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Medical Microbiology > 8. The rise of multi-drug resistant Non-fermenting Gram-negative bacilli > Flashcards

8. The rise of multi-drug resistant Non-fermenting Gram-negative bacilli Flashcards

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1
Q

What are NFGNBs?

A

Non-fermenting Gram-negative bacilli

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2
Q

Why are NFGNBs important pathogens?

A
  1. They are a massive group of organisms
  2. We are exposed to them all the time and in many ways.
  3. They often live in aqueous environments.
  4. Cause lots of infections in the lungs.
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3
Q

Why is Pseudomonas aeruginosa the most common NFGNB infection?

A
  1. It is the most abundant in human areas so is most likely to cause infections.
  2. It is the only NFGNB that can colonise the human gut.
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4
Q

How does Pseudomonas aeruginosa colonise the gut?

A
  1. The gut is anaerobic, so most non-fermenting bacteria wouldn’t be able to survive.
  2. They cannot process sugars without oxygen.
  3. Pseudomonas can actually do low levels of fermentation allowing it to colonise the gut.
  4. Biofilm formation can also help with survival in the gut.
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5
Q

Why is P. aeruginosa hard to treat?

A
  1. It only really causes infections in the very ill who often are on lots of antibiotics.
  2. They are slow growing, so they can normally be cleared by the immune system, but when they do cause infection, they are very resistant.
  3. This means they kill lots of people.
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6
Q

What antimicrobials can P. aeruginosa be resistant to?

A
  1. Quinolones
  2. Macrolides
  3. Trimethoprim
  4. Chloramphenicol
  5. Tetracyclins
  6. Sulphonomides.
  7. ß-lactams and ß-lactam inhibitors
  8. triclosan
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7
Q

How does efflux contribute to resistance in P. aeruginosa?

A
  1. P. aeruginosa produces many different efflux pumps relevant to antibiotics.
  2. About 10 different efflux pumps compared to 1 in E.coli
  3. There is more potential for efflux
  4. It has more efflux pumps due to being adapted to survive in the environment which is full of toxins and natural antimicrobials.
  5. Efflux is a good defence mechanism to remove molecules from itself.
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8
Q

What is the most important efflux pump in P. aeruginosa?

A

MexABoprM

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9
Q

How does mexABoprM contribute to resistance in P. aeruginosa?

A
  1. It is an important tripartite pump.
  2. It gives resistance when it is overexpressed due to mutation.
  3. Unlike acrABtolC in E.coli this pump can give resistance independently without another resistance mechanism.
  4. It can provide resistance to many different antibiotics.
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10
Q

Why are target site mutations uncommon in P. aeruginosa?

A
  1. Due to the presence of efflux pumps they are not needed to give resistance.
  2. They are a lot lower frequency than efflux overexpression, so they are less effective at giving resistance.
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11
Q

How does triclosan contribute to P. aeruginosa resistance?

A
  1. Triclosan is a biocide/disinfectant that can kill bacteria.
  2. The use of this can select for mutants that are resistant due to efflux.
  3. This also provides resistance to many antibiotics.
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12
Q

What mutations can lead to MexABoprC over expression?

A
  1. The main regulator is the transcriptional repressor MexR which binds to the P1 promoter.
  2. Mutation in MexR or the P1 promoter prevents binding and causes derepression of the mexABoprM pump and over expression.
  3. The other repressor is NalD, which binds to the P2 promoter.
  4. If NalD is lost by mutation, the P2 promoter is derepressed, and mexABoprC expression is increased.
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13
Q

How does NalC mutation lead to mexABoprC overexpression?

A
  1. NalC is a transcriptional repressor for PA3719/20.
  2. The protein produced by PA3719 binds to MExR and pulls it off the P1 promoter for mexABoprC.
  3. Loss of function mutation of NalC causes increased production of PA3719/20.
  4. This causes derepression and over expression of mexABoprC.
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14
Q

Why is mutation and over expression of mexABoprC so common?

A
  1. There are 3 genes that could be mutated to give overexpression.
  2. They are loss of function mutations so they happen at very high frequency.
  3. These mutations happen in about 1 x10^7 bacteria.
  4. The 3 different genes can cause slightly different resistance phenotypes.
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15
Q

What makes NFGNBs so resistant?

A

The efflux pumps, in combination with chromosomal and acquired resistance mechanisms.

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16
Q

What kind of infections do NFGNB cause?

A
  1. Bloodstream and respiratory infections like pneumonia.
  2. They are usually associated with plastic tubes like ports and central lines.
  3. NFGNBs are very good at sticking to plastic and forming biofilms which prevents them being wiped away.
  4. They can then get into the blood
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17
Q

What sites do NFGNB infect?

A
  1. plastic tubes
  2. Open wounds
  3. Burns (especially P. aeruginosa)
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18
Q

Where do P. aeruginosa infections come from?

A
  1. Usually contamination from a source in the environment like a sink.
  2. They can be from the flora, but this rarely causes infection, and if it does, it causes UTIs.
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19
Q

What does NFGNBs being environmental mean for infection?

A
  1. There is a lot of genetic variability in the bacteria which means lots of different resistance.
  2. Most infections come from a source, and if multiple patients have the same infection, it is usually all from the source not from each other.
  3. There is very little patient to patient transmission.
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20
Q

Who is most likely to be infected with NFGNBs?

A
  1. Immunosupressed people with plastic tubes.
  2. They have also usually had antibiotic treatment that reduces competition from commensals
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21
Q

How does NFGNBs get resistance?

A
  1. Mutation
  2. Acquisition
  3. They can gain both of these easily.
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22
Q

Why do NFGNBs have higher mortality then enterobacterales?

A
  1. They infect sicker patients.
  2. They are more aggressive infections.
  3. They are harder to treat due to resistance
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23
Q

What are the big 3 NFGNBs?

A
  1. Pseudomonas spp.
  2. Acinetobacter spp.
  3. Stenotrophomonas maltophilia
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24
Q

Where do most NFGNB infections come from?

A
  1. Central lines
  2. But a lot of the time, we don’t know where the infection comes from they just appear, especially in haematology patients.
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25
Q

What causes gut and UTI NFGNB infections?

A

Pseudomonas

26
Q

What is the epidemiology of P. aeruginosa in the UK?

A
  1. P. aeruginosa is the most common and the most aggressive in the UK
  2. Infect lots of burns
  3. In some parts of the world, there is pan resistant pseudomonas that can only be treated with colistin
  4. The formation of biofilms makes them hard to treat and increases virulence.
  5. Efflux doesn’t often give carbapenem resistance but pseudomonas encode Metallo ß-lactamases which can deal with carbapenems.
  6. OPRD porin loss affects carbapenem entry.
27
Q

What can be used to treat MDR resistant Pseudomonas?

A
  1. Colistin
  2. It is not very effective
  3. It is very toxic
28
Q

What is the epidemiology of Acinetobacter baumannii?

A
  1. 2nd most common NFGNB in the UK but most common in the hot and dry places.
  2. Only entered Europe from the 1st Gulf War.
  3. Survives well in hot dry environments.
  4. High genetic variability but specific clones are emerging in the UK with chromosomal resistance mechanisms.
  5. This includes OXA-23 enzymes that cause carbapenem resistance.
  6. Survives very well on surfaces over very long periods of time and can survive against disinfectants.
  7. They have less intrinsic resistance like efflux.
29
Q

How did the 1st gulf war bring Acinetobacter baumannii to Europe and the US?

A
  1. Sand got into wounds from desert warfare.
  2. They then got Acinetobacter baumannii infections.
  3. They were sent to Nottingham for treatment.
  4. This started an outbreak and caused it to spread around the UK and then the USA.
30
Q

What is the epidemiology of Stenotrophomonas maltophilia?

A
  1. It is intrinsically resistant to pretty much everything.
  2. Mostly respiratory and bacteraemia infections.
  3. Outbreaks are mainly due to contaminated water.
  4. Can still be treated by trimethoprim and sulphamethoxazole.
  5. Not very virulent so only really a problem in very sick patients like haematological oncology patients.
  6. Can make pseudomonas infections in the lungs worse by producing molecules that exacerbate infection.
31
Q

What are the intrinsic resistance mechanisms in stenotrophomonas maltophilia?

A
  1. Encoded on the chromosome
  2. ß-lactamases
  3. aminoglycoside resistance
  4. Efflux
32
Q

What is Cystic Fibrosis?

A
  1. A common and lethal autosomal recessive disorder.
  2. effects around 1/2500 births
  3. mutation results in a defective CFTR protein pump that causes salt imbalance across epithelial surfaces.
  4. The problems in the lungs is ultimately what kills people.
  5. More people are living longer with CF due to improved treatment. This means more patients are colonised by pseudomonas.
33
Q

Why does P. aeruginosa stay in CF patient’s lungs?

A
  1. CF causes thicker mucus which traps the bacteria and makes it hard to remove it.
  2. The innate immune system produces NO to kill the bacteria, but this gets stuck in the thick mucus. This causes damage to the lung tissue.
  3. This increases inflammation and more NO production and more damage and decreasing lung function.
  4. The mutation in CFTR leads to GM1 over expression. P. aeruginosa binds to GM1 to infect cells.
34
Q

What are some organism commonly in the lungs of CF patients?

A
  1. S. Aureus
  2. Haemophilus influenzae
  3. P. aeruginosa.
  4. Stenotrophomonas
  5. Aspergillus
35
Q

What is the timeline of colonisation of a CF patient?

A
  1. Mostly CF child patients are colonised with S. aureus usually from the skin of the parents. It is not hugely damaging.
  2. Then followed by H. influenzae that comes from the back of the throat and moves into the lungs.
  3. Later in adulthood they are colonised with P. aeruginosa. Most Adult CF patients live with P. aeruginosa.
36
Q

What happens in P. aeruginosa infection in CF patients?

A
  1. They are not ill all the time.
  2. There are cycle of increasing bacteria, more mucus, more coughing, hospitalisation, antibiotic treatment and recovery.
  3. Every cycle damages the lungs further and lung function declines.
37
Q

What is P. aeruginosa hypermutibility?

A
  1. It is the accumulation of mutations that lead to resistance through loss of transcriptional regulators.
  2. These mutations also increase biofilm formation through the mutation of transcriptional regulators, which helps protect the bacteria from antibiotics.
38
Q

What causes P. aeruginosa hypermutibility?

A
  1. Oxygen radicals are produced by the immune system to kill bacteria.
  2. If the radicals are trapped in the mucus, they just damage the bacteria not kill them.
  3. This causes causes oxidative damage to the DNA which induces mutations.
  4. The 1st mutations are often in DNA repair systems, which also increases the mutation rate and causes a massive amount of resistance.
39
Q

What is the ultimate result of P. aeruginosa infection in CF patients?

A
  1. Lots of lung damage and decline of lung function
  2. This needs a transplant, or the patient will die.
40
Q

What is a major difference in the P. aeruginosa infections in CF patients compared to others?

A

There is lots of patient to patient transmission.

41
Q

Why is P. aeruginosa transmitted from person to person in CF patients?

A
  1. New CF patients seek advice and support from older CF patients.
  2. The P. aeruginosa from the older patients colonise the new patients after spending lots of time together.
  3. This stimulates transmission of P. aeruginosa from patient to patient.
  4. Interactions between patients need to be changed to reduce transmission.
42
Q

Why is CF patients picking up P. aeruginosa from older patients concerning?

A
  1. The older patients have had lots of antibiotic therapy.
  2. Their P. aeruginosa is more likely to be resistant.
  3. This puts the newer patients further down the road of highly resistant infections and this is dangerous for the lungs.
43
Q

What is B. cepacia complex and how does it effect CF patients?

A
  1. It is a NFGNB.
  2. It is only relevant to CF patients and doesn’t infect other people.
  3. It is a very high risk organism.
  4. Present in around 8% of CF patients.
  5. Clonal and non-clonal types.
  6. Clonal types are more dangerous and transmit person to person
44
Q

What is the clinical progression of B. cepacia complex infections?

A
  1. Dependant on the type of stain you are infected with.
  2. Starts with no change in lungs function.
  3. Accelerates the decline of lung function.
  4. Fatal decline over short periods including septicaemia.
  5. Highly resistant to antimicrobials and circulating clones are often already resistant due to circulating mutations.
45
Q

What are the 2 main strains of B. cepacia complex infections?

A
  1. B. multivorans
  2. B. cenocepacia
46
Q

Which is the most transmissible and problematic strain of B. cepacia complex ?

A

B. cenocepacia

47
Q

What makes B. cenocepacia very transmissible?

A

It carries a cblA pilus that is very good at binding to lung epithelium and mucin components.

48
Q

B. multivorans infections

A
  1. All patients have different strains
  2. Not very virulent and doesnt do much.
  3. The infections is usually from the environment the person lives.
49
Q

B. cenocepacia infection

A
  1. Very transmissible
  2. Most infections are a single strain.
  3. High morbidity and mortality.
50
Q

Why are NFGNBs hard to treat?

A
  1. They are often resistant.
  2. If they are not resistant, they gain resistance through mutation, and treatment stops working.
51
Q

What is the 1st line treatment for NFGNBs?

A
  1. A fluoroquinolone like Levofloxacin
  2. But these cannot be given to children as they effect tendon formation.
  3. The exception is for child CF patients as there infections tend to be worse.
52
Q

Why was pipercillin/tazobactam introduce to treat NFGNBs?

A
  1. Mainly to treat P.aerginosa
  2. But often resistance can develop quickly
53
Q

how is trimethoprim/sulphamethoxazole use to treat NFNGBs?

A
  1. As a combination therapy
  2. Works pretty well
  3. Causes nephrotoxicity and is bone marrow suppressive.This is not good for immunocompromised patients.
54
Q

Why are tetracyclines not good for NFGNB treatment?

A

they are subject to efflux

55
Q

Why is colistin used to treat NFGNB and why is it dangerous?

A
  1. It is non-specific as it damages the bacterial membrane.
  2. It has no specific mechanisms to it
  3. It is very toxic so needs close monitoring while being given. Will destroy the kidneys.
56
Q

Why is decided on NFGNB treatment difficult?

A
  1. They often seem susceptible in lab tests then not work in the patient
  2. This is due to biofilm formation
  3. Mainly trying things out and hoping for the best
57
Q

What is the main way to prevent NFGNB infections?

A
  1. infection control
  2. This is super important to prevent the infection in the first place.
58
Q

Future of NFGNB treatment: Efflux pump inhibitors

A
  1. Hard to get the specificity for this due to the proton motive force.
  2. All human cells use it for respiration so you cannot prevent the pumps working this way.
  3. Hard to find a single molecule to block all efflux pumps
  4. Not a very realistic option
59
Q

Future of NFGNB treatment: Antimicrobial peptides/

A
  1. They insert in the bacterial membrane and pop them.
  2. Like defensins
  3. Could work in situations of skin and wound infections
60
Q

Future of NFGNB treatment: ß-lactamase inhibitors

A
  1. Subject to efflux
  2. Might work but not a long term solution
  3. Mostly work for enterbacterales.

Medical Microbiology (16 decks)

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