Hi my name is Valeria Bortolaia.
I am a senior researcher at the Technical University of Denmark.
Today, I will present a video lecture on introduction to antimicrobial resistance.
I have been working with this topic for more than 10 years, and
I find it very interesting and fascinating both from
a bacterial evolutionary perspective but
also very important from a public health perspective.
I hope that by the end of this lecture you will share
the enthusiasm for the topic together with me.
In the next 10-15 minutes,
I will talk about what is antimicrobial resistance
and why performing antimicrobial resistance surveillance.
As you can notice from here,
many times I will use the acronym AMR to actually indicate antimicrobial resistance.
Before going to answer these questions,
it is important that we set some definitions straight.
I believe that most of the time you have heard
the word antibiotic and not really antimicrobial.
So, when is it appropriate to talk about antibiotics
and when is it appropriate to talk about antimicrobials?
If we look at the definitions,
antibiotic is a substance that is produced by
microorganisms and has the capacity to inhibit or kill other microorganisms.
Differently, an antimicrobial is any substance that can affect microbial life,
including synthetic and semi-synthetic compounds and compounds of plant and animal origin.
Therefore, it is more appropriate in our field to use
the word antimicrobial because most of the compounds that we use in agriculture,
in veterinary and in clinical settings are actually
semi-synthetic derivatives of natural compounds or they are synthetic compounds,
which is why we usually talk about antimicrobial resistance.
But, what is antimicrobial resistance?
Antimicrobial resistance can be intrinsic or natural and the definition reads
as a structural or functional trait allowing tolerance by all members of a group.
If you look here at this cartoon,
you have here a yellow/orange cell depicted as a resistance cell.
If you have a population sharing the specific trait
of resistance to a specific antibiotics,
you will have an intrinsic resistance.
How can this happen?
There are different mechanisms,
basically three different categories.
One is the inaccessibility of the drug into the bacterial cell.
This is for example the reason for which
Gram-negative bacteria are intrinsically resistant to vancomycin.
Vancomycin cannot penetrate the outer membrane of Gram-negative bacteria and therefore,
the group, "Gram-negatives as the group", is resistant to the antibiotic.
Another mechanism can be the innate production of enzymes that inactivate the drug.
A classical example of this is ampicillin resistance in Klebsiella pneumoniae.
Klebsiella pneumoniae produces an enzyme that
inactivates ampicillin before it reaches its target.
A third category of mechanism of
intrinsic resistance is the lack of affinity of the drug for the bacterial target.
A classical example of this is cephalosporin resistance in Enterococcus species.
Enterococcus species lack the penicillin binding
proteins that have the affinity for the cephalosporins.
Another category of resistance is the acquired AMR.
Acquired AMR is due to changes in an initially susceptible population.
How can this happen? We have a similar cartoon to the one I showed before,
and you have the susceptible cells depicted in grey and the resistant in orange.
You have a normal population of bacteria but,
suddenly something happens in one of
them and it becomes resistant to a specific antibiotic.
How can this happen?
It could be mutations in conserved genes,
for example genes on the chromosome that mutate, and
the classical example is the resistance to fluoroquinolones in Escherichia coli,
where we have mutations in the DNA gyrase and topoisomerase,
enzymes that are there for
normal DNA processing. They mutate and they can confer resistance to fluoroquinolones.
Another way that brings a bacterium from grey to yellow from susceptible to resistant,
is the acquisition of new genes.
These genes can be acquired because bacteria in
their natural environment exchange genes by different methods,
and if these genes are captured by mobile genetic elements,
then they can move across bacteria and confer new traits to the cell in which they enter.
Now, that we have defined what is antimicrobial resistance,
it is very important that we understand why this is a top public health priority.
Antimicrobial resistance threatens our ability to treat
common infectious diseases, to perform medical procedures and major surgeries.
If we have bacteria that are
resistant to the antimicrobials that we use to treat the infection that they cause,
of course we cannot treat these infections,
we cannot cure the patients.
This has consequences like increased length of hospital stays or increased mortality,
and these consequences have a very high cost
both economic and but also from a societal point of view.
If you're familiar with the topic of antimicrobial resistance,
you might have read that it's quite difficult to
assess the mortality that is linked to antimicrobial resistance.
This is because people or patients usually dying from
antimicrobial resistant infections have other confounding factors like old age,
comorbidities, and so on.
But, despite the possible ways to look at the data,
there is somehow a consensus that AMR causes about 25,000 deaths per year in the EU,
about 700,000 deaths per year in the world
and, what is even more worrisome, is that inaction is
projected to cause millions of deaths globally every year.
This is because AMR is something that is spreading, and spreading very fast.
To convince you even more of the importance of AMR from a public health perspective,
I would like to show you also some different data,
for example about multidrug resistant tuberculosis.
According to a recent WHO document,
only 54 percent of patients infected by
multidrug resistant tuberculosis had actually successful treatment in 2016,
which means that only one out of two patients could actually be treated.
To talk about a different bug,
it has also been shown that people with a blood infection by MRSA,
that is Methicillin-resistant Staphylococcus aureus,
(one of the so-called superbugs because they're very difficult to treat)
have twice more likely the
probability to die compared to people with non-resistant form of the infection.
All these reasons, they are just a very small evidence among an ocean of evidences,
that AMR is actually extremely important.
International organizations such as the WHO, OIE and
FAO agree on different actions to tackle antimicrobial resistance.
One of these actions is actually antimicrobial resistance surveillance.
Antimicrobial resistance surveillance can have many goals.
First of all, it is extremely useful for
early detection of AMR strains of public health importance.
Second, it is very important to inform clinical therapy decisions
if we are aware of the resistance situation in an area or in a hospital for example,
it is possible to design treatment guidelines.
It is also necessary to guide the policy recommendations.
And finally, it is important to assess
the impact of resistance containment interventions.
Now, designing a surveillance program is something that is quite complicated,
because it will differ based on the main goal.
These goals can be hardly satisfied at the same level altogether,
so there should be focus on one or the other,
and due to limitations in time and resources,
very often we will need to select
specific pathogens and specific antimicrobials for surveillance.
But, one of the main advantages of using metagenomics is that it is
possible to do AMR surveillance
without having all these obstacles and all these limitations.
By doing AMR surveillance by metagenomics,
we will be able to detect and quantify the resistome in a sample,
where by resistome I mean or it is meant
the collection of antimicrobial resistance genes that are in the sample.
How is it possible to do this?
There are mainly two approaches.
One, is read-based metagenomics and mapping against AMR gene databases.
And the second approach is a genome-resolved metagenomics
and comparison to functional annotation databases.
You will hear more about this in the remaining part of the course,
but what is very important to know already from now is that, as I mentioned,
the resistome is the collection of intrinsic and acquired resistance genes in a sample.
Therefore, data interpretation is extremely
important for a correct outcome of AMR surveillance.
It is all from me for today.
I hope you will succeed in your metagenomics project.
Wish you best of luck and thank you for your attention.
Ana Sofia Ribeiro DuarteAssistant Professor
Tine Hald
Sünje Johanna PampAssociate Professor
Liese Van GompelPhD Candidate Epidemiology
Pimlapas LeekitcharoenphonPostDoc
