Antibiotic resistance – The faceless threat

Introduction:
The world is facing a potential post antibiotic era,which poses a serious threat to
both current and medical progres.A global rise in antibiotic resistant
bacteria,combined with a decline in the development of new antibiotics,has alarming
implications.These resistant bacteria significantly reduce the effectiveness of treating
infectious diseases and increase the risk of complications and death,particularly for
patients with bloodstream infections.
Those most at risk are individuals with weakened immune systems,such as cancer
patients,malnourished children and people living with HIV,for whom effective
treatment of severe infections is often essential for survival.Antibiotic resistance also
endangers advanced medical procedures such as organ transplants and prosthetic
implants,which relay on antibiotics to prevent infections and ensure patient
safety.Infectious diseases account for about one-fifth of global deaths,with
respiratory infections being the leading cause,responsible for nearly four million
deaths each year.Many of these deaths are considered preventable with better
access to healthcare.However,the global spread of antibiotic resistant bacteria raise
concern about the continued effectiveness of current treatments,particularly in
regions lacking access to second and third-line antibiotics.Despite widespread
awareness among medical professionals and policymakers about the growing
medical and economical impact on antibiotic resistance,meaningful action has been
limited.The weak international responses and failure to implement know solutions
are concerning.Global complacency must urgently be replaced with coordinated
efforts to address and mitigate the current and future consequences of antibody
resistance.

What are the facts about AMR?

Many alarming facts regarding AMR have accumulated, particularly over the last few
years.
●​ An increase in global resistance rates in many bacterial species
responsible for both community and healthcare -related
infections,e.g.,staphylococci,entero-cocci,and enterobacteriaceae
(E.coli,Salmonella spp,Shigella spp, Mycobacterium
tuberculosis)[1,5-7].
●​ The burgen of bacteremias due to E. coli, one of the most common
human pathogens,is increasing in Europe,mainly due to resistant
strains.[7]
●​ Emergence and dissemination of new mechanisms of
resistance,e.g,novel extended-spectrum
beta-lactamases(ESBL)[8].The spread of the new resistance gene,the
New Delhi metallo-beta-lactamase1(NDM-1) or other carbapenemases
 in Enterobacteriaceae is alarming because these “superbugs” are
resistant to most available antibiotics and can disseminate worldwide
very rapidly, in particular as a consequence of medical tourism[7].
●​ The rapid increase in the multi resistance of Gram-negative rods
stands in contrast to a steady decrease in methicillin-resistant
Staphylococcus aureus(MRSA) rates following the implementation of
successful infection control programmes in several high-income
countries,such as Belgium,France,UK,USA[5,7].In some other
countries, resistance to both gram-negative and gram-positive bacteria
is very high.
●​ Propensity to use last-line therapy(e.g.,carbapenems) to treat
health-care related and community acquired infections triggered by a
fear of infections caused by ESBL-producing
Enterobacteriaceae,despite the fact that these antibiotics should be
preserved as our last weapons against multi resistant Gram-negative
bacteria.
●​ Re-use of old drugs with poor safety and efficacy profiles and uncertain
pharmacokinetic characteristics (colistin) due to lack of alternative
drugs[9].

A global problem:
In the late 1940s, after less than a decade of penicillin being used to
treat patients with infectious diseases,unresponsive stains of the
bacterium Staphylococcus aureus,the leading causes hospital acquired
infections,were detected in England hospitals[3].A striking example of
biological evolution had begun: bacterial stain with natural and
acquired resistance were being selected as a result of the use of
antibiotics.About a decade later the first report on resistance to the
second generation of penicillins arrived;it came from a Boston
hospital,where methicillin- resistant strains of Staphylococcus
aureus(MRSA)had been identified [2].MRSA has become a symbol of
antibiotic-resistant bacteria and is without doubt one of the best studied
pathogens. Since the 1980s the frequency of isolates of MRSA among
Staphylococcus aureus has increased from close to zero to nearly 70%
in Japan and the Republic of Korea,30% in Belgium and around 40% in
UK and USA.It was discovered that mechanisms of resistance could be
spread horizontally between different stains and and different bacteria
and that, consequently, clones with multi resistant qualities could
develop.The problem soon became serious for other pathogens as
well.Infections caused by multiresistant bacterial strains such as
Acinetobacter and Stenotrophomonas can can in some cases on
longer be treated with modern antibiotics and the only available
treatment is an old antibiotic,colistin,earlier rejected for clinical
 purposes due to its toxic side effects.Globally,escalating levels of the
multiresistant intestinal pathogens Salmonella and Shigella cause
severe infections that are difficult to treat ,especially in children.In
Shigella stains from Indonesia,Thailand and India 80-90% resistance is
seen for two or more antibiotics[8].Resistance to remaining effective
therapy,such as fluoroquinolones,is steadily increasing,and the industry
pipeline for antibiotics against important intestinal pathogens is running
dry.No country on its own can also isolate itself from resistant
bacteria.Antibiotic resistant is a growing international problem affecting
both current and future generation.Resistance that develops in one
area of a country may easily spread nationwide.Globalisation with
increased migration,trade and travel,has widened the range for
infectious diseases.A resistant strain of Streptococcus pneumoniae,first
identified in spain,was soon afterwards found in
Argentina,Brazil,Taiwan,Malaysia,USA,Mexico,South Africa[7].Such
examples underline the facts that no single country can protect itself
from the threat of resistant bacteria as pathogens are spreading across
international,cultural and ethnic boundaries.Although the effects of
antibiotic resistance are more documented in industrialised
countries,there is a greater potential for harm in the developing
world,where many of the second and third line therapies for
drug-resistant infections are unavailable and unaffordable.

System failure:
A thorough inventory of biological compounds with antibiotic activity followed the
introduction of penicillin.Substances with different target mechanisms to attack
bacteria were developed into new categories of antibiotics by the pharmaceutical
industry and were eagerly used by medical professionals in their clinical practice.For
many years,society’s medical needs for antibacterial drugs were met by the
pharmaceutical industry.An apparent symbiosis between the interests of the
community and those of the industry prevailed.In the 1970s, innovative research to
develop new antibiotics gradually waned,and the focus of research and development
shifted to the fine-tuning of existing products.As resistance to antibiotics
accelerated,the fragile relation to break down.New antibiotics almost instantly faced
the problem of the evolution of bacterial resistance after being put on the market and
the short durability of antibacterial drugs was giving pharmaceutical companies cold
feet.The industry began increasingly to weigh up its liabilities towards shareholders
on the one hand and public trust and accountability to the community at large on the
other.Difficulties arose as financial performance confronted the common good.The
cleft between public and private interests grew wider with the development of
national and international drugs policies aimed at containing resistance and
restricting and rationalising the use of antibiotics[4]. Sharpened demands from
regulatory bodies have increase the development cost of new medicines,and
prioritising measures to secure optimal returns on investment have driven the
industry into other pharmaceutical areas with bigger and safer markets.At present
industry’s ventures are shifting from therapy for acute conditions towards long-term
treatment of chronic diseases.Prospective investments in antibiotics are more than
ever competing with drugs for musculo-skeletal and neurological diseases with 10 or
15 times greater “net present value”,a measure used by the industry to predict the
potential success of products.However,the need for antibiotics is anticipated to
remain consistently high.From a broad societal perspective,the industry might be
expected to supply communities with good drugs at affordable prices and provide
reliable information on them.Today,this is not the case.

The causes of resistance:

Resistance is a natural biological outcome of antibiotic use.The more we use the
drugs,the more we increase the speed of emergence and selection of resistance
bacteria.In human use around 80% of antibiotic consumption takes place in the
community and at least half of this is considered based on incorrect
indications,mostly viral infections[5].The mechanism behind this overuse are many
and intricate.The short term advantages of antibiotic use for patients,healthcare
worker and drug distributors seem to overweight concerns about future
consequences.The almost overwhelming complexity of factors influencing antibiotic
consumption includes cultural conceptions,patient demands,diagnostic
uncertainty,economic incentives,the level of training among health staff and
pharmacists,and advertising to prescribers,consumers and providers from the
pharmaceutical industry.In Europe,antibiotic consumption is four times higher in
France than in the Netherlands[2].Although the burden of disease is very similar in
the two countries.Studies from some developing countries show that several
antibiotics are generally prescribed at each consultation[3,6].The relationship
between antibiotic use and resistance is complex.Underuse,through lack of access
to antibiotics,inadequate dosing and poor adherence to therapy,may play as
important a role in driving resistance as overuse[9].The use of broad-spectrum
antibiotic agents as a substitute for precise diagnostics or to enhance the likelihood
of therapeutic success increases the rate of selection of resistant bacteria.In
addition,counterfeit and substandard drugs contribute to sub-optimal concentrations
of antibiotics,failing to control bacterial populations that are considered a risk factor
for developing resistance.It is estimated that over 50% of antibiotics worldwide is
purchased privately,from pharmacies or in the informal sector from street
vendors,without prescription.Half of the purchases are for one-day treatment or
less,an example reflecting the magnitude of the problem[4].Once resistant strains
are selected,their spread is promoted by factors such as overcrowding and poor
hygiene.One example is day care centres,which provide ample opportunities for the
transmission of infectious diseases and in particular,the emergence of resistant
Streptococcus Pneumoniae.The combination of the presence of young ,susceptible
children suffering from recurrent infections and the use of multiple, often broad
spectrum antibiotics makes such environments ideal for the carriage and
transmission of these bacteria.In the hospital setting, some bacterial clones have
been more successful than others in spreading extensively[7]. One example of the
rapid dissemination of such epidemic clones is the MRSA epidemic in England and
Wales where the frequency of MRSA among Staphylococcus aureus in blood
cultures increased from less than 5% in 1994 to present levels of just below 50%[6].

Antibiotics for non-human use:

Following the success in medicines for human beings,antibiotics have been
increasingly used to treat and prevent diseases in animals,fish and plants.Besides
this,subtherapeutic doses of antibiotics have been shown to have growth-enhancing effects
and have for decades been intensively used in animal rearing practices. In Europe and North
America,antibiotic use in the animal sector constitutes around half of the total consumption
[3].In 19887 more than 90% of the drugs used on animals in the US was administered
without veterinary consultation[4].Within the European Union most antibiotics in feedstuff
have have been prohibited for a number of years,but in many countries large numbers of
animals,irrespective of their health status,are exposed daily to sub- therapeutic
concentrations of antibiotics.Some growth promoters belong to groups of antibiotics, such as
glycopeptides,that are essential drugs in human medicine for the treatment of
serious,potentially life threatening infections.Emerging multiresistant bacteria from farm
animal are transmitted to humans mainly through the food chain or by the direct contact.The
parallel emergence in animals of resistant stains,especially of Salmonella and
Campylobacter,is continuously bringing in new clones that causes infections in human
beings[7].

The consequences:
For many years,medical professionals have defined antibiotic resistance as a major
public health problem.The issue has also received increased attention from several
international bodies and is now more generally recognised as a threat to global
health.Still,the consequences have not been sufficiently convincing to place this
issue high on political agenda.There may be several reason for this.Firstly public
finding research on antibiotic resistance has been low.In most industrialised
countries the problem has been considered an annoying but inevitable side effect of
antibiotic use,and the epidemiological and societal aspect of antibiotic resistance
have been neglected while the research agenda has been decided by the
pharmaceutical industry.This way of looking at the problem has been detrimental and
has caused a situation where today we face many fundamental knowledge gaps
including the health and economic consequences of antibiotic resistance,especially
in the community. Secondly,to describe the public health consequences of antibiotic
resistance is difficult and challenging because the problem of resistance involves
diverse pathogens,transmitted in unique ways,which causes a wide range of
diseases.The consequences for the patient,such as a prolonged disease or
increased mortality,which could be attributable to antibiotic resistance,are hidden
within a variety of clinical syndromes and the present difficulties of measuring the
resistance.Since antibiotic resistance is not of itself a disease entity,invisibility
characterises the issue,making it unknown and faceless for many people outside the
medical field.Thirdly,because of the previously continuous development of new
antibacterial agents it has been possible,in countries where new drugs are
affordable,to change the therapy to new antibiotics when resistance levels to older
ones have become “uncomfortably” high.This has not been possible in poor
countries where many of the second and third line therapies for drug- resistant
infections are unavailable,making the potential harm of resistance to first line
antibiotics considerably greater.The limited numbers of antibiotics in these countries
are becoming increasingly inadequate for treating infections,and necessary
antibiotics to deal with infections caused by resistant pathogens are absent from
many essential drug list[5].The situation is now changing in industrialised
countries,too.Because of the virtually empty pipeline of new drugs,clinicians are now
facing a situation where the likelihood of success from empiric antibiotic treatment is
reduced and where patients are sometimes infected with bacteria resistant to all
available antibiotics[6].

Mortality,costs and ecology:

Through the selection pressure caused by antibiotic use,a large pool of resistance
genes has been created.Today, we are starting to see the trip of the
iceberg.Slowly,the health impact is emerging.In the case of bloodstream infections
from MRSA,mortality is repeatedly being shown to be two to three times higher than
in infections with non- resistant strains[4,3,9].Failure of the initial antibiotic regimen
due to resistant bacteria increases the risk of secondary complications and a fatal
outcome,underscoring the clinical dilemma of empirical therapy and the prevailing
lack of rapid diagnostic tests.Recently,a study in intensive care demonstrated
significantly higher mortality among patients that received inadequate empirical
therapy,compare with those given adequate therapy (42 vs.17%)[7].Consequently,
there is a clear justification for initial broad-spectrum therapy in severe
infections.This moves us into a vicious circle where increase level of resistance
necessitate the use of broader,more potent antibiotics to secure patient survival but
where using these reserve antibiotics escalates the problem as resistance develops
and creates a situation where effective antibiotics are lacking[9].
Beside the medical consequences of antibiotic resistance, the problem is associated
with large societal costs.The most concrete example is the cost of drugs,as new
empirical treatments are needed to combat resistant pathogens.In 1997,estimates of
the annual health care costs associated with the treatment of resistant infections in
the US reached over USD 7 billion.In a district general hospital in the United
Kingdom,the cost of containing an MRSA outbreak in 1995 was greater than
400,000 pound.The figures produced so far probably underestimate the total current
costs of resistance as they are limited to health care costs,the majority of these
being incurred by the health care system[6].Further,none of these calculations
include any estimate of costs to be incurred by future generations,which almost
certainly will be larger than those being experienced currently[5].The economic and
health costs of resistance,serious enough in the industrialised world, are often made
more severe in developing countries.The economic, health and infrastructure
systems of these countries,resulting in irregular supply and availability of drugs and
often a dependence on unofficial sources,have led to extensive and inappropriate
use of drugs,resulting in infections from strains far more resistant than those
currently encountered in industrialised countries.
Antibiotic resistance is a global and intergenerational issue.The ecological
consequences are basically still unknown.Use of antibacterial drugs during the last
60 years has upset the balance in which microorganisms coexisted for millions of
years.Antibiotic compounds can currently be detected in liquid waste at animal
feedlots and fish breeding locations,in lake and groundwater supplies. Ecological
niches outside the healthcare sector are changin,as bacteria formerly susceptible to
antibiotics develop resistance to them. What are the long term health consequences
and potential environmental effects of reduced microbial diversity in the global
microbial flora through antibiotic use?Similarities with other environmental problems
can be seen,such as global warming and the reduction of the ozone layer where the
approaching impact is difficult to predict[4].

Conclusion:
Although the full magnitude of the consequences for society is still unclear,awaiting
more data before taking further actions to contain the development of resistance
bacteria is not an appealing option.Continued complacency is unjustifiable and even
unethical in contexts where the lack of effective antibiotics is most imminent.[7]
International collective action is essential,yet responsibility for health remains
predominant nationally. Consequently,there is a potentially significant disparity
between the problems and potential solutions associated with antibiotic resistance
and the institutions and mechanisms available to deal with them. Comprehensive
recommendations on rationalising antibiotic use,from the WHO, the European Union
and other organisations, get lost when it comes to translating them into action plans
in individual countries.The difficulties of enforcing these recommendations on a
global level are evident. Presently the links between the well formulated strategies at
the level of global society and their acceptance by national policy makers are weak.
To identify these barriers so as to prevent the message from repeatedly being
returned to sender is major challenge.To reverse the downward trend in research
and development of new antibiotics is another.[5]
The prevailing perplexity of the government in the face of the need to balance
commercial and community interests in this issue must be resolved.At present,public
and private interests are at odds– society’s continuously high needs contrasting with
the diminished accountability to the pharmaceutical industry. Incentives for the
development of new antibacterial drugs with novel mechanisms of action are
essential. But how to get out of this impasse? To attract the industry sufficiently to
return to investing in new antibiotics may require concrete measures,including
reducing the costs of research and development as well as securing the longer use
of products. These ideas are not new. In the area of neglected diseases an ‘orphan
drug system’ has developed to stimulate production of necessary drugs. Extended
patents have also been discussed as a way of directing industry investments.
Increasing the returns on investment is the obvious key factor in promoting drug
development within the existing framework;but can alternative options be found
outside the existing structures? Using a public health approach to fill preventive and
curative gaps in respect of diseases where the industry has lost interest would be an
attractive path to explore.[8]
How do we prevent the same pattern from continuously repeating itself:one in which
medical experts meet and compare escalating figures of resistance bacteria from
different parts of the world,discuss worst case scenarios but fail to reach out
successfully either to politicians or to society as a whole?Obviously,current efforts
are not enough to make the problem of antibiotic resistance a national political
priority in any country;therefore, other ways must be explored.Building strong public
awareness is vital if policy makers are to be stirred from their present dormant state
into taking actions.
References: