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2 organisms of concern for GP resistance
- staphylococcus
- enterococcus
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vertical evolution?
- acquired resistance
- chromosomal mutation
- due to antibiotic pressure
- i.e. during DNA replication, copying error occurs and genes are deleted partially or completely
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horizontal evolution
- acquired resistance
- acquisition of new genetic material from other resistant organisms
- occur btwn strains of species or different bacterial species
- conjugation, transduction, transformation
- i.e. S. aur resistance to methicillin and vanco
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what's plasmid?
- extrachromosomal DNA (separate from chromosomal DNA)
- can replicate independently
- circular and double stranded
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what's transposon?
in the plasmid, carry the resistant gene
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infections caused by staph aureus?
- SSTI
- osteomyelitis
- blood stream infxn
- endocarditis
- pneumonia, sinusitis (hospital)
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why is staph aur resistant to pcn?
- due to production of extracellular enzyme, penicillinase
- hydrolyze the amide bond of b-lactam ring of pcn and ampicillin
- carried by a plasmid
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why is staph aur resistant to oxacillin and methicillin?
- b/c mecA resistant gene
- encodes PBP2a which has dec affinity for oxacillin and other b-lactam drugs
- alteration of target site
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where is mecA gene carried?
mobile genetic element, SCC mec (staphylococcus cassette chromosome)
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which types of mec gene are MDR?
II and III
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which mec gene has resistance only in mecA gene?
type V
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which mecA gene are for hospital MRSA?
I, II and III
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which replicates faster? hospital MRSA or MSSA?
MSSA is faster
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which 2 mecA genes are for community MRSA?
IV and V
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which is more similar to MSSA? hospital vs. community MRSA
community
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why would community MRSA have more efficient trasnfer of resistance than hospital?
b/c small in size, replicates more rapidly, greater fitness of CA-MRSA mecIV gene
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how do you dx community acq MRSA?
- diagnosis made in outpatient setting or positive MRSA within 48h of hospital admission
- no hx of MRSA or colonization
- no hx of prior year of hospitalization, dialysis, surgery, NH/SNF/hospice
- no permanent indwelling catheter, medical device
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can you have comm-acq MRSA if you have catheter?
- nope
- medical device either
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can you have comm-acq MRSA if you have dialysis?
- nope
- neither surgery nor hospitalization
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CA-MRSA acquired a novel genetic element called ___ via ___ transmission, possibly from which bug? this is genomic sequencing of ___
- arginine catabolic mobile element (ACME)
- horizontal transmission
- staph epidermis
- USA 300 strain
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which has more frequent toxin production? hospital vs. community MRSA? name of the toxin?
- community
- panton-valentine leucocidin toxin (PVL): almost always produced in community
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HA-MRSA has enterotoxin __ and __.
CA-MRSA has enterotoxin __ and __.
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toxic shock syndrome toxin (TSST-1) may be produced by which MRSA? (hosp vs. comm)
what are the clinical syndromes?
- hospital
- rarely
- septic shock, necrotizing pneumonia, cSSTI
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activity of panton-valentine leucocidn gene?
it is associated with what kind of infxn?
which MRSA has this (hosp vs comm)?
- damage cell by making holes in membrane of erythrocyte and leukocyte. leads to massive tissue necrosis
- necrotic skin, pneumonia
- community MRSA
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PVL toxin has a relationship with which type of mec gene?
IV
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HA-MRSA has MDR. CA-MRSA has resistance limited to _____.
b-lactam and erythromycin
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HA-MRSA has USA strain ___ , while CA-MRSA has __ and ___.
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infections due to CA-MRSA?
- SSTI
- necrotizing fasciitis
- pneumonia (rare but very high mortality)
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infections due to HA-MRSA?
- blood stream infxn
- RTI
- UTI
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risk factors for MRSA?
- pediatric/postpartum
- homeless youth
- MSM
- incarcerated
- military recruits
- competitive atheletes
- IVDA
- GI disease
- native american, alaska native, pacific islander
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CA-MRSA tx?
- clindamycin
- tetracyclin (doxy, mino)
- FQ (levo, moxi)
- bactrim (2 DS bid)
- linezolid, vanco
- rifampin (must use as combo tx)
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HA-MRSA tx?
- vanco, lin, dapto
- q/d
- tige
- telavancin
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bactrim is for ___ MRSA. available formulation? bacteriostatic or cidal?
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advantages of clindamycin for CA MRSA?
- IV/PO
- distribute well into skin and skin structure
- inhibit toxin production and virulence factor in SA
- cheap
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disadvantage of clindamycin for CA MRSA?
- inducible resistance: must have D test (erythro(R) and clinda(S) MRSA can still induce clinda(R) during therapy so cannot use)
- clostridium dificile associated diarrhea
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what should you do before initiating clindamycin for CA MRSA? name of the resistance gene? explain
D test
- MLSb(ribosomal subunit alteration): cross resistance of macrolide/lincosamide/streptogramin
- this is induced by erythromycin
- erythro(R) and clinda(S) MRSA can still induce clinda(R) during therapy so cannot use
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is FQ used commonly for CA MRSA? how about HA MRSA?
- CA: often avoided b/c rapid resistance
- HA: nope. inc incidence of MRSA colonization
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downside of linezolid if prolonged use?
- bone marrow suppression
- neuropathy
- optic neuritis
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mechanism of resistance of VISA?
thicken organism's cell wall (diff mechanism from VRSA so they are not linked)
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can you use vanco for VISA? why?
- nope
- VISA thickens organism's cell wall. vanco gets trapped in the outer layer and cannot enter cytoplasm thus cannot carry its abx action
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is hVISA (heterogeneous) susceptible to vanco?
- yes
- but contain subpopulation of organisms with borderline vanco MIC btwn S and I.
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mechanism of resistance for VRSA? relate it with vanco mechanism
- acquired a vanA vancomycin resistant gene from e.faecalis by conjugal transfer of plasmid DNA (located on transposon)
- vanco directly binds cell wall precursors and prevents cross linking of D-ala-D-ala. VRSA makes D-ala-D-lac so vanco binds weakly.
- (basically produce different amino acid)
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is VRSA evolved from VISA?
- nope
- different mechanism of resistance
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mech of resistance for FQ for MRSA?
- spontaneous mutation causing change to amino acid in the enzymes essential for DNA replication
- place in the enezyme, QRDR: ParC on topoisomerase IV and GyrB on DNA gyrase (clinically significant)
- rarely efflux pump (you can overcome with high dose)
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clindamycin mech of resistance gene? where are they carried?
- erm genes
- MSSA-erm (C) carried on plasmid
- MSSA-erm (A) carried by transposon
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which enterococcus has more resistance? faecium vs. faecalis?
- faecium
- faecalis is very sensitive
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mech of resistance of enterococcus?
- vanA and vanB
- alter target for vancomycin from D-ala-D-Ala to D-ala-D-lactate
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if you have significant anti-enterococcal activity, does it promote VRE colonization?
- nope
- if lacking, then promotes VRE
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if there is a high anaerobic activity, does it promote VRE?
- yes
- if low, then it does not promote VRE colonization
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if high concentration secretion in human bile, VRE colonization is promoted. t or f?
- true
- if low concentration, it does not promote VRE colonization
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is ceftriaxone great for VRE?
it's great for bilirary but risk for VRE colonization.
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which is better for VRE? timentin vs. zosyn
zosyn
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does extended spectrum cephalo increase VRE colonization?
yes
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does oral vanco increase VRE colonization?
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does metronidazole increase VRE colonization?
yes, b/c has anaerobic coverage
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does timentin increase VRE colonization?
yes
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does zosyn increase VRE colonization?
supposedly decrease
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tx options for VRE?
- telavancin
- tige
- linezolid
- dapto
- oritavancin
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dual MOA of telavancin
- inhibit cell wall synthesis
- disrupt membrane barrier function
- bactericidal, conc dep
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what does telavancin cover?
- MRSA, MSSA, streptococcus, enterococcus faecalis
- off label: VISA, VRSA
- SSTI
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how is the t/2 of telavancin?
it's long~ advantage
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SE of telavancin?
- foamy urine
- taste disturbance, inf-related reaction, insomnia, nausea
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tigecycline treats which infxn? what organisms does it cover?
- cSSTI, CAP, IA
- GP: MRSA, MSSA, e.faecalis
- in vitro VRE
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linezolid covers which organisms?
- MRSA, MSSA, e.faecium
- e.faecalis, e. faecium in vitro
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which infxn does linezolid cover?
cSSTI, uSSTI, CAP, HAP
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dapto is FDA approved for which organisms? how about in vitro?
- FDA: MSSA, MRSA, e.faecalis, streptococcus
- in vitro: VRE
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can dapto cover VISA?
- thickened cell wall on organism hindered penetration of dapto into cell membrane, esp if staph has high MIC to vanco.
- need high dose
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MRSA resistance to linezolid and dapto has to do with...? (MOR)
reduced binding of drug to target site
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oritavancin has strong activity vs. ___
- staph aureus
- active vs. VRE, VRSA
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oritavancin can cover which infxn?
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advantage of oritavancin?
long t/2
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