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Micro - Mechanisms of Resistance (Contributing factors (antimicrobial use,…
Micro - Mechanisms of Resistance
Basis
evident since 1940s
major worldwide problem
natural selection: resistant strains persist + predominate
chromo mutation
can be inherent (e.g. all gram -ves are resistance to vancomycin)
genetic exchange
transformation
transduction
conjugation (plasmids)
transposition
accumulation of multiple resistances to unrelated antibiotics (e.g. MRSA)
antibiotic Tx kills most sensitive strains 1st, then intermediate, then resistant
if Tx stopped prematurely resistant organisms remain + cause relapse
Problems caused by AMR
untxable infections
time lost with inappropriate Tx
longer hosp stay (increased risk of subsequent infections)
increased antibiotic use
more toxic. less effective, more expensive drugs required
Contributing factors
antimicrobial use
availability of OTC antimicrobials
inadequate infection control
patient non-compliance (can be due to SEs or a long confusing regimen)
Tx length too short
increasingly elderly pop
increasing travel
overcrowding in healthcare + childcare facilities
subtherapeutic dosing
low penetration to body sites
Mechanisms of AMR
inactivating enzymes inactivate agent (destroy/alter it) before it reaches target
b-lactamases
cleave b-lactam ring
convert active penicillin to inactive penicillate
also inactivate cephalosporins
produced by most staph
ESBL
destroy penicillin, 1GC, 2GC, 3GC
produced my some gram -ve (E Coli, P aeruginosa)
carbapenase
produced by some gram -ve
destroy carbapenems (e.g. meropenem)
sometimes can be overcome with b-lactamase inhibitors (clavulanate in co-amoxiclav, tazobactam in piptazobactam)
aminoglycoside-modifying enzymes
adds chemical groups to antibiotic - alters structure + interferes with its transport
bacterial cell becomes impermeable
harder for drugs to gain entry (decreased penetration)
changes in porins in outer membrane in gram -ve bacteria or transport proteins
common in P aeruginosa - gentamicin resistance
pumps (drug efflux)
can't accumulate or reach its target
new protein pumps synthesised
e.g. in tetracyclines/quinolone-resistant gram -ve bacteria
energy-dependent, powered by ATP
altered target (binding site modification - no recognition)
PBP2 in MRSA (encoded by mecA gene)
streptomycin binds to 30S + macrolides bind to 50S - cam be prevented be 1 single AA change
bacteria acquires alternative metabolic pathway (metabolic bypass)
e.g. alter pathway for purine nucleotide synthesis (other than THF)
resistant to sulphonamides + trimethoprim
multiple ones can be seen in 1 bacterium
b-lactam resistance
drug elimination, evasion + exclusion
penicillin-resistant gram +ves: target modification + agent destruction (PRSP)
penicillin-resistant gram -ves: target modification,agent destruction, permeability changes (inherent - outer membrane)
quinolone resistance
plasma mediated
target modification
chemical groups added to DNA gyrase/topoisomerase IV
gene = Qnr
efflux pumps
gene = Aac(6')-16-er
pleitrpic (also in flurorquinolones + aminoglycosides)
Aminoglycoside resistance
modifying enzymes (inactivation)
target modification (methylation of 16S rRNA)
key prevention strategies
IPC
optimise use (effective Dx + Tx)