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Clinical pathology > Theme 3- part 3 > Flashcards

Theme 3- part 3 Flashcards

1
Q

What are antibiotics?

A

Antibiotics- antibacterial agents made by organisms to fight other organisms

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2
Q

What are the causes of resistance?

A
  • selection pressure
  • transmission of resistant organisms
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3
Q

What is selection pressure?

A
  • Bacteria are constantly subject to spontaneous gene mutations
  • Mutations that confer a survival advantage favour the growth and propagation of the mutant strain
  • If the organism is growing in the presence of a sub-inhibitory concentration of antibiotics (concentration that allows to still grow) the development of a resistance gene will confer a survival advantage
  • The resistant mutant will have a survival advantage and out-compete other strains
  • A resistant strain is born
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4
Q

What is transmission of resistant organisms?

A
  • Resistant bacteria gain access to the human microbiome directly or via environmental sources (fomites)
  • Once parent organisms are established in the microbiome, resistance genes can be transferred between bacteria of different species
  • The result is a human microbiome that contains a mixture of sensitive and resistant bacteria
  • If the microbiome is exposed to antibiotics, sensitive bacterial strains will die out and strains carrying resistance genes will become the dominant strains
  • Subsequent endogenous infection is more likely to be caused by antibiotic-resistant organisms- resistant become dominant. If bowel colonized by organisms resistant to antibiotics and patient gets UTI from bowel flora so endogenous infection
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5
Q

What are the two distinct ways in which antibiotic resistance can arise in a patient?

A
  • Exposure to antibiotics- spontaneous mutation
  • Transmission of resistant organisms
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6
Q

What are the methods used to prevent antibiotic resistance?

A
  • Reducing antibiotic exposure to the minimum safe level - antibiotic stewardship
  • Minimising transmission through infection prevention & control (IPC)
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7
Q

When are antibiotic resistant organisms less fit than strains that don’t carry resistant genes?

A
  • Resistance mutations usually affect vital bacterial cell functions-E.g cell wall construction, DNA synthesis etc
  • For this reason antibiotic resistant organisms are often less fit than strains that do not carry resistance genes
  • Therefore, if antibiotic exposure is ceased, the resistant organisms will often be out-competed and replaced with sensitive organisms
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8
Q

How do you identify resistance?

A
  • Antimicrobial sensitivity testing
  • Detection of antimicrobial resistance genes- Genes that are known to encode resistance mechanisms
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9
Q

What is antibiotic sensitivity testing? How does it work?

A
  • Try to grow the organism in the presence of an antibiotic
  • If it grows in the presence of a high concentration (high MIC- minimum inhibitory concentration) it is “resistant”
  • If it is killed at a low concentration (low MIC) it is “sensitive”
  • Therefore, the lower the MIC the more sensitive is the organism, resistant has high MIC to bacterial agents
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10
Q

What is liquid media microtitre plate susceptibility testing?

A
  • Plate with 96 wells
  • Add antibiotic, control no antibiotic and no bacteria
  • Put in left then make doubling dilutions- from LHS to RHS high concentration to low concentration
  • Add organism tested to the microtitre plate and incubate it
  • Incubation shows growth of the organism and can see if resistant
  • After incubation, original colour no growth. Dark orange if growth.
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11
Q

The further over to the left of the plate the more or less resistant?

A

Further over to left it grows the more resistant it is. The further over to the right that it grows, the more susceptible it is. The further to left grows in high concentration of antibiotics, hasn’t been inhibited by antibiotic.

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12
Q

What is the MIC for antibiotic 1?

A

Read MIC- look at antibiotic 1- organism has been inhibited in cell A9, Ab concentration is 0.125. MIC is 0.125 for the antibiotic of that organism.

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13
Q

What antibiotic inhibits the growth fully?

A

4 and 5- antibiotic inhibits the growth- most sensitive

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14
Q

Then compare MIC values with breakpoint values- worked out on basis of Ab concentration that is available in the body in the site of infection.

If organism MIC lower than the breakpoint, organism more or less sensitive?

A

If organism MIC lower than the breakpoint, organism is sensitive.

If organism MIC higher than breakpoint MIC then said to be resistant

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15
Q

For antibiotic 1 and 3 what is sensitive? what is resistant?

A
  • Ab 1- breakpoint set at 0.5, MIC was 0.125, lower concentration so organism sensitive to Ab 1.
  • Ab3- MIC higher than breakpoint so resistant
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16
Q

How is disk sensitivity testing carried out? If the zone inhibition is larger than breakpoint is organism sensitive or not sensitive?

A
  • Add organism
  • Add antibiotics
  • Impregnated into filter discs
  • Incubate
  • Growth on parts of plate
  • Compare zone sizes
  • Zone around antibiotic where hasn’t grown- zone of inhibition. Compare the zone of inhibition with predetermined zone of inhibtion which is a breakpoint for sensitivity. If zone inhibition is larger than the breakpoint zone then organism is sensitive. If smaller is resistant.
  • Organism is sensitive to antibiotic, resitant to B etc. Resistant of E- as not out of zone of inhibition
17
Q

Detection of antibiotic resistance genes how?

A

Nucleic acid amplification tests- Mainly the polymerase chain reaction (PCR)

18
Q

Detection of antibiotic resistance gene can be applied to what sample types?

A

Can be applied to any sample type

  • Nose/skin – MRSA testing
  • Rectal/faecal – Carbapenemase producing Enterobacterales (enteric gram negative bacilli) (CPE)
19
Q

Advantages of detectiion of antibiotic resistance genes?

A

Sensitive and fast

20
Q

Disadvantages of detection of antibiotic reistance genes?

A
  • Presence of a resistant gene does not always correlate with resistance- needs to be switched on
  • Genotypic testing won’t record new resistant mechanisms that haven’t been recorded
21
Q

What are the resistance mechanisms?

A

Innate and acquired

22
Q

What are the innate resistance mechanisms?

A

Usually relates to permeability/entry of the antibiotic into the cell

23
Q

What are resistant innate agents?

A
  • Gram-negatives - glycopeptides, daptomycin
  • Gram-positives - aztreonam, colistin
  • Anaerobes and Streptococci- aminoglycosides
24
Q

What are acquired resistance mechanisms?

A

Acquisition of a gene that encodes an antibiotic resistance mechanism from an organism

  • New mutation
  • Horizontal transfer (see later)

Usually an antibiotic-modifying enzyme or a target alteration

25
Q

What are resistant mechanisms?

A
  • Absent target
  • Decreased permeability
  • Target modification
  • Enzymatic degradation
  • Drug efflux
26
Q

If there is an absent target what is the cell resistant to?

A
  • Antibacterial agents/fungi
  • Antiviral agents/bacteria
27
Q

If there is a decreased permeability what is the cell resistant to?

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
28
Q

If the target modification is affected what is the cell resistant to?

A

Target modification- changed shape so can’t bind

Flucloxacillin: MRSA- Altered penicillin-binding protein does not bind β-lactams

Vancomycin: VRE- Altered peptide sequence in Gram-positive peptideoglycan, Reduces binding of vancomycin 1000-fold

Trimethoprim: Gram-negative bacilli- Mutations in dihydrofolate reductase gene

29
Q

If enzyme degredation to the cell what is it resistant to?

A

Enzymatic degradation- Ab enters cell and engages with enzyme before hitting target

  • Penicillins and cephalosporins: β-lactamases- “Penicillinase”, extended-spectrum β-lactamases (ESBL) and carbapenemases
  • Other enzymes inactivate aminoglycosides, chloramphenicol
30
Q

If drug efflux in the cell how does that cause resistance?

A
  • Multiple antibiotics, specially in Gram-negative organisms
  • Antifungal triazoles and Candida spp.
31
Q

Many resistance mechanisms are encoded by single genes E.g. antibiotic-modifying enzymes, altered antibiotic targets. What are reistant genes encoded in?

A
  • Circular DNA sequences transmitted within and between species
  • Mainly by conjugation
32
Q

How do resistant genes spread?

A

Horizontal and vertical transfer

33
Q

What is horizontal transfer?

A
  • 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
34
Q

What is vertical transfer?

A
  • Chromosomal or plasmid-borne resistance genes transferred to daughter cells on bacterial cell-division
  • When resistant gene in bacterial chromosome and divides and multiplies will have resistant genes in cells
35
Q

What are the risks of empiric therapy?

A
  • Risk of under-treatment if ‘traditional’ antibiotic is used- if give drug that is resistant to a certain organism and is prevalent in the population then risk of under treating
  • Use of excessively broad-spectrum treatment if risk of resistance is taken into account
36
Q

What are the risks of targeted therapy?

A

Requires use of alternatives which may be:

  • Expensive e.g. linezolid, tigecycline, daptomycin vs. flucloxacillin for MRSA
  • Toxic e.g. colistin vs. meropenem for CPE
  • ‘Last line’- vicious circle- if we use broad spectrum as we have to then organisms become resistant then need to use more broad spectrum e.g. carbapenems for multi-resistant Enterobacterales
37
Q

How do we monitor antibiotic reistance?

A

Local surveillance- alert and inform local authorities

National surveillance

  • Submission of isolates of particular concern to reference laboratories
  • Longitudinal data collection to inform national antibiotic policies

International surveillance- ECDC (European centre for disease prevention)

38
Q
A

Clinical pathology (8 decks)

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