Transcript non-b-lactam antibiotics

Medical oral
microbiology I – lecture
(ZLLM0421p)
Antibiotics III (mechanisms of
resistance, factors of resistance)
Ondřej Zahradníček
[email protected]
Resistance of microbes
to antimicrobial agents
Primary resistance: all strains of a
given species are resistant. Example:
b-lactam antibiotics have no effect to
mycoplasmas, that have no cell wall.
 Secondary resistance: mutants that
are not susceptible are formed, and at
selection pressure of the antibiotic
they start to be majority. (Escherichia
may be susceptible to ampicillin, but in
recent times resistant strains are more
frequent than before)
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http://www.nearingzero.net/screen_res/nz149.jpg
Mechanisms of resistance I
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Microbe disables entrance of antibiotic into
the cell
Microbe causes active efflux of an antibiotic
from the cell
Microbe changes the target receptor or
offers a false receptor to the antibiotic
Microbe subdues metabolic changes that
disable the common effect of the antibiotic in
the usual target structure
Microbe splits the antibiotic enzymatically
(e. g. a b-lactamase splits b-lactam antibiotics)
New mechanisms are found all the time…
http://www.powerpak.com/index.asp?show=lesson&page=courses/10132/les
son.htm&lsn_id=10132
Mechanisms of resistance II:
mutual differences
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Some of them are coded on chromosomes
Some are coded on plasmids, and plasmids
may be transmitted intra- or interspecies
Some are like „either - or“, so antibiotics
either do, or do not function, and if they do
not function, even elevated dosage of
antibiotics is no help
In some other resistance may be overcome by
elevation of antibiotic dose (especially in
aminoglycosides and fluoroquinolones)
In the second case, the phenotypic testing is
more difficult than in the first one
http://www.adrian.edu/c
hemistry/th/Somelinks/S
pages/jtessmer/why.php
Efflux (active
expulsion of
antibiotics
out)
A stronger quinolone
(ciprofloxacin) is still effective,
but the weaker one
(norfloxacin) already not. But
even at using the stronger it is
necessary to be careful!
www.microbes-edu.org/etudiant/antibio3.html.
Mechanisms of resistance in
b-lactam antibiotics
b-lactam antibiotics are the most commonly used
antibiotics, so their resistance factors require
more detailed description
 Change of penicillin binding proteins, (PBP),
for example in strains of MRSA
 Production of b-lactamases, for example:
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Staphylococcal penicillinases
Penicillinases of Enterobacteriaceae family
Cephalosporinases of various microbes
Extended-spectre b-lactamases
Decreased membrane permeability
b-lactamases
There exist many types of them,
they may have effect against all or
majority, or just some of b-lactam
antibiotics
 They may be code chromosomally
or on plasmids
 Basic principle is always splitting of
the b-lactamic circle
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TEM-1 b-lactamase
of E. coli
Change of PBP (penicillin binding
proteins)
http://www.proteinexpert.com/RD-services/Protein-engineering.php
Resistance – survey
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As we have seen, there exist lots of
mechanisms of resistance, and also many
possibilities of genetic coding of them
So it is not possible to consider them „all the
same“:
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Some are epidemiologically important, some of
them are not
Some only concern one antibiotic, some of them
the whole group or several groups
Some can be overcome by elevated dosing of an
antibiotic (so it is rather a quantitative switch –
„worse effect“, common in aminoglycosides)
In some of the it is „either-or“. In such case
resistance cannot be solved by higher doses
Transmission
of resistance
http://www.mja.com.au/p
ublic/issues/177_06_1609
02/col10836_fm.html
Transmission
of genes for
resistance
by different
ways
www.scq.ubc.ca/?p=410
Selection of
resistant
strains
www.answers.com/topic/antibiotic-resistance-gif.
Another reason for lack of in vivo
effect at in vivo effectivity:
bacteria in a biofilm
Bad effect of antibiotics may be
used here by
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Charge of the adhered cells
Decreases multiplication of bacteria
Mechanisms of intercellular
signalisation (quorum sensing)
Influence of host immunity response
Various other influences
Solution
Think about the real possibility, that
(especially in some types of infection)
bacteria exist not just in planctonic
form, but also as biofilm (especially in
some types of infections)
 To use combinations of antibiotics
 Besides MIC, also make tests for
MBEC, and not only to individual
antibiotics, but also to combinations
 Use other treatment than just
antibiotics (catheter exchange, local
treatment etc.)
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Epidemiologically
important strains
Common causative agents of
nosocomial infections
 Complication of
hospitalisation, complication
of operations, deterioration
of health status, death of
hospitalised people
 Enormous costs of treatment
 Medialisation of problematic
following panic (often not
constructive)
They are used also in politics 
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http://www.bloggerheads.com/anne_milton/2
005/04/superbugs-and-super-anne.html
(MRSA etc.)
Medialisation concerns mostly MRSA
http://tahilla.typepad.com/petsmrsa/bella_moss_media_national_papers/index.html
Medialisation of these topics
It concerns some types (especially MRSA)
 Often it influences healthcare staff
 People have often fear of MRSA, but they omit
other also important resistances (VRE, ESBL,
MLS resistance of staphylococci)
Similar situation exist also in some other
microbial diseases („flesh-eating streptococci“,
„mad cows“, „bird flu“ – they often have their
common names)
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The fear is often abused but
commercial sector that offers
„surely MRSA-proof“ kits
www.healthtec.co.uk/mrsa.htm
Fear of the public (including
healthcare staff, e. g. nurses)
should be converted to be more
constructive actions (behaviour that
really leads to decrease of risky
behaviour in relation with the disease)
 on the other hand, any non-constructive
panic, that follows in pressure for nonreasonable examination of persons that
are not in risk, useless use of
pharmacotherapy etc., should be
eliminated
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MRSA, or
bird flu?
www.whale.to/b/bird_flu_h.html.
VRE (vancomycin resistant
enterococci)
http://www.morgenwelt.de/typo3temp/5ce14d39b5.jpg
Enterococci – characteristics
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Enterococci are primarily resistant to lots of
antibiotics (including all cephalosporins, but
also macrolides, lincosamids, worse effect of Vpenicillin)
Enterococcus faecium (less pathogenous, but
more resistant than E. faecalis) is also
primarily resistant to ampicillin
Treatment may be done using co-trimoxazole,
tetracycline, quinolones. Glycopeptides
(vancomycin, teicoplanin) are a reserve. The
problem is if even such reserve antibiotics do
not function; and just this is a problem in
VRE strains.
VRE in Brno
In Institute of microbiology of St.
Ann‘s faculty hospital, we have
individual cases of VRE
 More common presence of VRE
strains is seen in Brno-Bohunice
faculty hospital
 Probable reason: VRE are common in
patients with cancer of lymphatic
cells, and in Brno these patients are
mostly present in Bohunice hospital
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Drugs of choice are linezolid
(ZYVOXID) and
quinupristin/dalfopristin (SYNERCID)
www.aic.cuhk.edu.hk/web8/enterococcus_faecium.htm
Meticilin
resistant
staphylococci
(MRSA)
www.daikoh.net/service/creansysytem.html
History of MRSA
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Originally also staphylococci were
susceptible to penicillin, soon they started to
be resistant by action of penicillinase
Methicillin was firstly used in 1960,
something later also oxacillin and nafcillin
(because of various reasons many countries
rather use oxacillin or nafcillin than methicillin)
First epidemic outbreak of MRSA was seen
in 1963, but then the MRSA ratio was 0.4 %. In
1973 it was already 10 % and 2004 even 43 %
(data from the U. S.)
The resistance problem is based on change of
„penicillin binding proteins“
MRSA as a problem of
today‘s medicine
More seniors of in population
 Use of treatment influencing immunity
 Using of intravenous catheters and
implants inside body
 Use (and abuse) of antibiotics
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All this are determining factors that
influence risk of (not only) MRSA
MRSA is not more virulent than
any other strain of S. aureus
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Although many people would not believe it, as
to the ability of a bacterium to cause the
disease (virulence), average MRSA strains
are quite the same as all the average
other golden staphylococci.
Resistance to oxacillin
is not a special
virulence factor. These
strains are not more,
but also not less
virulent than other
strains.
www.metrowestcleangear.com/MRSA.htm
Staphylococcus aureus (MRSA)
www.aic.cuhk.edu.hk/web8/mrsa.htm
Not all MRSA strains are
the same
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There exist big differences between MRSA
strains
There exist a population of so called EMRSA
– epidemic MRSA, these are common as
nosocomial strains. They use to be
polyresistant and e. g. resistance to
erytromycin is commonly combined to the
resistance to lincosamids
On the other hand, there exist also so called
community strains of MRSA, that are usually
quite susceptible to many common (non-blactam) antibiotics. In Central Europe these
strains are (good luck) more common than
EMRSA stains.
Actual situation in Brno
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There exist individual cases of MRSA in all
hospitals, sometimes including out-patients
Good luck, big epidemiological outbreaks
are not common, especially because of
common knowledge concerning necessity of
keeping rules for care for MRSA patients
Some strains are well effective against
other antibiotics, only some strains are
polyresistant
Golden staphylococcus
www.sanger.ac.uk/Info/Press/2004/040624.shtml
MRSA – management
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Antistaphylococcal vaccination
Elimination of nasal carriership of golden
staphylococcus (only in indicated persons,
e. g. prior to surgery)
Actions leading to decrease of infection of
venous catheters
Less frequent use of dialysation canulas
Actions leading to less catheter infections,
especially in patients with haemodialysis and
peritoneal dialysis
According to www.ndteducational.org/goldsmithslide.asp
Reporting and strain
identification
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All suspicious strains of MRSA should be well
checked and in case of real positivity they are
reported to clinical station and also to hospital
epidemiology
A part of communication between microbiology
and department is consultation of treatment
of infection, that should be suitable and have
sufficient duration, it is a real infection and not
just colonisation
In case of a MRSA finding on a ward, the
measures should be taken that lead to prevent
transmission of infection to other patients
What treatment?
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In community strains of MRSA it is possible to
use non-b-lactam antibiotics, if the strain is
susceptible in vitro (macrolides, tetracyclins,
co-trimoxazole)
In polyresistant strains it is necessary to
glycopeptidic antibiotics (vankomycin,
teicoplanin). That also means not using these
antibiotics for common infections to keep them
effective against serious infections
In case of resistance to glycopeptides, or their
contraindication caused by bad status of the
patient, it is possible to use linezolid or some
other newer drugs (quinu-/dalfopristin)
Examination for MRSA
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In indicated patients, examination is mostly
done as nasal and perineal swab, eventually
also wound swab, swab of tracheostomia etc.
(it depend on the individual patient)
In such patients, also regular screening
during all hospitalisation is usually
performed
Indicated patients = patients, that have
history of MRSA, they come from wards with
MRSA, or they come for some „risky type
surgeries“
MRSA in
Europe
2014
http://ecdc.europa.eu/en/activities/surveillance/EARS-Net/database/Pages/maps_report.aspx
VISA and VRSA
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These are golden staphylococci intermediary
resistant (I) or completely resistant (R) to
vancomycin, eventually also teicoplanin
They start to occur since 1997
Until now rare in Europe, a something more
frequent in the USA
Genes for resistance probably acquired from
enterococci
Should not be underestimated, although not
seen commonly in recent Europe
Solution: let glycopeptides as reserve
antibiotics for indicated cases only
From MRSA to VRE and VRSA
www.ndt-educational.org/goldsmithslide.asp
MLSB
resistance
www.szu.cz/cem/zpravy/zpr0306/klinda.htm
Characteristics of MLSB resistances
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It is shared resistance to macrolides,
lincosamids and streptogramin B.
In concerns namely staphylococci, but similar
resistance patterns can be also seen in various
species of streptococci
Not all strains resistant to erytromycin has this
shared resistance. Especially community strains
of golden staphylococci have commonly just an
isolated resistance to erytromycin
In some cases it is an induced type of a
resistance: erytromycin induces resistance to
lincomycin or clindamycin. In that case none of
them should be used
Extended spectre b-lactamases (ESBL)
http://www.kbc-zagreb.hr/index.php?link=klinike_i_zavodi&action=21&id=2
ESBL – extended spectre b-lactamases
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b-lactamases TEM, SHV, CTX etc.
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they are seen mostly in Enterobacteriae family:
Klebsiella pneumoniae, Escherichia coli, but
sometimes also in G– non-fermenters
there exist many types of them
genes for them are in plasmids, mutations are
frequent, new variants occur
Among b-lactam antibiotics, only carbapenems
remain effective
Metalo-b-lactamase
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they are seen in G– non-fermenters
they are active also against carbapenems
susceptible are monobactams (azthreonam)
rare in Enterobacteriaceae family
Inductors and selectors of
b-lactamases
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Production of some b-lactamases may be
induced by use of an antibiotic (inductor).
An example of an inductor is coamoxicillin
More dangerous than inductors are
selectors: quite effective antibiotics, that
kill the susceptible part of population, and
only highly resistant (polyresistant) strains
would remain. Example: 3rd generation
cephalosporins. Decrease of their use led
to decrease of ESBL positive strains in all
hospitals where tried
www.medscape.com/viewarticle/413080_31
Consumption of cephalosporins
vs. ESBL
Actual situation in Brno
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In the St. Ann‘s faculty hospital ESBLs are
unfortunately quite frequent. Locally it
might be successful to decrease their
frequency on some departments,
nevertheless, globally they are still common
They are common mostly on urology,
internal department, and dept. of
anaesthesiology/intensive care – often
nosocomial and chronic
The problem started to increase after 2000
with ESBL-producing Klebsiella, later also
Escherichia coli and many other species
Therapy
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Meropenem, imipenem, eventually non-blactam antibiotics (quinolones, polypeptides,
aminoglycosides – of course only if the strains
are susceptible and there are no
contraindications because of e. g. toxicity)
Cephalosporins of 4th generation or
combination of 3rd generation cephalosporins
with inhibitors of b-lactamase are not
recommended also in case that they look as
effective at in-vitro testing
The expenses for this therapy are very
high, sometimes > 10 000 CZK/day
Prevention
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Similar measures are taken as for MRSA:
basic rules against nosocomial illnesses
As the Enterobacteriaceae family are
intestinal bacteria often colonizing UTI (and
urinary catheters), the accurate nursing
care concerning patients (especially
those with catheters) is very important
Targeted treatment by narrow-spectre
antibiotics
Eventually screening of intestinal carriership
(not common)
b-lactamase ampC type
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These are also b-lactamases with broad spectre
of effect, but they are different from ESBL-type
extended spectre b-lactamases
There exist constitutive ampC blactamases; if found, the diseases caused by
producers are treated like those caused by
ESBL producers, with one exception – it is also
possible to use 4th generation cephalosporins
There exist also inducible ampC blactamases, where resistance occurs only at
induction, e. g. by clavulanic acid.
Interpretation is „susceptible, but at long term
therapy the failure of treatment is possible
Principles of „antibiotics policy“
From the lecture of dr. Jindrák from Hospital Homolka,
Prague, for farmacology education of medical students
reduced antibiotic use for treatment
(globally)
 more space for targeted therapy rather than
empiric treatment (= with use of
microbiology laboratory testing of specimens,
including atb susceptibility)
 elimination of not accurate and wrongly
indicated therapy
 elimination of wrong antibiotic choice
 elimination of wrong dosage and duration of
the therapy
This if from dr. Jindrák, further notes are my own
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How to reduce use of antibiotics
Do not use antibiotics for viral
infections
 Do not use antibiotics for non-infectious
diseases
 Do not use antibiotics „just to be sure“
„we are used to“ or „it is patient‘s wish“
 Do not use „prophylaxis“ if it is not
indicated (especially in surgery)
 Do not use antibiotics supposed to be
used generally for topic treatment,
especially if treatment is not indicated
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Patients, too, should be informed
www.irishhealth.
com/index.html?l
evel=4&id=853.
In sites with normal microflora
antibiotics often have an
unwanted effect
www.yakult.co.uk/Public/h
cp/probiotics/why.asp
Individualisation of antibiotics
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Each use of antibiotic should be individual,
doctors should use certain antibiotic and certain
dosage corresponding the specific situation of
an individual patient
It is not recommended to have just
„antibiotics for possible future use“ either
at home or in a hospital
http://www.firstscience.com/home/cartoons/st
range-matter-antibiotic-resistancerecruitment_163.html
Antibiotic centres (Czechia)
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They exist at larger microbiology
laboratories
They try to cooperate with clinical doctors,
making rules for prophylaxis or eventual nottargeted treatment
They make consultations for individual
patients
In some reserved antibiotics the centre
should agree with prescription
Various other countries have their own
system, but usually there exist at least some
limitations for prescription
Economy of antimicrobial
treatment
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In history, the economical point of view used
to be in accordance with the microbiology
one: targeted treatment with narrow
spectre antibiotics were usually also
cheaper. Unfortunately, recently there exist
some quite cheap, but broad spectre (and so
not recomendable) drugs
Another problem: sometimes classic
(recommended) drugs are not interesting
for farmaceutical companies, they tend to
offer us new (but not recommended) drugs,
sometimes „old good“ drugs are not available
Cooperation with
veterinary medicine
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One possible problem at a complex solving
of antibiotic problem is also veterinary use
of antibiotics
Sooner, antibiotics were used also for other
than therapeutic reasons in animals. Now
this use is forbidden in the EU
So only therapeutic use of antibiotics is
allowed, and it is necessary to use
antibiotics that are not commonly used in
humans. Even this is not always sufficient
(cross-resistances)
http://www.time.com/time
/covers/1101020121/antibi
otics.html (autor Roberto
Parada)
Antibiotic use
in EU (1997)
www.agbioforum.org/v3n23/v3n2
3a13-follet.htm
Nice day!
http://medicineworld.org/news/news-archives/health-news/1243577370-Sep-28-2006.html