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Southampton, United Kingdom
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Martinez M.,U.S. Food and Drug Administration | Silley P.,MB Consult Ltd
Handbook of Experimental Pharmacology | Year: 2010

This chapter provides an overview of our current understanding of the mechanisms associated with the development of antimicrobial drug resistance, international differences in definitions of resistance, ongoing efforts to track shifts in drug susceptibility, and factors that can influence the selection of therapeutic intervention. The latter presents a matrix of complex variables that includes the mechanism of drug action, the pharmacokinetics (PK) of the antimicrobial agent in the targeted patient population, the pharmacodynamics (PD) of the bacterial response to the antimicrobial agent, the PK/PD relationship that will influence dose selection, and the integrity of the host immune system. Finally, the differences between bacterial tolerance and bacterial resistance are considered, and the potential for non-traditional anti-infective therapies is discussed. © 2010 Springer-Verlag Berlin Heidelberg.


Ashbolt N.J.,U.S. Environmental Protection Agency | Amezquita A.,Unilever | Backhaus T.,Gothenburg University | Brandt K.K.,Copenhagen University | And 15 more authors.
Environmental Health Perspectives | Year: 2013

Background: Only recently has the environment been clearly implicated in the risk of antibiotic resistance to clinical outcome, but to date there have been few documented approaches to formally assess these risks. Objective: We examined possible approaches and sought to identify research needs to enable human health risk assessments (HHRA) that focus on the role of the environment in the failure of antibiotic treatment caused by antibiotic-resistant pathogens. Methods: The authors participated in a workshop held 4-8 March 2012 in Québec, Canada, to define the scope and objectives of an environmental assessment of antibiotic-resistance risks to human health. We focused on key elements of environmental-resistance-development "hot spots," exposure assessment (unrelated to food), and dose response to characterize risks that may improve antibiotic-resistance management options. Discussion: Various novel aspects to traditional risk assessments were identified to enable an assessment of environmental antibiotic resistance. These include a) accounting for an added selective pressure on the environmental resistome that, over time, allows for development of antibiotic-resistant bacteria (ARB); b) identifying and describing rates of horizontal gene transfer (HGT) in the relevant environmental "hot spot" compartments; and c) modifying traditional dose-response approaches to address doses of ARB for various health outcomes and pathways. Conclusions: We propose that environmental aspects of antibiotic-resistance development be included in the processes of any HHRA addressing ARB. Because of limited available data, a multi-criteria decision analysis approach would be a useful way to undertake an HHRA of environmental antibiotic resistance that informs risk managers.


Schwarz S.,Institute of Farm Animal Genetics | Silley P.,MB Consult Ltd | Silley P.,University of Bradford | Simjee S.,Elanco Animal Health | And 4 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2010

The accurate performance of antimicrobial susceptibility testing of bacteria from animal sources and the correct presentation of the results is a complex matter. A review of the published literature revealed a number of recurring errors with regard to methodology, quality control, appropriate interpretive criteria, and calculation of MIC50 and MIC90 values. Although more subjective, there is also no consensus regarding the definition of multiresistance. This Editorial is intended to provide guidance to authors on how to avoid these frequently detected shortcomings. © The Author 2010.


Silley P.,MB Consult Ltd. | Silley P.,University of Bradford | De Jong A.,Bayer AG | Simjee S.,Elanco Animal Health | Thomas V.,Intervet Innovation GmbH
International Journal of Antimicrobial Agents | Year: 2011

Antimicrobial surveillance systems in Denmark (DANMAP), The Netherlands (MARAN), Spain (VAV) and Sweden (SVARM) as well as the European Antimicrobial Susceptibility Surveillance in Animals (EASSA) were reviewed. Data have been considered for extended-spectrum cephalosporins, fluoroquinolones and macrolides against food-borne and commensal bacteria. The greatest challenge arises from the lack of agreement between programmes on what is meant by resistance through the use of different interpretive criteria. Indeed, it is shown here that the extent of the differences depends on the antibacterial compound being investigated, the methodology and the interpretive criteria used. This emphasises a need to agree a definition for resistance and for epidemiological cut-off values and to consider harmonising the antimicrobials used in surveillance. This analysis of the data highlights the usefulness of using both epidemiological cut-off values and clinical resistance breakpoints for the purpose of detection of decreased susceptibility and development of clinical resistance, respectively. It is concluded that harmonisation in resistance monitoring programmes is needed since there is potential for data to be appropriately used within risk analysis, providing the opportunity to implement appropriate risk management steps as a response to the public health issues arising from changes in antibiotic resistance in food-borne pathogens and commensal organisms. © 2011 Elsevier B.V. and the International Society of Chemotherapy.


Silley P.,MB Consult Ltd | Silley P.,University of Bradford | Simjee S.,Elanco Animal Health | Schwarz S.,Institute of Farm Animal Genetics
OIE Revue Scientifique et Technique | Year: 2012

Surveillance and monitoring studies of antimicrobial resistance in bacteria of human and animal origin and antimicrobial consumption in humans and animals have been conducted in various countries throughout the world. In the veterinary field, in particular, programmes have been installed which target bacteria of zoonotic, foodborne and/or veterinary relevance. Each year, the European Surveillance of Veterinary Antimicrobial Consumption project summarises and evaluates antimicrobial consumption in ambulatory and hospital care in many European countries. In contrast, antimicrobial consumption data in veterinary medicine are available from only a few countries and the type of information that is collected or reported varies. To address this challenge, the European Surveillance of Veterinary Antimicrobial Consumption project was launched by the European Medicines Agency in September 2009 and has just published its first report. This comparison of the different studies for surveillance and monitoring of antimicrobial resistance and antimicrobial consumption in humans and animals shows the need to improve harmonisation.


Pruden A.,Virginia Polytechnic Institute and State University | Joakim Larsson D.G.,Gothenburg University | Amezquita A.,Unilever | Collignon P.,Australian National University | And 11 more authors.
Environmental Health Perspectives | Year: 2013

Background: There is growing concern worldwide about the role of polluted soil and water environments in the development and dissemination of antibiotic resistance. Objective: Our aim in this study was to identify management options for reducing the spread of antibiotics and antibiotic resistance determinants via environmental pathways, with the ultimate goal of extending the useful life span of antibiotics. We also examined incentives and disincentives for action. Methods: We focused on management options with respect to limiting agricultural sources; treatment of domestic, hospital, and industrial wastewater; and aquaculture. Discussion: We identified several options, such as nutrient management, runoff control, and infrastructure upgrades. Where appropriate, a cross-section of examples from various regions of the world is provided. The importance of monitoring and validating effectiveness of management strategies is also highlighted. Finally, we describe a case study in Sweden that illustrates the critical role of communication to engage stakeholders and promote action. Conclusions: Environmental releases of antibiotics and antibiotic-resistant bacteria can in many cases be reduced at little or no cost. Some management options are synergistic with existing policies and goals. The anticipated benefit is an extended useful life span for current and future antibiotics. Although risk reductions are often difficult to quantify, the severity of accelerating worldwide morbidity and mortality rates associated with antibiotic resistance strongly indicate the need for action.


de Jong A.,Bayer AG | Stephan B.,Bayer AG | Silley P.,MB Consult Ltd | Silley P.,University of Bradford
Journal of Applied Microbiology | Year: 2012

The potential for transmission of antibiotic-resistant enteric zoonotic bacteria from animals to humans has been a public health concern for several decades. Bacteria carrying antibiotic resistance genes found in the intestinal tract of food animals can contaminate carcasses and may lead to food-borne disease in humans that may not respond to antibiotic treatment. It is consequently important to monitor changes in antimicrobial susceptibility of zoonotic and commensal organism; in this context, there are a number of veterinary monitoring programmes that collect bacteria in food-producing animals at slaughter and determine their susceptibility against antibiotics relevant for human medicine. The data generated are part of the risk analysis for potential food-borne transmission of resistance. There has been much debate about the use of fluoroquinolones in veterinary medicine, and so, this review will consider the fluoroquinolone data from two surveys and compare them to national surveillance programmes. At the outset, it must be pointed out that there is, however, a lack of agreement between several programmes on what is meant by the term 'fluoroquinolone resistance' through use of different definitions of resistance and different resistance breakpoints. An additional aim of this paper is to clarify some of those definitions. Despite the debate about the contribution of antibiotic use in veterinary medicine to the overall resistance development in human pathogens, the data suggest that clinical resistance to fluoroquinolones in Escherichia coli and nontyphoidal Salmonella is generally uncommon, except for a few countries. Ongoing surveillance will continue to monitor the situation and identify whether this situation changes within the respective animal populations. For the benefit of both the epidemiologist and the clinician, it would be strongly advantageous that national monitoring surveys report both percentages of clinical resistance and decreased susceptibility. © 2011 Bayer Animal Health GmbH. Journal of Applied Microbiology © 2011 The Society for Applied Microbiology.


Wendlandt S.,Institute of Farm Animal Genetics | Schwarz S.,Institute of Farm Animal Genetics | Silley P.,MB Consult Ltd | Silley P.,University of Bradford
Annual Review of Food Science and Technology | Year: 2013

Prior to the 1990s, most methicillin-resistant Staphylococcus aureus (MRSA) was hospital-associated (HA-MRSA); community-associated MRSA (CAMRSA) then began to cause infections outside the health-care environment. The third significant emergence of MRSA has been in livestock animals[livestock- associatedMRSA(LA-MRSA)]. Thewidespread and rapid growth in CA-MRSA and LA-MRSA has raised the question as to whetherMRSA is indeed a food-borne pathogen. The observations on animal-to-animal and animal-to-human transfer of LA-MRSA have prompted research examining the origin of LA-MRSA and its capacity to cause zoonotic disease in humans. This review summarizes the current knowledge about MRSA from foodproducing animals and foods with respect to the role of these organisms to act as food-borne pathogens and considers the available tools to track the spread of these organisms. It is clear thatLA-MRSAandCA-MRSAand even HA-MRSA can be present in/on food intended for human consumption, but we conclude on the basis of the published literature that this does not equate to MRSA being considered a food-borne pathogen. Copyright © 2013 by Annual Reviews.


Silley P.,MB Consult Ltd | Silley P.,University of Bradford
Food Security | Year: 2013

Antimicrobials are used in the food chain. It is often not appreciated that the requirements for a sponsor of a veterinary antimicrobial drug intended for use in food-producing animals are more onerous than those for companion animals or indeed for man. This is primarily because of the issue of potential drug residues being ingested in the human diet. Indeed this is the rationale behind the Harmonised VICH Guideline 36. It is argued that this current trilateral (EU-Japan-USA) scientific guidance is appropriate to determine the safety of antimicrobial residues in the food chain; much of this thinking has been developed from previous considerations of these matters. In this contribution we will discuss this approach, which addresses the complexity of the human intestinal flora and reduces uncertainty when determining microbiological acceptable daily intakes, and make some concluding remarks with respect to food safety and security with respect to the use of antimicrobials. A variety of toxicological evaluations are performed to establish the safety of veterinary drug residues in human food and as part of such evaluation for veterinary antimicrobial drugs is the safety of their residues on the human intestinal flora; this is an important step in ensuring the safety of the food supply. © 2013 Springer Science+Business Media Dordrecht and International Society for Plant Pathology.


Silley P.,MB Consult Ltd | Silley P.,University of Bradford
OIE Revue Scientifique et Technique | Year: 2012

The Clinical and Laboratory Standards Institute and the European Committee on Antimicrobial Susceptibility Testing can be considered the major international contributors to antimicrobial susceptibility testing. In this review, the author considers the differences between the respective organisations, examines the terminology used in antimicrobial susceptibility testing and argues for an urgent need to harmonise these definitions. While this may seem somewhat surprising, the terminology used to define resistance does differ. In this context, attention is given to the trend for 'resistance' to be defined by the epidemiological cut-off value, ratherthan by the long-established clinical breakpoint. The author goes on to discuss susceptibility testing methodologies and present an approach to setting clinical breakpoints.

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