The increasing challenge to health care attributable to antimicrobial resistance, and the subsequent absence of access to effective antimicrobials, is of worldwide concern. There is a real threat that the public health gains from improved access to antimicrobials, including the improvements in childhood survival, could be undermined.
1 Understanding the scientific basis of antimicrobial resistance is essential to combating this public health threat. This understanding should cover the resistance mechanisms, enabling novel approaches to diagnostics and therapeutics, through to the drivers of antimicrobial resistance in society and the environment, essential for the development of appropriate interventional policies.
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4The many factors contributing to the present worldwide status of antimicrobial resistance are reviewed in this Series paper, with a particular focus on emergence of resistance, transmission, bacterial fitness, and potential for reversibility. The evidence for, and the role of, important drivers of antimicrobial resistance are considered and assessed in the context of the community (including the environment and agriculture) and in health-care systems.
Please see appendix for a list of supplementary references. From this evidence, stakeholders can engage with issues specific to their area of practice, yet also be mindful of cross-sectoral interconnectivity and the need for a One Health approach to antimicrobial resistance.
Emergence of resistance
1) Why does resistance emerge within a micro-organism?
Through a darwinian selection process microorganisms have developed robust mechanisms to evade destruction from many toxic substances. Most antimicrobial drugs are naturally produced by microorganisms, including environmental fungi and saprophytic bacteria, or are synthetic modifications of them, with only a few drugs (eg, sulphonamides and fluoroquinolones) being wholly synthetic. The protective mechanisms that have evolved include preventing entry of or exporting the drug, producing enzymes that destroy or modify the antimicrobial, or making changes to the antimicrobial target. Therefore, antimicrobial resistance could be considered to simply represent the darwinian competition from natural microorganism-derived antimicrobial molecules. Functional meta-genomic studies of soil microorganisms have shown a widespread diversity of genetic determinants conferring antibiotic resistance, of which only a fraction have been described in human pathogens.
5 One example where a naturally occurring resistance mechanism has had an effect on human health is the resistance developed against β-lactam antimicrobial drugs, in which the enzymes (β-lactamases) that inactivate these antimicrobial molecules have existed for millions of years.
6
The production of antimicrobial molecules by saprophytic organisms were originally thought to inhibit the growth of neighbouring organisms, providing a competitive advantage in the local environment; however, some studies suggest a more complex interaction. First, the concentration of antimicrobial molecules in the soil seems to be too low to inhibit growth of other bacteria.
7 Second, evidence suggests that even sublethal concentrations of antimicrobials have substantial effects on bacterial physiology, increasing the rate of microbial adaptive evolution and possibly acting as signalling molecules influencing microbial and host gene expression.
8 Of particular note are some saprophytic bacteria that produce carbapenems (an important class of broad-spectrum antimicrobials in clinical use) in which the genes implicated in the synthesis of carbapenems might also have a role in the quorum-sensing apparatus (the mechanism through which a colony of microorganisms coordinates growth and gene expression) or formation of biofilms.
6 This process leads to further questions about the unintended effects of antimicrobial drugs, with our understanding of their potential effect on microorganisms, beyond their inhibitory action, remaining incomplete.
9
Emergence of resistance to synthetic antimicrobials also occurs. This resistance has unfortunately been widely exemplified in the case of fluoroquinolones, for which in Escherichia coli isolated from patients in Europe, fluoroquinolone resistance is now at 10–40%.
10 Many resistance mechanisms have emerged including alteration of target (a DNA-gyrase), increased efflux (export of a drug out of the microorganism), fluoroquinolone inactivation (by an aminoglycoside N-acetyltransferase), and protection of the target by DNA-binding proteins (known as Qnr).
11
Even though many microorganisms in the environment, and organisms including plants and animals, naturally produce antimicrobial substances, little evidence exists to suggest that this contributes significantly to the selection of antimicrobial-resistant microorganisms in their native environment.
7 Therefore, the many and varied human, animal, and agricultural uses of antimicrobials should be considered key worldwide drivers of antimicrobial resistance.
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2) Why does antimicrobial resistance emerge at the individual human level?
Neonates are rapidly colonised by Enterobacteriaceae after birth, irrespective of whether they are breast fed or not. A study in India of a cohort of breast fed babies noted that at 1-day old, 14·3% harboured Enterobacteriaceae that contained an enzyme that inactivates β-lactam drugs, an extended-spectrum β-lactamase (ESβL), yet this increased to 41·5% of babies by day 60.
14 The environment, drinking water, and food are probably the most important means for establishing the normal (healthy) gut microflora. Antimicrobial-resistant bacteria have been found in every environment examined so far including Antarctica, the sea, soil, drinking water,
15 and various food products.
16 This polymicrobial, variably antimicrobial-resistant, commensal microbiome (microorganisms that are not causing infection at that body site eg, the gastrointestinal tract or skin) is established at an early age.
In a pristine (ie, free from external antimicrobial selection pressure) ecosystem, antimicrobial-resistant and non-resistant species coexist in a stable balance.
17 The human microbiota is no exception, and commensal microorganism populations in human beings include species that are naturally resistant to some antimicrobials. Selective pressure is exerted by any condition (eg, antimicrobial exposure) that allows microorganisms with inherent resistance or newly acquired mutations or resistance genes to survive and proliferate.
6 Antimicrobial use exerts such selective pressure on commensal human microflora, and pathogens, increasing the risk of recovery of resistant organisms from patients.
12
Use of antimicrobials in clinical medicine has exposed the human microbiota to unprecedented high concentrations of these drugs. In-vivo development of de-novo resistance within a human individual has been recorded during treatment courses with a range of antimicrobials including, worryingly, carbapenems.
18 In some patients, such as those with cystic fibrosis, there are increased rates of mutation in the infecting bacteria (ie, they are hypermutable). Some antimicrobials exacerbate this hypermutability, promoting selection of resistance.
19
3) Why does resistance emerge at the population level in humans and animals?
Antimicrobials are among the most commonly prescribed drugs used in human medicine, yet up to 50% of all antimicrobials prescribed to people are considered unnecessary.
20 This use, misuse, or overuse of antimicrobial drugs is considered to be a major driving force towards antimicrobial resistance.
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In human beings, the concentration of antibiotic prescribing might be highest in inpatient settings, with 30–40% of patients on antibiotics in European hospitals.
23 However, the overall quantity of antimicrobial prescribing is highest in the community.
24 Even though guidelines recommend prudent use, needless prescriptions are seen even in countries with low rates of prescription.
25 However an overall reduction in prescriptions for antimicrobials has been reported in some settings over the past decade, with a modest reduction in antimicrobial resistance recorded.
26 The role of educating prescribers is crucial in overcoming antimicrobial misuse or overuse and is seen to be effective in primary care
27 and secondary care.
28Additionally, raising awareness of the fundamentals of antimicrobial use in the general public is equally essential.
29
However, although the link between human antimicrobial use and resistance seems clear cut, this association is complex.
30 Confounding factors mean a uniform approach to understanding resistance cannot be taken. These factors include pathogen–drug interactions, pathogen-host interactions, mutation rates of the pathogen, emergence of successful antimicrobial-resistant clones, the transmission rates of pathogens between human beings, animals, and the environment, cross-resistance, and selection of co-resistance to unrelated drugs. Importantly, at the human population level, public health factors such as rates of vaccine uptake,
31 different systems of health care, the role of migration and tourism, sanitation, and population densities, also influence the prevalence of resistance.
30
More antimicrobials are used in food production than in human beings,
22 with marked national differences in the number of antimicrobial drugs used in food-producing animals, varying a 100-fold from 4 mg to 400 mg of antimicrobial per kg of meat produced in European countries.
32 Various studies have shown that antimicrobial resistance has, at least in part, emerged as a result of the selective pressure exerted by antimicrobial use outside of human medicine, namely in veterinary medicine,
33 food-animal and fish production,
34,
35 and agriculture.
22
In summary, the role of antimicrobial use in driving the emergence of resistance is likely to be specific to each drug and to each microorganism, as is the effect of changes in this use. This means that policies need to be mindful of this complexity in addressing selection pressure and that an integrated approach is adopted across both the community (including agriculture and the environment) and health-care structures.
Transmission of resistance
1) How does transmission of resistance occur between micro-organisms?
In addition to selection of antimicrobial resistance through mutations in genes encoded on a microbe's chromosome, new genetic material can also be exchanged between organisms. This process can provide the host cell and its progeny with new genetic material encoding antimicrobial resistance and can occur through several mechanisms, of which perhaps the most important is plasmid transmission (figure 1).
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40 Antimicrobials influence this, not only by exerting a selective pressure towards emergence of antimicrobial resistance, but also by inducing transfer of resistance determinants between microorganisms.
41
Figure 1Transmission of genetic material between microorganisms
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2) How does human-human transmission drive resistance?
Modelling of transmission dynamics has improved understanding of how human–human transmission contributes to the spread of pathogens and antimicrobial resistance.
21,
22 In the community, faecal–oral transmission, often through failures in sanitation, plays an important part, particularly for resistant Enterobacteriaceae.
42 Transmission can also occur through sexual encounters; for Neisseria gonorrhoeae, core groups have contributed to widespread dissemination of resistant clones.
43 Perhaps where the dynamics of transmission are best understood is in the context of health-care-associated infections. Using meticillin-resistant Staphylococcus aureus (MRSA) as an example, modelling suggests duration of patient stay and contamination of health-care workers' hands both contribute to continuing transmission.
44Use of whole-genome sequencing has enabled more detailed epidemiological analysis, providing rapid, fine resolution sequencing to help with mapping outbreaks and delineating transmission points.
45 What is missing, perhaps, is a better understanding of how movement and flow of patients, and the built environment, affect resistance transmission within,
46 and between,
47 health-care institutions. Moreover, the inability to rapidly identify resistant microorganisms with appropriate and efficient diagnostic tests is likely to further contribute to continuing transmission in health-care settings.
During the last 10 years the human microbiota has acquired antimicrobial resistant Enterobacteriaceae on an unprecedented scale. In some parts of the world the carrier rate of ESβL-positive Enterobacteriaceae in the gut is more than 50%,
48 and travel has been clearly associated with increased risk of gut colonisation with these organisms. In a prospective study from the Netherlands, 8·6% of travellers were colonised with ESβL-producing Enterobacteriaceae before travel, but 30·5% acquired gut colonisation during travel, with independent risk factors being travel to south and east Asia.
49 More recently, and perhaps more worryingly, is the spread of carbapenem resistance mechanisms across the world, and between organisms, with New Delhi metallo-β-lactamase (NDM),
15 Klebsiella pneumoniaecarbapenemase,
50 and OXA-48
51 enzymes being among those of greatest concern (figure 2).
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54 Travel-related human–human spread has also been evident for Gram-positive organisms, notably in the spread of antimicrobial-resistant Streptococcus pneumoniae from Spain to Iceland.
55
Figure 2Worldwide travel routes and emergence of antimicrobial resistance
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Population-based strategies to interrupt human–human transmission, including through interventions such as mass drug administration and vaccination, might alter the transmission dynamics of pathogens and resistance determinants. Evidence for this approach is strongest for vaccines, in which their use can result in reduction or elimination of the target organism, reducing the need for antimicrobial treatment and selection of antimicrobial resistance.
56Targeting vaccines against strains with drug resistance has been suggested, and provision of even slightly higher rates of protection for drug-resistant over drug-sensitive strains might be an effective method in controlling antimicrobial resistance.
57 Finally, controlling antimicrobial resistance through use of targeted, vaccine-induced replacement strains has been proposed.
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3) What is the role of animals and the environment in driving transmission of resistance?
The potential for transmission of antimicrobial-resistant microbes from animals to human beings, and the association between use of antimicrobial growth promoters in farm animals and transmission of resistant bacteria, were recognised in the 1960s.
59 Antimicrobial resistance that arises in animal husbandry is now well established and affects zoonotic pathogens such as Salmonella serovars
60 and Campylobacter spp;
61 the mechanisms of resistance are indistinguishable in bacteria isolated from animals or human beings. Bacteria, and mobile genetic elements conferring resistance, linger on animal skin and in faeces and by various means can be transferred between bacteria, and bacteria can make their way to human beings.
62 Despite the subsequent accumulation of this and other evidence, and the publication of the seminal report by Swann on this issue more than 40 years ago,
30,
63 a European ban on the use of antimicrobials for growth promotion in livestock did not occur until 2006, and outside the European Union such use still occurs widely, including in the USA. The effect on patterns of resistance from changing use of antimicrobials in animal health care continues to be well described.
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This interweaving of animal and human microbial ecosystems extends to both commensals and opportunistic pathogens, including species such as E coli, enterococci, and Staphylococcus aureus. Evidence supporting transmission from livestock to human beings of ESβL and AmpC-β-lactamase genes on plasmids and of E coli clones, most likely through the food chain, have been reported.
64 Phylogenetic evidence from whole-genome analyses of 51 Enterococcus faecium strains goes further and supports the hypothesis that the epidemic hospital-adapted lineage emerged from a population that included mostly animal strains.
65Human infections with MRSA have been classified by their putative sources, such as health-care associated or community associated. However, human MRSA cases associated with exposure to pigs (livestock-associated MRSA [LA-MRSA]) have been described,
66 as have MRSA skin and soft-tissue infections associated with proximity to crop field pig manure and livestock operations.
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The contribution of the environment to antimicrobial resistance is also concerning. Use of metals in agriculture (for example when copper is applied directly as a bactericide or fungicide),
68 and even natural occurrence of metals in certain geographical areas,
69 can select for resistance; of more concern is that many metals co-select for antimicrobial resistance.
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70Even the commonly used nitrogen fertilisers could affect the soil content of antibiotic resistance genes, causing shifts in the relative abundance of microorganisms.
5 The importance of sewage and waste processing in environment–human transmission is also clear. This stems from antimicrobials and antimicrobial metabolites entering not only from human waste processing, but also from pharmaceutical industry pollution. As a result, many potentially pathogenic antimicrobial resistance microbes have been isolated from pre-treatment and (importantly) post-treatment sewage systems.
42,
71 The subsequent detection of antimicrobials and antimicrobial-resistant microbes in surface water and ground water
35,
42reinforces the environmental need for preventive action to be taken.
In summary, the worldwide acquisition, persistence, and transmission of antimicrobial-resistant microbes by people, animals, and the environment is hugely affected by no access to clean water, open rather than closed sewage systems, variation in health-care infection-control practices, inadequate provision of antimicrobials and diagnostics, farming systems with suboptimum regulation of antimicrobials, and high population densities (figure 3, appendix). Although some of these issues exist in high resource settings, they are likely to represent particularly important drivers of antimicrobial resistance in low-income and middle-income countries.
Figure 3Role of modifiable drivers for antimicrobial resistance: a conceptual framework
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The complex issues of fitness and reversibility of antimicrobial resistance
1) Does antimicrobial resistance affect the fitness of micro-organisms?
There is a perception that antimicrobial-resistant microbes might be less fit (ie, less able to grow or cause an infection) than their antimicrobial susceptible counterparts. This situation would mean that reducing the burden of resistance might simply be achieved through removing the selective pressure of antimicrobials, leading to antimicrobial-resistant microbes losing out in darwinian competition with the susceptible strains. Unfortunately, this is frequently not the case and can be seen in two important classes of antimicrobials, the fluoroquinolones and the β-lactams.
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In the case of fluoroquinolones (man-made antimicrobials), clonal expansion has given rise to a worldwide high prevalence of resistance in several bacteria. This increase is exemplified by whole-genome sequencing of an epidemic MRSA strain (EMRSA-15; ST22)
73 and Clostridium difficile O27.
74 Furthermore, widespread dissemination of fluoroquinolone-resistant clones of E coli ST131 exists,
75 whereas fluoroquinolone-resistant Salmonella enterica serovar Typhi
72and N gonorrhoeae
76 are not uncommon.
This development and worldwide spread of fluoroquinolone-resistant bacteria suggests resistance to this class of drugs is unlikely to be a burden to the bacterium. Mutations that alter the target of antimicrobials (such as gyrA, in the case of fluoroquinolones) can change bacterial physiology, potentially making them less fit. Yet compensatory mutations that restore fitness to wild-type levels might explain, in part, why clinical isolates resistant to this class of drugs have proliferated and spread. As a specific example, mutations detected in a fluoroquinolone-resistant strain of E coli were experimentally reconstructed. Strains with single mutations were less fit than the parental strain; however, two or more mutations in combination increased the fitness of the bacterium to similar or greater levels than that of the antimicrobial-susceptible strain.
77 Therefore, once selected, fluoroquinolone-resistant mutants are able to persist and thrive even in the absence of fluoroquinolone antimicrobials.
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The carriage of mobile genetic elements such as plasmids, which often contain several antimicrobial resistance genes, has also been proposed to reduce bacterial fitness. However, carriage of natural plasmids with no antimicrobial resistance genes is common, and might confer a benefit to hosts, thereby promoting expansion of plasmid-carrying strains.
78 For example, an IncK plasmid (named pCT), which carries one antimicrobial resistance gene (encoding the ESβL CTX-M-14) has no detectable fitness effect when introduced into new host strains and has spread worldwide in diverse E coli strains from animals, human beings, and the environment.
79 As such, absence of antimicrobials might not lead to a reduction in the prevalence of this type of third generation cephalosporin-resistance.
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2) Is emergence of resistance reversible?
One strategy to reduce the development and spread of antimicrobial resistance is to lower the selective pressure by limiting or suspending the use of antimicrobials. This strategy is based on the assumption that resistant microorganisms will be outnumbered by susceptible strains if the selective advantage of possessing the resistance determinant is diminished,
81 but as noted, this is not always true (panel 1). Mathematical models have increasingly been used to identify, predict, and help design intervention programmes for antimicrobial resistance.
92These models support antimicrobial exposure as central to resistance emergence and spread, but importantly do find correlations between reduction in antimicrobial use and reduction in antimicrobial resistance, at both the individual patient
93 and human population levels.
94
Panel 1
Complete eradication of antimicrobial resistance in populations of microbes after reduced selective pressure from antimicrobials is not straightforward. Resistance determinants are easy for microbes to acquire and might persist at low, but detectable, levels for many years in the absence of particular antimicrobials,
95 and in turn, antimicrobial resistant microbes can persist for many years on human and animal skin and as faecal flora without any further exposure or selection pressure.
96 The absence of a clear correlation between reduced use of antimicrobials and decreased antimicrobial resistance can be explained by the interplay of several factors. One factor is context, such as whether the system is open (ie, continuous inflow and outflow, in which the incoming population has a differing frequency of antimicrobial resistance) or closed (ie, a community in which migration is restricted). At the level of the microbe, other factors include the nature of the resistance mechanisms (and level of fitness cost), the propensity for horizontal gene transfer and transmissible elements, and cross-selection and co-selection mechanisms.
77 Cross-selection and co-selection are highly pertinent because many bacteria are multidrug resistant owing to the presence of several antimicrobial resistance genes; therefore, only by reducing use of all drugs to which resistance is encoded will the prevalence of a multidrug-resistant microbe decrease, and only then if this is beneficial to the bacterium.
Approaches to optimising antimicrobial use
1) How should antimicrobials be used to preserve effectiveness and delay resistance in humans?
The published work on antimicrobial resistance across many different diseases converges on a remarkably consistent set of recommendations for prevention and containment.
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98 These principles focus on improvement of diagnosis and prescription practices, reduction of antimicrobial use in animal husbandry, fish farming, agriculture, and environmental exposure in general, development of new antimicrobials, guarantee of access to essential medicines of assured quality, and improvement of surveillance. Despite these generic principles being acknowledged, implementation has been slow.
99 However, some disease-specific approaches have been tried, and the evidence suggests that several approaches could be beneficial if tested and validated on a wide range of infectious diseases (panel 2).
Panel 2
In a world where patients often need urgent effective treatment, some antimicrobial optimisation strategies present practical challenges. Analysis of antimicrobial stewardship programmes, and their implementation in varied health-care settings, is an area of vigorous academic pursuit, and although many lessons have clearly been learnt,
28 gaps in our knowledge still exist.
100 The human and economic costs of overcoming these challenges, and filling these gaps, are likely to be small compared with unchecked resistance, which might mean drugs have to be withdrawn and replaced with newly developed alternatives, or worse, the inability to treat at all.
101 Furthermore, beyond optimisation of antimicrobial use, development and implementation of robust infection prevention and control initiatives at national and local levels should be established to curtail onwards transmission of antimicrobial-resistant microbes.
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2) How should antimicrobials be used to preserve effectiveness and delay resistance in animals?
The evidence for reversibility of antimicrobial resistance in the context of animal health has been noted as complex (panel 1); however, three principles are clear. First, antimicrobials used as animal growth promoters and for inappropriate routine infection prevention in herds should be banned. Second, access to non-medicated animal feed for farmers should be improved. Third, use of specific classes of antimicrobials should be restricted to either human beings or animals.
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Approaches to optimisation of antimicrobial use in both human and animal health should be integrated and coordinated, with shared learning, understanding, and participation in environmental interventions. Such a One Health approach, integrating human medicine, veterinary medicine, public health, and environmental science in specialties including surveillance, development of new diagnostics and therapeutics, and interlinking research and education should enable creation and implementation of more comprehensive and effective policies. Coordinated action and application of these might prolong the therapeutic life of present antimicrobials, and should be a high priority for all.
What gaps in our knowledge need addressing?
The need to address the research gaps in antimicrobial resistance has never been more keenly felt. However, identification of priorities, increase of research funding, and targeting research activity should be coordinated and cohesively addressed. The construction of a worldwide database of previous and present antimicrobial resistance projects has been advocated,
102but irrespective of this, several areas have particular priority.
First, understanding of how to minimise the selection of antimicrobial resistance is fundamental, including understanding of how to optimise antimicrobial use. This approach requires detailed analysis to define optimum durations and dosage of therapy in specific patient groups (including infants, pregnant women, undernourished, obese, and co-infected patients).
103,
104 The absence of basic knowledge about ideal prescribing regimens represents a significant gap. Furthermore, as noted (panel 2), some previously advocated strategies to combat antimicrobial resistance need further assessment, including investigation of antimicrobial prescribing combinations. Many of these matters can only be investigated through translational research, including novel educational methods,
105 and through implementation of international networking and collaborations. A reorganisation of antimicrobial resistance funding to support such translational work is needed.
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Second, in support of optimisation of antimicrobial use, improved targeting through rapid infection diagnostics should be enabled. Although this method has been widely advocated,
20,
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97 it has been slow to be implemented, due partly to technical and financial barriers,
22 but also issues around innovation adoption.
106 An example is next generation sequencing, which is likely to radically change microbiological diagnostics, but costs, data pipelines, and clinical confidence in interpreting results have yet to be resolved.
107 An alternative technological development already widely in use, namely matrix-assisted laser desorption/ionisation time-of-flight, allows rapid microorganism identification, and potentially also antimicrobial susceptibility testing.
108 These avenues are suitable for secondary care, but for primary care optimising antimicrobial use through near-patient inflammatory marker assays has growing evidence.
109 For low-income and middle-income countries, diagnostic options several-fold cheaper, with less need of logistic infrastructure, are needed and a focus on chromogenic tests might provide avenues for exploration.
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Third, although new drug discovery is essential (and through use of novel laboratory methods, drug discovery has taken a leap forward)
111 research on the quality of currently used antimicrobials is also urgently needed. The issue of substandard antimicrobials is a potentially significant driver of resistance and little is known on the international extent of the problem.
2 Engaging policy makers, prescribers, antimicrobial providers, and the public in ensuring access and assuring quality of antimicrobials should be an essential component of addressing antimicrobial resistance.
Fourth, understanding of how to effectively reduce the prevalence of resistant organisms and their transmission underpins much of the research needed. In the context of human–human transmission, delineating not just effective, but cost-effective interventions to optimise antimicrobial use, reduce transmission, and prevent environmental contamination with antimicrobial resistance and antimicrobials is essential. To address this balance through minimisation of antimicrobial use in agriculture and aquaculture while meeting the ever-increasing worldwide food demands, is also a fundamental challenge. Adopting a One Health lens to identify gaps in understanding at these interfaces, and then construct integrated research strategies to bridge them, is likely to be a productive way forward. Inherent in this area of research is improvement towards a greater level of detail from surveillance (ie, fine resolution geographical and temporal information) to identify associations between antimicrobial use and misuse, and to clearly identify successful interventions. However, present surveillance data are rarely standardised or reported in a timely way and are often aggregated, making interpretation problematic; without access to individual patient outcomes data are of little use. Making primary data available internationally, and standardising which markers of resistance and species are tracked across international boundaries, might be one avenue to harmonise these efforts
22,
97 and is potentially possible to a fine resolution
112 with automated methods.
113 Such information can provide early warning of emerging resistance and allow prompt implementation of efforts to preserve and maximise the useful therapeutic life of present antimicrobials. This coordinated approach has been successfully implemented for malaria and could be productively applied to other pathogens.
Finally, at the level of the microorganism, continued investigation is needed to generate new insights into the basic mechanisms of resistance, gene transfer, and adaptive bacterial evolution. This includes investigating the role of persistence and host–pathogen interactions and their contribution to antimicrobial resistance
114 and antimicrobial resistance reversal. Pursuing areas such as these might uncover new targets for improved therapeutics and diagnostics. Areas of particular therapeutic interest
97,
115 include small molecules to attenuate bacterial virulence and disrupt biofilm formation,
116 bacteriophage therapy,
117 the potential for eco-biological approaches,
118 identification of drug targets that select for reduced bacterial fitness during development of antimicrobial resistance,
8 and enhancement of host immune responses
56,
57,
58 including host-directed therapy.
119
Conclusion
Many of the drivers of antimicrobial resistance have a common origin in inappropriate use of antimicrobials in human and animal health care or in agriculture, or from environmental contamination. Although our understanding of antimicrobial resistance is far from complete, the existing evidence base is sufficient to allow targeted policies to be developed in several areas.
2,
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4 Such strategies to reduce antimicrobial resistance should consider the role and effect of many factors, including the resistance mechanisms, species of microorganism, the particular antimicrobial, as well as the setting and context. So far, all evidence suggests that no single solution exists and several overlapping and synergistic approaches will be needed. Furthermore these approaches should be coordinated at national and international levels, while engaging local stakeholders to ensure widespread implementation. The approaches should be mindful of any potential unintended consequences (including possible impact on access to necessary antimicrobials
2 and patient outcomes) and should share a strong overarching goal to ensure access to effective antimicrobial therapies for this generation and for the future.
Contributors
All authors contributed to the literature search, interpretation of published information, writing, and contribution to figure content for their respective areas of expertise. AHH and LSPM edited, structured, and coordinated the complete manuscript and the figures and panels. All authors reviewed and approved the final version of the manuscript.
Declaration of interests
AHH and LSPM have previously consulted for bioMérieux. All other authors declare no competing interest.
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