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1. CP - Core Microbiology > (2) Mechanisms of antibiotic resistance > Flashcards

(2) Mechanisms of antibiotic resistance Flashcards

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1
Q

What is the “antibiotic era”?

A

Term used to describe the time since the widespread availability of antibiotics to treat infection

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2
Q

What is the “post-antibiotic era”?

A

Term used to describe the time after widespread antibiotic resistance has reduced the availability of antibiotics to treat infection

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3
Q

Give some examples of organisms that are resistant to the antibiotics traditionally used to treat them

A
  • MRSA
  • vancomycin/glycopeptide-resistant enterococci (VRE/GRE)
  • extended-spectrum B-lactamase-producing enterobacteriaceae (ESBL)
  • NDM-1 producing gram-negative bacilli
  • multi-drug resistant tuberculosis (MDR-TB)
  • extremely-drug resistant tuberculosis (XDR-TB)
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4
Q

How does antibiotic resistance affect treatment in empiric therapy?

A
  • risk of under-treatment (if “traditional” antibiotic is used)
  • risk of excessively broad-spectrum treatment (if risk of resistance is taken into account)
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5
Q

How does antibiotic resistance affect treatment in targeted therapy?

A

Requires use of alternatives which may be

  • expensive
  • “last line”
  • toxic
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6
Q

Antibiotic resistance may mean that more expensive alternatives have to be used instead of the “traditional” antibiotic. Give an example of this

A

Linezolid, tigecycline, daptomycin vs. flucloxacillin for MRSA

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7
Q

Antibiotic resistance may mean that a “last line” alternative has to be used rather than the “traditional” antibiotic. Give an example of this

A

Meropenem vs. ciprofloxacin for multi-reistant enterobacteriaceae

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8
Q

Antibiotic resistance may mean that a toxic alternative has to be used rather than the “traditional” antibiotic. Give an example of this

A

Colistin vs. meropenem for NDM-1 producers

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9
Q

What are the reasons for sensitivity testing?

A
  • to enable transition from “empiric” to “targeted” antibiotic therapy
  • to explain treatment failures
  • to provide alternative antibiotics in the case of treatment failure or intolerance/adverse effects
  • to provide alternative oral antibiotics she IV therapy no longer required
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10
Q

What is the basic principle of sensitivity testing?

A
  • culture of microorganism in the presence of antimicrobial agent (solid or liquid media)
  • determine whether MIC is above predetermined “breakpoint” level (high enough to kill the organism, sustained in the body for long enough using practicable dosing regimens)
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11
Q

What are the basic stages in sensitivity testing? (solid media - disk susceptibility testing)

A
  1. add organism
  2. add antibiotics
  3. incubate
  4. read and interpret results
  5. “clinical interpretation”
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12
Q

What is the zone of inhibition?

A

The area on the plate. surrounding the disc of antibiotic, where the bacteria have not grown enough to be visible

The size of the zone of inhibition will depend on how effective the antibiotic is/ how sensitive the bacterium is to the antibiotic

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13
Q

What are the basic steps in sensitivity testing? (liquid media - micro titre plate susceptibility testing)

A
  1. add antibiotic
  2. add organism
  3. incubate
  4. read MIC
  5. compare with breakpoint
  6. interpret result
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14
Q

What are the limitations of sensitivity testing (disk susceptibility and micro titre plate susceptibility testing)?

A
  • the infection may not be caused by the organism that has been tested
  • the correlation between antimicrobial sensitivity and clinical response is not absolute
  • certain organisms are “clinically resistant” to antimicrobial agents even where in vitro testing indicates susceptibility
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15
Q

The correlation between antimicrobial sensitivity and clinical response is not absolute. What does this mean?

A

A patient with an infection caused by a specific microorganism is MORE LIKELY to respond if treated with an antibiotic to which the organism is sensitive than one to which it is resistant. But it is not definite!!

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16
Q

Certain organism are susceptible to antibiotics in vitro but are resistant in vivo. Why is this?

A

Sometimes resistance genes may be expressed in vivo in response to antibiotic exposure.

Eg. AmpC B-lactamase genes in enterobacteriaceae

Hence the need for “clinical interpretation”

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17
Q

Give some resistance mechanisms that antibiotics use

A
  1. no target (= no effect)
  2. reduced permeability (drug cannot get in)
  3. altered target (= no effect)
  4. over-expression of target (effect diluted)
  5. enzymatic degradation (drug destroyed)
  6. efflux pump (drug expelled)
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18
Q

Why might there be an absent target?

A

If the infection is non-bacterial

Antibacterials being used against fungi and viruses with no effect

19
Q

Give 2 examples of where a bacteria would be resistant to an antibiotic due to reduced permeability

A
  • 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
20
Q

Why are anaerobic organisms resistant to gentamicin?

A

Uptake of gentamicin (aminoglycosides) requires O2 dependent active transport - therefore the walls of anaerobic organisms have reduced permeability to gentamicin

21
Q

Gram-negative bacilli have outer membranes that are impermeable to which antibiotic?

A

Vancomycin

22
Q

Give some examples of microorganisms that are resistant to specific antibiotics due to target alteration

A
  • MRSA (flucloxacillin)
  • VRE (vancomycin)
  • gram-negative bacilli (trimethoprim)
23
Q

How is MRSA resistant to flucloxacillin?

A

Target alteration

Altered penicillin-binding protein (PBP2, encoded by MecA gene) does not bind B-lactams

24
Q

How is VRE resistant to vancomycin?

A

Target alteration

Altered peptide sequence in gram-positive peptidoglycan (D-ala-D-ala to D-ala-D-lac)

This reduces binding of vancomycin 1000-fold

25
Q

VRE is resistant to vancomycin due to target alteration. What is the change in the peptide sequence in the peptidoglycan?

A

D-ala D-ala

changed to

D-ala D-lac

26
Q

How are gram-negative bacilli resistant to trimethoprim?

A

Target alteration

Mutation in dhr (dihydrofolate reductase gene)

27
Q

Gram-negative bacilli have a mutation which makes them resistant to trimethoprim. What is this mutation in?

A

dhr

dihyrdofolate reductase gene

28
Q

Which antibiotics can be affected by enzymatic degradation?

A
  • penicillins and cephalosporins
  • gentamicin
  • chloramphenicol
29
Q

Pencillins and cephalosporins can be broken down by the resistant bacteria by enzymatic degration. Which enzymes break them down?

A

B-lactamases (including ESBLs and NDM-1)

30
Q

Gentamicin can be broken down by the resistant bacteria by enzymatic degradation. Which enzymes break it down?

A

Aminoglycoside modifying enzymes

31
Q

Chloramphenicol can be broken down by the resistant bacteria by enzymatic degradation. Which enzyme breaks it down?

A

Chloramphenicol acetyltransferase (CAT)

32
Q

Which bacteria uses drug efflux as a method of resistance?

A

Gram-negative organisms particularly

Multiple antibiotics

Also antifungal triazoles and candida spp.

33
Q

Many resistance mechanisms are encoded by a single gene. Which ones

A
  • antibiotic-modifying enzymes (B lactamases including ESBL - penicillins and cephalosporins, amino glycoside-modifying enzymes - gentamicin)
  • altered antibiotic targets (penicillin binding protein 2 - PBP two prime - in MRSA, peptide sequence in VRE peptidoglycan)
34
Q

In which structures can resistance genes be encoded in?

A

Plasmids

35
Q

What are plasmids?

A

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

36
Q

What is horizontal transfer of resistance enabled by?

A

Transposons and integrons

37
Q

In horizontal transfer of resistance, how are DNA sequences transferred?

A

DNA sequences designed to be transferred from plasmid to plasmid and/or from plasmid to chromosome - often contain “cassettes” with multiple resistance genes

38
Q

What happens in vertical transfer of resistance?

A

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

39
Q

What are the stages in horizontal transfer and vertical transfer of resistance?

A
  1. antibiotic resistance gene on plasmid
  2. gene may stay on plasmid and/or integrate into chromosome
  3. plasmid transferred between organisms by conjugation
  4. gene may stay on plasmic and/or integrate into chromosome
  5. “new” organism has antibiotic resistance
  6. antibiotic resistance transferred on cell division (VERTICAL)
40
Q

What are the consequences of antibiotic exposure in terms of antibiotic resistance?

A
  • sensitive strains exposed to antibiotics at sub-lethal concentrations (clinical, agriculture)
  • chance of survival will be enhanced by development of resistance (spontaneous mutation, acquisition of resistance gene)
  • resistant strain will out-compete sensitive strains
  • resistance perpetuated by vertical transfer
41
Q

In what 2 ways can an organism develop resistance?

A
  • spontaneous mutation

- acquisition of resistance gene

42
Q

Why does exposure to antibiotics cause a problem when you have a mixture of sensitive and resistant strains? (eg. normal flora in hospitalised patients)

A

Resistant strains will have survival advantage and will become the dominant colonising strains - subsequent endogenous infection more likely to be caused by resistant strains

43
Q

What are the 4 main guidelines concerning safest antibiotic use?

A
  1. never use an antibiotic unless it is 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 (guidelines, textbooks, microbiologists)

1. CP - Core Microbiology (8 decks)

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