Antibiotic resistance

Question 1

What is meant by the ‘abx era’ and the ‘post-abx era’?

Answer 1

Abx era = term used to describe the time since the widespread availability of abx to treat infection
Post-abx era = term used to describe the time after widespread abx resistance has reduced the availability of abx to treat infection

Question 2

What does MRSA stand for?

Answer 2

meticillin resistance stapaureus

Question 3

What does VRE/GRE stand for?

Answer 3

Vancomycin/ glycopeptide resistance enterococci

Question 4

What does ESBL stand for?

Answer 4

Extended spectrum beta-lactamase producing enterobacteriaceae

Question 5

What does MDR-TB stand for?

Answer 5

Multi-drug resistant tuburculosis

Question 6

What does XDR-TB stand for?

Answer 6

Extremely drug resistance TB

Question 7

Name 5 common organisms resistant to the drugs traditionally used to treat them?

Answer 7

1) MRSA
2) VRE/GRE
3) ESBL
4) MDR-TB
5) XDR-TB

Question 8

Other than those which are common name 2 organisms also resistant to many abx?

Answer 8

1) Enterobacteriaceae resistant to amoxicillin, ciprofloxacin, gentamicin, carbapenems
2) Pseudomonas resistant to ceftazidime, carbapenems etc.

Question 9

How does the risk of abx resistance effect empiric therapy? 2

Answer 9

• Risk of under-treatment - if traditional abx is used so dont kill the organism
• Risk of excessively broad-spectrum treatment - if risk of resistance is taken into account

Question 10

How does the risk of abx resistance effect targeted therapy? 3

Answer 10

Requires the use of alternatives which may be:

1) Expensive - eg. linezolid, tigecycline, daptomycin vs. flucoxacillin for MRSA
2) Last line - eg. meropenem vs. ciprofloxacin for multi-resistant enterobacteriaceae
3) Toxic - eg. colistin vs. meropenem for NDM-1 producers

Question 11

What are the 4 reasons for use of sensitivity testing?

Answer 11

1) To enable transition from empiric to targeted therapy
2) To explain treatment failures
3) To provide alternative abx in case of treatment failure or intolerence/adverse effects
4) To provide alternative oral abx when IV therapy is no longer required

Question 12

What is the basic principle abx sensitivity testing?

Answer 12

1) Culture of micro-organism in the presence of antimicrobial agent - solid or liquid media
2) Determine whether minimum MIC is above a predetermined breakpoint level - high enough to kill the organism and sustained in the body for long enough using practible dosing regimes

Question 13

In terms of abx sensitivity testing what is meant by a ‘breakpoint level’?

Answer 13

The breakpoint level is a known value. Its the concentration of that abx which can feasibly be available in the body

Question 14

What are the 5 steps in abx sensitivity testing?

Answer 14

1) Add organism
2) Add abx
3) Incubate
4) Read and interpret results
5) Clinical interpretation (measure size of zone of inhibition around abx disc)

Question 15

Why can microtitre plate (liquid media) susceptibility testing be more useful that solid media testing?

Answer 15

You can use the abx at varying concentrations and get a more accurate measurement of the MIC

Question 16

Give 3 main limitations of abx sensitivity testing?

Answer 16

1) The infection may not be caused by the organism which has been cultured
2) The correlation between antimicrobial sensitivity and clinical response is not absolute
3) Certain organisms are ‘clinically resistant’ to microbial agents even when in vitro testing indicates susceptibility

Question 17

Why are some organisms clinically resistant to microbial agents even when in vitro testing indicates susceptibility? Give an example

Answer 17

Resistance genes may be expressed in vivo in response to abx exposure
eg. AmpC beta-lactamase genes in enterbacteriaceae

Question 18

Give the 6 common resistance mechanisms?

Answer 18

1) No target - hence no effect
2) Reduced permeability - drug cant get in
3) Altered target - no effect on altered target
4) Over-expression of target - effect diluted
5) Enzymatic degradation - produce an enzyme which destroys the drug
6) Efflux pump - drug expelled from bacterial cell

Question 19

What is a common reason for absent target causing abx resistance?

Answer 19

Used to treat fungal or viral infections - ie. treatment fails as the infection is non bacterial

Question 20

Why are gram negative bacteria resistant to vancomycin?

Answer 20

Gram negatives have an outer membrane which is impermeable to vancomycin
ie. mechanism is reduced permeability

Question 21

Why are anaerobic organisms resistant to gentamicin?

Answer 21

Uptake of aminoglycosides requires O2 dependent active transport mechanisms - no O2 in anerobes

Question 22

By what mechanism is MRSA resistant to flucoxacillin?

Answer 22

Altered target

Altered penicillin binding protein which does not bind beta lactams

Question 23

By what mechanism is VRE resistant to vancomycin?

Answer 23

Altered target

Altered peptide sequence in gram-positive peptidoglycan

Question 24

By what mechanism are gram-negative bacilli resistant to trimethoprim?

Answer 24

Altered target

Mutations in dhr (dihydrofolate reductase gene)

Question 25

One mechanism of resistance to penicillins and cephalosporins is enzyme degradation, which enzyme is produced to break them down?

Answer 25

B-lactamases (including ESBLs and NDM - 1)

Question 26

A mechanism of resistance to gentamicin is enzyme degradation, which enzyme is produced to break it down?

Answer 26

Aminoglycoside modifying enzymes

Question 27

A mechanism of resistance to chloramphenicol is enzyme degradation, which enzyme is produced which breaks it down?

Answer 27

Chloramphenicol acetyltransferase (CAT)

Question 28

Drug efflux as a mechanism of resistance is used against which 2 abx?

Answer 28

1) Multi abx - specially in gram-negative organisms

2) Antifungal triazoles and candida ssp

Question 29

Mechanisms of resistance are usually encoded in how many genes?

Answer 29

Single genes eg. those for abx modifying enzymes and altered abx targets

Question 30

Resistance genes tend to be encoded in what?

Answer 30

plasmids - circular strand of transferred within species and less commonly between species, mainly by conjugation

Question 31

Which 2 structures enable horizontal transmission of resistance genes?

Answer 31

transposons and integrons

Question 32

What is meant by a cassette and transponsons and integrons?

Answer 32

transponsons and integrons are dna sequences designed to be transferred from plasmid to plasmid and/or from plasmid to chromosomes - they often contain a cassette with multiple resistance genes

Question 33

What is meant by vertical transfer of resistance?

Answer 33

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

Question 34

Describe the steps in horizontal transmission of abx resistance genes? 6

Answer 34

1) gene on plasmid
2) gene may stay on plasmid and/or integrate into the chromosome
3) plasmid transferred between organisms by conjugation
4) gene may stay on plasmid and/or integrate into chromosome
5) ‘new’ organism has abx resistance
6) abx resistance transferred on cell division

Question 35

Give the 5 consequences of abx exposure in terms of the development of resistance?

Answer 35

1) sensitive strains exposed to abx at sub lethal conditions eg. clinical and agricultural
2) Chance of survival will be enhanced by development of resistance (spontaneous mutation, aquisition of resistance genes)
3) Resistant strain will out compete sensitive strains
4) Resistance perpetuated by vertical transfer
5) Mixtures of sensitive and resistant strains (eg. normal gut flora) exposed to abx - resistant strains have a survival advantage and will become the dominant colonising strains, subsequent endogenous infection more likely to be caused by resistant strains

Question 36

What 4 steps can be taken to avoid problems with using abx?

Answer 36

1) Never use an abx unless absolutely necessary
2) Always use the most narrow spectrum agent available
3) Use combination therapy if indicated
4) Be willing to consult expert information sources