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RESISTANCE
9.21.12
agent
Reduced accumulation of the agent
Limited uptake
Active Efflux
Fluoroquinolone
s
Mechanism of Resistance
ESBLs
chromosomal
cephalosporinases
of -lactamases
new -lactamases resistant to inhibitors
chromosomal cephalosporinases
porin mutations
efflux pump overproduction (excluding
imipenem)
zinc metalloenzymes and other lactamases
alterations in DNA topoisomerase
efflux mechanisms
permeability changes
hyperproducers
xx
xx
Antimicrobial
Exposure
xx
Resistant Strains
Rare
xx
xx
xx
Resistant Strains
Dominant
Target Alterations
PBPs: in cell membrane
S. pneumoniae, MRSA
Intrinsic resistance, enterococci, gonococci, H. infl
D-Ala-D-Ala target: VRE
VanA, VanB, VanC, VanD
Alterations in ribosomes
Cell membrane changes
proteins
all involved in the final stages of the synthesis of
peptidoglycan, which is the major component of
bacterial cell walls
More common R mechanism for gram positive
organisms
Enzyme Production
Aminoglycoside modifying enzymes
B-lactamases:
Four structural classes:
Class A: R of S aureus to penicillin, R of E coli to ampicillin and
cephalothin plasmid mediated
Class B: hydrolyze carbapenmens/pens/cephs -chromosomal
Class C: chromosomal, active against cephalosporins
Class D: plamid mediatated
B-lactamase
B-lactame ring
Cefipime
Increased stability to B-lactamase
Increased penetration into gram-positive
Ceftriaxone
-Lactamases: Overview
Large, diverse family of enzymes
Widely dispersed in gram-positive (chromosoaml
ESBLs
AmpC -lactamases
carbapenemases
-Lactamases
Major groups for gram-neg
TEM-wide spread-plasmid and transposon
Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus
cephalosporins
-lactamase
1960
TEM-2SHV
TEM-1
Extended spectrum-lactamase
1980s
Cefotaxime
TEM, SHV
CTX
ESBL-Mediated Resistance
Contain a number of mutations that allow them to
ESBLs
Not as catalytically efficient
Inhibited by -lactamase inhibitors
Susceptible to cefoxitin and cefotetan in vitro only
ESBLs
Rupp ME et al. Drugs. 2003;63:353365.
Amp-C
Confer resistance cephamycins (cefotetan,
inducible
Not susceptible to inhibitors
AmpC- vs ESBL-Mediated
Resistance
Different phenotypic characteristics
AmpC type -lactamases typically encoded on
in
8.5% K pneumoniae samples
6.9% K oxytoca samples
4% E coli samples
Carbapenemases
beta-lactamases with versatile hydrolytic capacities.
Ability to hydrolyze penicillins, cephalosporins,
Metallo-b-lactamases (MBLs)
Major R in pseudomonas, acinetobacter, and enterobacter
Confer High level of R
Serine b-lactamases
Oxacillinases or D b-lactamases (OxaA)
Not as Diverse
Found mostly in acinetobacter
Confer only low level of hydrolytic activity therfore another R is necessary to
raise MIC
Class A carbapenemases
Found in pseudomonas and enterobacter, but predominant type is found on a
plasmid in Klebsiella
Mechanisms of Bacterial
Resistance to Fluoroquinolones
Mutations in DNA gyrase and topoisomerase
Overexpression of efflux pump system
Bacterial membrane permeability changes
resistant1
Mechanisms of resistance include1,2
production of ESBLs or AmpC -lactamases
increased efflux of antibiotic agent
decreased outer membrane permeability
DNA gyrase mutations
aminoglycoside modifying enzymes
P aeruginosa involve
(MexA-MexB-OprM)
upregulation of other efflux system may be involved (crossresistance to fluoroquinolones)
Carbapenems: Resistance
Issues
Carbapenem nucleus
Ertapenem
Imipenem
Mutated or
missing
D2 porin
D2 Porin (OprD)
Outer
membrane
Periplasm
Cytoplasmic
membrane
Penicillin-binding
proteins (PBPs)
PBP
1
PBP
2
PBP
3
PBP
4
PBP
5
Mechanisms of Carbapenem
Resistance: Impermeability
OprD forms narrow transmembrane channels that
well as carbapenems
mechanism sometimes selected by fluoroquinolones,
rarely by carbapenems
MRSA
Methicillin resistance is acquired via Mec A
mobile chromosomal element called staphylococcal cassette
chromosome (SCCmec)
SCCmec types I, II, and III and are multidrug resistant-large cassettes
Health-care associated
SCCmec type IV and type V not multidrug resistant
Community associated
MecA
Encodes penicillin binding protein (PBP) 2a
Weak affinity for methicillin and all beta-lactams
Substitutes for the usual PBP 1-3 that have a high affinity for betalactams
Speculation of origination from CoNS
S. Pneumoniae
Pencillin
Decreased affinity to PBP
Can be overcome with high dose
Macrolides
Genetic changes to binding target on ribosome-high
S. pneumoniae
Fluoroquinilones
Bind to either gyrase or topoisomerase or both
Resistance from mutations in gyrA or parC
reduce binding of the drug to the site of activity
Mutations are step wise
One mutation and R to cipro and levo
More than one needed for gemi and moxi
Tetracyclines
Proteins are produced that package the drug into vessicles which
are extruded from the cell
Enterococcus
Intrinsic (chromosomal, naturally occurring) resistance to
B-lactam
10 to 1000 times more drug to inhibit an average Enterococcus than an
average Streptococcus
Due to penicillinase production and PBP5 production
Aminogylcosides
Low level to streptocmycin and gentimicin
Synergism causes cell wall agent to become bactericidal
High level to tobramycin
Enterococcus-Intrinsic
Clindamycin-gene encoding efflux pump
TMP-SXZ In vitro appears susceptible but in vitro is resistant
Can utilize preformed folic acid
Enterococcus
Genetic transfer to acquire new resistance
One mechanism, involving pheromone-responsive
plasmids, causes plasmid transfer between E. faecalis
isolates at a very high frequency .
Another mechanism involves plasmids that can transfer
among a broad range of species and genera, although
usually at a moderately low frequency .
A third mechanism (conjugative transposition) involves
transfer of specialized transposons at low frequency but
to a very broad range of different kinds of bacteria .
Conjugative transposons are relatively nonselective in
their host range and are one of the few types of elements
known to have crossed the gram-positive/gram-negative
barrier in naturally occurring clinical isolates and to then
cause resistance in these various hosts
Enterococcus
Acquired
High level resistance to amnioglycosides
Loose synergy ability as well