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Medical Microbiology > 6. Multi-drug resistant Enterbacterales as a serious nosocomial threat. > Flashcards

6. Multi-drug resistant Enterbacterales as a serious nosocomial threat. Flashcards

1. To describe the key enterobacterales species relevant for the community and healthcare-associated infection and the common diseases caused. 2. To link with other lectures to explain how multi-drug resistance can emerge with specific examples, including intrinsic and acquired mechanisms. 3. To particularly discuss how multiple resistance mechanisms can come together to give resistance to carbapenems and the ß-lactam/ß-lactamase inhibitor combination.

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1
Q

What are Enterobacterales?

A

Mainly gut bacteria that is in the intestines of us and various other animals

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2
Q

What are nosocomial infections?

A

Healthcare-associated infections, mainly caused by opportunistic pathogens.

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3
Q

What is the most common enterobacterales?

A

E. coli

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4
Q

What are enterbacterales nosocomial often associated with?

A

Medical interventions like catheters, surgery or ventilators.

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5
Q

Common enterobacterales nosocomial infections: UTIs

A
  1. They start with catheters getting contaminated with faecal bacteria.
  2. This can cause blockages, biofilms and infections.
  3. The infection can then ascend through the kidneys and into the bloodstream.
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6
Q

Common enterobacterales nosocomial infections: bloodstream infections

A
  1. Sometimes for port but more often from surgical site infections, ascending UTIs and chemotherapy.
  2. From surgeries where the gut is in contact with the blood. These could colon cancer surgery, appendix surgery or liver surgery,
  3. Chemotherapy makes the gut lining more permeable so bacteria can get through.
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7
Q

Common enterobacterales nosocomial infections: Pneumonias

A

Very common in ventilated patients and faecal bacteria getting into the tubing and causing infection.

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8
Q

How are community infections different from nosocomial infections?

A
  1. Most UTIs are from the community and caused by E.coli.
  2. Around 30% of community UTIs result in sepsis which leads to a community burden.
  3. This leads to patients being rushed to A&E.
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9
Q

What is another important cause of nosocomial infections?

A

Klebsiella spp. But mostly K. pneumoniae

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10
Q

Why is Klebsiella an important nosocomial infection?

A
  1. It is the 2nd most common enterobacterales nosocomial infection.
  2. It is not really present in the community.
  3. It is less common in faeces so a less common infection but it is a worse infection.
  4. K. pneumoniae is very virulent and often very resistant
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11
Q

What are some other notable nosocomial enterobacterales infections?

A
  1. They are less common due to being less abundant in faeces.
  2. However they are often more serious infections.
  3. Caused by Citrobacter spp. and Enterobacter spp.
  4. Worse in children as they are more likely to carry them. Particularly a problem in child chemo patients.
  5. They are an increasing cause of bacteraemia in immunocompromised patients especially those needing haematology treatment.
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12
Q

Why is local enterobacterales bacteraemia statistics biased? (from BNSSG)

A
  1. It is based on culture positive tests.
  2. Only 30% of these culture positive blood with develop an infection as bacteria are only present in low numbers.
  3. Often, during treatment for suspected sepsis, IV antibiotics are given straight away so the sample would have antibiotic in it preventing its growth.
  4. They tend to be an underrepresentation of the actual numbers.
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13
Q

What can we learn from local enterobacterales bacteraemia data?

A
  1. The source of the infection.
  2. Mostly UTIs
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14
Q

Why are enterobacterales a number 1 priority?

A
  1. Due to the number of infections.
  2. Due to the healthcare burden.
  3. Due to resistance.
    (They don’t cause a lot of deaths)
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15
Q

Enterobacterales Resistance enzymes: ESBLs

A
  1. Mostly class A enzymes
  2. Enterobacterales carry lots of ESBLs
  3. This provides resistance to 3rd gen cephalosporins, 4th gen cephalosporins, aztreonam but not cephamycins.
  4. They are still sensitive to ß-lactam inhibitors like clavulanic acid and tazobactam.
  5. Have KPC, which is an ESBL with carbapenemase activity.
  6. Both KPC and CTX-M-15 are very common in E.coli and klebsiella.
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16
Q

Enterobacterales Resistance enzymes: AmpC ß-lactamase

A
  1. A class C enzyme.
  2. Hydrolyses all penicillins, 1st/2nd/3rd gen cephalosporins and cephamycins and monobactams.
  3. Doesn’t provide 4th gen cephalosporin resistance but we don’t use these in the UK.
  4. Doesn’t provide carbapenem resistance.
  5. Inhibitors don’t work apart from avibactam, which doesn’t work as well.
  6. They are not ESBLs.
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17
Q

How does ampC provide cephalosporin resistance in E.coli?

A
  1. AmpC is on the E.coli chromosome.
  2. Not normally highly expressed.
  3. Over expression can be driven if a mutation is gained in the promoter.
  4. This drives transcription.
  5. This causes 3rd gen cephalosporin resistance.
  6. This is NOT an inducible mechanism.
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18
Q

How does inducible AmpC work in less common Enterobacterales?

A
  1. These bacteria can sense the presence of antibiotics and switch on the ampC ß-lactamase gene.
  2. This gene is inducible by ampicillin and ß-lactamase inhibitors.
  3. AmpC is not inducible by oxyimio (3rd gen) cephalosporins, so inducible ampC doesn’t give resistance to these.
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19
Q

How does oxyimio cephalosporin use drive resistance?

A
  1. The use of 3rd gen cephalosporins creates a selection pressure for ampC mutant enterobacterales.
  2. These mutants hyperproduce AmpC all the time and can resist 3rd gen cephalosporins.
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20
Q

How to do mobile AmpC genes cause resistance?

A
  1. Mobile ampC can move to bacteria that wouldn’t normally have ampC mediated resistance like bacteria without ampC or without inducible ampC.
  2. These come from a few sources like Aeromonas and Enterobacterales.
  3. As they are on plasmids, ampC is highly expressed all the time.
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21
Q

How is ampC mobilised?

A

Via an ISECp transposon, which is the same as CTX-M. This insertion sequence moves genes from the chromosome to the plasmid.

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22
Q

What are common mobilised ampC variants?

A

CMY-2
DHA-1

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23
Q

What do we rely on to treat bloodstream infections?

A

3rd gen cephalosporins

24
Q

What makes treating resistant infection possible?

A

By knowing what resistance mechanisms are circulating in the population, clinicians can give treatment that will work first time treatment is given.

25
Q

What are sequence types?

A

Genetic families of bacteria that show relation to each other.

26
Q

What is the most common strain of urinary E.coli in BNSSG?

A
  1. ST131
  2. Very common strain in humans
  3. Very commonly resistant
  4. Has lots of virulence genes that are good at causing infection.
  5. All the ST131 clones will be closely related and often transmitted through the faecal-oral route.
27
Q

What is the most common resistance mechanism in community E.coli infections?

A
  1. CTX-M-15
  2. This is an ESBLs
  3. Causes 3rd gen cephalosporin resistance.
  4. Most other resistance is caused by CTX-M variants
  5. There are a few ampC producers
28
Q

How can CTX-M producing infections be treated?

A
  1. Using ß-lactams and ß-lactamase inhibitors
  2. This provides a clear treatment plan.
29
Q

What is the definition of multidrug resistance?

A

Resistance to at least 3 different classes of Antimicrobial drug

30
Q

What are the 3 classes of antibiotic resistance that matter for enterobacterales for treatment?

A
  1. Aminoglycosides
  2. 3rd gen cephalosporins
  3. (Fluoro)Quinolones
31
Q

What causes MDR?

A
  1. Multiple mutations
  2. Efflux up regulation and permeability reduction
  3. MDR plasmids
32
Q

What is the most common way to gain multidrug resistance?

A

Acquiring an MDR plasmid

33
Q

What are MDR plasmids?

A
  1. Mobile genetic elements that carry resistance to multiple Antimicrobials
  2. Normally, a pre-evolved gene cassette contained in integrons.
  3. Large plasmids with over 100 genes, including genes for self-mobilisation and resistance.
34
Q

What are integrons?

A
  1. Genetic elements that allow efficient capture and expression of exogenous genes
  2. Contain site-specific recombination sites to collect genes
35
Q

What means different gene cassettes can join together in integrons?

A
  1. They have to have the same insertion sequence like IS26.
  2. This means the gene cassette can join together by homologous recombination of the insertion sequence.
36
Q

How can reducing permeability provide intrinsic resistance?

A
  1. Reducing the number of porins in the plasma membrane
  2. Increasing the number of efflux pumps in the membrane
37
Q

How do efflux pumps provide resistance?

A

They pump molecules outside of the cell like antibiotics.

38
Q

How does reducing porins provide resistance?

A
  1. They are needed for antibiotics to enter so reducing them reduces the amount of antibiotic entering the cell.
  2. They are non-specific so you can reduce entry of a lot of drugs.
39
Q

What is the AcrAB-TolC efflux pump?

A
  1. It is found in lots of membrane and is important for resistance.
  2. Overproduction of AcrAB-TolC contributes to resistance by reducing susceptibility to antibiotics.
  3. They are not enough to provide resistance by themselves and require another resistance mechanism.
40
Q

How is AcrAB-TolC overproduced by derepression?

A
  1. It is encoded as an operon
  2. AcrR is a transcriptional repressor that regulates acrAB-tolC expression.
  3. Mutation happen in the AcrR gene or binding site causing derepression and overproduction of the efflux pump.
  4. This raises the MIC of a variety of drugs.
41
Q

How is AcrAB-TolC overproduced by activation?

A
  1. MarA and RamA are the same protein in different bacteria.
  2. They are an activator of acrAB-tolC gene expression.
  3. They bind the promoter and displace AcrR and activates transcription.
  4. MarA/RamA overexpression causes overproduction of acrAB-tolC
42
Q

How is MarA/RamA overproduced?

A
  1. the marA/ramA transcriptional repressor marR is lost through mutation.
  2. This loss means MarA is constantly produced therefore acrAB-tolC is constantly produced.
43
Q

What are the functions of MarA/RamA?

A
  1. Activation of acrAB-tolC gene
  2. Reduction in porin expression
44
Q

How does MarA/RamA reduce porin expression?

A
  1. It activates micF expression
  2. micF is an antisense RNA for the ompF porin gene.
  3. This prevents the expression of ompF porins
45
Q

what resistance mechanisms are activated through MarA/RamA mutation?

A
  1. acrAB-tolC up-regulation
  2. ompF porin reduction
46
Q

Which will make a more resistant bacteria: AcrR mutation or MarA mutation?

A

MarA mutation as AcrR mutation only causes acrAB-tolC upregulation.

47
Q

What gives total carbapenem resistance?

A

mobile carbapenemases like NDM and KPC

48
Q

Do you need a true carbapenemase to be carbapenem resistant?

A
  1. No
  2. Enzymes like OXA-48, like carbapenemases, are not very good at hydrolysing carbapenems.
  3. Mechanisms to reduce antibiotic concentration like porin loss can make these enzymes more effective so can provide carbapenem resistance.
  4. Enterobacterales are good at combining these mechanisms.
49
Q

Why are OXA-48 like enzymes common in Europe?

A
  1. 3rd generation cephalosporin resistance has led to the use of piperacillin/tazobactam to treat these infections.
  2. This then kills ESBL-producing bacterial infections.
  3. Bacteria producing OXA-48 like enzymes have a selection advantage.
  4. This then selects for OXA-48 like enzymes that are resistant to piperacillin/tazobactam treatment.
  5. This causes carbapenem resistance through OXA-48 like enzymes.
50
Q

What other ways of carbapenem resistance are there?

A

ESBL production and ampC production that can weakly degrade carbapenems alongside porin loss or efflux provides resistance.

51
Q

What is CMY?

A

An ampC variant that is mobile.

52
Q

How can CMY producing bacteria have resistance to ertapenem?

A
  1. CMY doesn’t normally give carbapenem resistance by itself.
  2. This bacteria also has a mutation in RamA/R causing porin loss and efflux increase.
  3. This reduces ertapenem concentration so CMY can slowly mop up the rest.
53
Q

Why is Ertapenem resistance worrying?

A

It is often given in the community as it only needs to be given once a day.

54
Q

How can resistance mechanisms work together to make an MDR bacteria, using K. pneumoniae as an example?

A
  1. RamR mutation causing porin loss and efflux increase
  2. OXA-232 production which is weakly carbapenemase
  3. This infection is treatable like ß-lactam and ß-lactam inhibitors
  4. Addition of KPC-3 leads to ß-lactam resistance.
  5. Addition of KPC-3-D178Y mutant leads to avibactam resistance but still treatable with carbapenems.
  6. The addition of ompK36 mutant reduces porin expression and makes the infection resistant to all possible treatment including carbapenems.
55
Q

Why is Klebsiella very good at resistance?

A
  1. It is naturally less permeable.
  2. It is very good at producing ß-lactamases with around 5 produced at a time.
  3. when it produces KPC it is the most abundant protein in the cell.

Medical Microbiology (16 decks)

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