Transcript Primarily bactericidal antibiotics

Medical oral
microbiology I – lecture
(ZLLM0421p)
Antibiotics I (introduction, survey,
cell-wall acting antibiotics)
Ondřej Zahradníček
[email protected]
How to fight with microbes
Imunisation – use of natural processes
in the organism
 Decontamination methods – crude
physical and chemical influences, action
outside the organism
 Antimicrobial drugs – fine, targeted
action inside the organism, the aim is
maximal action against the microbe and
minimal influence to the host organism
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Types of antimicrobial drugs
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Drugs for general treatment
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Antiparasitarian drugs against parasites
Antimycotics against mycotic organisms
Antivirotics against viruses
Antituberculotics against mycobacteria
Antibiotics against other bacteria, including former
antibacterial chemoterapeutics (originally only
natural origin drugs were counted into antibiotics)
Drugs for topic treatment: antiseptics
(originally disinfectants that may be used inside
the organism, or antibiotics, especially those
too toxic to be used for general tratment)
Why are antibiotics the most
important group
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Fungal and parasital infections are important,
nevertheless far from being as frequent as
bacterial diseases
Viral diseases are very common, but usually
self-limited  for majority of them
symptomatic treatment is recommended
(exceptions: herpesviral diseases, HIV, heavy
influenza etc.)
Bacterial diseases are nearly always treaded
with antibiotics (causal treatment) – so
knowledge about them is important
Should we kill microorganisms?
At decontamination we always have to
kill microbes (microbicidal effect)
 At use of antimicrobial drugs it may be
sufficient to inhibit bacterial growth;
patient‘s immunity helps us
 Nevertheless, this is not valid for acute
situations and immunocompromised
patients, when we always try to use
microbicidal effect
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Action of influences on microbes I
lower survival
lower growth limit
limit (bactericidal) (inhibitory)
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upper growth
upper survival
limit (inhibitory) limit (bactericidal)
At action of an influence like pH the axe
has both upper and lower extremes
upper growth
upper survival
limit (inhibitory) limit (bactericidal)
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action of antimicrobial agents (but
also e. g. disinfectants) only right part
of the axe has a logical sense
MIC, MBC, MBEC
MIC – minimal inhibitory
concentration means the limit
concentration that is just sufficient to
stop the growth of microbes
MBC – minimal bactericidal
concentration – survival limit for
bacteria. (For viruses we use „minimal
virucidal concentration“ etc.)
MBEC – minimal biofilm erradication
concentration: concentration destroying
„forever“ microbioal biofilm
Primarily bactericidal and primarily
bacteriostatic antibiotics
Primarily bactericidal antibiotics =
effect of drug is primarilly killing (e. g.
action of cytoplasmic membrane –
bacteria cannot survive it)
Primarily bacteriostatic antibiotics
usually stop bacterial growth (we get the
MIC, but not MBC level). MBC is usually
very high for them and cannot be used in
practice (the antibiotic in such
concentration would be toxic also for
human cells)
Primarily bactericidal and
primarily bacteriostatic atb
Primarily bactericidal antibiotic
CONCENTRATIONS
toxicity for the macroorganism
Primarily bacteriostatic antibiotic
atb concentration
THERAPEUTICAL
To the cell wall (bactericidal)
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β-lactamic antibiotics
Glycopeptidic antibiotics (partially)
To cytoplasmic membrane – polypeptids
(bactericidal)
To nucleic acids – quinolones (bactericidal)
To proteosynthesis: aminoglykosides (bactericidal);
makrolids, tetracyclins, linkosamids, amphenicols
(bacteriostatic)
To metabolism – sulfonamids, bacteriostatic
Primarily bacteriostatic antibiotics are not
recommended for treatment in acute states and
immunocompromised persons!
BAKTERIOSTATIC
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BAKTERICIDAL
Mechanisms of antibiotic action
β-lactamic antibiotics
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Their structure contains β-lactamic circle
They act on the cell wall
They are baktericidal, but they act well only
on multiplying bacteria that build their cell
wall
They are nearly non-toxic (human cells have
no cell wall), but they have allergic side
effect
This „super-group“ is subdivided into
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Penicillins (derrivatives of penicilanic acid)
Cephalosporins (derrivatives of cephalosporanic acid)
Monobactams
Carbapenems
Various forms of „classic“
(Fleming‘s) penicillin
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Parenteric (injection) forms (acidolabile)
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Benzylpenicillin (G-penicilin), intavenous, drug of
choice for many infections (see further)
Procaine-benzylpenicillin, intramuscullar. More
difficult keeping the level in blood – even higher
doses have no effect
Benzatin-benzylpenicillin, intramuscullar, for
Streptococcus and Treponema only
Orally administered forms (acidostabile)
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Fenoxymetylpenicilin (V-penicillin). Drug of
choice for streptococcal tonsillitis, in sequention
therapy = we start
therapy after G-penicilln etc. *Sequention
with an injection antibiotic and
we continue by an orally
Penamecillin
administered one
Oral penicillins: V-penicillin…
… and penamecillin
G-penicillin as a drug of choice
(just for illustration)
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Meningitis and sepsis caused by meningococci,
pneumococci and streptococci
Pneumococcal pneumonia.
Endokarditis caused by so called „alpha-streptococci“
Heavy streptococcal and clostridial infections of soft
tissues.
Anaerobic infections caused by spore-non-forming
anaerobes (except Bacteroides fragilis), e. g. aspiration
pneumonia and lung abscess
Actinomycosis.
Neuroborreliosis.
Source: Consensus of
use of antibiotics of
Anthrax, diphtheria, erysipelois
Subcomission for
Neurosyphilis, congenital syphilis.
antimicrobial use of
J. E. Purkyně Czech
Medical Society
Depot forms of penicillin
(the level of antibiotic is maintanted in the body after administration)
Depot forms of penicillin for long-term use
Antistaphylococcal penicillins
Spectre is enlarged: it works against
staphylococci, but not other bacteria
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Methicillin – used in some countries, exists in
abbreviation „MRSA“ (methicillin resistant
S. aureus)
Oxacillin – used in some other countries
(including Czechia). Only used for
staphylococcal and mixed
staphylococcal/streptococcal infections. On the
other hand, it should not be replaced by other
drugs except if there is a reason for it (allergy
etc.)
Nafcillin is an alternative for both, used
especially in the U. S.
Aminopenicillins:
Ampicillin and amoxicillin
Effect is enlarged to some Gramnegative bacteria, but also Grampositive enterococci and other bacteria
 Ampicillin is useful mostly in injection
form, oral use is not recommended (it
should be replaced by amoxicillin)
 Amoxicillin (AMOCLEN) is recommended
e. g. for treatment of middle ear
infection, sinusitis, even if we do not
know the causative agent (common
agents are susceptible)
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Problem: β-lactamases
Many bacteria produce various types of
β-lactamases, either primarily (always)
or secondarily (just some strains). In
that case, amoxicillin might have no
effect
 Possible solution: support the antibiotic
by so called β-lactamase inhibitor,
that enables effect of that
aminopenicillin.
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β-lactamase inhibitors – 1
Bacterium
„BELA“ The Dog
(a β-lactamase)
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When we act by a single antibiotic, it is
inactivated by a bacterial β-lactamase.
β-lactamase inhibitors – 2
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ACID
When a βlactamase has a
more attractive
substrate to be
chosen, it is used
instead, and the
antibiotic can act.
Examples of
antibiotics
potentiated by
β-lactamase
inhibitors
From FN USA intranet
β-lactamase inhibitors are not
always sufficiently effective
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Unfortunately, β-lactamase inhibitors are
effective only in some „not so strong“ types of βlactamases
There exist also extended specter β-lactamases
(ESBL – see later), where inhibitors are not sufficient
(the treatment is not effective although we use
them) and we have just a few β-lactam antibiotics
that have effect against them
Nevertheless, some effect can be seen also in
these β-lactamases. This is used in diagnostics,
where we observe difference in effect of certain
antibiotic with : without inhibitor
Co-ampicilin and co-amoxicilin
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Co-ampicillin = ampicillin (antibiotic) +
sulbactam (β-lactamase inhibitor), known for
example as a drug UNASYN
Co-amoxicilin = amoxicillin (antibiotic) +
clavullanic acid (AUGMENTIN, AMOKSIKLAV etc.)
These combinations should not be used in
situation where amoxicillin alone is sufficient:
they induce formation of β-lactamases. On the
other hand, they are useful in resistant
bacteria.
Carboxypenicillins:
Carbenicillin and ticarcillin
Ureidopenicillins: Piperacillin
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Unlike the previous, they have larger spectre
against so called Gram-negative nonfermenters (e. g. genus Pseudomonas).
They cannot be used against
enterobacteria producing β-lactamases;
also here, there exist combinations with βlactamase inhibitors
They are drug of choice in Pseudomonas
infections and infections caused by other
Gram-negative non-fermenters
Cephalosporins 1
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They are partially related to penicillins
Cross allergies between penicillins and
cephalosporins are less frequent than
between penicillins mutually. In urgent need it
is possible to use cephalosporins when the
patient is referred to be allergic to penicillins
(the continual monitoring is needed)
Some resistences are common, some other
are particular for penicillins only/cephalosporins
only/only some preparations
In comparison with penicillins they are more
frequently eliminated by urine, so they can
be used for some UTI rather than penicillins
Cephalosporins 2
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All enterococci and listerias are resistant to all
cephalosporins – although some penicillins (not
„Fleming‘s“ penicillin) are well effective
Sometimes a group of cephamycins is concidered a
specific group. This group contains cefoxitin
(MEFOXIN), eventually cefotetan. They have better
effect against anaerobic bacteria. Other authors
consider cephamycins to be just a special subgroup
inside 2nd generation cephalosporins
Cephamycins are also used in diagnostics, e. g.
for checking, if the strain is MRSA or not they are
better than direct use of methicillin/oxacillin
Cephalosporins 3
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I. generation: effect mostly against G+
bacteria, but also some enterobacteria.
Examples: Cefalotin (KEFLIN), cefazolin
(CEPHAZOLIN; ANCEF, KEFZOL), cephalexin,
cefadroxil (DURACEF, DURICEF, CEFADROXYL)
II. generation: better effect against bacteria
from Enterobacteriaceae family, nevertheless,
some of them (Enterobacter sp., Serratia sp.,
Proteus vulgaris etc.) are primarily resistant.
Effect against G+ bacteria is slightly worse.
Examples: Cefuroxime (ZEFU, ZINNAT, ZINACEF,
CEFTIN, BIOFUROKSYM, XORIMAX), cefaclor
(CECLOR , DISTACLOR, KEFLOR, RANICLOR),
cefprozil
Cephalosporins 4
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III. generation: much better effect against
enterobacteria (including those resistant to I.
and II. generation), some also against G–
non-fermenters including Pseudomonas. Not
suitable (although may be effective) againts
G+ bacteria. Disadvantage: they are
selectors of so called extended spectre βlactamases. Examples:
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No anti-Pseudomonas effect: Ceftriaxone
(ROCEPHIN, good access to CSF  used for
meningitis treatment), cefotaxime (CLAFORAN),
cefdinir (SEFDIN, ZINIR, OMNICEF, KEFNIR)
Can be used against Pseudomonas:
cefoperazone (CEFOBID), ceftazidime (MEEZAT,
FORTUM, FORTAZ)
Cephalosporins 5
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IV. generation: effective also against
producers of so called ampC β-lactamases
(but not ESBL β-lactamases). Examples:
cefepime (MAXIPIME), cefpirome (CEFROM)
V. generation: the only β-lactam antibiotics
effective against MRSA strains*. Example:
ceftaroline (ZINFORO)
*MRSA are strains of Staphylococcus aureus with
alteration of penicillin binding protein (PBP),
restistant not only against methicillin/oxacillin, but
also all other β-lactam antibiotic. More later.
Cephalosporins of I.
and II. generation
3. generation
Monobactams
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Monobactams are β-lactam antibiotics related
to penicillins and cephalospoins. Their β-lactam
ring is alone and not fused to another ring (in
contrast to most other β-lactams). They work
only against aerobic Gram negative bacteria (e.
g., Neisseria, Pseudomonas).
The only commercially available monobactam
antibiotic is aztreonam (AZACTAM).
Carbapenems
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Carbapenems are β-lactam antibiotics used
for the treatment of infections known or
suspected to be caused by multidrug-resistant
(MDR) bacteria. Their use is primarily in people
who are hospitalized.
They are the only betalactams with effect
against ESBL-producers. On the other hand,
carbapenemase producers are resistant.
Examples: Imipenem (TIENAM) and Meropenem
(MERONEM) for both Pseudomonas and ESBL
caused infections; Ertapenem (INVANZ) for
ESBL, but not Pseudomonas caused infection
Glycopeptidic
antibiotics
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Also have effect to cell wall synthesis, but they are
unrelated with β-lactams. They are only suitable for
G+ bacteria.
Side-effects: red man syndrome, an idiosyncratic
reaction to bolus caused by histamine release;
nephrotoxicity including renal failure and interstitial
nephritis;deafness, which is reversible once therapy
has stopped.
They are used as reserve drugs, for example for
MRSA strains
Examples: vancomycin (EDICIN) and less toxic, but
more expensive teicoplanin (TARGOCID). New lipoglycopeptide telavancin (VIBATIV) is now also used,
and also related lipopeptide daptomycin (CUBICIN).
Good bye!
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