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Medical Microbiology > 14. Methods of combating antibiotic resistance > Flashcards

14. Methods of combating antibiotic resistance Flashcards

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1
Q

What does antibiotic resistance drive?

A
  1. The emergence and re-emergence of certain infectious diseases.
  2. Particularly nosocomial infections
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2
Q

What needs to be remembered about multi-drug resistance?

A
  1. It is still relatively rare.
  2. It is increasing and an issue.
  3. MDR infections are focused around certain population groups that have lots of contact with healthcare settings and frequent courses of antibiotics.
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3
Q

Why does being in lots of contact with healthcare increase the risk of MDR Infections?

A
  1. Antibiotic use selects for resistance.
  2. Being around healthcare makes it more likely to pick up a resistant bacteria as they are mostly in other sick people
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4
Q

What is the biggest worry regard antibiotic resistance?

A
  1. Increasing rates of resistance in community infections
  2. The rates of this differ from country to country.
  3. Low and middle income countries have more of this due to unregulated antibiotic use.
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5
Q

What kinds of resistant bacteria are the biggest worry?

A
  1. ESBL producing gram-negative bacteria.
  2. This normal confers 3rd generation cephalosporin resistance.
  3. They also can have resistance to fluoroquinolone and aminoglycosides.
  4. This means these bacteria are resistant to the 3 main classes of antibiotics we use.
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6
Q

Where else can multi-drug resistance develop?

A
  1. In veterinary isolates
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7
Q

What do the implications of antibiotic resistance depend on?

A

The antibiotic access in that country.

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8
Q

What resistance is threatening for countries with limited access to antibiotics?

A
  1. Resistance to basic 1st line antibiotics.
  2. This is because those are the only antibiotics they have access to.
  3. These countries tend to have worse sanitation, increasing community transmission and unregulated use of antibiotics
  4. Infectious diseases are more common and general health is worse leading to more antibiotic use
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9
Q

What resistance is threatening for countries with plenty of access to antibiotics?

A
  1. There needs to be more resistance to cause a problem as there are other treatment options.
  2. so MDR tends to be the issue
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10
Q

What happens if we don’t do anything about antimicrobials resistance?

A
  1. Lower and middle income countries will see the effects first and worst.
  2. There will then be knock-on effects on everyone else.
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11
Q

What can we do the reduce the rise of resistance?

A
  1. Reduce inappropriate prescription of antibiotics.
  2. Inhibition of resistance proteins
  3. Inhibition of mutation or horizontal gene transfer.
  4. Better infection control
  5. New antimicrobials
  6. Alternatives to antimicrobials
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12
Q

Why is reducing antibiotic prescription difficult?

A
  1. Antibiotics save lives and they need to be prescribed for people who need them.
  2. You need to give the right antibiotic for the right infection at the right time for the right patient.
  3. You need to treat patients now while retaining the ability to treat future patients.
  4. Inappropriate prescription is the problem.
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13
Q

What long-term effects does antibiotic use have on resistant infections?

A
  1. If you take an antibiotic it can take up to a year before your risk of developing a resistant infection does back to baseline
  2. This is due to the reduced competition from the microbiome that the antibiotics have killed.
  3. You are also more likely to pick up resistant bacteria from the environment that can go on to cause a resistant infection.
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14
Q

What is the driving force of antibiotic resistance?

A

Antibiotic use

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15
Q

What types of resistance show up in countries with limited antibiotic access?

A
  1. They have more resistance to the antibiotics they can access.
  2. This is because they are used more as they are the only option.
  3. These countries rely on these limited antibiotics so resistance causes lots of issues.
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16
Q

What happens in countries that use lots of antibiotics?

A

They get lots of resistance

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17
Q

What tends of resistance show in countries with plenty of antibiotic access?

A
  1. They have less resistance to those antibiotics
  2. This is due to being able to change which antibiotics are used to treat the resistant infection.
  3. These mean no antibiotic is used enough to drive resistance.
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18
Q

What factors are associated with decreasing resistance?

A
  1. High governance index
  2. High health expenditure
  3. Better infrastructure
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19
Q

Why doesn’t usage seem to have a statistically significant effect on antibiotic resistance levels?

A
  1. It could be due to different patterns of use in the past
  2. The measure were based on just one day.
  3. However, it does agree with some farm-based studies that usage isn’t hugely related to resistance levels.
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20
Q

What surprising factor is associated with increasing resistance levels?

A
  1. High education levels
  2. With more educated people you would expect more rational use of antibiotics.
  3. However this is not the case
  4. They have fewer children so they are more precious. this leads to demand for antibiotics in children when they are not needed.
  5. Undergo global travel which increases the chance of transmission.
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21
Q

Is climate change associated with resistance?

A
  1. Vaguely but due to its complexity its is hard to quantify.
  2. But climate change does drive other factors that can drive infections and resistance.
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22
Q

Does reducing antibiotic use always reduce resistance?

A

No it can depend on the mechanism of resistance and the fitness cost.

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23
Q

What happened to resistance to sulphamethoxazole when use stopped?

A
  1. It was used to treat UTIs
  2. They stopped using it due to high resistance in E coli.
  3. They stopped using it for 8 years yet resistance increased.
  4. This shows that just reducing the use of the antibiotic doesn’t always cause resistance to drop.
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24
Q

What types of resistance does decreased use of the antibiotic cause decreased resistance?

A
  1. Generally mutation mediated resistance.
  2. Especially to fluoroquinolones
  3. This is being seen in the reduce use of fluoroquinolones in urinary E coli infection.
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25
Q

What types of resistance does decreased use of the antibiotic not effect the resistance levels?

A

Normally plasmid-mediated resistance or cases of altered metabolism

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26
Q

Why does resistance not decrease in all cases of decreased use?

A
  1. Fitness cost
  2. Virulence or resistance mechanism
  3. Co-selection using another Antimicrobial
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27
Q

How does fitness affect levels of antibiotic resistance?

A
  1. When you stop using an antibiotic, you want a fight between the susceptible and resistant bacteria. You want the susceptible ones to win.
  2. Resistance tends to come with a fitness cost reducing the growth rate.
  3. So, if you are not selecting the resistant strain, the susceptible ones will out-compete them.
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28
Q

How can antibiotic resistance provide a growth advantage?

A
  1. Resistance doesn’t always have a fitness cost.
  2. Sulphamethoxazole works by targeting the enzyme that makes the vitamin folic acid.
  3. Resistance to sulphamethoxazole works by making folic acid through another mechanism without that enzyme.
  4. This makes the bacteria fitter even when no antibiotic is present.
29
Q

Why is fitness a poor indicator of success?

A
  1. Fitness often refers to growth
  2. In the real world, bacteria don’t always grow rapidly.
  3. Instead of a growth advantage, resistance could increase virulence or transmissibility, which is successful.
30
Q

How can resistance to one antibiotic be selected by another antibiotic?

A
  1. Resistance mechanisms often are encoded on plasmids.
  2. These often carry multiple resistance mechanisms.
  3. There are also chromosomal mechanisms like mutations or efflux.
  4. Use of a different antibiotic to treat infections can select for that resistance as well as the resistance of other antibiotics encoded in the same bacteria.
31
Q

What current antibiotic guidelines are there for primary care?

A
  1. Antibiotics are given without microbiological testing.
  2. This means everyone is given the same antibiotic unless they are in a risk group.
  3. We need try and help given a more accurate antibiotic.
32
Q

What current antibiotic guidelines are there for sepsis?

A
  1. Antibiotics need to be given within an hour.
  2. This leads to empiric treatment being a last resort broad spectrum antibiotic as you want it to work.
  3. Without functioning antibiotics morbidity and mortality increase.
33
Q

How is current antibiotic susceptibility testing done?

A
  1. Disc susceptibility testing with zones of inhibition.
  2. Done direct from urine or blood.
  3. Limited by the time bacteria take to grow enough to be visible by eye. Not good for sepsis patients.
34
Q

How can rapid antibiotic susceptibility testing be done?

A
  1. Reduced the amount of time to about 2-3 hours. This is still too slow.
  2. Use Redox reactions based on respiration.
  3. See the respiration using dyes which shows you how much bacteria are growing.
  4. More dye = more bacterial growth = resistance
35
Q

What is sub-cellular fluctuation imaging?

A
  1. Microscopy to see if the bacteria are moving/wiggling.
  2. If you add an antibiotic and the wiggling stops, then the bacteria are susceptible.
  3. Can identify susceptibility in minutes.
  4. Idea is for this to be used in primary care as it directly uses urine samples.
  5. The patient can leave will more accurate treatment
  6. It doesn’t work for sepsis patients and blood samples as there are not enough bacteria in the blood to do this.
36
Q

What are BactAlert Blood cultures?

A
  1. A machine in which blood samples are grown up and tested for the presence of bacteria
  2. Grown to get a high enough concentration for the bacteria to be detectable.
  3. Works by measuring the production of CO2 to see if the bacteria are growing. The culture bottles have sensors in them.
  4. Can take 24-72 hours and you still need to do antibiotic susceptibility testing.
37
Q

How could sequencing techniques be used to detect antibiotic susceptibility?

A
  1. Could use amplification based sequencing approaches.
  2. You can look for specific resistance mechanisms like MecA.
  3. Can be useful for blood stream infections
38
Q

What are the disadvantages of using sequencing based approaches for antibiotic susceptibility testing?

A
  1. You can only look at resistance to 1 drug by 1 mechanism at a time.
  2. You don’t identify the pathogen.
  3. You need to create a comprehensive panel of tests to identify the resistance.
39
Q

Could you use whole genome sequencing for antibiotic susceptibility testing?

A
  1. Yes
  2. You could identify the species.
  3. You can identify what resistance genes are present.
  4. You could tell the source of infection, like if it is from another patient.
40
Q

What are the problems with using whole genome sequencing for antibiotic susceptibility testing?

A
  1. Proteins make bacteria resistant, and there is not always a good correlation between resistance and the presence of a gene.
  2. The amount of gene expression is important.
  3. Especially in genes that effect the background permeability.
41
Q

What mistakes can happen when using whole genome sequencing for antibiotic susceptibility testing?

A
  1. When based on the presence of genes it was predicted that bacteria would be susceptible.
  2. However a significant amount of critical errors were made.
  3. Antibiotics that were used didn’t work and this could harm patients.
42
Q

What else needs to be considered when designing antibiotic susceptibility testing methods?

A
  1. Background permeability as it works with resistance genes.
  2. Whole genome sequencing is not a good predictor unless it can factor in the expression of efflux and porin genes.
  3. Proteomics might be a better approach or looking for changes in the promoter or regulation sequences.
43
Q

What makes sequencing based antibiotic susceptibility testing complex?

A
  1. There are a large number of different resistance mechanisms.
  2. This means many different combinations can lead to resistance.
  3. Including efflux, porins, mutations and mobile genes.
  4. It can be hard to find the combination that applies to a specific infection.
44
Q

What are very important mechanisms of resistance?

A
  1. Mutation
  2. horizontal gene transfer
45
Q

What is the bacteria DNA damage response?

A

the SOS response

46
Q

How does the SOS response work?

A

1.LexA is a transcriptional repressor for the SOS genes.
2. When DNA is damaged RecA is recruited to the site and binds to the break.
3. It brings LexA with it.
4. After prolonged stress, RecA protease degrades LexA.
5. This activates the DNA damage response
6. This includes an error-prone DNA polymerase, which introduces mutations to the bacteria.
7. This is one way bacteria can mutate and adapt.

47
Q

What antibiotic works by causing DNA damage?

A

Fluoroquinolones cause dsDNA breaks and increase the mutation rate.

48
Q

What happens if you inhibit the SOS damage response?

A
  1. You can reduce the mutation rate of the bacteria.
  2. You can also make fluoroquinolones more potent.
49
Q

How can you inhibit the SOS response in bacteria?

A
  1. Have mutant LexA.
  2. Inhibit RecBCD.
50
Q

How was inhibiting RecBCD shown to inhibit the SOS response?

A
  1. Using phage proteins like GamS.
  2. These mimic DNA and can interact with RecBCD.
  3. This inhibit the SOS response.
  4. Phages have evolved to do this for their own purposes.
  5. When these were put into bacteria they become susceptible to fluoroquinolones.
51
Q

How does inhibiting RecBCD make fluoroquinolones more potent?

A
  1. Inhibiting RecBCD prevents the SOS DNA damage response.
  2. This means they cannot repair the breaks caused by fluoroquinolones.
  3. This makes fluoroquinolones more potent.
52
Q

What can be developed to help fluoroquinolone resistance?

A

A chemical inhibitor of RecBCD to be given alongside fluoroquinolones.

53
Q

Could inhibiting plasmid conjugation aid resistance?

A
  1. Some chemicals can reduce the transfer frequency of plasmids.
  2. Which can reduce the acquisition of resistance.
54
Q

What can inhibit plasmid conjugation?

A
  1. Using AZT, which is an early retroviral drug that can limit conjugation.
  2. By blocking the SOS DNA damage response.
55
Q

Why is repurposing existing drugs beneficial?

A
  1. They are already licensed
  2. You already know the safety and toxicity.
56
Q

What else does the SOS response do?

A

Causes horizontal gene transfer to increase

57
Q

What would the purpose of inhibiting plasmid conjugation be?

A
  1. Unclear how useful it would be.
  2. Who are you giving it to and when.
  3. Plasmid transfer happens in colonisation or in the environment not in an infected person.
  4. We cannot just put AZT everywhere.
  5. It is a nice idea but what can it actually do
58
Q

What other methods or treating antibiotic resistance could be try?

A
  1. Specific vaccines
  2. Phage therapy
59
Q

What is the aim of using specific vaccine to treat bacteria infection?

A
  1. They are trying to reduce the colonisation of people with certain organisms.
  2. This could potentially reduce opportunistic infections later on.
60
Q

What was the 1st specific bacterial vaccine in trials for this purpose?

A
  1. Done for ST131 which is a uropathogenic E coli.
  2. It is the most common E coli isolate in the western world.
  3. Causes lots of UTIs and bloodstream infections.
61
Q

Can we vaccinate against ST131 E coli to reduce bacteria infections?

A
  1. Yes
  2. It was shown that you could reduce UTIs caused by ST131
  3. However you didn’t see a reduction in other from other E coli and other bacteria
62
Q

What causes most recurrent UTIs?

A

Usually an anatomical issue that causes lots of faecal bacteria to get into the urinary tract.

63
Q

What could the application of specific vaccines to reduce bacterial infections be?

A
  1. Not useful for whole pathogens or infections.
  2. Could be used to reduce infections of resistant strains.
  3. Can be about reduces the resistance of infections not the number.
64
Q

What are the issues of using specific vaccines to reduce infections?

A
  1. Who do you give it to
  2. How does it interact long term with the microbiome.
  3. Is what takes its place worse.
65
Q

What could be a better use of vaccination to reduce bacterial infection?

A
  1. To reduce viral respiratory disease
  2. This will reduce the inappropriate use of antibiotics that are given for viral infections.
  3. Like the new RSV vaccine
66
Q

When has phage therapy been shown to work?

A
  1. In emergency last resort cases.
  2. And the patients has still normally died
  3. Not from side effects but from the infection
67
Q

What are the problems with phage therapy?

A
  1. There have never been proper clinical trials or long term studies.
  2. It has only been done as last resort treatments.
  3. The failures of phage treatment tend not to be reported.
  4. how do you get the phage to the bacteria
68
Q

Why could you quickly see resistance to phage therapy?

A
  1. They bind to the bacterial surface.
  2. This can easily be changed by the bacteria
69
Q

What could a more realistic use of phages be?

A
  1. As something to decontaminate the environment.
  2. Touchpoint or water source cleaning
  3. Not will not really be a therapeutic thing.

Medical Microbiology (16 decks)

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