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A number of resistant bacterial pathogens have become the focus of recent concern in human medicine. Studies and facts on use of antibiotics in animals suggest that animal sources contribute little to the problem. The current pursuit of zero risk by banning some antibiotics in Europe is not a sensible precaution but rather an abdication of responsibility based on science. ; Includes bibliographical references

Zulqarnain Baloch,1,* Bilal Aslam,2,* Saima Muzammil,2 Mohsin Khurshid,3 Muhammad Hidayat Rasool,2 Ke Ma4 1College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; 2Department of Microbiology, Government College University Faisalabad, Faisalabad, Pakistan; 3College of Allied Health Professionals, Directorate of Medical Sciences, Government College University Faisalabad, Faisalabad, Pakistan; 4College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China *These authors contributed equally to this work Abstract: Antibiotic therapy has a dual impact: wanted, in which it immediately inhibits the growth of bacteria and the unwanted, which is responsible for the evolution of antibiotic resistance. The dissociation of therapeutic effectiveness from the possible risk of the antibiotic resistance may be attained by taking the advantage of specific relations between these drugs, and the methods in which mutations associated with resistance against a specific antibiotic may modify these relations or it may increase the sensitivity of the bacterium to the other antibiotics. Although the practical implementation of this notion needs considerable advancement and confirmation that depends upon the improvements in the field of genomics and diagnostics, these interventions propose new paradigms, which may confine or inverse the evolution of antibiotic resistance. Keywords: antibiotic resistance, inversion, mutations, bacteria, evolution

The fight against antibiotic resistance must be strengthened. We propose actions that U.S. government agencies and private sector entities can take to build a more comprehensive effort. These actions can increase the viability of investing in new antibiotics, ensure the quality and stewardship of all antibiotics, and make responses to emerging resistance more informed. Success requires the thoughtful exercise of federal authority and a firm commitment to share data and reward developers for the value generated with new, life-saving antibiotics.

The scarcity of novel antibiotic compounds in a time of increasing resistance rates has begun to ring alarm bells at the highest echelons of government. Large new financial incentives to accelerate antibiotic research and development, such as market entry rewards (MERs), are being considered. However, there is little focus on how to sustain the efficacy of new, promising antibiotics reaching the market. Currently, inappropriate use of antibiotics is commonplace, which has accelerated resistance development. In an attempt to halt this trend, antibiotic stewardship policies are being implemented in many resource-rich settings. Unfortunately, this has not yet had an impact on the amount of antibiotics being prescribed globally. One important hurdle is misalignment of incentives. While governments and health services are incentivized to promote prudent use of this common good, pharmaceutical companies are incentivized to increase volume of sales to maximize profits. This problem must be addressed or else the major efforts going into developing new antibiotics will be in vain. In this paper we outline an approach to realign the incentives of pharmaceutical companies with wider antibiotic conservation efforts by making a staged bonus a component of an MER for antibiotic developers when resistance to their drug remains low over time. This bonus could address the lack of stewardship focus in any innovation-geared incentive.

The scarcity of novel antibiotic compounds in a time of increasing resistance rates has begun to ring alarm bells at the highest echelons of government. Large new financial incentives to accelerate antibiotic research and development, such as market entry rewards (MERs), are being considered. However, there is little focus on how to sustain the efficacy of new, promising antibiotics reaching the market. Currently, inappropriate use of antibiotics is commonplace, which has accelerated resistance development. In an attempt to halt this trend, antibiotic stewardship policies are being implemented in many resource-rich settings. Unfortunately, this has not yet had an impact on the amount of antibiotics being prescribed globally. One important hurdle is misalignment of incentives. While governments and health services are incentivized to promote prudent use of this common good, pharmaceutical companies are incentivized to increase volume of sales to maximize profits. This problem must be addressed or else the major efforts going into developing new antibiotics will be in vain. In this paper we outline an approach to realign the incentives of pharmaceutical companies with wider antibiotic conservation efforts by making a staged bonus a component of an MER for antibiotic developers when resistance to their drug remains low over time. This bonus could address the lack of stewardship focus in any innovation-geared incentive.

The scarcity of novel antibiotic compounds in a time of increasing resistance rates has begun to ring alarm bells at the highest echelons of government. Large new financial incentives to accelerate antibiotic research and development, such as market entry rewards (MERs), are being considered. However, there is little focus on how to sustain the efficacy of new, promising antibiotics reaching the market. Currently, inappropriate use of antibiotics is commonplace, which has accelerated resistance development. In an attempt to halt this trend, antibiotic stewardship policies are being implemented in many resource-rich settings. Unfortunately, this has not yet had an impact on the amount of antibiotics being prescribed globally. One important hurdle is misalignment of incentives. While governments and health services are incentivized to promote prudent use of this common good, pharmaceutical companies are incentivized to increase volume of sales to maximize profits. This problem must be addressed or else the major efforts going into developing new antibiotics will be in vain. In this paper we outline an approach to realign the incentives of pharmaceutical companies with wider antibiotic conservation efforts by making a staged bonus a component of an MER for antibiotic developers when resistance to their drug remains low over time. This bonus could address the lack of stewardship focus in any innovation-geared incentive.

Antibiotics have natural functions, mostly involving cell-to-cell signaling networks. The anthropogenic production of antibiotics, and its release in the microbiosphere results in a disturbance of these networks, antibiotic resistance tending to preserve its integrity. The cost of such adaptation is the emergence and dissemination of antibiotic resistance genes, and of all genetic and cellular vehicles in which these genes are located. Selection of the combinations of the different evolutionary units (genes, integrons, transposons, plasmids, cells, communities and microbiomes, hosts) is highly asymmetrical. Each unit of selection is a self-interested entity, exploiting the higher hierarchical unit for its own benefit, but in doing so the higher hierarchical unit might acquire critical traits for its spread because of the exploitation of the lower hierarchical unit. This interactive trade-off shapes the population biology of antibiotic resistance, a composed-complex array of the independent "population biologies." Antibiotics modify the abundance and the interactive field of each of these units. Antibiotics increase the number and evolvability of "clinical" antibiotic resistance genes, but probably also many other genes with different primary functions but with a resistance phenotype present in the environmental resistome. Antibiotics influence the abundance, modularity, and spread of integrons, transposons, and plasmids, mostly acting on structures present before the antibiotic era. Antibiotics enrich particular bacterial lineages and clones and contribute to local clonalization processes. Antibiotics amplify particular genetic exchange communities sharing antibiotic resistance genes and platforms within microbiomes. In particular human or animal hosts, the microbiomic composition might facilitate the interactions between evolutionary units involved in antibiotic resistance. The understanding of antibiotic resistance implies expanding our knowledge on multi-level population biology of bacteria. ; The authors' work was sponsored by grants from the European Union (PAR-241476 and EvoTAR-282004), the Instituto de Salud Carlos III – Ministry of Economy and Competitiveness of Spain (FIS-PS09-02381; FIS-PI10-02588, PI12-01581), and the Regional Government of Madrid in Spain (PROMPT- S2010/BMD2414). The authors are also grateful to the Spanish Network for the Study of Plasmids and Extrachromosomal Elements (REDEEX) for encouraging and funding cooperation among Spanish microbiologists working on the biology of mobile genetic elements (grant BFU 2012-0079-E/BMC; Spanish Ministry of Science and Innovation). ; Peer reviewed ; Peer Reviewed

Bilal Aslam,1 Wei Wang,2 Muhammad Imran Arshad,3 Mohsin Khurshid,1,4 Saima Muzammil,1 Muhammad Hidayat Rasool,1 Muhammad Atif Nisar,1 Ruman Farooq Alvi,1 Muhammad Aamir Aslam,2 Muhammad Usman Qamar,1 Muhammad Khalid Farooq Salamat,5 Zulqarnain Baloch6 1Department of Microbiology, Government College University Faisalabad, Faisalabad, Pakistan; 2NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, China; 3Institute of Microbiology, University of Agriculture Faisalabad, Faisalabad, Pakistan; 4College of Allied Health Professionals, Directorate of Medical Sciences, Government College University Faisalabad, Faisalabad, Pakistan; 5Neurobiology Division, The Roslin Institute, University of Edinburgh, Edinburgh, UK; 6College of Veterinary Medicine, South China Agricultural University, Guangzhou, China 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. Keywords: antibiotics, multidrug resistance, evolution, alternative therapies

Prochlorococcus is responsible for a significant part of CO2 fixation in the ocean. Although it was long considered an autotrophic cyanobacterium, the uptake of organic compounds has been reported, assuming they were sources of limited biogenic elements. We have shown in laboratory experiments that Prochlorococcus can take up glucose. However, the mechanisms of glucose uptake and its occurrence in the ocean have not been shown. Here, we report that the gene Pro1404 confers capability for glucose uptake in Prochlorococcus marinus SS120. We used a cyanobacterium unable to take up glucose to engineer strains that express the Pro1404 gene. These recombinant strains were capable of specific glucose uptake over a wide range of glucose concentrations, showing multiphasic transport kinetics. The Ks constant of the high affinity phase was in the nanomolar range, consistent with the average concentration of glucose in the ocean. Furthermore, we were able to observe glucose uptake by Prochlorococcus in the central Atlantic Ocean, where glucose concentrations were 0.5-2.7 nM. Our results suggest that Prochlorococcus are primary producers capable of tuning their metabolism to energetically benefit from environmental conditions, taking up not only organic compounds with key limiting elements in the ocean, but also molecules devoid of such elements, like glucose. ; European Union. Seventh Framework Programe. 227799 ; Ministerio de Educación y Ciencia. BFU-2009-08008/BMC ; European Social Fund. BFU2010-19544 ; Universidad de Córdoba. BFU-2009-08008/BMC y P07-CVI-3055

Anthropogenic influences in the southern polar region have been rare, but lately microorganisms associated with humans have reached Antarctica, possibly from military bases, fishing boats, scientific expeditions, and/or ship-borne tourism. Studies of seawater in areas of human intervention and proximal to fresh penguin feces revealed the presence of Escherichia coli strains least resistant to antibiotics in penguins, whereas E. coli from seawater elsewhere showed resistance to one or more of the following antibiotics: ampicillin, tetracycline, streptomycin, and trim-sulfa. In seawater samples, bacteria were found carrying extended-spectrum β-lactamase (ESBL)-type CTX-M genes in which multilocus sequencing typing (MLST) showed different sequence types (STs), previously reported in humans. In the Arctic, on the contrary, people have been present for a long time, and the presence of antibiotic resistance genes (ARGs) appears to be much more wide-spread than was previously reported. Studies of E coli from Arctic birds (Bering Strait) revealed reduced susceptibility to antibiotics, but one globally spreading clone of E. coli genotype O25b-ST131, carrying genes of ESBL-type CTX-M, was identified. In the few years between sample collections in the same area, differences in resistance pattern were observed, with E. coli from birds showing resistance to a maximum of five different antibiotics. Presence of resistance-type ESBLs (TEM, SHV, and CTX-M) in E. coli and Klebsiella pneumoniae was also confirmed by specified PCR methods. MLST revealed that those bacteria carried STs that connect them to previously described strains in humans. In conclusion, bacteria previously related to humans could be found in relatively pristine environments, and presently human-associated, antibiotic-resistant bacteria have reached a high global level of distribution that they are now found even in the polar regions.

Background The international community strongly advocates the implementation of multi-sectoral surveillance policies for an effective approach to antibiotic resistance, in line with the One Health concept. To comply with these international recommendations, the Vietnamese government has issued an inter-ministerial surveillance strategy for antibiotic resistance, including an integrated surveillance system. However, one may question the ability and willingness of surveillance stakeholders to implement the collaborations required. To assess the feasibility of operationalising this strategy within the national context, we explored the role of key stakeholders in the strategy, as well as their abilities to comply with it. Methods We conducted a qualitative approach based on an iterative stakeholder mapping and analysis, in three distinct steps: (1) a description of the structure of the national surveillance strategy (literature review, key informant interviews); (2) an analysis of the key stakeholders' positions regarding the strategy (semi-structured interviews); (3) the identification of factors influencing the operationalisation of the collaborative surveillance strategy (comparison of data collected at the first and second steps). Results The mapping of the surveillance system, as well as the characterisation of key stakeholders according to organisational and functional attributes, underlined that inter-sectoral surveillance initiatives do exist, but that the organisation of the national surveillance system remains highly silo-oriented. Based on stakeholder perspectives, we identified seven factors that may influence the implementation of the One Health strategy at national level: governance and operational frameworks, divergence of institutional cultures, level of knowledge, technical capacities, allocation of resources, conflicting commercial interests and influence of international partners. Conclusions The study suggests that the operationalisation of the collaborative surveillance strategy requires the full adhesion of stakeholders and the provision of appropriate resources. Based on these findings, we have proposed a guidance framework together with recommendations to move towards a more suitable governance and operational model for One Health surveillance of antibiotic resistance in Vietnam. To lever and promote successful inter-sectoral collaboration, a participatory "learning by doing" process could be applied to guide, frame and mentor stakeholders through the identification of appropriate levels of collaboration, depending on the expected positive impacts on the value of surveillance.

Background The international community strongly advocates the implementation of multi-sectoral surveillance policies for an effective approach to antibiotic resistance, in line with the One Health concept. To comply with these international recommendations, the Vietnamese government has issued an inter-ministerial surveillance strategy for antibiotic resistance, including an integrated surveillance system. However, one may question the ability and willingness of surveillance stakeholders to implement the collaborations required. To assess the feasibility of operationalising this strategy within the national context, we explored the role of key stakeholders in the strategy, as well as their abilities to comply with it. Methods We conducted a qualitative approach based on an iterative stakeholder mapping and analysis, in three distinct steps: (1) a description of the structure of the national surveillance strategy (literature review, key informant interviews); (2) an analysis of the key stakeholders' positions regarding the strategy (semi-structured interviews); (3) the identification of factors influencing the operationalisation of the collaborative surveillance strategy (comparison of data collected at the first and second steps). Results The mapping of the surveillance system, as well as the characterisation of key stakeholders according to organisational and functional attributes, underlined that inter-sectoral surveillance initiatives do exist, but that the organisation of the national surveillance system remains highly silo-oriented. Based on stakeholder perspectives, we identified seven factors that may influence the implementation of the One Health strategy at national level: governance and operational frameworks, divergence of institutional cultures, level of knowledge, technical capacities, allocation of resources, conflicting commercial interests and influence of international partners. Conclusions The study suggests that the operationalisation of the collaborative surveillance strategy requires the full adhesion of stakeholders and the provision of appropriate resources. Based on these findings, we have proposed a guidance framework together with recommendations to move towards a more suitable governance and operational model for One Health surveillance of antibiotic resistance in Vietnam. To lever and promote successful inter-sectoral collaboration, a participatory "learning by doing" process could be applied to guide, frame and mentor stakeholders through the identification of appropriate levels of collaboration, depending on the expected positive impacts on the value of surveillance.

Background The international community strongly advocates the implementation of multi-sectoral surveillance policies for an effective approach to antibiotic resistance, in line with the One Health concept. To comply with these international recommendations, the Vietnamese government has issued an inter-ministerial surveillance strategy for antibiotic resistance, including an integrated surveillance system. However, one may question the ability and willingness of surveillance stakeholders to implement the collaborations required. To assess the feasibility of operationalising this strategy within the national context, we explored the role of key stakeholders in the strategy, as well as their abilities to comply with it. Methods We conducted a qualitative approach based on an iterative stakeholder mapping and analysis, in three distinct steps: (1) a description of the structure of the national surveillance strategy (literature review, key informant interviews); (2) an analysis of the key stakeholders' positions regarding the strategy (semi-structured interviews); (3) the identification of factors influencing the operationalisation of the collaborative surveillance strategy (comparison of data collected at the first and second steps). Results The mapping of the surveillance system, as well as the characterisation of key stakeholders according to organisational and functional attributes, underlined that inter-sectoral surveillance initiatives do exist, but that the organisation of the national surveillance system remains highly silo-oriented. Based on stakeholder perspectives, we identified seven factors that may influence the implementation of the One Health strategy at national level: governance and operational frameworks, divergence of institutional cultures, level of knowledge, technical capacities, allocation of resources, conflicting commercial interests and influence of international partners. Conclusions The study suggests that the operationalisation of the collaborative surveillance strategy requires the ...

Background The international community strongly advocates the implementation of multi-sectoral surveillance policies for an effective approach to antibiotic resistance, in line with the One Health concept. To comply with these international recommendations, the Vietnamese government has issued an inter-ministerial surveillance strategy for antibiotic resistance, including an integrated surveillance system. However, one may question the ability and willingness of surveillance stakeholders to implement the collaborations required. To assess the feasibility of operationalising this strategy within the national context, we explored the role of key stakeholders in the strategy, as well as their abilities to comply with it. Methods We conducted a qualitative approach based on an iterative stakeholder mapping and analysis, in three distinct steps: (1) a description of the structure of the national surveillance strategy (literature review, key informant interviews); (2) an analysis of the key stakeholders' positions regarding the strategy (semi-structured interviews); (3) the identification of factors influencing the operationalisation of the collaborative surveillance strategy (comparison of data collected at the first and second steps). Results The mapping of the surveillance system, as well as the characterisation of key stakeholders according to organisational and functional attributes, underlined that inter-sectoral surveillance initiatives do exist, but that the organisation of the national surveillance system remains highly silo-oriented. Based on stakeholder perspectives, we identified seven factors that may influence the implementation of the One Health strategy at national level: governance and operational frameworks, divergence of institutional cultures, level of knowledge, technical capacities, allocation of resources, conflicting commercial interests and influence of international partners. Conclusions The study suggests that the operationalisation of the collaborative surveillance strategy requires the ...