Antibiotic resistance Flashcards Preview

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Flashcards in Antibiotic resistance Deck (17):
1

Give examples of extremely drug resistant microbes?

Meticillin-resistant Staphylococcus aureus (MRSA)
Vancomycin/glycopeptide-resistant enterococci (VRE/GRE)
Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL)
NDM-1 producing Gram-negative bacilli
Multi-drug resistant tuburculosis (MDR-TB)
Extremely-drug resistant tuberculosis (XDR-TB)

2

How does antibiotic resistance affect empiric therapy?

- Risk of under-treatment if “traditional” antibiotic is used
- Risk of excessively broad-spectrum treatment if risk of resistance is taken into account

3

How does antibiotic resistance effect targeted therapy?

Requires the use of alternatives which may be expensive, last line or toxic.

4

What are the main reasons for antibiotic sensitivity testing?

- To enable transition from “empiric” to “targeted” antibiotic therapy
- To explain treatment failures
- To provide alternative antibiotics in case of
- Treatment failure
- Intolerance/adverse effects
- To provide alternative oral antibiotics when IV therapy no longer required

5

How is antibiotic sensitivity testing performed?

- Culture of micro-organism in the presence of antimicrobial agent

-Determine whether MIC (see previous lecture) is above a predetermined “breakpoint” level
- High enough to kill the organism
- Sustained in the body for long enough using practicable dosing regimens

6

What are the limitations of antibiotic sensitivity testing?

- The infection may not be caused by the organism that has been tested

- The correlation between antimicrobial sensitivity and clinical response is not absolute
- A patient with an infection caused by a specific micro-organism is more likely to respond if treated with an antibiotic to which the organism is “sensitive” than one to which it is “resistant”

- Certain organisms are “clinically resistant” to antimicrobial agents even where in vitro testing indicates susceptibility
Resistance genes may be expressed in vivo in response to antibiotic exposure

7

List possible antibiotic resistance mechanisms.

1. No target – no effect
2. Reduced permeability – drug can’t get in
3. Altered target – no effect
4. Over-expression of target – effect diluted
5. Enzymatic degradation – drug destroyed
6. Efflux pump – drug expelled

8

Give examples of reduced permeability resistance?

- Vancomycin:Gram-negative bacilli
- Gram-negatives have an outer membrane that is impermeable to vancomycin

- Gentamicin:anaerobic organisms
- Uptake of aminoglycosides requires an O2 dependent active transport mechanism

9

Give examples of target alteration resistance.

- Flucloxacillin: MRSA
- Altered penicillin-binding protein (PBP2’, encoded by MecA gene) does not bind β-lactams

- Vancomycin: VRE
- Altered peptide sequence in Gram-positive peptideoglycan (D-ala D-ala  D-ala D-lac)
- Reduces binding of vancomycin 1000-fold1

- Trimethoprim: Gram-negative bacilli
- Mutations in dhr (dihydrofolate reductase gene)

10

Give examples of enzymatic degradation resistance.

- Penicillins and cephalosporins: β-lactamases (including ESBLs and NDM-1)
- Gentamicin: aminoglycoside modifying enzymes
- Chloramphenicol: chloramphenicol acetyltransferase (CAT)

11

Give examples of drug efflux resistance.

- Multiple antibiotics, specially in Gram-negative organisms1
- Antifungal triazoles and Candida spp.

12

Give examples of resistance mechanisms encoded by single genes.

- Antibiotic-modifying enzymes
- e.g. beta lactamases degrade beta lactam ring (penicillins, cephalosporins)
- Aminoglycoside-modiying enzymes (gentamicin)


- Altered antibiotic targets
- Penicillin-binding protein 2’ (“PBP two prime”) in MRSA
- Peptide sequence in VRE peptidoglycan

13

What are plasmids and how can they transmit resistance?

- Circular DNA sequences transmitted within species and (less commonly) between species
- Mainly by conjugation

14

What is the horizontal transfer of resistance?

- Enabled by transposons and integrons
- DNA sequences designed to be transferred from plasmid to plasmid and/or from plasmid to chromosome
- Often contain “cassettes” with multiple resistance genes

15

What is the vertical transfer of resistance?

Chromosomal or plasmid-borne resistance genes transferred to daughter cells on bacterial cell-division.

16

What might happen if antibiotics are used an sub-clinical doses regularly (i.e. in the agricultural industry)

- Chance of survival will be enhanced by development of resistance
- Spontaneous mutation
- Acquisition of resistance genes
- Resistant strain will out-compete sensitive strains
- Resistance perpetuated by vertical transfer

17

What might happen if mixtures of sensitive and resistant strains are exposed to antibiotics.

- Mixtures of sensitive and resistant strains (e.g. normal flora in hospitalised patients) exposed to antibiotics
- Resistant strains will have survival advantage and will become the dominant colonising strains
- Subsequent endogenous infection more likely to be caused by resistant strains

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