-
risk factors for GN resistance?
- age >65
- previous abx exposure
- hosp admission >2 or more days in preceding 90d
- residence NH, ECF
- fecal incontinence
- indwelling catheter
- mechanic vetilation
- tube feed
- hepatic failiure and long term HD
-
ceftriaxone not working for pseudo is what kind of resistance? innate vs. developing
innate
-
cefepime not working for pseudo is what kind of resistance? innate vs. developing
developing
-
notorious resistant bugs? - ESKAPE
- GP: E.faecium, S.aureus
- GN: K.pneumo, A.baumanni, P. aeru, Enterobacter spp
-
ESBL producing bacteria are?
e.coli, klebsiella
-
which cephalo induces ESBL producing bacteria?
3rd gen cephalo
-
definition of MDR?
- resistant to equal to or > 3 of the following classes:
- B lactam (cephalo, monobact, pcn, carba)
- FQ
- AG
-
definition of pan-resistant?
resistant to ALL avail abx options
-
4 mechanisms of GN resistance
- production of enzyme (destroy integrity of abx)
- mutation at binding site (abx can't bind)
- down regulate outer membrane protein (abx can't get into periplasmic space)
- efflux pump (remove out abx)
-
if bacteria produce enzyme to resist abx, what can you use?
suicide substrate sulbactam can overcome!
-
mechanism of resistance of p.seudo?
- mechanism #3: down regulate outer membrane protein (prevent abx from getting into periplasmic space); reduced permeability
- mechanism #4: efflux pump
-
mechanism of resistance of imipenem?
- loss of 54-kD outer membrane protein (OprD)
- (mechanism #3) down regulate outer membrane protein (prevent abx from getting into periplasmic space) reduced permeability
-
which is better vs. bacteria resistance and why? imi vs. mero
- imi doesn't work once OprD is lost (54kD outer membrane protein)
- mero needs two steps (upregulation of MexAB-OprM efflux pump AND OprD loss)
-
mechanism of resistance of acinetobacter?
- mech #4: efflux pump
- need double cover abx
-
mech of resistance of FQ?
- mech #2: binding site mutation
- mutation of topoisomerase II (gyrA) and IV (parC)
- this results in increase MIC
- (gyrA mutation is most impt and occurs before parC mutation)
-
mech of resistance of AG? which is the weakest AG?
- mech #1: production of enzyme
- 3 enzymes: acetyl-, adenyl-, and phophoryl-transferases
- 1) they chemically modify AG structure
- 2) interfere with drug transport
- 3) prevent AG from binding to 30S rib subunit
- gent usu goes down first, then amik and tobra
-
most common and clincially sig resisstance mechanism displayed by ALL GN bacilli?
production of b-lactamase
-
how to b-lactamase work?
hydrolyze the b-lactam chem structure and inactivate the drug
-
4 categories of b-lactamases (bush-jacoby medeiros classification)
- 1) cephalosporinase
- 2a) ESBL
- 2b) cerbapenemase
- 3) metallo-b-lactamase
-
examples of ESBL (2a)? what do these do? how are they inhibited
- TEM-10
- SHV-2
- CTX-M
- they hydrolyze ESC
- (chromosomally encoded or plasmid and transposon mediated)
- inhibited by clavulanate
-
2 major machanism of resistance for ESBL (2a)?
- selection of point mutant of TEM and SHV type plasmid-mediated b-lactamses
- genes encoding CTX-M type enzymes thru horizontal gene transfer (CTX-M 15 is globally dominant strain)
-
how to you test ESBL resistance (2a)?
- ceftazidime MIC >2ug/ml
- confirmed if MIC changes upon clavulanic acid addition
-
to what abx is ESBL resistance (2a) resistant to? where is resistant mechanism carried on?
- all cephalo (except cefoxitin and cefotetan - cephamycin)
- pcn (except zosyn)
- aztreonam
- also FQ, bactrim, AG
- mech carried on plasmid
-
DOC for ESBL (2a) treatment (e.coli and kleb)?
- imi, mero!
- alt: erta, tige, AG, FQ (only for UTI)
-
can AmpC cephalosporinase (1) be inhibited by b-lactamase inhibitors, like clavulanic acid and tazobact?
nope!
-
what b-lactamase resistance does klebsiella have?
- AmpC cephalosporinase (1)
- ESBL (2a)
- carbapenemase (2b)
-
what b-lactamase resistance does e.coli have?
ESBL (2a)
-
to what abx is AmpC-cephalosporinase (1) resistant to?
- all cephalo!!! (including cefoxitin, cefotetan - cephamycin)
- also zosyn as well
-
what is the DOC and alt tx for AmpC-cephalosporinase (1) bugs?
-
action of AmpC cephalosporinase (1)?
loss of outer membrane porins and/or over expression of efflux pump
-
action of carbapenemase (2b)?
- hydrolyze carbapenem and other b-lactam abx
- basically ESBL resistance + carba
-
klebsiella with carbapenemase (2b) resistance. what to use?
-
pseudo with carbapenemase (2b) resistance. what to use?
- polymixin
- AG
- (cannot use tige unlike klebsiella b/c innate resistance)
-
Acinetobacter with carbapenease (2b) resistance. what to use?
- tige
- polymixin
- amipicillin/sulbact
- AG
- (highlighted = DOC)
-
examples of carbapenemase (2b)?
-
examples of metallo-b-lactamase (3) ?
-
what b-lactamase resistance does pseudomonas have?
- carbapenemase (2b)
- metallo-b-lactamase (3)
-
what b-lactamase resistance does acinetobacter have?
- innate cephalosporinase AmpC (1)
- ESBL (2a)
- metallo-b-lactamase (3)
- mutation in topoisomerase, AG modifying enzyme, reduced expression of outer membrane protein, efflux
-
3 organisms that have metallo-b-lactamase as resistance?
- pseudo
- enterobactericiae
- acinetobacter
-
metallo-b-lactamase (3) is resistant to? this mechanism is carried on?
- carba
- ceftazidime, cefepime
- zosyn
- carried on integron (easily transferable)
-
metallo-b-lactamase (3) is sensitive to which abx?
- tige
- polymixin
- aztreonam (for pseudo)
-
when you have ESBL, which abx class is most reliable?
carbapenem (slide 34)
-
which conditions/abx can fail to achieve PD target?
- FQ
- under dose (thus use high dose AG)
- slide 35
-
4 agents in which the MICs of drug increase up to 100 fold due to ESBL?
- cefotaxime
- ceftriaxone
- cefepime
- zosyn
-
3 reasons for increased mortality in ESBL?
- more serious or deep seated enterobacter spp infxn
- higher organism burden
- inadequate or delayed abx tx
-
what is NDM-1?
what abx can tx this?
- new delhi metallo-b-lactamase
- presence of carbapenem resistant gene
- colistin, tige, maybe aztreonam
-
SE issue with imipenem/cilastatin?
- seizure
- (careful with dose)
-
which has more activity vs. pseudo?
a) imi
b) mero
c) erta
d) dori
mero and dori
-
which has more activity vs. acinetobacter?
a) imi
b) mero
c) erta
d) dori
imipenem
-
which has no activity vs. pseudo nor acinetobacter?
a) imi
b) mero
c) erta
d) dori
erta
-
which binds stronger to ribosome? tetracycline vs. tigecycline
tige binds 5x more
-
is tigecycline active vs. metallo-b-lactamase producing kleb and e.coli?
yes
-
is tigecycline active vs. ESBL producing kleb and e.coli?
yes
-
is tigecycline active vs. KPC producing kleb and e.coli?
-
is tigecycline active vs. acinetobacter?
only in vitro activity so cannot tell if S, I or R
-
which conditions is tige indicated?
- cSSTI
- IA (anaerobe, GN, MRSA)
- CAP +/- bacteremia (but doesn't stay in blood long)
-
is tige active vs. pseudo?
no
-
is tige active vs. providencia
no
-
is tige active vs. morganella?
no
-
is tige active vs. proteus?
no
-
does tigecycline have high urine concentration?
- nope, rapidly moves into tissues thus not in urine and blood (slide 44)
- you can inc urinary conc of tige by using high dose (slide 48)
-
for VAP tx, which is better, carba vs. tige? (slide 44)
carba
-
enterobactericiae is sensitive vs.? (put in order) slide 49
-
colistin is aka ___
polymixin E (slide 50)
-
polymixin is __ depedent and is it cidal or static?
-
actions of polymixin?
- bind phospholipid in the outer membrane of GN
- cell wall destabilize and cell death
-
is polymixin active vs. p.aeru?
yes
-
is polymixin active vs. acinetobacter?
yes
-
is polymixin active vs. k.pneumo?
yes
-
is polymixin active vs. e.coli (MDR)?
yes
-
is polymixin active vs. proteus?
nope
-
is polymixin active vs. providencia?
nope
-
is polymixin active vs. burkholderia?
nope
-
is polymixin active vs. nesseria or serratia?
nope
-
SE of polymixin? which has less SE (polymixin B vs. E)
- nephro and neuro tox
- colistin (E) has less
-
what to use to tx peritonitis with k.pneumoniae (ESBL)?
polymix B + amik + mero
-
does sulbactam have activity vs. acinetobacter?
yes!
-
how to tx severely ill pseudo empirically?
- combo therapy!
- zosyn or ceftazidime + cipro or AG
- (b-lactam + AG)
-
which is better to use for kleb pneumo?
carba mono vs. carba + polymix
- carba + polymix
- lower mortality
-
for KPC (2b), which is better?
polymix mono vs. AG+ polymix+ tige
combo is better
-
what's ME 1036?
what bug does it cover, not cover?
- IV carba (phase I)
- covers MRSA, VRE, ESBL e.coli and kleb
- NO pseudo
-
what's PZ-60? what bugs does it cover?
- IV carba
- good vs. MRSA and GN
- no pseudo and acineto
-
what's sulopenem?
active vs. which bug?
- IV and PO penem
- good vs. ESBL enterobact, GP, anaerobe
-
what's tomopenem? active vs. which bug?
- carbapenem
- active vs. p.aeru
- cSSTI, HAP
-
what's PTK-0796? what spectrum does it have?
- IV and po aminomethylcycline
- active vs. MRSA, VRE, some resistant GN patho (acineto)
-
what do metallo b-lactamase inhibit ME1071 (CP 3242) med cover?
pseudo and acineto
-
what's BAL 30376?
- b-lactam b-lactamase inhibitor
- acineto
- pseudo
- b lactamase enterobacteriaceae
-
what does "squeezing the balloon phenomenon" mean?
- antibiotic rotation
- may develop resistance elsewhere
- not good
-
how to prevent GN resistance? what abx to use?
- bactrim
- cipro
- third gen cephalo
- AG
-
acinetobacter surprives long time on surfaces. what can you do for ICU pts?
chlorhexidine skin disinfection to reduce skin contamination
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