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The Antimicrobial Resistance Crisis: Causes, Consequences, and Management
The Antimicrobial Resistance Crisis: Causes, Consequences, and Management
PUBLIC HEALTH
School of Medical and Molecular Biosciences, University of Technology, Sydney, NSW, Australia
Asia Pacific Natural Hazards Research Group, School of Geosciences, University of Sydney, Sydney, NSW, Australia
ithree Institute, University of Technology, Sydney, NSW, Australia
Edited by:
Christina Maria Joseph Elisabeth
Vandenbroucke-Grauls, VU University
Medical Center, Netherlands
Reviewed by:
Johann Pitout, University of Calgary,
Canada
Fiona Walsh, National University of
Ireland Maynooth, Ireland
*Correspondence:
Carolyn Anne Michael , School of
Medical and Molecular Biosciences,
University of Technology, Broadway,
Sydney, NSW 2001, Australia
e-mail: [email protected]
The antimicrobial resistance (AMR) crisis is the increasing global incidence of infectious
diseases affecting the human population, which are untreatable with any known antimicrobial agent. This crisis will have a devastating cost on human society as both debilitating
and lethal diseases increase in frequency and scope. Three major factors determine this
crisis: (1) the increasing frequency of AMR phenotypes among microbes is an evolutionary
response to the widespread use of antimicrobials; (2) the large and globally connected
human population allows pathogens in any environment access to all of humanity; and (3)
the extensive and often unnecessary use of antimicrobials by humanity provides the strong
selective pressure that is driving the evolutionary response in the microbial world. Of these
factors, the size of the human population is least amenable to rapid change. In contrast,
the remaining two factors may be affected, so offering a means of managing the crisis: the
rate at which AMR, as well as virulence factors evolve in microbial world may be slowed by
reducing the applied selective pressure. This may be accomplished by radically reducing
the global use of current and prospective antimicrobials. Current management measures to
legislate the use of antimicrobials and to educate the healthcare world in the issues, while
useful, have not comprehensively addressed the problem of achieving an overall reduction
in the human use of antimicrobials. We propose that in addition to current measures and
increased research into new antimicrobials and diagnostics, a comprehensive education
program will be required to change the public paradigm of antimicrobial usage from that of
a first line treatment to that of a last resort when all other therapeutic options have failed.
Keywords: antibiotic, antimicrobial resistance, global crisis, horizontal gene transfer, public perception
INTRODUCTION
The microbial world, being the sum of all of those organisms that
are too small to be discerned with the human eye, is diverse, abundant, and ubiquitous. Containing not only bacteria and viruses
but also vast numbers of many different types of multicellular
organisms (1, 2), the microbial world is also the basis of the global
ecology. These apparently invisible organisms inhabit all ecological
niches on this planet, including every surface, cavity, and cellular
milieu of every human. The majority of these microbial passengers are largely benign or even beneficial to their human hosts
through their interactions with the wider ecology. However, some
few are active predators, causing damage, morbidity, and even
lethal outcomes. The gross effect of these pathogens is infectious
disease. While a small proportion of the overall microbial diversity, pathogens are nevertheless numerous and diverse and have
evolved many ways of both reaching and then taking advantage of
the biological resource represented by their human prey.
In order to combat infectious disease, a suite of chemicals
known as antimicrobial agents that are effective in limiting, preventing, or eliminating the growth of microbial predators has
been developed. The majority of these antimicrobials originated
in natural products where they were originally used by various
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Michael et al.
response to the widespread and indiscriminate use of antimicrobials. Combined with the increasingly large and connected human
population upon the Earth, prevalent antimicrobial resistance
(AMR) will see the rise of not only debilitating but also potentially lethal epidemics for which there is no effective treatment.
Such epidemics may be global in extent and ongoing in tenure,
and so represent the urgent consequences of the current AMR
crisis (8).
In this work, we shall review the causes of the AMR crisis and
the current and developmental measures to address it. We also
address the likelihood that no solution to this crisis will be definitive, and that continual management of this issue will be required
across human society. Finally, we shall propose actions additional
to those already being taken to assist in addressing and managing
this crisis.
disease. That this crisis has come to a turning point now is the
inevitable co-incidence of a number of factors within the ecology
of the planet and humanitys place within it.
MICROBIAL CAUSES
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Human population
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Over prescription
The first source of overuse in clinical practice is the empirical use of antimicrobials by clinicians. This random application
of antimicrobials is largely due to the practical shortcomings in
rapidly and accurately diagnosing infectious disease, its causative
pathogen and perhaps most importantly, the susceptibility of
the pathogen to a particular antimicrobial therapy. Such accurate diagnosis currently requires multiple laboratory-based tests
that can often take days or even weeks to complete. Understandably, the presentation of a patient with life threatening symptoms
requires immediate action. Often, this action takes the form of the
simultaneous administration of many different antimicrobials in
the hope that one will be useful in controlling the unidentified
pathogen. This over-application of antimicrobials usually occurs
in extreme cases in hospital-based patients and so is relatively controlled, though the development and implementation of rapid and
accurate diagnostics would alleviate this problem (26).
Much more widespread than the empirical treatment of acutely
ill patients is the serial application of antimicrobials by general
practitioners (27). This situation arises when a patient presents
to a practitioner with an ailment possibly due to an infectious
pathogen. Rather than always testing for pathogen and antimicrobial sensitivity, the practitioner often prescribes an antimicrobial
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Entrenched methodologies
Prescribed antimicrobials are generally applied in a fixed regimen, dictating the dose, rate, and period. Typically, such regimens
last 57 days, though many have now been extended to 14 days or
even longer. The fundamental assumption behind such extended
regimes is that high dosages over long periods will eradicate the
infecting pathogen from the body. However, recent studies demonstrate that the rates of relapse are not significantly higher in
patients where the treatment regime ceases as symptoms diminish, as compared to those taking the full course of treatment (29,
30). By limiting courses of treatment to the minimum dose and
period required to achieve a clinical result, the selective pressure
on non-combatant organisms within the patient and the wider
environment will be limited, and hence so will the speed of the
overall microbial adaptive response.
PUBLIC PERCEPTION AND BEHAVIOR
The practice of not completing prescribed courses of antimicrobial treatment may not materially affect the immediate clinical
outcome to the patient. However, where the balance of the course
is hoarded against a perceived future need, the potential for misapplication of antimicrobial therapy to non-susceptible organisms
is significantly increased.
Non-prescription purchase
Controlled access to antimicrobials is not global. In many countries, the production and sale of antimicrobials is relatively or
completely unregulated. This results in the production of therapeutic materials of extremely variable quality that are available
In addition to the commercial pressure encouraging the agricultural usage of antimicrobials, an even more concerted campaign
has been directed at the general public. The premise of this campaign is that humans need to be completely and permanently
clean at a microscopic level. That is, in order to ensure our continued health and happiness, our skins, mouths, and guts must be
routinely cleansed of all microbial life. Additionally, other surfaces that we may come into contact with such as tables and
floors must also be routinely disinfected. It is true that in some
situations, such as in food preparation and in handling potentially infectious material, precautions against microbial infection
are necessary. However, the general and complete eradication of
microbes from both domestic surfaces and ourselves is neither
necessary nor possible or even beneficial to health. Recent anecdotal evidence suggests that the development of a comprehensively
equipped immune system requires exposure to environmental
antigens (32). This exposure develops a cohort of specific antibody generating cells that are present throughout life and is also
the basis by which vaccination is effective. Normally, such cellular
cohorts and the immunities they trigger are generated in younger
years and are supplemented with exposure to novel antigens later
in life. By limiting the exposure to environmental antigens through
the over-insistence oncleanenvironments the developing suite of
immunities may be limited in both children and adults. As a result,
with the increasing incidence of such compromised immune system versatility, less virulent infections are more easily able to cause
morbidity and mortality (33).
Effective and diverse marketing campaigns convince the general
public of the necessity of overarching cleanliness. The profitable
nature of such campaigns has now produced a vast range of
antimicrobial products routinely used in society. These products
now include antimicrobials in everything from floor cleaners to
eye-drops. The diversity of such products in public use contrasts
strikingly with the relatively few effective disinfection methods
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VACCINATION RELUCTANCE
SUMMARY
The ability of the microbial world to accommodate all existing and
in all likelihood all future antimicrobial therapies, indicates that
there will not be a durable solution to the AMR crisis. Similarly,
the large and increasing human population dictates that increasing
numbers of untreatable infections will have an increasingly deleterious effect on both individuals and society. The ongoing nature of
the AMR crisis will therefore require a shift in the general perception of antimicrobials and their use at all levels of society so that
the effectiveness of both existing and prospective antimicrobials
will be protected and extended for as long as possible. Additionally,
current efforts to research and develop new antimicrobial materials, therapies, and diagnostics will need to be supported and
extended so as to ensure that novel solutions become available
before older therapies become ineffective.
In order to extend the efficacy of current antimicrobials within
the human population, their use should be minimized wherever
possible. Such restricted usage requires the application only of
antimicrobials to which the infecting pathogen is sensitive, applied
for the minimum amount of time and in the minimum dose
required in order to achieve the desired clinical effect. Further,
the elimination products from the use of antimicrobials should
as far as possible be prevented from entering the wider environment. To achieve this goal, the continuation of both legislative
and professional control will certainly be required. Additionally,
the education of both the corporate world and the general public will be required so as to reduce the demand for antimicrobials
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DISCUSSION
The factors contributing to the origins of the AMR crisis are
threefold. These are the increasingly large and connected human
population, the protean ability of the microbial world to adapt to
environmental challenges and the profligate overuse of antimicrobials by human society. We assume that by modifying any or all of
these factors, the crisis may be ameliorated.
The size, extent, and connectedness of the human population are not readily subject to influence. This means, firstly, that
humanity will continue to be exposed to virtually all existing and
presumptive pathogens. Secondly, the entire microbial ecosystem is potentially subject to the antimicrobials used by human
society. Consequently, novel pathogens, arising as zoonoses and
through other means are exposed to the global antimicrobial use,
and so resistance in these new pathogens will also continue to
increase (38).
Importantly, the demonstrated ability of the microbial adaptive
mechanisms to provide effective answers to all environmental
challenges encountered over the last 3 billion years indicates that
resistance to current antimicrobials will continue to occur as long
as a strong selective pressure is imposed upon microbial populations. Additionally, the ability of microbial adaptation to take
advantage of even synthetic materials suggests that resistance to
existing future antimicrobial strategies will also arise. Therefore,
it is likely that there will be no single long-lasting solution to the
problem of resistant infectious disease.
The adaptive ability of microbes provides the necessary flexibility for the microbial world to cope with environmental change, and
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CONCLUSION
The current AMR crisis is likely to be a permanent feature of
human society, causing increased human suffering and attendant
social costs. Managing this crisis so as to limit its effect upon
humanity will require a fundamental shift in the global perception
of antimicrobial usage. We believe that such a shift is certainly
possible and that the first steps in achieving this must be taken as
soon as possible.
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Conflict of Interest Statement: The authors declare that this work was conducted
in the absence of any commercial or financial relationships that could be construed
as a potential conflict of interest.
Received: 20 July 2014; accepted: 01 September 2014; published online: 16 September
2014.
Citation: Michael CA, Dominey-Howes D and Labbate M (2014) The antimicrobial
resistance crisis: causes, consequences, and management. Front. Public Health 2:145.
doi: 10.3389/fpubh.2014.00145
This article was submitted to Infectious Diseases, a section of the journal Frontiers in
Public Health.
Copyright 2014 Michael, Dominey-Howes and Labbate. This is an open-access
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