Elsevier

The Lancet

Volume 387, Issue 10014, 9–15 January 2016, Pages 176-187
The Lancet

Series
Understanding the mechanisms and drivers of antimicrobial resistance

https://doi.org/10.1016/S0140-6736(15)00473-0Get rights and content

Summary

To combat the threat to human health and biosecurity from antimicrobial resistance, an understanding of its mechanisms and drivers is needed. Emergence of antimicrobial resistance in microorganisms is a natural phenomenon, yet antimicrobial resistance selection has been driven by antimicrobial exposure in health care, agriculture, and the environment. Onward transmission is affected by standards of infection control, sanitation, access to clean water, access to assured quality antimicrobials and diagnostics, travel, and migration. Strategies to reduce antimicrobial resistance by removing antimicrobial selective pressure alone rely upon resistance imparting a fitness cost, an effect not always apparent. Minimising resistance should therefore be considered comprehensively, by resistance mechanism, microorganism, antimicrobial drug, host, and context; parallel to new drug discovery, broad ranging, multidisciplinary research is needed across these five levels, interlinked across the health-care, agriculture, and environment sectors. Intelligent, integrated approaches, mindful of potential unintended results, are needed to ensure sustained, worldwide access to effective antimicrobials.

Introduction

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.2, 3, 4 The 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.

Section snippets

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

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).15, 36, 37, 38, 39, 40 Antimicrobials influence this, not only by exerting a selective

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

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.10, 20, 21, 22, 97, 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

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,102 but irrespective of this, several areas have particular priority.

First, understanding of how to minimise the selection of

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, 3, 4 Such strategies to reduce antimicrobial resistance should consider the role and effect of many factors, including the

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