemaker Lena,Eggleston Karen,Kammili Nagamani,Kolli Prasanthi,Bhattacharya Jay The Lancet. Infectious diseases INTRODUCTION:The decreasing effectiveness of antimicrobial agents is a growing global public health concern. Low-income and middle-income countries are vulnerable to the loss of antimicrobial efficacy because of their high burden of infectious disease and the cost of treating resistant organisms. We aimed to assess if copayments in the public sector promoted the development of antibiotic resistance by inducing patients to purchase treatment from less well regulated private providers. METHODS:We analysed data from the WHO 2014 Antibacterial Resistance Global Surveillance report. We assessed the importance of out-of-pocket spending and copayment requirements for public sector drugs on the level of bacterial resistance in low-income and middle-income countries, using linear regression to adjust for environmental factors purported to be predictors of resistance, such as sanitation, animal husbandry, and poverty, and other structural components of the health sector. Our outcome variable of interest was the proportion of bacterial isolates tested that showed resistance to a class of antimicrobial agents. In particular, we computed the average proportion of isolates that showed antibiotic resistance for a given bacteria-antibacterial combination in a given country. FINDINGS:Our sample included 47 countries (23 in Africa, eight in the Americas, three in Europe, eight in the Middle East, three in southeast Asia, and two in the western Pacific). Out-of-pocket health expenditures were the only factor significantly associated with antimicrobial resistance. A ten point increase in the percentage of health expenditures that were out-of-pocket was associated with a 3·2 percentage point increase in resistant isolates (95% CI 1·17-5·15; p=0·002). This association was driven by countries requiring copayments for drugs in the public health sector. Of these countries, moving from the 20th to 80th percentile of out-of-pocket health expenditures was associated with an increase in resistant bacterial isolates from 17·76% (95% CI 12·54-22·97) to 36·27% (31·16-41·38). INTERPRETATION:Out-of-pocket health expenditures were strongly correlated with antimicrobial resistance in low-income and middle-income countries. This relation was driven by countries that require copayments on drugs in the public sector. Our data suggest cost-sharing of antimicrobials in the public sector might drive demand to the private sector in which supply-side incentives to overprescribe are probably heightened and quality assurance less standardised. FUNDING:National Institutes of Health. 10.1016/S1473-3099(15)00149-8
    Global trends in antimicrobial resistance in animals in low- and middle-income countries. Van Boeckel Thomas P,Pires João,Silvester Reshma,Zhao Cheng,Song Julia,Criscuolo Nicola G,Gilbert Marius,Bonhoeffer Sebastian,Laxminarayan Ramanan Science (New York, N.Y.) The global scale-up in demand for animal protein is the most notable dietary trend of our time. Antimicrobial consumption in animals is threefold that of humans and has enabled large-scale animal protein production. The consequences for the development of antimicrobial resistance in animals have received comparatively less attention than in humans. We analyzed 901 point prevalence surveys of pathogens in developing countries to map resistance in animals. China and India represented the largest hotspots of resistance, with new hotspots emerging in Brazil and Kenya. From 2000 to 2018, the proportion of antimicrobials showing resistance above 50% increased from 0.15 to 0.41 in chickens and from 0.13 to 0.34 in pigs. Escalating resistance in animals is anticipated to have important consequences for animal health and, eventually, for human health. 10.1126/science.aaw1944
    Urban informal settlements as hotspots of antimicrobial resistance and the need to curb environmental transmission. Nadimpalli Maya L,Marks Sara J,Montealegre Maria Camila,Gilman Robert H,Pajuelo Monica J,Saito Mayuko,Tsukayama Pablo,Njenga Sammy M,Kiiru John,Swarthout Jenna,Islam Mohammad Aminul,Julian Timothy R,Pickering Amy J Nature microbiology Antimicrobial resistance (AMR) is a growing public health challenge that is expected to disproportionately burden lower- and middle-income countries (LMICs) in the coming decades. Although the contributions of human and veterinary antibiotic misuse to this crisis are well-recognized, environmental transmission (via water, soil or food contaminated with human and animal faeces) has been given less attention as a global driver of AMR, especially in urban informal settlements in LMICs-commonly known as 'shanty towns' or 'slums'. These settlements may be unique hotspots for environmental AMR transmission given: (1) the high density of humans, livestock and vermin living in close proximity; (2) frequent antibiotic misuse; and (3) insufficient drinking water, drainage and sanitation infrastructure. Here, we highlight the need for strategies to disrupt environmental AMR transmission in urban informal settlements. We propose that water and waste infrastructure improvements tailored to these settings should be evaluated for their effectiveness in limiting environmental AMR dissemination, lowering the community-level burden of antimicrobial-resistant infections and preventing antibiotic misuse. We also suggest that additional research is directed towards developing economic and legal incentives for evaluating and implementing water and waste infrastructure in these settings. Given that almost 90% of urban population growth will occur in regions predicted to be most burdened by the AMR crisis, there is an urgent need to build effective, evidence-based policies that could influence massive investments in the built urban environment in LMICs over the next few decades. 10.1038/s41564-020-0722-0
    Government policy interventions to reduce human antimicrobial use: A systematic review and evidence map. Rogers Van Katwyk Susan,Grimshaw Jeremy M,Nkangu Miriam,Nagi Ranjana,Mendelson Marc,Taljaard Monica,Hoffman Steven J PLoS medicine BACKGROUND:Growing political attention to antimicrobial resistance (AMR) offers a rare opportunity for achieving meaningful action. Many governments have developed national AMR action plans, but most have not yet implemented policy interventions to reduce antimicrobial overuse. A systematic evidence map can support governments in making evidence-informed decisions about implementing programs to reduce AMR, by identifying, describing, and assessing the full range of evaluated government policy options to reduce antimicrobial use in humans. METHODS AND FINDINGS:Seven databases were searched from inception to January 28, 2019, (MEDLINE, CINAHL, EMBASE, PAIS Index, Cochrane Central Register of Controlled Trials, Web of Science, and PubMed). We identified studies that (1) clearly described a government policy intervention aimed at reducing human antimicrobial use, and (2) applied a quantitative design to measure the impact. We found 69 unique evaluations of government policy interventions carried out across 4 of the 6 WHO regions. These evaluations included randomized controlled trials (n = 4), non-randomized controlled trials (n = 3), controlled before-and-after designs (n = 7), interrupted time series designs (n = 25), uncontrolled before-and-after designs (n = 18), descriptive designs (n = 10), and cohort designs (n = 2). From these we identified 17 unique policy options for governments to reduce the human use of antimicrobials. Many studies evaluated public awareness campaigns (n = 17) and antimicrobial guidelines (n = 13); however, others offered different policy options such as professional regulation, restricted reimbursement, pay for performance, and prescription requirements. Identifying these policies can inform the development of future policies and evaluations in different contexts and health systems. Limitations of our study include the possible omission of unpublished initiatives, and that policies not evaluated with respect to antimicrobial use have not been captured in this review. CONCLUSIONS:To our knowledge this is the first study to provide policy makers with synthesized evidence on specific government policy interventions addressing AMR. In the future, governments should ensure that AMR policy interventions are evaluated using rigorous study designs and that study results are published. PROTOCOL REGISTRATION:PROSPERO CRD42017067514. 10.1371/journal.pmed.1002819
    Antimicrobial de-escalation in critically ill patients: a position statement from a task force of the European Society of Intensive Care Medicine (ESICM) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Critically Ill Patients Study Group (ESGCIP). Tabah Alexis,Bassetti Matteo,Kollef Marin H,Zahar Jean-Ralph,Paiva José-Artur,Timsit Jean-Francois,Roberts Jason A,Schouten Jeroen,Giamarellou Helen,Rello Jordi,De Waele Jan,Shorr Andrew F,Leone Marc,Poulakou Garyphallia,Depuydt Pieter,Garnacho-Montero Jose Intensive care medicine BACKGROUND:Antimicrobial de-escalation (ADE) is a strategy of antimicrobial stewardship, aiming at preventing the emergence of antimicrobial resistance (AMR) by decreasing the exposure to broad-spectrum antimicrobials. There is no high-quality research on ADE and its effects on AMR. Its definition varies and there is little evidence-based guidance for clinicians to use ADE in the intensive care unit (ICU). METHODS:A task force of 16 international experts was formed in November 2016 to provide with guidelines for clinical practice to develop questions targeted at defining ADE, its effects on the ICU population and to provide clinical guidance. Groups of 2 experts were assigned 1-2 questions each within their field of expertise to provide draft statements and rationale. A Delphi method, with 3 rounds and an agreement threshold of 70% was required to reach consensus. RESULTS:We present a comprehensive document with 13 statements, reviewing the evidence on the definition of ADE, its effects in the ICU population and providing guidance for clinicians in subsets of clinical scenarios where ADE may be considered. CONCLUSION:ADE remains a topic of controversy due to the complexity of clinical scenarios where it may be applied and the absence of evidence to the effects it may have on antimicrobial resistance. 10.1007/s00134-019-05866-w
    Bystander Selection for Antimicrobial Resistance: Implications for Patient Health. Morley Valerie J,Woods Robert J,Read Andrew F Trends in microbiology Antimicrobial therapy promotes resistance emergence in target infections and in off-target microbiota. Off-target resistance emergence threatens patient health when off-target populations are a source of future infections, as they are for many important drug-resistant pathogens. However, the health risks of antimicrobial exposure in off-target populations remain largely unquantified, making rational antibiotic stewardship challenging. Here, we discuss the contribution of bystander antimicrobial exposure to the resistance crisis, the implications for antimicrobial stewardship, and some novel opportunities to limit resistance evolution while treating target pathogens. 10.1016/j.tim.2019.06.004
    Antimicrobial resistance challenged with metal-based antimicrobial macromolecules. Abd-El-Aziz Alaa S,Agatemor Christian,Etkin Nola Biomaterials Antimicrobial resistance threatens the achievements of science and medicine, as it deactivates conventional antimicrobial therapeutics. Scientists respond to the threat by developing new antimicrobial platforms to prevent and treat infections from these resistant strains. Metal-based antimicrobial macromolecules are emerging as an alternative to conventional platforms because they combine multiple mechanisms of action into one platform due to the distinctive properties of metals. For example, metals interact with intracellular proteins and enzymes, and catalyse various intracellular processes. The macromolecular architecture offers a means to enhance antimicrobial activity since several antimicrobial moieties can be conjugated to the scaffold. Further, these macromolecules can be fabricated into antimicrobial materials for contact-killing medical implants, fabrics, and devices. As volatilization or leaching out of the antimicrobial moieties from the macromolecular scaffold is reduced, these medical implants, fabrics, and devices can retain their antimicrobial activity over an extended period. Recent advances demonstrate the potential of metal-based antimicrobial macromolecules as effective platforms that prevent and treat infections from resistant strains. In this review these advances are thoroughly discussed within the context of examples of metal-based antimicrobial macromolecules, their mechanisms of action and biocompatibility. 10.1016/j.biomaterials.2016.12.002
    MEGARes 2.0: a database for classification of antimicrobial drug, biocide and metal resistance determinants in metagenomic sequence data. Doster Enrique,Lakin Steven M,Dean Christopher J,Wolfe Cory,Young Jared G,Boucher Christina,Belk Keith E,Noyes Noelle R,Morley Paul S Nucleic acids research Antimicrobial resistance (AMR) is a threat to global public health and the identification of genetic determinants of AMR is a critical component to epidemiological investigations. High-throughput sequencing (HTS) provides opportunities for investigation of AMR across all microbial genomes in a sample (i.e. the metagenome). Previously, we presented MEGARes, a hand-curated AMR database and annotation structure developed to facilitate the analysis of AMR within metagenomic samples (i.e. the resistome). Along with MEGARes, we released AmrPlusPlus, a bioinformatics pipeline that interfaces with MEGARes to identify and quantify AMR gene accessions contained within a metagenomic sequence dataset. Here, we present MEGARes 2.0 (https://megares.meglab.org), which incorporates previously published resistance sequences for antimicrobial drugs, while also expanding to include published sequences for metal and biocide resistance determinants. In MEGARes 2.0, the nodes of the acyclic hierarchical ontology include four antimicrobial compound types, 57 classes, 220 mechanisms of resistance, and 1,345 gene groups that classify the 7,868 accessions. In addition, we present an updated version of AmrPlusPlus (AMR ++ version 2.0), which improves accuracy of classifications, as well as expanding scalability and usability. 10.1093/nar/gkz1010