Antibiotics resulted in a resistance crisis in the

Antibiotics are
compounds which acquire the capability to efficiently inhibit the growth of
unwanted microorganisms by targeting specific bacterial processes or
structures. They have now been recognised as one of the greatest discoveries of
the 20th century due to their proven limitless capabilities in treating
bacterial infections over the past 70 years. They have not only played a vital
role in major advances in surgery and medicine but also allowed for the
increase of expected lifespans across many patients of all ages and
ethnicities, by simply altering the outcome of bacterial infections. Therefore,
it comes as no surprise that there has been an acceleration in the number of
antibiotics issued since their discovery. Now 90% of antibiotic prescriptions
are being prescribed by general practitioners; with respiratory tract
infections being identified as the leading cause for the increase. (Llor and
Bjerrum, 2014)  Consequently, with this
growth there has also been rapid rise in antibiotic resistance and the
evolution of “superbugs” which have unfortunately resulted in complications,
severe infections, increased mortality and longer hospital stays for many
patients. In the UK alone it is now predicted by 2050 that antibiotic-resistant
superbugs will cause more fatalities than cancer. (Papp-Wallace et al., 2011)   

 

In the 1940s shortly
after the discovery of penicillin, which is known as the “golden age” of
antibiotic research, there opened a new era of treatment to a range infectious
diseases which saved millions of lives. Nonetheless, penicillin was not
extensively used until the 2nd World War to treat serious infections in many
soldiers’ wounds. From here it became one of the most successful antibiotics
controlling once devastating bacterial infections.

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However, the overuse
of penicillin resulted in a resistance crisis in the 1950s as the bacteria
became immune to its inhibitory effects. In response to this, novel beta-lactam
antibiotics were developed but it took minimal time for the first recorded
cases of methicillin resistant staphylococcus aureus (MRSA) to occur in the UK
in 1962.  (Gould, 2016) (Jacoby, 2009)  

 

In 2016 during the
Olympic games in Brazil, it became apparent that drug resistant bacteria were
not only a concern in clinical settings. It was discovered that in one of the
bodies of water which was prepared for use for the canoe and rowing teams
contained drug-resistant bacteria. It is now known that the issue stemmed from
sewage, which contaminated the local waterways of Rio. This allowed for the
breeding of both viruses and bacteria in the bodies of the water surrounding
the city. This alarming example posed as a model for how if this issue
continues to escalate at the current rate and becomes a trend globally of how
it can potentially cause an immense threat to future drug-resistant outbreaks.
Especially as once these resistant strains enter the environment and manage to
infect water sources it will be immensely difficult to control, as these
resistant bugs have the potential to infect humans and transfer their genetic
material to non-resistant bacteria. (Med.nyu.edu, 2018)

 

The two ways in
which antibiotic resistance occur are through random genetic mutations or by
acquiring a plasmid which encodes for resistance from another bacterium.
Mutations of endogenous genes are the major contributing factor of cellular
resistance which occurs through lateral gene transfer also known as conjugation
and this involves the gene transfer of resistance of components such as
plasmids and transposons from one microorganism to the another. In terms of
random genetic mutations, this is essential in order for natural selection to
occur. The law of evolution states that organisms within a species who are best
adapted to their environment and possess these favourable characteristics from
a selection of these mutations are passed onto future generations. In terms of
bacteria, if one bacterium develops a favourable mutation which prevents it
from being killed by an antibiotic, that one bacterium is capable of surviving
and being able to pass down that trait to future generations. This results in
the prevalence of the antibiotic resistance gene within the gene pool so that
the antibiotic eventually becomes ineffective.

 

These altered
genetics lead to bacterial resistance through a number of mechanisms including;
the active efflux of drugs into the cell surroundings through the membrane-bound
efflux transporters; the inactivation of drugs by hydrolysis (for example by
?-lactamase); the preventation of the entry of drugs with the use of permeation
barriers such as the Gram-negative outer membrane; making the drug targets
unrecognizable to the drug by modifications of drug targets. (Penesyan,
Gillings and Paulsen, 2015)

 

Though microbial or
cellular resistance is the primary cause of the spread of antibiotic resistance
by the use of therapeutic agents, a range of social and administrative elements
are now also known to contribute to the spread of resistance. In many developed
countries such as the United Kingdom one of the primary contributing factors to
the problem is the over-prescriptions of antibiotics by general practitioners,
or even the absence of suitable guidance. For example, in the UK alone, between
2010 and 2013 the prescriptions of antibiotics collectively increased by 6%
which included in general practices where it increased by 4%, in hospital
inpatients where it increased by 12% and in other community prescriptions where
it increased by 32%. A combination of macrolides, tetracycline’s and
penicillin’s have been recognized as the most highly prescribed antibiotics in
the UK with tetracycline posing as an example of a broad-spectrum antibiotic. (nhs.uk,
2018) (Penesyan, Gillings and Paulsen, 2015)

 

A broad-spectrum
antibiotic is one that is determined by its ability to inhibit or kill a
combination of both gram-positive and gram-negative bacteria. Due to their
powerful effects this type of antibiotic poses the greatest threat to the
development to antimicrobial resistance as they promote evolutionary pressures
which accelerate the rates of resistance. This antibiotic is the most commonly
utilized in general practices and hospitals when a bacterial infection is
suspected but the causative agents of the infection remains unknown. Due to its
powerful effects, it therefore comes as no surprise that the rates of
prescription of broad spectrum antibiotics have increased the most in UK
hospitals with the UK’s prescription being twice the average in the EU. In
general, such inappropriate practices are common and are often adopted by
diagnostic uncertainty, lack of patient follow up, reduced knowledge in terms
of optimal therapies and high levels of patient demand. (nhs.uk, 2018) (Penesyan,
Gillings and Paulsen, 2015)

 

From a social
perspective, certain types of human behaviour also play a vital role in the
development and promotion of resistance. For example, non-compliance and
patient self-medication are of particular importance. Patient self-medication
commonly includes insufficient, unnecessary ill-timed dosing. In addition, in
some cases patients have been pressuring the physician to prescribe antibiotics
for simple cold and flu infections, with a recent study revealing that 97% of
patients receiving the antibiotics upon request. Non-compliance usually occurs
when individuals discontinue the course of medication as soon as the symptoms
of the infection disappear, or some are unable to afford the full course of
medication or simply forget to take it. (nhs.uk, 2018) (Barker, 2001)

 

Clinical settings
surprisingly also contribute to the growing issue of resistance as they can be
viewed as fertile grounds for resistant microbes to flourish in at a rapid
rate. Hospitals deal with a great number of patients on a daily basis, many
with suppressed immune systems in close proximity of each other, and they
regularly treat them with prolonged antimicrobial therapy. Drug resistant
microbes are most prevalent in teaching and large hospitals as these
environments contain the greatest number of high risk patients. Furthermore,
failure of healthcare workers to follow simple control measures to prevent the
spread of infection such as; changing their gloves following the examination of
a patient or washing their hands regularly contributes to the growing issue
further. The main modes of transmission of drug-resistant organisms amongst
patients includes; directly from a source point such as contaminated equipment
or indirectly with the contaminated hands of staff or the contaminated
surrounding environment.

 

In response to this,
for the past 15 years, hospitals have spent approximately £250 million on
better infection awareness and have implemented two primary forms of
intervention.

One form includes
limiting the use of antimicrobials and the second consists of enforcement of
intensive infection-control programs. Major components of these intervention
programmes include; strict antibiotic protocols, disinfection of equipment and
implementation of patient care practices such as; hand washing, barriers set
between infected patients and isolation. (Knobler, 2003) (Barker, 2001)

 

The antimicrobial
stewardship programme is an example of an intensive infection control programme
enforced within the UK and targeted to improve the control of antimicrobial
resistance by enhancing the manner in which antimicrobials are prescribed
across the NHS. The programme consists of a variety of measures which include;
directly promoting the active intravenous to oral switch therapy to help reduce
the unnecessary antimicrobial costs; or indirectly by advocating the promotion
of timed deliveries of antimicrobials to decrease the chances of drug-related
adverse events with their added associated costs such as treatment failure and
sub-therapeutic dosing. It is vital that all healthcare providers ensure that
the Antimicrobial Stewardship Programme is in place as recent surveys have
indicated that up to 50% of antibiotics are still used inappropriately up until
today. (Chandy et al., 2013)

 

The regulatory frameworks
imposed by the government are with guidance from National bodies and Department
of Health. These support the UK’s national initiatives to improve antibiotic
prescribing and control of infection across hospitals and incorporate many of
the antimicrobial stewardship programmes measures. For example, The Health and
Social Care Act 2008 advocates the preventation and control of infection as it
ensures that registered providers of health and social care services comply
with the Care Quality Commission registration requirement for cleanliness and
infection control.  In practice, this is
done by judging the registered provider upon how well they comply to the 10
main principles of the act which includes antimicrobial prescribing. (Gov.uk,
2018)

 

In 2012, minor
changes were made to the act in order to strengthen the relationship between
the Monitor (the regulator of the NHS trusts), the Care Quality Commission
(CQC) and the establishment of Healthcare to ensure greater levels of clarity
within the healthcare system. For example, to ensure the regulations initially
imposed in 1999 by the Department of Health supporting primary care clinicians
prescribe antibiotics was up to date, in 2010 the Public Health England
released an updated and modified antibiotic guidance for primary care
clinicians to follow. (Johnson, 2015) (Chandy et al., 2013)

 

Surveillance is
another vital factor required to monitor and prevent the prevalence of
infectious diseases so the public require reduced demand of antibiotics. As
there is currently no global system implemented which monitors antibiotic
resistance, it is critical that the legal duty of reporting information is done
to protect the community from highly contagious infectious diseases. In 2001
the European Surveillance of Antimicrobial consumption initiative was launched,
where all EU members including the UK signed up. Each EU member has a
designated network of experts accumulating data on antimicrobial usage which is
then collated and utilized to report annual trends of antibiotic resistance not
only in the country but across Europe. In terms of combatting the issue of drug
resistance, improving surveillance has been recognized as a top priority in the
UK and implementing such systems will help to monitor trends of antibiotic
resistance. Without these laws in place it could consequently lead to more
fatalities of the general public emphasizing their importance in the modern-day
society. (Fidler, 1998) (Ashiru-Oredope et al., 2012) (Johnson, 2015)

 

In spite of the high
level of effectiveness of antibiotics, the ethical predicaments they raise in
terms of redistribution still remain in various scenarios involving the doctor
and patient. As a result of the increasing risk of contracting superbugs with
extended use of antibiotics, doctors have been prescribing patients with severe
infections a lower dose of the antimicrobial compound. Consequently, leaving
the patient with improper treatment course. Therefore, antibiotic restrictions
raise many controversial questions for all parties involved such as patients
and doctors. For example, doctors are left with the strenuous task of choosing
between the welfare of the patient and the directive of the healthcare system
to restrict the prescription of antibiotics. This is also being planned to be
supported with penalties in UK causing conflict of interest, as the patient
will be under the false impression that they are gaining the optimal care and
will frequently be unaware of the antibiotic restriction polices. Therefore,
this leaves the majority of patients misinformed about their treatment. In
recent years the downstream consequences of restricting antibiotics are only
beginning to become increasingly apparent, as the concept of what the best or
most effective treatments in terms of the amount of dose varies amongst
different groups. For example, suboptimal therapy which fails to eradicate a
bacterial infection leaves the patient exposed to the chance of adverse effects
and in the long term the increased risk of antibacterial resistance. Failure to
treat the patient where the risk of the poor outcome overcomes the risk of the
adverse outcome can also be viewed as ethically unacceptable. (Garau, 2006) (Littmann
and Viens, 2015)

 

Over the past ten
years the rate of development of antibiotics has been significantly hindered in
comparison to the production rate of new more specific antibiotics.
Consequently, this has increased the demand for the production of new more
specific antibiotics which are capable of targeting mutant bacteria. However,
the current pipeline of new antibiotics shows a direct mismatch between the
demand of drugs required and the number of novel drugs being created in
response to the rising levels of antibiotic resistance. For instance, the
rising trend of resistance to carbapenems which is the broadest spectrum
antibiotic used to treat against a variety of potentially life-threatening
infections was found to only have three compounds under development in 2015.
This is alarming as this only leaves three compounds which acquire the
capability to actively work against the increasing majority of bacteria
resistant to carbapenems. Furthermore, as a whole the total antibiotic pipeline
presently consists at a scarce number of 40 products which is significantly
less than what is required in order to match the rising number of drugs
becoming resistant. In addition, the best part of these 40 products are
targeted towards easier to treat infections which are of less concern in the
overall context of the drug resistance challenge.  Presently antibiotics are primarily reserved
for individuals with acute infections and new drugs are only utilized in cases
in which the older drugs become ineffective due to antibacterial resistance.
This has left pharmaceutical companies reluctant to invest into the development
of new drugs which leaves the question of who holds responsibility for the
development of new drugs. If they aren’t made at the rising demand of the
resistance crisis we are threatening the future populations from critical resources.
Furthermore, to add to the growing issue the lack of new antibiotics could
potentially lead to increasing future fatalities from minor infections which we
are able to treat now and can result in further huge economic costs for the
NHS. (Chandy et al., 2013) (Leibovici, Paul and Ezra, 2011) (Papp-Wallace et
al., 2011) (Gov.uk, 2018) (Amr-review.org, 2018)

 

To maximize the
impact on fighting the battle of antibiotic resistance there have been several
key areas recognized by Public Health England and by partner organizations as
requiring further attention. The first key area is improvement of infection
preventation to limit the emergence of multi-drug resistant microbes in both
humans and animals. The second is optimizing prescribing practice as this is
the primary driver in the spread of antibiotic resistance. The third is advancing
professional training and education to educate both doctors and patients
better. The fourth is bettering the access and utilization of surveillance data
to allow for the analysis of the impact of antibiotic use on the patient
outcome and the development rates of resistance. The fifth is to improve the identification
and prioritization of antimicrobial research needs, to ensure that key
questions are addressed. The sixth is strengthening international
communications as antibiotic resistance is a global issue in which the UK is
playing a leading role. The UK is currently influencing both European and
international thinking by raising the issue at an international level making it
a concern for everyone by already securing commitments to ensure further
action.  (Barber, Swaden-Lewis and
Harker, 2018) (Gov.uk, 2018)

 

Overall, the harsh reality is that as a modern
society we have almost reached a point where we will not be able to treat
everyday minor diseases or infections, due to the rapid spread of multi-drug
resistant bacteria. Our current medical system relies heavily on the widespread
availability of effective antimicrobials and with current antibiotic pipeline
drying up rapidly due to limited funding, not taking the necessary measures
promptly could be leading us to some disastrous outcomes one of which can
potentially leave the NHS in even greater debt.