The antibiotics

Clinical categorisation of an
Antibiogramm
 Sensitive(S): probability of
acceptable therapeutic
success in the case of
systemic treatment with
recommended dose
 Resistant(R): high likelihood
of therapeutic failure
 Intermediate (I): doubtful
therapeutic success
 Two types of resistance

 Natural:
 Resistance always obtained for the same bacteria:
 Normal and well-known mechanism
 Concerns all strains of a species (Wild type)
 e.g.: Proteus mirabilis resistant to Tetracycline

 Acquired:
 New resistance acquired by genetic mutation
 Abnormal mechanism
 Concerne certaine strains of a sensitive species
 This resistance may appear and disappear
 e.g.: ESβ L and Klebsiella pneumoniae
 Parametr of resistance
evaluation : the MIC
 The minimal inhibitory concentration or MIC is the lowest concentration of AB
capable of inhibiting the visible culture
 Expressed in mg/l
 Measure of bacterostasis

MIC = 2mg/l Control without AB

Concentrations of
antibiotics (mg/l)
 Definition of resistance
 A resistant strain has a MIC Number Wild
significantly greater than wild Of strains strains
strains? Resistant
strains
 The resistance is coded by a
resistance gene MIC (mg/l)
 Which determine a biochemic
mechanism of resistance
MIC model:
 Situated on chromosome or plasmid MIC model: 128mg/l
1mg/l
 Where dose the genes of
resistance come from?
 Nutritional antibiotics
 Livestock feed
(« Growth factors »)
 Antibiotics similar to those
in medicine
 Transfer to normal flora by
food
 Impregnation of household
items and children toys with AB
Clinical reasons of
resistant emergence
 Over use of broad
spectrum antibiotics
 Incorrect diagnosis
 Unnecessary prescription
 Improper use of
antibiotics by patients
 Selection pressure by the
medical treatments
 Bacterial strategy to resiste to antibiotics

Antibiotic action step

 Pass through the outer membrane

(Gram -)
Block the antibiotic before entry
Hydrolyse the antibiotic
 Diffuse in the periplasmic space (Gram
-)
Hydrolyse the antibiotic
 Pass through the peptidoglycane
 Pass through the cytoplasmic
membrane
Push the antibiotic out
 Diffuse in the cytoplasm
Inactivate the antibiotic
 Bind with the target
 The different resistance mechanisms
 Gram - Resistance Mechanisms
Impermeability Eflux

Enzymes
production
PBP Modification  
DNA gyrase mutationRibosome mutation
 The different resistance mechanisms

 Gram + Resistance Mechanisms Eflux

  

Enzymes
production
PBP Modification  
DNA gyrase mutationRibosome mutation
Destruction of β -lactamines by
beta-lactamases
Enzymatic inactivation of an aminoglycosid

Gentamicin
acethylase

 transfer
Inhibition toward adenylase
Ribosomal target phosphorylase
Modification of β -lactames target
(PBPs)

•Synthesis of a PBP which lost the affinity

for the antibiotic and kept its enzymatic activity
•Ex : - PBP 2a, additional
Methicillin resistant staphyllococcus aureus (MRSA)

• Causes resistance to all of beta-lactames

 The in vivo resistance
 Many of bacteria acts just on bacteria ,that
actively dividing
 β -lactames are less active on dormant bacteria
 In vivo the bacteria are protected
 Biofilms and micro-colonies
 The targets of AB can disappear in vivo
 Cell wall defective streptococci and endocarditis
 Natural defenses are essential to healing

Dissociation between the activity in vitro and in vivo

Bacterial resistance to
antibiotics

Genetic of resistance
 Genetic support of natural resistance

The chromosome

 Stable
 Vertical transmission
 to descendants

 No horizontal transmission
 not transferable from one

bacteria to another
 The genetic support of acquired resistance

 Acquired resistance can be due to:

 A mutation within the chromosome

 A transfer of a gentic material (Plasmid -

Transposon) coding for a specific resistance
 Plasmids - Transposons

 A plasmid is an independent,
extrachromosomal DNA molecule which can
replicate but which does not recombine with
host DNA

 A transposon is a short DNA molecule which

can recombine into the host chromosome
 The genetic support of acquired resistance

 Mutations in chromosomal genes

 Spontaneous
 Stable
 Vertical transmission
 No horizontal transmission
 The genetic support of acquired resistance

 Transposon:

 Stable
 Vertical
transmission
 Horizontal
transmission
 The genetic basis of acquired resistance

 Plasmid

 Unstable in the absence of the antibiotic

 Vertical transmission (to daughter
cells)
 Horizontal transmission: transfer
occurs from one bacterium to another (including
the possibility of transfer to a member of a
different species)
 Acquired Resistance

 Resistance transfer
 Enzyme Production
 Enzymes produced by the bacteria to
inactivate the antibiotic

Constitutive Inducible Derepressed

ENZYMATIC
RESISTANCE

Plasmidic Chromosomic
 Enzyme Production

Constitutive: constant
level of production
independent of the
presence of an inducer

Presence of
the antibiotic
Inducible: produced in low
quantities but increases in
the presence of the
inducer
e.g.: Cefoxitin, Imipenem
 Production
Repressor
RNA polymerase

DNA
Resistant gene

The resistance gene is not expressed due to the

binding of the repressor to the DNA, which blocks As it’s a
the transcription. reversible
Repressor + Inducer effect
which goes
RNA polymerase back
to its initial
stage
in absence
of inducer
Resistant gene
Antibiotic acting as an inducer will modify the repressor
which will not bind to the DNA, allowing the gene
responsible of the resistance to be expressed
 Enzyme Production
Repressor
RNA polymerase

DNA Resistant gene

RNA polymerase Modified

Repressor

Resistant gene
DNA mutation of the repressor gene will lead to a modified
repressor which will not bind to the DNA and therefore allows
the gene responsible of the resistance to be expressed at a
high level.

It’s called derepressed enzyme

 Kinds of resistance

Cross resistance
 The same resistance mechanism affects
several antibiotics within a same family.
 e.g.: a Gentamycin-resistant staphylococci is resistant to all
aminoglycosides.

Associated resistance
 affects several antibiotics in different
families
 e.g.: Associated resistance of Enterobacteriaceae to β −lactams
and aminoglycosides (ESBL and AAC 6').
Some examples of
resistance
 Glycopeptides; for example: are
only active on Gram poistive
bacteria; because they are large
molecules that could not penetrate
the outer membrane of gram
negative bacteria
 Prevents synthesis of
peptidoglycan
Enterobacteria and beta-
lactamines
 Chromosomic:
 Penicillinase

 Cephalosporinase

 Carbapenemase

plasmidic: ESBL, cephamycinase

Extended spectrum beta-
lactamases: ESBL
 Also active on 3rd generation of
cephalosporins and aztreonam
 These enzymes mainly produced by
hospital strains of gram negative bacilli
 The beta lactamases are resistantes to
inhibitors(not inhibited by clavulanic
acid ;sulbactam or tazobactam
Hemophilus influenza
 treatment;:
penicillins;sulfonamides;
macrolides, fluoroquinolones:
 Mecanisms of resistance to
betalactamines:
 Production of beta lactamase
 Modification of PBPs
St.aureus and beta
lactamines
 Production of beta lactamases; plasmidic
origin
 Modification of target; chromosomic origin

 Resistance to methicillin:

§Production of methicillinase
§Hyperproduction of betalactamase
§ Decrease in the synthesis or and / or the
affinity of a PBP
Ps.aeruginosa
 Efflux pumps
 Production of cehpalosporinases
and beta lactamase (natural and
acquired)
 Change of permeability
Enterococci
 Treated by beta lactamine or
glycopeptide with an
aminoglycoside
 Penicillinase; cephalosporinase
 VRE (Vancomycin resistant
enterococci)
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