Download Föreläsning antibiotika omfattande 2011

2011-04-04
Antibiotika
PÅL
2011
copyright Per-Åke Lundberg 2011
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copyright Per-Åke Lundberg 2011
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Verkningsmekanismer
Antibakteriella läkemedel
Hämning av:
Cellväggssyntes
Proteinsyntes
Nukleinsyrasyntes
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Normalflora
Bakterier som vi bär på utan att bli sjuka!
På huden
I munhålan
I tunn/tjocktarm
Staphylococcus epidermis
Bacteroides
Bacteroides
Staphylococcus aureus
Streptokocker
Clostridium perfringens
Propionibacterium acnes
Pneumokocker
Clostridium difficile
Meningokocker
Enterokocker
Escherichia coli
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Grampositiva bakterier
och infektioner – Exempel
Kocker
Stavar
Enterokocker
UVI
Pneumokocker
Lunginflammation,
öroninflammation,
bihåleinflammation
Klostridier
Mykobakterier
Stelkramp
Tuberkulos
Sårinfektion
Blodinfektion,
rosfeber,
halsfluss,
scharlakansfeber
Stafylokocker
Streptokocker
G+
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Gramnegativa bakterier
och infektioner – Exempel
Kocker
Stavar
Neisseria
Gonorré, meningit
Moraxella
catharralisÖroninflammation,
bihåleinflammation
Escherichia coli
Shigella
Salmonella
H.influenzae
Klebsiella
Proteus
Pseudomonas
aeruginosa
UVI
Dysenteri
Tyfoid
Öroninflammation
UVI,
lunginflammation
UVI, sårinfektion
UVI, sårinfektion
G-
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Definitions
•
•
An antibiotic is a substance produced by a
microorganism, which, in minute amounts, is able
to inhibit other microorganisms. Therefore, this
term is properly applied only to compounds
directly derived from microorganisms.
An antibacterial agent is any compound – natural,
synthetic or semisynthetic – that is clinically useful
in the treatment of bacterial infections.
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När började det….?
Kloramfenikol
Glycylcykliner
Tetracykliner
Streptograminer
Aminoglykosider
Makrolider
Kinoloner
Sulfonamider
Penicilliner
Glykopeptider
Linkosamider
1930
1940
1950
1960
Cykliska
lipopeptider
Trimetoprim
1970
Oxazolidinoner
2000
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Alexander Fleming
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Chain & Florey :
Penicillinet kan
användas kliniskt !
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Patienter med svår lung-inflammation
Penicillinet (1941) ökade chansen att överleva från 10% till 90%
Det behövs att 1,25 personer får penicillin för att rädda ett liv !
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Bacteriostatic vs. bactericidal
•
•
•
Bacteriostatic agents (ex. sulfonamides,
chloramphenicol) inhibit bacterial growth.
Bactericidal agents (ex. penicillin, streptomycin)
significantly reduce (99.9%) the number of viable
bacteria in the culture (killing effect).
Bactericidal effect in vivo is obtained in cooperation
with host’s defense mecha-nisms.
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Kemoterapeutika / Antibiotika
.
Förvärvande av infektion på sjukhus betecknas nosokomial infektion
(efter 48 timmar på sjukhus);
infektion förvärvad utanför sjukhus är samhällsförvärvad infektion.
MIC
MBC
Smalspektrum / bredspektrum
Ekoskugga
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Vad är MIC? MBC ?
Tiden över MIC styr effekten
Bild: Kjell Ström Production
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SIR = tolkning av
resistensbestämningen
• S = Känslig
• Infektionen kan förväntas svara på behandling med detta
antibiotikum vid dosering rekommenderad för denna typ av
infektion. Bakterien har inga påvisade resistensmekanismer
mot medlet
• I = Intermediär
• Behandlingseffekten med detta medel är osäker.
Bakterien har förvärvat låggradig resistens mot medlet eller
har naturligt lägre känslighet för medlet.
• R = Resistent
• Klinisk effekt av behandling med detta medel är osannolik.
Bakterien har förvärvat betydelsefulla resistensmekanismer
eller är naturligt resistent mot medlet.
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Tid över MIC
Exempel PcV
Dosering
T>MIC vid
MIC=0.03 mg/l
T>MIC vid
MIC=0.5 mg/l
1gx2
25 %
8%
2gx2
29 %
13 %
1gx3
38 %
13 %
2gx3
44 %
19 %
1gx4
50 %
17 %
Källa: RAF
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Att dosera antibiotika...
Dosering och behandlingstid
Bild: Kjell Ström Production
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Postantibiotisk effekt
Bild: Kjell Ström Production
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Skillnad bakteriecell jmf humancell
•
•
•
•
Cellvägg/cellmembran (peptidoglykan)
Folsyrasyntes (DHPS)
Ribosomen (subenheter)
DNA-gyras
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Modes of Antimicrobial Action
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INHIBITOR OF PEPTIDOGLYCAN
SYNTHESIS
•
Nearly all bacteria posses peptidoglycan in their cell walls,
but this macromolecule is absent from mammalian cells selective toxicity
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Penicillins
• Vary in
– Resistance to gastric acid
– Oral bioavilability
– Core Structure of β lactam Antibiotics
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Mechanism of Action of
Penicillins
• Bactericidal
• Interfere with bacterial cell
wall synthesis
– Penicillin-binding proteins
(PBPs)
– Inactivation of transpeptidases
• Prevent cross–linking of
peptidoglycan
– Activation of autolytic enzymes
• Causes lesions in bacterial cell
wall
• Time-dependent killing
action
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Inhibition of Cell Wall Synthesis
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Clinical Uses
• Narrow Spectrum Penicillinase-suceptible agents:
•
Penicillin G: prototype
• Therapeutic use
•Common streptococci, meningococci, grampositive bacilli and spirochetes
• Drug of choice for syphilis; not longer for
gonorrhea
• Penicillin V: oropharyngeal infections
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Very Narrow Spectrum penicillinase
penicillinase-resistant Drugs
• β-lactamase Resistant
• Methicillin,
• prototype, rarely use due to nephrotoxicity potential
• Primary use: staphylococcal infections
• Nafcillin
• Relatively acid stable but poorly absorbed
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Wider spectrum Penicillinase
Penicillinase--susceptible drugs
• Amino-penicillins: Ampicillin and Amoxicillin
• Wider spectrum of activity than penicillin G
• Bactericidal for both gram-positive and gram-negative bacilli
• Therapeutic Indications:
• Upper respiratory infections : sinusitis, otitis media, acute
exacerbations of chronic bronchitis
• Urinary tract infections (UTIs)
• Meningitis (N. meningitidis)
Enterococci;Listeria monocytogenes;Escherichia coli;Haemophilus
influenzae;Moraxella catarrahalis
• ampicillin is synergistic with amynoglycosides in Enterococcal
and listeria infections
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Adverse effects of Penicillins
• Hypersensitivity reactions
• Urticaria, severe pruritus, fever, joint swelling, hemolytic
anemia, nephritis, and anaphylaxis
– Ampicillin- high incidence of skin rashes
• Diarrhea and nausea: the intestinal flora is affected with oral
penicillins
– Overgrowth of yeast and gram positive bacteria
– Pseudomembranous colitis
• Neurotoxicity: epileptic patients at risk
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Penicillinallergi
Reaktion
Tid efter
behandlingsstart
Åtgärd
Utslag utan klåda
(exantem)
Kan komma snabbt
Ingen (fortsatt
behandling)
Utslag med klåda alt.
som sprids alt. + andra
allergisymtom
2-3 dagar om man
tidigare fått pc, annars 714 dagar
Avbruten kur.
Läkarkontakt.
Provokationstest.
Testdos innan ny pcbehandling.
Anafylaktisk chock
Inom 1 timme vid p.o
dos, snabbare vid i.v.
(Patienten måste ha haft
pc tidigare.)
Akutvård. Alla
betalaktamer
kontraindicerade.
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Mechanism of Resistance
• Hydrolysis of the beta-lactam ring results in
loss of antibacterial activity
– Formation of beta-lactamases (penicillinases)
• Most staphylococci
• Many Gram-negative organisms
– Inhibition of penicillinases
• Clavulanic acid
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Mechanism of Resistance
• Formation of β-lactamases
(penicillinases)
• Staphylococcus
• E. coli and H. influenza
•
Structural changes in penicillinbinding proteins (PBPs)
• Responsible for methicillinresistance in staphylococci and
penicillin G in pneumococci
•
Structural changes in porins
• Resistance in P. aeruginosa
• Changes in the porin structure in
copyright Per-Åke Lundberg 2011
the outer cell wall membrane
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Beta-lactam antibiotika
Penicilliner
Cephalosporiner
S
R
O
S
R
N
N
O
COOH
COOH
Carbapenemer
Monobactamer
C
R
R
R
O
N
COOH
Bredspekterum, verkar också på
anaerobe, beta-lactamase prod. och på
Pseudomonas
O
N
OSO3
bara effekt på Gram-negativa bakterier
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Inhibitors of Cell Wall Synthesis
β-Lactams
• Penicillins
• Cephalosporins
• Carbapenems
• Monobactams
Polypeptides
• Vancomycin
• Bacitracin
• Fosfomycin
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Cephalosporins
• Cephalosporins are among the
most frequently prescribed
class of antibiotics.
• They are structurally and
pharmacologically related to
the penicillins.
• They are less susceptible to
penicillinases produced by
staphylococcus
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Cephalosporins
• Cephalosporins are bactericidal agents and have the
same mode of action as other beta-lactam
antibiotics bind to PBP’s on bacterial cell membrane
to inhibit the synthesis of the peptidoglycan layer of
bacterial cell walls(such as penicillins).
• Good distribution throughout the body
• CSF penetration
• pneumococci, meningococci, H. influenza
• Tissue penetration including bone
copyright Per-Åke Lundberg 2011
Cephalosporin Type
First generation
Cefazolin, Cephalexin
Second Generation
Cefaclor, Cefamandole,
Cefoxitin
Third Generation
Cefotaxime, Ceftazidime,
Ceftriaxone
Fourth Generation
Cefepime, Cefpirome
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Spectrum
Narrow spectrum similar to
narrow spectrum penicillins;
sensitive to β-lactamases
Increased activity toward gramnegative organisms; increased
stability
Even broader in spectrum and
more resistant to β-lactamases
Gram-positive and gram-negative activity
(P. aeruginosa); includes gram-negative
and multiple-drug resistance
patternsMany can cross blood brain
barrier and are effective in meningitis
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Adverse effects of Cephalosporins
• Hypersensitivity
• avoided or used with care in patients allergic to penicillins
• Local pain after IM injection and thrombophlebitis after IV
administration
• Increased nephrotoxicity when administered together with
aminoglycoside
• Acetaldehyde accumulation – disulfiram-like effect with
cefamandole and cefotetan (second-generation) or cefoperazone (thirdgeneration)
• Bleeding – antivitamin K effects with cefotetan or
cefoperazone
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COMPOUNDS THAT INHIBIT
MEMBRANE INTEGRITY
Polymixins :
• The bactericidal activity results from their interaction with the
bacterial cytoplasmic membrane modify the structure which
disturb the active transport of some molecules through it.
• Membranes containing the phospholipid phosphatidyl
ethanolamine (in Gram negative bacteria) are sensitive to
polymixin.
• They also have affinity to mammalian membranes, but bind less
readily.
• orally in enteritis; parenterally in urinary tract infections.
• They don’t penetrate the blood-brain barrier (not efficient in
meningitis).
• Toxicity: nephrotoxic, neurotoxic.
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Other β-lactam Antibiotics
Carbapenems
Monobactams
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Other antibiotics inhibitors of cell wall
synthesis
• Vancomycin (o,p)
• β-lactamase-resistant gram-positive bacteria
• Prevents polymerization of linear peptidoglycan; block
incorporation of new subunits in the peptidoglycan molecule.
•first choice antibiotic in infections produced by methicillin resistant
staphylococci (MRSA) and penicillinase producing enterococci.
• Slow IV injection
•Adverse effects:
•phlebitis;
•chills and fever
•“Red man/red neck syndrome” Sudden redness that spreads
over the upper body and neck and is due to intravenous
vancomycin
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Other antibiotics inhibitors of cell wall
synthesis
• Bacitracin
• Inhibits peptidoglycan synthesis by binding to a
lipid carrier that transports cell wall precursors;
• Wide variety of gram-positive organisms
• Restricted to topical application is nephrotoxic
and ototoxic when given parenterally;
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Other antibiotics inhibitors of cell wall
synthesis
•Fosfomycin
•Antimetabolite inhibitor inactivating the bacterial
transferase
• Effective against gram-negative bacteria that infect
the urinary tract
• May be synergistic with beta-lactam and quinolone
antibiotics in specific infections
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Other inhibitors of cell wall synthesis
• Cycloserine: inhibits incorporation of Dalanine into an oligopeptide in the cytoplasm.
• An antibiotic effective against Mycobacterium
tuberculosis.
•For the treatment of tuberculosis, it is classified
as a second line drug
•its use is only considered if one or more first
line drugs cannot be used.
• Potential neurotoxicity: tremors. seizures,
psychosis
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Other inhibitors of cell wall synthesis
• Daptomycin
• A novel lipopeptide antibiotic used in the
treatment of certain infections caused by
Gram-positive organisms.
• Active against vancomycin-resistant
strains of enterocci (VRE) and
staphylococci.
• Toxicity: May cause myopathy
•Creatinine phosphokinase should be
monitored
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Compounds that inhibit enzymic
process in nucleic acid synthesis
• Inhibitors of DNA gyrase
• Inhibitors of RNA polymerase
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Antibiotikas angreppspunkter i
bakterier
DNA replikation
Quinoloner
(ex. Ciprofloxacin)
Metronidazole
RNA syntesen
Rifampin
Rifabutim
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Inhibitors of DNA gyrase
Bacterial DNA gyrase is composed of two subunits A
and two subunits B
Various quinolones derivatives (norfloxacin,
enoxacin, ofloxacin and ciprofloxacin) binds to the A
subunits of DNA gyrase, prevent replication of
damaged DNA lethal to the cell
Mammalian cells posses a gyrase that differs in
structure from bacterial gyrase selective activity
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Quinolones
• Mechanism of action. Bactericidal; they inhibit DNA
gyrase.
• Antibacterial spectrum. First generation quinolones
are active only on Enterobacteriaceae.
• Fluoroquinolones have extended spectrum, being
also active on Ps. aeruginosa, staphylococci, gramnegative cocci and coccobacilli, Legionella
pneumophila, chlamydia and mycoplasmas.
• They are inactive on streptococci and anaerobic
bacteria.
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Quinolones
• Administration. Nalidixic acid is given orally, but it
realizes active concentrations only in the kidneys.
Fluoroquinolones are systemic quinolones, which, after
oral administration, realize active concentrations in
tissues and CSF, having good penetration in the cells.
• Adverse effects. Fluoroquinolones determine
photosensitivity after exposure to the sunlight. They
have limited applications in children.
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Inhibitors RNA polymerase
•
•
Rifamycins, ex. rifampicin,
binds to the β subunit and
interference the ability of this
enzyme to initiate RNA
synthesis.
Rifampicin no effect on RNA
polymerase from mammalian
cells selective action
copyright Per-Åke Lundberg 2011
Rifampicin
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INHIBITORS OF PROTEIN
SYNTHESIS
• Protein synthesis is inhibited by several antibiotics,
some are selective toxic towards bacteria.
• The selectivity of clinically useful arises from their
ability to bind selectively to bacterial rather than
mammalian ribosomes
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Ribosomes
•
•
Function
– protein production
Structure
– ribosomes contain rRNA & protein
– composed of 2 subunits that combine to carry out protein synthesis
– The primary target of a number of antibacterial drugs : ribosomal RNA,
rather than ribosomal protein.
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Prokaryote vs eukaryote ribosomes
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Ribosomes
• P site (peptidyl-tRNA site)
– holds tRNA carrying growing polypeptide chain
• A site (aminoacyl-tRNA site)
– holds tRNA carrying next amino acid to be added to
chain
• E site (exit site)
– empty tRNA
leaves ribosome
from exit site
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Stages in Protein Synthesis
1.
2.
3.
4.
5.
Synthesis of aminoacyl-tRNAs
Initiation of protein synthesis
Recognition of internal codons
Peptide bond formation and translocation
Termination of protein synthesis
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Synthesis of
aminoacyl-tRNAs
• Aminoacyl tRNA synthetase
– enzyme which bonds
amino acid to tRNA
– energy stored in
tRNA-amino acid bond
• unstable
• so it can release amino acid at
ribosome
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Initiation of protein synthesis
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Classification of Antimicrobial Drugs
By Mechanism of Action
• Inhibitors of Cell Wall Synthesis
• Inhibitors of Protein Synthesis
• Inhibitors of Metabolism
• Inhibitors of Nucleic Acid Synthesis & Function
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Antibacterial agents that inhibit the protein
synthesis
1.
2.
3.
4.
Aminoglycosides
Tetracyclines
Chloramphenicol
Macrolides – lincosamides –
streptogramines (MLS group)
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Protein Synthesis Inhibitor
• It is a substance which stops or slows the growth
or proliferation of cells by disrupting the
processes that lead directly to the generation of
new proteins.
• Most of the antibiotics in this group are
bateriostatic inhibitors of protein synthesis acting
at the ribosomal level.
• With the exception of tetracyclines, the binding
sites for these antibiotics are on the 50S
ribosomal subunit.
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Inhibitors of Protein Synthesis
Tetracyclines
Aminoglycosides
Demeclocycline
Doxycycline
Minocycline
Tetracycline
Amikacin, Gentamycin,
Neomycin, Netilmicin,
Streptomycin,
Tobramycin
Macrolides
Chloramphenicol
Clindamycin
Azithromycin
Clarithromycin
Erythromycin
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Tetracyclines
• This is a family of antibiotics that have a four-ring
structure.
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Tetracyclines
• prevent protein synthesis both 70S and 80S ribosomes, although 70S
ribosomes are more sensitive arises from their concentration
within bacterial.
They are broad-spectrum agents that inhibit binding of the
aminoacyltRNA to the 30S ribosomal subunit in bacteria thus, they
stop peptide elongation..
copyright Per-Åke Lundberg 2011
•
Tetracyclines
Broad-spectrum antibacterials, active on gram-positive and gramnegative, aerobic and anaerobic organisms. They are also active on:
spirochete, mycoplasmas, chlamydia, rickettsia.
• Alternative drugs in treatment of syphillis, acne vulgaris,
chronic bronchitis
• The action is bacteriostatic
• given orally, they are well absorbed. They don’t realize active
concentrations in CSF.
• They are not eliminated by urine, so, they are not effective in urinary
tract infections.
• The clinical use of tetracyclines is generally confined to adults.
– This is because tetracyclines affect bone development and can cause staining of
teeth in children.
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Adverse effects of Tetracyclines
• Deposition in growing bones and primary teeth in
small children
• Contraindicated in
• pregnancy : tooth enamel dysplagia and irregularities in
bone growth
• breast-feeding women
• children under 8 years of age: crown deformation
• GI disturbances
• nausea, vomiting, diarrhea, superinfections, colitis
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Resistance Mechanisms
• Widespread plasmid-mediated
resistance
• plasmid-encoded efflux pumps
• Decreased intracellular accumulation due to decreased
influx or increased efflux due to active pump
• Modification of tetracycline binding site and/or
production of proteins that interfere with the binding
• Enzymatic inactivation
• Altered ribosomal subunits
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Streptogramines
These antibiotics can be classified
into two major group, A (ex.
steptogramin A) and B
(ex.streptogramin B).
These antibiotic are bacteriostatic
and inhibit protein synthesis
directed by 70S ribosomes
Group A distort the ribosomal A
site inhibit the binding of
aminoacyl-tRNA and the peptidyl
transferase action
Group B block translocation of the
growing polypeptide chain from A
site to P site
Group A and B exhibit a synergism
towards Gram positive bacteria.
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Aminoglycoside-aminocyclitol group
•
•
Neomycin, kanamycin, amikacin,
tobramycin, and gentamicin :
bactericidal aminoglycosides
bindings to the 30S subunit at
multiple sites, is tighter than 50S
subunit. These antibiotics inhibit
translocation.
Spectinomycin : an aminocyclitol
bacteriostatic, binding to ribosomal
DNA, inhibit translocation by
preventing the movement between
ribosomes and mRNA in polypetides
elongation
Peptidyl
transferase
EF-G
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Aminoglycosides
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Aminoglycosides
• Bactericidal inhibitors of protein synthesis
• GENTAMICIN
• TOBRAMYCIN
• STREPTOMYCIN
• Amikacin
• Kanamycin
• Neomycin
• Netilmicin
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Aminoglycosides Mode of Action
• Bactericidal inhibitors of protein synthesis
• Transport can be enhanced by cell wall synthesis inhibitors
• They bind irreversibly to the 30S subunit of bacterial
ribosomes which disturbs the protein synthesis and produce
non-functional proteins.
• in at least 3 ways:
– Block the formation of the initiation complex
– Misreading of the code on the mRNA template
– Inhibition of translocation
– in association with penicillins or vancomycin are synergistic
against enterococci and
viridans streptococci.
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Aminoglycosides Interfering with the Translocation of
tRNA from the AA-site to the P
P--site
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Aminoglycosides Resistance
• Predominant mechanism is production of
enzymes that inactivate functions responsible
for drug activity.
– Group Transferases
• Changes in ribosomal binding site
• Membrane impermeability to aminoglycosides
results in resistance to all aminoglycosides
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Aminoglycosides Pharmacokinetics
• Are distributed well into ECF CSF, respiratory
secretions, and bile.
• They are active on facultative anaerobic gram-negative
bacilli and on staphylococci. Gentamycin, tobramycin,
amikacin and netilmycin are also active on Pseudomonas
aeruginosa.
• Streptomycin is particularly active on mycobacteria,
Yersinia pestis and Brucella
Intraventricular injection is often required to reach
intraventricular levels high enough to treat meningitis.
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Aminoglycosides Adverse Effects
• Ototoxicity and neurotoxicity concentration dependent
– May be irreversible
• Symptoms and signs of vestibular damage are vertigo,
nausea, vomiting, nystagmus, and ataxia.
• Neuromuscular blockade is a rare pharmacological effect.
– A curare-like block may occur at high doses
• Occasionally antagonism of factor V may result in bleeding
• Nephrotoxicity
• Allergic skin reactions
• concentrations very close to the toxic ones (their serum
Lundberg 2011
concentrations have copyright
to bePer-Åke
checked).
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Antibiotikas angreppspunkter i
bakterier
Protein syntes
50S Ribosomer
Chloramphenicol
Macrolider
Clindamycin
copyright Per-Åke Lundberg 2011
Protein syntes
30S Ribosomer
Aminoglycosider
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Tetracyklin
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CHLORAMPHENICOL
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Chloramphenicol
the first antimicrobial compound synthesized in the laboratory.
• Reversibly binds to 50S ribosomal subunits of susceptible
organisms inhibiting the peptidyltransferasepreventing amino
acids from being transferred to growing peptide chains thus
inhibiting protein synthesis.
• A broad spectrum bacterostatic agent binds to 70S bacterial
ribosomes but not the 80S type
• is bacteriostatic against most bacteria, but it is bactericidal
against
Haemophilus influenzae, Neisseria meningitidis, Streptococcus
pneumoniae. active against most aerobic and anaerobic
bacteria except P. aeruginosa
• It is active against intracellular bacteria (it is the first choice
antibacterial in the treatment of typhoid fever,
• It is also useful in H. influenzae meningitis because it penetrates the
blood-brain barrier.
•
can be given orally or in injections,
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Mode of action
growing polypeptide
Chloramphenicol
(binds to 50S and inhibits
formation of peptide bond)
50S
tRNA
mRNA
30S
direction of
ribosome travel
70S bacterial
ribosome
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Metabolism & Drug Interaction
• Resistance
• Conferred by the formation of
acetyltransferase (inactivates antibiotic) and
inability of drug to penetrate the organism
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Adverse Effects of Chloramphenicol
• Central nervous system: Confusion, delirium, depression, fever,
headache
• Dermatologic: Angioedema, rash, urticaria
• Gastrointestinal: Diarrhea, enterocolitis, glossitis, nausea,
stomatitis, vomiting
• Hematologic: Aplastic anemia, bone marrow suppression,
granulocytopenia, hypoplastic anemia, pancytopenia,
thrombocytopenia
• Ocular: Optic neuritis
• Miscellaneous: Anaphylaxis, hypersensitivity reactions, Gray
syndrome
•
Superinfections: Prolonged use may result in fungal or bacterial superinfection,
including C. difficile-associated diarrhea (CDAD) and pseudomembranous
colitis;
– CDAD has been observed >2 months postantibiotic treatment.
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Chloramphenicol - Toxicity.
• In newborn or premature, chloramphenicol
produces gray baby syndrome because the liver
is incapable to conjugate the compound.
• In adults, there is a dose-dependent toxic effect
on the bone marrow, which is reversible.
• In a very low number of patients (1: 25000), a
dose independent toxic effect may appear – the
irreversible, lethal bone marrow aplasia.
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Fusidic acid
• A narrow-spectrum steroidal
antibiotic that inhibits protein
synthesis in prokaryotic and
eucaryotic subcellular systems.
• This antibiotic forms a stable
complex with the ribosomes
which is unable for a further
round of translocation lack of
toxicity
Peptidyl
transferase
EF-G
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Lincosamides
• Lincosamides, ex.
lincomycin and
chlorinated derivatives,
inhibit the peptidyl
transferase function of
the bacterial 50S
ribosomal subunit
Peptidyl
transferase
EF-G
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Macrolides
• Group of compounds characterized by a
macrocyclic lactone ring to which deoxy sugars
are attached
• Erythromycin, prototype drug
• Clarithromycin and azythromycin are
semisynthetic derivatives of erythromycin
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Macrolides
erythromycin
clarithromycin
Bakteriostatiskt.
Proteinsynteshämmare. Binder 23S rRNA i 50S subenheten.
Hindrar förflyttning av ribosomen peptidyl tRNA utefter mRNA. and
cause premature peptide chain termination.
Hög intracellulär koncentration, fundamentalt för effekten på
intracellulära bakterier.
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Mode of action
growing polypeptide
50S
tRNA
Macrolides: erythromycin
(binds to 50S preventing
movement of ribosome
along mRNA)
mRNA
30S
direction of
ribosome travel
Bakteriostatiskt. Proteinsynteshämmare. Binder 23S rRNA i 50S subenheten.
bacterial ribosome
Hindrar förflyttning av ribosomen70S
utefter
mRNA.
Hög intracellulär koncentration, fundamentalt för effekten på intracellulära
bakterier.
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Antimicrobial spectrum of macrolides
• Bacteriostatic or bactericidal
Erythromycin Antibacterial spectrum: erythromycin is active
against gram-positive cocci and bacilli, including anaerobes,
Erythromycin is the alternative to penicillin in the treatment of
group A streptococcal infections.
• Mycoplasma infections
• Community-acquired pneumonia
• Legionnaire's disease
• Chlamydial infections (respiratory, neonatal, ocular or
genital)
• Diphteria and pertussis(kikhosta)
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Macrolides
• The new macrolides (clarithromycin,
azithromycin) are also active on gram-negative
bacteria: Moraxella catarrhalis, Haemophilus
influenzae.
• Clarythromycin is active in the treatment of
Helicobacter pylori gastritis and in infections
with Mycobacterium avium-intracellulare.
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Toxic effects of Macrolides
• Severe GI distress
• dose-related
• most common side effect especially associated with
erythromycin, less with clarithromycin.
• nausea and vomiting
• Jaundice
• hypersensitivity reaction to the ester form of erythromycin
• Contraindicated in patients with hepatic dysfunction
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Macrolides Resistance
• Three (3) mechanisms have been identified:
• reduced permeability of the cell membrane or active
efflux
• production of esterases that hydrolyzed macrolides
•Modification of the ribosomal binding site (so-called
ribosomal protection)
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Clindamycin
• Antibacterial mechanism is similar to that of
macrolides although no chemically related
• Inhibit protein synthesis by interfering with the
formation of initiation complexes and with
amynoacyl translocation reactions
• The binding site for clindamycin is identical with
that for erythromycin
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Clindamycin
• Drug of choice for
• severe anaerobic infections in abdomen, female
genital tract, aspiration pneumonia; in combination
with cephalosporins and amynoglycosides
•prophylaxis of endocarditis in valvular disease
patients who are allergic to penicillin
•Moderate to moderate-severe Pneumocystis carinni
pneumonia in AIDS patients; in combination with
primaquine
• AIDS-related toxoplasmosis; in combination with
pyrimethamine
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Clindamycin
• Adverse Effects
• Common: Diarrhea, nausea, and skin rashes
• Impair lever function (with or without jaundice)
• neutropenia
• Enterocolitis
•Cause: Toxigenic C. difficile
•Treatment: Metronidazole or Vancomycin
• Resistance
• Mutation of the ribosomal receptor site
• Modification of the receptor by a methylase
• Enzymatic inactivation of clindamycin
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Compounds that interrupt
nucleotide metabolism
Antibiotics that interfere with the biosynthesis of tetrahydrofolic acid
(THFA), a donor of one-carbon units at several stages in purine and
pyrimidine synthesis.
DHPS : Dihydropteroate synthase
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DHFR : Dihydrofolate reductase
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Antibiotikas angreppspunkter i
bakterier
Metabolism
Anti-metaboliter
Folinsyre
Sulfonamid
Trimetoprim
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Sulfonamides: Mechanism of Action
• Bacteriostatic action
• Prevent synthesis of folic acid required for
synthesis of purines and nucleic acid by inhibiting
dihidropteroate synthetase.
• Does not affect human cells or certain bacteria—
they can use preformed folic acid
• active on:
Gram-positive and gram-negative bacteria, except
Pseudomonas aeruginosa;
Chlamydia.
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Compounds that interrupt
nucleotide metabolism
Sulphonamides are
alternative substrate that
bind more tightly to DHPS
than PABA formation of
inactive folate-like
analogues.
DHPS is absent from
mamalian cells selective
activity.
PABA : p-aminobenzoic acid; DHPS : Dihydropteroate synthase; DHFR :
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Dihydrofolate reductase, Sx : Sulphamethoxazole
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Compounds that interrupt
nucleotide metabolism
Sulphonamides (exp. Sulphamethoxazole) are structural analogues of
PABA (p-aminobenzoic acid)
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Compounds that interrupt
nucleotide metabolism
Trimethoprim)
competitively inhibit
bacterial DHFR. Although
mammalian cells posses
DHFR, these drugs are
highly selective towards
the bacterial enzymes.
A combination of
appropriate
sulphamethoxazole and
trimethoprim
(cotrimoxazole) would
offer theurapeutic
advantages through
double blockade of the
folate pathways
PABA : p-aminobenzoic acid; DHPS : Dihydropteroate synthase; DHFR :
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Dihydrofolate reductase, Sx : Sulphamethoxazole, Tp : Trimethoprim
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Trimethoprim
• Mechanism of action. Bacteriostatic. It inhibits
folic acid synthesis by blocking dihidrofolate
reductase.
• Antibacterial spectrum. Similar to
sulfonamides.
• Adverse effects. It may produce skin rash or
bone marrow depression.
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Sulfonamides: Side Effects
Body System
Effect
GI
Nausea, vomiting, diarrhea,
pancreatitis
Other
Convulsions, crystalluria,
toxic nephrosis, headache,
peripheral neuritis, urticaria
Blood
Hemolytic and aplastic
anemia, thrombocytopenia
hud
Photosensitivity, exfoliative
dermatitis, Stevens-Johnson
syndrome, epidermal
necrolysis
increased concentrations of non-conjugated bilirubine in newborn.
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Resistensutveckling
Antibiotikaresistens
Spontana
kromosomala mutationer
Naturlig
Upptag av
resistensgener
Förvärvad
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Antibiotika resistens
1. Genuin resistens (arts-/genusrelateret)
f.ex. Gram-positive/ Gram-negative
2. Nyutvecklad resistens
f.ex. penicillin-resistens hos
stafylocker o pneumokocker
a. nyförvärvade resistensgener
b. anhopning av mutationer i målet
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Resistens kan uppstå på olika sätt
1. Försämrad tillgänglighet till bakteriecellen
Förändrad genomsläpplighet eller ”utpumpningsmekanism”
2. Förändring av bindningsstället
Förändrad struktur hos PBP, ribosomer, enzymer
3. Produktion av inaktiverande enzym
Hydrolyserande enzymer t.ex. betalaktamas
4. Biokemisk by-pass mekanism
Bakterier som t.ex. kan ta upp färdig folsyra
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Biochemical mechanisms of resistance to antibiotics
•The principal mechanisms are as follow.
• Production of enzymes that inactivate the drug: for example βlactamases, which inactivate penicillin; acetyltransferases, which
inactivate chloramphenicol; kinases and other enzymes, which
inactivate aminoglycosides.
Biochemical mechanisms of resistance to antibiotics
• Alteration of the drugbinding sites foraminoglycosides,
erythromycin, penicillin.
• Reduction of drug uptake by the bacterium: for example
tetracyclines.
• Alteration of enzyme pathways: for example dihydrofolate
reductase becomes insensitive to trimethoprim.
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Antibiotika Resistensmekanismer
Antibiotikum
Ändrat mål
Ändrat upptag
Inaktivering
Aminoglycosider
+
-
+
+
++
++
Tetracyklin
-
+
-
+
Beta-lactam
Chloramphenicol
Macrolider
Glycopeptider
Lincosamider
Fucidin syre
Sulphonamider
Trimetoprim
Quinoloner
Rifampicin
++
+
++
++
++
-
++
+
+
++
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Förvärvad resistens
Horisontell överföring av gener
mellan bakterier
Konjugation – Överföring av DNA
mellan bakterier
Transduktion – Överföring av DNA
genom fager (bakterievirus)
Transformation – upptag av DNA från
omgivningen
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Genetic transfer
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Antibiotikaresistens
är en oundviklig konsekvens av antibiotikabehandling
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Resistenta bakterier
MRSA
Meticillinresistenta S. aureus
MRSE
Meticillinresistenta S. epidermidis
PRP/PNSP
Penicillinresistenta pneumokocker/
Pneumokocker med nedsatt
känslighet för penicillin
ESBL
Enterobacteriaceae som producerar
Extended
spectrum betalactamases
VRE
Vankomycinresistenta enterokocker
Anmälningspliktiga enligt smittskyddslagen PNSP,
MRSA, VRE och ESBL
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Antalet fall av MRSA
Sverige
Källa Smittskyddsinstitutet
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Miljöpåverkan
Ekoskugga
Utdrag – exempel:
Sedan mars 2006
finns miljödata om
antibiotika i FASS
på www.fass.se.
Detta gäller dock
inte alla antibiotika
ännu
Källa fass.se
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Antibiotikaanvändning
EU-länderna
Total användning av antibiotika i öppenvård under 2002
DDD per 1000 inv/dag
Sverige
Källa: H. Goossens Lancet 2005; 365: 579–87
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Hur motverka resistensutveckling?
Använd antibiotika som har effekt mot den aktuella
bakterien, gärna med:
•
Kort ekoskugga
•
Total absorption
Ny lag trädde i
kraft 1/7 2006
Begränsa användningen av antibiotika
Hygieniska åtgärder, undvik trängsel
Ev. kombinationsbehandling
Växelbruk mellan olika antibiotika
Resistensövervakning
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Vårda antibiotika !
Det måste gå !
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Resistensbestämning med disk på agarplattor
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Tidsberoende antimikrobiell verkan.
Antimikrobiella läkemedelsklasser
Alla betalaktamer inklusive
Pencilliner samt aminopenicilliner,
cefalosporiner, karbapenemer
Den antimikrobiella verkan beror på hur länge
läkemedelskoncentrationen överstiger tröskelvärdet mellan doserna
Betydelse
Doseras ofta, betalaktamer oralt minst tre gånger om dagen
Långsam infusion effektivare än snabb infusion eller bolusdos
Konstant infusion effektivast
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Antimikrobiella läkemedelsklasser
Aminglykosider
Fluorokinoloner
Metronidazol
Den antimikrobiella effekten beror på maximal
läkemedelskoncentration
Betydelse
Tillförs i höga doser
Kan ges mera sällan
Snabb infusion teoretiskt sett effektivast, p.g.a. toxicitet bör infusionen
ges i över 30–60 minuter
Konstant eller mycket lång infusion borde undvikas
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