Transcript 0-Resistance-Antimicrobial-Drugs-vaccines

Batterjee Medical College
Batterjee Medical College
Antimicrobial Drugs:
Mechanism of Action
Dr. Manal El Said
Head of Microbiology Department
Batterjee Medical College
Antimicrobial Drugs:
Resistance
Four main mechanisms of antibiotic resistance are:
(1) enzymatic degradation of drug
(2) modification of drug's target
(3) reduced permeability of drug
(4) active export of drug.
• Most drug resistance is result of genetic change in
organism, caused either by chromosomal mutation or
acquisition of plasmid or transposon.
Batterjee Medical College
Antimicrobial Drugs:
Major Mechanisms of Bacterial Resistance
Batterjee Medical College
Antimicrobial Drugs:
Major Mechanisms of Bacterial Resistance
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Bacterial resistance to antibiotics—producing an enzyme to destroy or inactivate the antibiotic. This
animation can be found at The Grapes of Staph: Doc Kaiser's Microbiology Website,
http://student.ccbcmd.edu/~gkaiser/goshp.html.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Bacterial resistance to antibiotics—producing an altered enzyme to which the antibiotic no longer binds.
This animation can be found at The Grapes of Staph: Doc Kaiser's Microbiology Website,
http://student.ccbcmd.edu/~gkaiser/goshp.html.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Bacterial resistance to antibiotics—producing an altered ribosomal subunit to which the antibiotic no
longer binds. This animation can be found at The Grapes of Staph: Doc Kaiser's Microbiology Website,
http://student.ccbcmd.edu/~gkaiser/goshp.html.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
A bacterium producing altered porins that block passage of the antibiotic through the outer membrane of
a gram-negative bacterium.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
A bacterium producing an altered transport (carrier) protein that prevents transport of the antibiotic
through the cytoplasmic membrane.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
A bacterium producing transporter molecules that pump the antibiotic out of the bacterium.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
A bacterium producing greater amounts of the limited enzyme being tied up or inactivated by the
antimicrobial agent. Although some enzyme is tied up by the drug, there is still enzyme available to react
with its substrate and produce end products.
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Antimicrobial Drugs:
Resistance: Genetic Basis of Resistance
• Chromosomal mutations typically:
-Change target of drug so that drug does not bind
-Change membrane so that drug does not penetrate well
into cell.
• Chromosomal mutations occur at low frequency (perhaps 1
in 10 million organisms).
• It often affect only one drug or one family of drugs.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Genetic Basis of Resistance
• Plasmids cause drug resistance by encoding enzymes
that degrade or modify drugs.
• Plasmid-mediated resistance occurs at higher frequency,
often affecting multiple drugs or families of drugs.
• Resistance plasmids (R plasmids, R factors) carry two
sets of genes:
- One set encodes enzymes that degrade or modify drugs
- Other encodes proteins that mediate conjugation
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Genetic Basis of Resistance
• Transposons are small pieces of DNA that move:
- from one site on bacterial chromosome to another or,
- from bacterial chromosome to plasmid DNA.
• Transposons often carry drug resistance genes.
• Many R plasmids carry one or more transposons.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Genetic Basis of Resistance
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Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
•Resistance to penicillins & cephalosporins is mediated by
three main mechanisms:
(1) degradation by β-lactamases (most important)
(2) mutations in genes for penicillin-binding proteins
(3) reduced permeability.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
• Resistance to vancomycin is caused by change in Dalanyl-D-alanine part of peptide in peptidoglycan to Dalanine-D-lactate, resulting in inability of vancomycin to
bind.
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Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Resistance to aminoglycosides is mediated by three main
mechanisms:
(1) modification of drug by phosphorylating, adenylylating,
& acetylating enzymes
(2) mutations in genes encoding one of 30S ribosomal
proteins
(3) reduced permeability.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Resistance to tetracyclines is caused by either
- reduced permeability
- active export of drug from bacterium.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Resistance to erythromycins is caused by plasmid-encoded
enzyme that methylates 23S ribosomal RNA, thereby blocking
binding of the drug.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Resistance to sulfonamides is due to plasmid-encoded
enzymes that actively export drug from bacterium.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Resistance to quinolones is caused by mutations in gene
encoding bacterial DNA gyrase.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Resistance to rifampin is caused by mutations in gene
encoding bacterial RNA polymerase.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Resistance to isoniazid is due to loss of bacterial peroxidase
(catalase) that activates isoniazid to metabolite that inhibits
mycolic acid synthesis.
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Antimicrobial Drugs:
Nongenetic Basis of Resistance
• Drugs may not reach bacteria located in center of abscess
• Certain drugs, such as penicillins, will not affect bacteria
that are not growing.
• Presence of foreign bodies makes successful antibiotic
treatment more difficult.
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Antimicrobial Drugs:
Antibiotic Sensitivity Testing
The minimal inhibitory concentration (MIC)
It is lowest concentration of drug that inhibits growth of
bacteria isolated from patient (it is not known whether
inhibited bacteria have been killed or just have stopped
growing).
The minimal bactericidal concentration (MBC)
It is lowest concentration of drug that kills bacteria isolated
from patient.
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Antimicrobial Drugs:
Use of Antibiotic Combinations
• Two or more antibiotics are used to:
- treat life-threatening infections before cause has been
identified,
- prevent emergence of resistant bacteria during prolonged
treatment regimens
- achieve synergistic (augmented) effect.
Batterjee Medical College
Antimicrobial Drugs:
Use of Antibiotic Combinations
• Synergistic effect is one in which effect of two drugs given
together is much greater than sum of effect of two drugs
given individually.
• Example of synergy is marked killing effect of combination
of penicillin & aminoglycoside on enterococci compared to
minor effect of either drug given alone.
Batterjee Medical College
Antimicrobial Drugs:
Use of Antibiotic Combinations
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Bacterial Vaccines
Immunity to certain bacterial diseases can be induced by:
• Immunization with bacterial antigens (active immunity)
• Administration of preformed antibodies (passive immunity).
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Active Immunity
Active immunity can be achieved by vaccines consisting of:
(1) bacterial
capsular
polysaccharides,
bacteria (either killed or live, attenuated)
(2) purified proteins isolated from bacteria.
toxoids,
whole
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Active Immunity
Vaccines containing capsular polysaccharide as immunogen
are directed against :
•Streptococcus pneumoniae
•Haemophilus influenzae
•Neisseria meningitidis
•Salmonella typhi.
Capsular polysaccharide is
conjugated to carrier protein
to
enhance
antibody
response.
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Active Immunity
•Two vaccines contain toxoids as immunogen:
- Diphtheria
- Tetanus.
• Toxoid is inactivated toxin that has lost its ability to cause
disease but has retained its immunogenicity.
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Active Immunity
Two
vaccines
contain
purified
bacterial
proteins
as
immunogen:
• Acellular pertussis vaccine: combination with diphtheria &
tetanus toxoids
It is recommended for all children.
• Anthrax vaccine: contains purified proteins
It is recommended only for individuals who are likely to be
exposed to organism.
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Active Immunity
• BCG
vaccine
against
tuberculosis
contains
live,
attenuated Mycobacterium bovis & is used in countries
where the disease is endemic.
• One of vaccines against typhoid fever contains live,
attenuated Sal. typhi.
• Vaccines against cholera, plague, typhus, & Q fever contain
whole killed bacteria.
• These vaccines are used only to protect those likely to be
exposed.
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Passive Immunity
Passive Immunity
• Antitoxins for prevention & treatment of :
- Tetanus
- Botulism
- Diphtheria.
• These three diseases are caused by exotoxins.
• Antitoxins (antibodies against exotoxins) bind to exotoxins
& prevent their toxic effects, i.e., they neutralize toxins.
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Passive–Active Immunity
• This involves providing both immediate (but short-term)
protection in form of antibodies & long-term protection in
form of active immunization.
• Example of use of passive-active immunity is prevention of
tetanus in unimmunized person who has sustained
contaminated wound.
• Both tetanus antitoxin & tetanus toxoid should be given.
• They should be given at different sites so that antibodies
in antitoxin do not neutralize toxoid.
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Recommended Immunization Schedule
Batterjee Medical College
Recommended Immunization Schedule
Batterjee Medical College
Recommended Immunization Schedule