INHOUDSTAFEL
Principes van antibiotica resistentie............................................................................................................3
Genetische basis van resistentie................................................................................................................3
Resistentie door spontane mutatie in endogene genen................................................................. 3
Resistentie door verwerving van exogenen....................................................................................3
Mechanismen van resistentiegenen overdracht............................................................................. 4
Mechanisme van resistentie........................................................................................................... 6
Bèta-lactams.............................................................................................................................................. 6
Werkingsmechanisme.................................................................................................................... 6
Resistentiemechanismen............................................................................................................... 7
Glycopeptiden - Vancomycine....................................................................................................................8
Werkingsmechanisme.................................................................................................................... 8
Resistentiemechanisme................................................................................................................. 9
Macroliden..................................................................................................................................................9
Werkingsmechanisme.................................................................................................................... 9
Resistentiemechanismen............................................................................................................... 9
(Fluoro)quinolones................................................................................................................................... 10
Werkingsmechanisme.................................................................................................................. 10
Resistentiemechanismen............................................................................................................. 10
Oorsprong van resistentiegenen.............................................................................................................. 11
Beta-lactams.................................................................................................................................................12
Antibiotica.................................................................................................................................................12
Mechanismen van antibiotica....................................................................................................... 12
Spectrum van antibiotica.............................................................................................................. 12
Kinetiek.........................................................................................................................................13
Veiligheid en allergieën.................................................................................................................14
Beta-lactam antibiotica............................................................................................................................. 14
Resistentiemechanisme............................................................................................................... 15
Bijwerkingen van beta-lactam antibiotica..................................................................................... 16
Penicilline..................................................................................................................................... 17
Cloxacilline................................................................................................................................... 18
Amoxicilline + clavulaanzuur........................................................................................................ 18
Ceftriaxone................................................................................................................................... 19
Meropenem.................................................................................................................................. 19
Non-bèta-lactams......................................................................................................................................... 20
Non-bèta-lactam antibiotica......................................................................................................................20
Gram-negatieve resistentie is booming....................................................................................................20
WHO Global Action Plan (2015)...................................................................................................20
AWaRe......................................................................................................................................... 20
Macroliden................................................................................................................................................21
Azithromycine............................................................................................................................... 22
Fluoroquinolones......................................................................................................................................23
Ciprofloxacine...............................................................................................................................23
Resistentiemechanismen............................................................................................................. 24
Sulfonamides............................................................................................................................................24
Co-trimoxazole............................................................................................................................. 24
, Tetracyclines.............................................................................................................................................26
Indicaties voor gebruik..................................................................................................................26
Nevenwerkingen...........................................................................................................................27
Urinary antibiotica.....................................................................................................................................27
Nitrofurantoine.............................................................................................................................. 27
Fosfomycine................................................................................................................................. 28
Moeilijk te behandelen gram+ infecties.................................................................................................... 28
Vancomycine................................................................................................................................ 28
Clindamycine................................................................................................................................ 29
Clostridium difficile........................................................................................................................31
Linezolid....................................................................................................................................... 31
Moeilijk te behandelen gram– infecties.................................................................................................... 32
Aminoglycosiden.......................................................................................................................... 32
Gentamicine........................................................................................................................... 33
Amikacine............................................................................................................................... 34
Polymyxines................................................................................................................................. 35
Colistine = polymyxine E........................................................................................................ 35
Nieuwe combinatieproducten....................................................................................................... 36
Alternatieve producten..................................................................................................................36
Antibioticagebruik........................................................................................................................................39
Resistentie terugdringen.......................................................................................................................... 39
Optimaal antibioticagebruik...................................................................................................................... 39
1
,WHO-classification
critical priority Acinetobacter baumannii
● carbapenem-resistent
Pseudomonas aeruginosa
● carbapenem-resistent
Enterobacteriaceae (E. coli)
● carbapenem-resistant
● 3e generatie cephalosporine-resistent
high priority Enterococcus faecium
● vancomycin-resistent
Staphylococcus aureus
● vancomycine-resistent
● methicilline-resistent
Helicobacter pylori
● clarithromycine-resistent
Campylobacter species
● fluoroquinolone-resistent
Salmonella species
● fluoroquinolone-resistent
Neisseria gonorrhoeae
● 3e generatie cephalosporine-resistent
● fluoroquinolone-resistent
medium priority Streptococcus pneumoniae
● penicilline-ongevoelig
Haemophilus influenzae
● ampicilline-resistent
Shigella species
● fluoroquinolone-resistent
2
, Principes van antibiotica resistentie
Genetische basis van resistentie
spontane mutatie in endogene genen = genen die de bacteriën zelf bezitten (species-specifiek)
● structurele genen
○ uitgebreid spectrum van enzymatische activiteit
○ modificatie van target site in de bacterie waarop AB normaal zou binden
○ transport defect
● regulerende genen: verhoogde expressie
verwerving van exogene genen
● meestal regulerende genen die coderen voor inactiverende enzymen of gemodificeerde targets
● mechanismen van DNA-overdracht
○ conjugatie: uitwisseling van plasmiden via cel-cel contact (vooral gram–)
○ transformatie: opname van naakt DNA uit de oplossing/omgeving (vooral gram+)
○ transductie: overdracht van DNA via bacteriofagen (= bacterieel virus)
expressie van resistentie genen: omkeerbare inductie-/repressiesystemen kunnen resistentiefenotypes
beïnvloeden
Resistentie door spontane mutatie in endogene genen
1. populatie van delende bacteriën (elke 20 minuten worden 2 cellen geproduceerd vanuit één
moedercel)
2. groei en deling produceert natuurlijk voorkomende mutanten (loss of function of gain of function)
3. bacteriën blijven multipliceren, af en toe aanleiding gevend tot verschillende mutanten
4. blootstelling aan selectieve druk van antibiotica
5. bacteriën worden gedood of groei wordt voorkomen, behalve voor specifieke resistente mutanten
= uitselectie van resistentie
6. mutanten met de minste fitness-cost prolifereren en verspreiden
Resistentie door verwerving van exogenen
1. twee populaties van verschillende bacteriën groeien in dezelfde omgeving
2. uitwisseling van DNA en mobiele genetische elementen vindt plaats tussen bacteriën met lage
frequentie
3. gevoelige bacteriën verwerven resistentiegenen die aanwezig zijn op een mobiel genetisch element
4. cellen met verworven resistentie prolifereren en gevoelige bacteriën worden gedood of groei
voorkomen
voorwaarde: aanwezigheid van bacterie met resistentiegenen
3
Principes van antibiotica resistentie............................................................................................................3
Genetische basis van resistentie................................................................................................................3
Resistentie door spontane mutatie in endogene genen................................................................. 3
Resistentie door verwerving van exogenen....................................................................................3
Mechanismen van resistentiegenen overdracht............................................................................. 4
Mechanisme van resistentie........................................................................................................... 6
Bèta-lactams.............................................................................................................................................. 6
Werkingsmechanisme.................................................................................................................... 6
Resistentiemechanismen............................................................................................................... 7
Glycopeptiden - Vancomycine....................................................................................................................8
Werkingsmechanisme.................................................................................................................... 8
Resistentiemechanisme................................................................................................................. 9
Macroliden..................................................................................................................................................9
Werkingsmechanisme.................................................................................................................... 9
Resistentiemechanismen............................................................................................................... 9
(Fluoro)quinolones................................................................................................................................... 10
Werkingsmechanisme.................................................................................................................. 10
Resistentiemechanismen............................................................................................................. 10
Oorsprong van resistentiegenen.............................................................................................................. 11
Beta-lactams.................................................................................................................................................12
Antibiotica.................................................................................................................................................12
Mechanismen van antibiotica....................................................................................................... 12
Spectrum van antibiotica.............................................................................................................. 12
Kinetiek.........................................................................................................................................13
Veiligheid en allergieën.................................................................................................................14
Beta-lactam antibiotica............................................................................................................................. 14
Resistentiemechanisme............................................................................................................... 15
Bijwerkingen van beta-lactam antibiotica..................................................................................... 16
Penicilline..................................................................................................................................... 17
Cloxacilline................................................................................................................................... 18
Amoxicilline + clavulaanzuur........................................................................................................ 18
Ceftriaxone................................................................................................................................... 19
Meropenem.................................................................................................................................. 19
Non-bèta-lactams......................................................................................................................................... 20
Non-bèta-lactam antibiotica......................................................................................................................20
Gram-negatieve resistentie is booming....................................................................................................20
WHO Global Action Plan (2015)...................................................................................................20
AWaRe......................................................................................................................................... 20
Macroliden................................................................................................................................................21
Azithromycine............................................................................................................................... 22
Fluoroquinolones......................................................................................................................................23
Ciprofloxacine...............................................................................................................................23
Resistentiemechanismen............................................................................................................. 24
Sulfonamides............................................................................................................................................24
Co-trimoxazole............................................................................................................................. 24
, Tetracyclines.............................................................................................................................................26
Indicaties voor gebruik..................................................................................................................26
Nevenwerkingen...........................................................................................................................27
Urinary antibiotica.....................................................................................................................................27
Nitrofurantoine.............................................................................................................................. 27
Fosfomycine................................................................................................................................. 28
Moeilijk te behandelen gram+ infecties.................................................................................................... 28
Vancomycine................................................................................................................................ 28
Clindamycine................................................................................................................................ 29
Clostridium difficile........................................................................................................................31
Linezolid....................................................................................................................................... 31
Moeilijk te behandelen gram– infecties.................................................................................................... 32
Aminoglycosiden.......................................................................................................................... 32
Gentamicine........................................................................................................................... 33
Amikacine............................................................................................................................... 34
Polymyxines................................................................................................................................. 35
Colistine = polymyxine E........................................................................................................ 35
Nieuwe combinatieproducten....................................................................................................... 36
Alternatieve producten..................................................................................................................36
Antibioticagebruik........................................................................................................................................39
Resistentie terugdringen.......................................................................................................................... 39
Optimaal antibioticagebruik...................................................................................................................... 39
1
,WHO-classification
critical priority Acinetobacter baumannii
● carbapenem-resistent
Pseudomonas aeruginosa
● carbapenem-resistent
Enterobacteriaceae (E. coli)
● carbapenem-resistant
● 3e generatie cephalosporine-resistent
high priority Enterococcus faecium
● vancomycin-resistent
Staphylococcus aureus
● vancomycine-resistent
● methicilline-resistent
Helicobacter pylori
● clarithromycine-resistent
Campylobacter species
● fluoroquinolone-resistent
Salmonella species
● fluoroquinolone-resistent
Neisseria gonorrhoeae
● 3e generatie cephalosporine-resistent
● fluoroquinolone-resistent
medium priority Streptococcus pneumoniae
● penicilline-ongevoelig
Haemophilus influenzae
● ampicilline-resistent
Shigella species
● fluoroquinolone-resistent
2
, Principes van antibiotica resistentie
Genetische basis van resistentie
spontane mutatie in endogene genen = genen die de bacteriën zelf bezitten (species-specifiek)
● structurele genen
○ uitgebreid spectrum van enzymatische activiteit
○ modificatie van target site in de bacterie waarop AB normaal zou binden
○ transport defect
● regulerende genen: verhoogde expressie
verwerving van exogene genen
● meestal regulerende genen die coderen voor inactiverende enzymen of gemodificeerde targets
● mechanismen van DNA-overdracht
○ conjugatie: uitwisseling van plasmiden via cel-cel contact (vooral gram–)
○ transformatie: opname van naakt DNA uit de oplossing/omgeving (vooral gram+)
○ transductie: overdracht van DNA via bacteriofagen (= bacterieel virus)
expressie van resistentie genen: omkeerbare inductie-/repressiesystemen kunnen resistentiefenotypes
beïnvloeden
Resistentie door spontane mutatie in endogene genen
1. populatie van delende bacteriën (elke 20 minuten worden 2 cellen geproduceerd vanuit één
moedercel)
2. groei en deling produceert natuurlijk voorkomende mutanten (loss of function of gain of function)
3. bacteriën blijven multipliceren, af en toe aanleiding gevend tot verschillende mutanten
4. blootstelling aan selectieve druk van antibiotica
5. bacteriën worden gedood of groei wordt voorkomen, behalve voor specifieke resistente mutanten
= uitselectie van resistentie
6. mutanten met de minste fitness-cost prolifereren en verspreiden
Resistentie door verwerving van exogenen
1. twee populaties van verschillende bacteriën groeien in dezelfde omgeving
2. uitwisseling van DNA en mobiele genetische elementen vindt plaats tussen bacteriën met lage
frequentie
3. gevoelige bacteriën verwerven resistentiegenen die aanwezig zijn op een mobiel genetisch element
4. cellen met verworven resistentie prolifereren en gevoelige bacteriën worden gedood of groei
voorkomen
voorwaarde: aanwezigheid van bacterie met resistentiegenen
3
