Antibiotic Resistance

Front 1

5 ways bacteria can develop antibiotic resistance:

Back 1

Mutation
Plasmid
Transposon, insertion elements
Transformation - from environment
Transduction - from bacteriophage

Front 2

4 Antibiotic resistance mechanisms:

Back 2

*Drug does not reach its target
*Drug is inactivated
*Target is altered
*Alternative metabolic pathway (competition of substrates)

Front 3

Drug doesn't reach its target; how does this happen?

Back 3

*Permeability
*Porins (outer membrane gram negative)
*Transport proteins
-import (aminoglycosides)
-export (efflux)

Front 4

Resistance Mechanisms--The Drug is Inactive, how does this happen?

Back 4

*Antibiotic is inactivated (destroyed)
*Antibiotic is not activated

Front 5

Resistance Mechanisms--Altered Target; how does this happen?

Back 5

*Target is altered so that the drug (antibacterial agent) no longer binds to the target

Front 6

Describe ß-Lactam resistance: 4 general mechanisms:

Back 6

*Beta-lactamases (inactivate drug)
*Porins (entry; drug does not reach its target)
*Efflux pumps (drug does not reach its target)
*Altered penicillin binding proteins (altered target)

Front 7

Significance of ß-lactamases:

Back 7

*Beta-lactamases inactivate beta-lactam ring so that the compound is no longer active
*Very common mechanism of resistance
*Many (>1,000) beta-lactamases
*e.g. penicillinase (1% of dry weight) in Staphylococcus aureus carried on a plasmid, inducible
*In gram negative bacteria the beta-lactamase is located in the periplasmic space
*Numerous beta-lactamases in gram negative organisms

Front 8

How do porin alterations confer antibiotic resistance to ß-lactams?

Back 8

*Porins in gram negative bacteria allow passage of beta-lactam antibiotic through the outer membrane
*Pseudomonas aeruginosa lacks classical high-permeability porins; hence beta-lactam can not reach its target in the periplasmic space
*Mutations in porins

Front 9

How do efflux pumps confer resistance to ß-lactams?

Back 9

*Not a common mechanism for beta-lactam resistance
*Pseudomonas aeruginosa contains efflux pumps that actively removes beta-lactam antibiotics from the periplasmic space

Front 10

Describe the significance of altered PBPs in ß-lactam resistance:

Back 10

*Altered target
*Differences in binding affinity of specific PBP (penicillin binding proteins) may explain differences in activity among different bacteria
*Alteration of several PBPs must decrease for an organism to be resistant
*MRSA transposon with PBP2b
*S. pneumoniae mosaic genes (transformation)

Front 11

Describe Vancomycin Resistance:

Back 11

*Enterococci that are vancomycin resistant (VRE) contain a plasmid with at least seven genes involved in the production of D-alanyl-D-lactate that does not bind to vancomycin
*S. aureus (VRSA) contain enterococcal vancomycin resistance genes

Front 12

What are the 4 mechanisms of macrolide resistance?

Back 12

*Modified ribosome (altered target) methylated
*Efflux pumps
*Modified ribosome: point mutation (rRNA)
*Modified ribosome: ribosomal protein

Front 13

How are targets altered to develop macrolide resistance?

Back 13

*Phenotype MLSB
*Resistance to macrolides, lincosamides and streptogramin type-B
*Bacterial ribosome is methylated (A2058) so that these antibiotics do not bind to their target
*Methylase expressed constitutively or inducibly in strep and staph
*Cross resistance to all MLSB compounds: macrolides, lincosamides, and streptogramin type-B

Front 14

How do efflux pumps cause macrolide resistance?

Back 14

*Remove macrolides from the cell’s interior
*Energy dependent
*mef gene in streptococci uses proton motive force; most common mechanism of resistance in S. pneumoniae in United States

Front 15

How do altered ribosomes contribute to macrolide resistance?

Back 15

*Point mutations A2059G

*Mutations/insertions of ribosomal protein L4 or L22 in Streptococcus pneumoniae

Front 16

Clinical Significance of Antibiotic Resistance:

Back 16

*Delay in instituting appropriate treatment
*Increased morbidity and mortality
*Must use costlier antibiotics
*Newer antibiotics result in new toxicities and selection pressure
*Not always clear how to best use antibiotics
*Role of combination therapy to prevent emergence of resistance
*Antibiotics in animal feeds and other uses

Front 17

General rules for treatment of infections:

Back 17

*Remove foreign body
*Drain abscess and remove necrotic tissue
*Appropriate antibacterial
-Most active against infecting bacteria
-Narrow spectrum
-Least toxic
-Cost

Front 18

Describe misuse and overuse of antibiotics:

Back 18

*Using antibiotics to treat untreatable infections, e.g. viral infection
*Using antibiotics to treat bacterial infections when there is no impact on natural history of infection
*Treating fever of undetermined origin with antibiotics
*Improper dosing
-too much
-too little
*Relying on antibiotics alone
-removal of foreign body
-surgical drainage of abscess
*Lack of adequate bacteriological information
-Cultures not obtained
-Or cultures obtained after antibiotics are started

Front 19

History of staph aureus resistance:

Back 19

*Penicillin
Penicillinase (1945)

*Methicillin
MRSA (1961) multidrug resistant

*Vancomycin
VRSA (2002) vancomycin resistant MRSA

Front 20

What all can strep pneumoniae be resistant to?

Back 20

Penicillin
Cefotaxime/ceftriaxone
Erythromycin (macrolides)
TMP/SMX
Tetracycline
Chloramphenicol
Quinolones
Rifampin

Front 21

What drug must you use in resistant klebsiella pneumonia?

Back 21

tigecycline (a bacteriostatic)