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AMR: antimicrobial resistance mechanisms - Coggle Diagram
AMR: antimicrobial resistance mechanisms
Innate, intrinsic
(Genus- or species specific property of bacteria)
Mycoplasma spp. are intrinsically resistant to β-lactams
Enterobacteria are intrinsically resistant to macrolides
Enterobacteria are intrinsically resistant to penicillin G (benzypenicillin
Mechanisms to reduce innate resistance: Semi-synthetic modification of penicillin G creates ampicillin (an aminopenicillin)
Acquired
Mutation
Streptomycinresistance in
E.coli (single-step
mutation in rpsL)
HGT
Tetracyclineresistance in
Gram + and
Gram – species
(tetA, tetK)
Beta-lactamase
production in
staphylococci (blaZ)
Single clinical outcome. Mix of HGT and mutation: Fluoroquinolone resistance: Gram-negatives.
Most commonly high level resistance that required the cuncurrent presence of 3 mutations (structural alteration of the target).
Occurs stepwise
• DNA gyrase (gyrA and gyrB)
• Topoisomerase IV (parC and parE)
Decreased permeability – down-regulation of outer membrane porins
• Overexpression of efflux pumps
• Plasmid-mediated quinolone resistance
▪ FQ degradation (aac(6′)-Ib-cr)
▪ Efflux pumps (qepA)
▪ Disruption of the interaction with FQs by binding to topoisomerases (Qnr family)
Phenotype MDR Multidrug resistance
Multidrug-resistant (MDR)
Multidrug-resistant (MDR)
Non-susceptible to ≥1 agent in ≥3 antimicrobial categories
Extensively drug-resistant (XDR)
Non-susceptible to ≥1 agent in all but ≤2 categories
Pandrug-resistant (PDR)
Non-susceptible to all antimicrobial agents
Mechanisms of AMR (innate or acquired)
Drug inactivation (disintegration / modification)
E.g. β-lactamases produced widely by
staphylococci (blaZ)
• Render penicillin, amoxicillin etc inactive =
penicillin-resistant
• Acquisition of new gene
Overcoming β-lactamase activity
Amoxicillin-clavulanic acid
Clavulanic acid stops β-lactamase before the enzyme destroys the amoxicillin
Decreased uptake / increased efflux
Active transport of the
antimicrobial out of the
bacterial cell
E.g. Tetracycline efflux
pump (e.g. tetA in Gram –
ve; tetK in Gram+) keeps
concentration of tetracycline
within the cell below MIC =
tetracycline-resistant
Target modification / protection
E.g. Ribosome structural
alteration in E. coli (rpsL
mutation) prevents streptomycin
distortion = streptomycin resistant
• Mutation conferring resistance
Both intrinsic and acquired multidrug resistant pathogen
Pseudomonas aeruginosa has wide-ranging and unpredictable susceptibility
patterns
• Intrinsic resistances
• ‘Mega-plasmids’
• Multidrug-resistant efflux pump
Multidrug efflux pumps
Pseudomonas aeruginosa
MexAM-OprM
• Aztreonam, gentamicin, tobramycin, tetracycline
E. coli
AcrAB-TolC
• Chloramphenicol, fluoroquinolones, fusidic acid, rifampicin, tetracycline, ethidium
bromide, bile salts etc
• Upregulated in clinical isolates
• Upregulated following exposure to antibiotics
• Upregulated in biofilms
MRSP (MRSA)
Methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus pseudintermedius
What do we already know about staphylococci?
• Already producing β-lactamase – so resistant to
penicillin, ampicillin etc.
But MRSA/MRSP are resistant to ALL β-lactams mecA acquisition Carried on ‘Staphylococcal cassette chromosome (SCCmec)’ – MGE that is chromosomally integrated
Implications: S. aureus is the human commensal
• Cattle (mastitis)
S. pseudintermedius is the canine
commensal
ESBL-Enterobacterales e.g. E.coli & Klebsiella spp.
Narrow-spectrum β-lactamases (penicillinases) quite commonly produced by variety
of bacterial species
More recent emergence of β-lactamases which target
• ALL penicillins
• ALL cephalosporins (including 4th generation)
• Designated ‘bla’ and a type e.g. blaCTX-M, blaTEM, blaSHV etc
Suspicions of ESBL: Enterobacterales
• E. coli
• Klebsiella spp.
• Enterobacter spp.
• Proteus spp.
True ESBL susceptible to amoxy-clav
AmpC co-carriage
• Cephalosporinase (but susceptible to 4th gen)
• NOT inhibited by clavulanic acid
Carbapenemase-producing Enterobacterales (CPE)