antibacterial resistance Flashcards
eucats?
EUCAST (European Committee on Antimicrobial Susceptibility Testing)
definitions of antimicrobial susceptibility and resistance
Clinically Susceptible (S)
• a micro-organism is defined as susceptible by a level of antimicrobial activity associated with a high likelihood of
therapeutic success
• a micro-organism is categorized as susceptible (S) by applying the appropriate breakpoint in a defined phenotypic test
system
• this breakpoint may be altered with legitimate changes in circumstances
Clinically Intermediate (I)
• a micro-organism is defined as intermediate by a level of antimicrobial activity associated with indeterminate therapeutic
effect
• a micro-organism is categorized as intermediate (I) by applying the appropriate breakpoints in a defined phenotypic test
system
• these breakpoints may be altered with legitimate changes in circumstances
Clinically Resistant (R)
• a micro-organism is defined as resistant by a level of antimicrobial activity associated with a high likelihood of therapeutic
failure.
• a micro-organism is categorized as resistant (R) by applying the appropriate breakpoint in a defined phenotypic test system
• this breakpoint may be altered with legitimate changes in circumstances
Clinical breakpoints are presented as S<x>x, <y>y mg/L</y></x>
MIC?
Minimum Inhibitory Concentration
(MIC)
– The lowest concentration of drug that
inhibits visible growth of organism
after appropriate incubation
Resistance is?
Resistance is
– Intrinsic
• Fundamental characteristic of a bacteria
–Acquired
• A new characteristic achieved either by
mutation of existing DNA or acquisition of
new genetic material
moganella morganniii and enterobacter cloacae MIC?
morg- 128
clocae - 2.
epidemiologucal ut off = 2mg/L
basic mechnisms of resistqance?
target site modification
antibiotic modifying enzymes
imprmeability ( cell wall, or periplasmic membrane)
efflux (pumpthe AB out)
types of efflux pumps?
spread of resistance?
Mutational resistance (if via a single
mutational event) can happen quite
easily
–Rifampicin resistance
• Requires a single mutation in the gene for
the target (RNA polymerase)
Mutational resistance
• Transfer of genetic material
– Plasmids
• Transfer between bacteria (conjugation)
–Mobile genetic elements
• Integrons
• Transposons
Move genes around the
chromosome and between
chromosome and plasmids
SOME ABs (eg quinolones (ciprofloxacin)) that act on
DNA may promote the transfer of genetic material
Transfer of organisms
resitqnce in S.pneumoinae?
BTS guidelines suggest amoxicillin or a
macrolide (erythromycin, clarithromycin) for treatment of CAP
how S.pneumoniae s resitant?
Altered penicillin binding proteins (PBPs)
– PBPs (targets for all β-lactams) are enzymes involved
in cell wall formation
• S. pneumoniae is ‘naturally transformable’
– Picks up bits of DNA floating in the environment and
mixes it into its own chromosome
• Altered PBPs have developed on many occasions
(as mosaic genes)
– May have different affinities for different β-lactams
– Generally PRSP remain more sensitive to
cefotaxime/ceftriaxone
macrolide site of action?
Inhibit protein synthesis
– growing peptide passes through peptide exit
channel in 50S ribosomal subunit
– MLDs interact with 23s rRNA in upper portion of
exit channel
– main contacts with
• A2058/9 in domain V
• A752 in domain II
• Inhibit 50s subunit
assembly
macrloide restistance?
• 3 main mechanisms
– target site modification of 23s rRNA
– drug efflux
– target site modification of ribosomal
proteins
• Some cross resistance between the chemically
un-related agents:
– macrolides (erythromycin)
– lincosamides (clindamycin)
– streptogramin B
target site modification of 23s rRNA?
Erm genes in S. aureus,
S. pneumoniae,
S. pyogenes
– encode methylase that methylates A2058
– cross resistance to MLD, MLSB phenotype
lincosamides (clindamycin),
streptogramin B
– inducible or constitutive
• Also (much less commonly)
mutations at active site (helicobacter)
drug efflux?
mefA found in S. pyogenes and S. pneumoniae
(prev mefE)
– low level MLD resistance M phenotype
– no cross resistance with lincosamides/
streptogramins
• msrA found in S. aureus
– cross resistance between
MLDs and streptogramins
MS phenotype
target site modification of ribosomal proteins?
Mutations in L4 or L22 ribosomal proteins now
described in S. pneumoniae
S. pyogenes
S. aureus
• non-transferable chromosomal mutation
• variable effect on cross resistance
beta-lactam resistane in saureus?
1940 - Penicillin introduced
• 1940s - β-lactamase appeared in S. aureus
• Now β-lactamase in >90% of S. aureus
• 1960s/70s – β-lactams developed that were stable to the
staphylococcal β-lactamase:
– Methicillin / flucloxacillin
– Cephalosporins
– Co-amoxiclav - combination of amoxicillin plus a β-lactamase
inhibitor (clavulanate)
• 1960s – MRSA emerged (resistant to all β-lactams)
• 1990s – MRSA spread to become a worldwide problem.
action of blactam in MSSA
cell wall synthesis in glycopeptide resistant enterococci>
rsitant therpeutic options?
