Mechanisms of Resistance

Question 1

Aminoglycosides

Answer 1

Gentimicin, tobramycin, amikacin, streptomycin
MOA: bind to mRNA in decoding region of 30S subunit
MOR:
- can’t penetrate cell of anaerobes
- inactivated by microbial enzymes
(Amikacin and streptomycin are most resilient)

Question 2

Beta-lactams

Answer 2

Penicillins, cephs, carbapenems, monobactams
MOA: binds to PBP and inhibits cell wall synthesis (peptidoglycan layer)
MOR: alteration of PBP
Beta-lactamase production

Question 3

Staphylococcus aureus penicillin resistance (same mech. as MRSA)

Answer 3

Resistance to penicillin mediated by mecA gene

Codes a PBP (2a) which has a low affinity for beta-lactams

Question 4

Coagulase-negative staph (CONS)

Answer 4

S. epidermidis
S. saprophyticus
Altered PBP (2a) via mecA gene

Question 5

S. pneumoniae

same mech. PenRSP

Answer 5

Resistance via decreased affinity of penicillin to 1+ PBPs
This can be overcome by using a higher dose or change to a ceph
Note: not cross resistant with other beta-lactams, but more likely to be resistant to macrolides, tetracyclines)

Question 6

H. influenzae

Answer 6

Enzymatic degradation via beta-lactamase production

Apicillin can be used if bacterial load is low

Question 7

Enterococci

Answer 7

Intrinsic resistance to:
Ceph, aminoglycosides, clindamycin, SMX/TMP
Acquired resistance:
Ampicillin via altered PBP 5
E. faecium more likely to be amp resistant

Question 8

Gram-negative beta-lactam resistance

Answer 8

E.g. E. coli, Pseudomonas
Enzyme inactivation via beta-lactamase production
Porin mutation

Question 9

Extended spectrum beta lactamases

Answer 9

E.g Klebsiella, E. coli
Via drug inactivation
Consider in all nosocomial infections with these and previous beta-lactam use. Must treat with carbapenem

Question 10

When would we suspect ESBL (extended spectrum beta-lactamases)?

Answer 10

Often see 2nd gen ceph susceptibility

General rule: if E. coli or Klebsiella and resistant to ceftriaxone/ceftazidime (3rd gen ceph) then consider it ESBL

Question 11

AmpC beta lactamase

Answer 11

A chromosomal enzyme that can hydrolyze penicillins, 1 & 3rd gen cephs
--> Is INDUCIBLE via pathway that recycles cell-wall peptidoglycans
Similar appearance to ESBL but DIFFERENT BUGS
SE(now K)ACHIMP
Serratia
Enterobacter (Klebsiella)
Aeromonas
Citrobacter
Hafnai alvei
Indole + Proteus (vulgaris)
Morganella
Providencia

Question 12

Carbapenemase producting Enterobacteriaceae (CPE)

Answer 12

Rare
Produce enzymes that hydrolyze carbapenems
* K. pneumoniae has the strongest association*
Transferred on plasmaid
We would want to consider if K. pneumo or Enterobacteriaceae which is not improving on carbapenem therapy

Question 13

Macrolides

Answer 13

MOA: Bacteriostatic, inhibit protein synthesis through 50S subunit
MOR: alteration of target by methylation (MSLb) from erm genes
Active efflux (via mef/msrA genes - not clindamycin)
Drug inactivation
Can have cross resistance w/ lincosamides and type B stroptogramins b/c same binding site

Question 14

S. aureus clindamycin resistance

Answer 14

COULD BE 2 OPTIONS:
Alteration of target via erm genes (inactivates erythromycin and clind.) OR
Efflux pump (clind. OK) - affects macrolides/B-type streptog.
Can determine via D-test. If D-zone appears, do not use clindamycin

Question 15

Quinolone Resistance

Answer 15

MOA: bind to DNA gyrase/topoisom. and prevent DNA replication/repair
MOR: mutation in target
Change intracellular concentration via altered entry/efflux (but uncommon)
Can also have mutation in the subunits that cause high-level resistance

Question 16

Metronidazole

Answer 16

MOA: formation of reactive intermediates that damage DNA
MOR: uncommon, but inactivating enzyme nitroimidazole reductase in Bacteroides spp.

Question 17

Rifampin

Answer 17

MOA: inhibits beta subunit of RNA pol in prokaryotes
MOR: mutations in rpoB gene that encodes that beta subunit
We never us rifampin as a monotherapy

Question 18

Tetracyclines

Answer 18

MOA: inhibit 30s ribosome, prevent access of aminoacyl tRNA to the A site of the mRNA-ribosome complex
Note: S. aureus can be resistant to tetra but suscept. to minocycline
MOR: efflex pumps via tet genes
Protective proteins (uncommon) causes cross resistance to all tetras but maybe not tigecycline

Question 19

SMX-TMP

Answer 19

MOA: analogue of dihydrofolate, competitively inhibits DHFR (to make DNA)
MOR: some intrinsically resistant b/c impaired binding to DHFR like Bacteroides, Neisseria, Clostridium
Can overproduce DHFR, alter binding, or bypass the pathway

Question 20

Vancomycin

Answer 20

MOA: Binds to D-ala D-ala of peptidoglycan precursor to prevent elongation of cell wall
MOR: acquired via cell wall change to lower permeability
Acquired/intrinsic: alter target site

Question 21

Which bacteria are intrinsically resistant to vancomycin?

Answer 21

Erysipelothrix
Leuconostoc
Pediococcus
Lactobacillus

Question 22

Vancomycin Resistant Enterococcus

Answer 22

Van genes:
Van A/B: is inducible, and transferable. Most common
Van D: constitutive by enzymes that change the D-ala D-ala to D-ala D-lac so vancomycin can’t bind

Question 23

Vancomycin resistant S. aureus

Answer 23

TWO OPTIONS

1. VRSA, occurs from van A gene like Enterococcus (VERY HIGH MIC)
2. VISA, due to thickened cell wall

Question 24

Multi-drug resistant example

Answer 24

P. aeruginosa

1. overexpresses AmpC beta lactamase
2. Mutations cause loss of porins
3. Efflux pumps