The rise of Multi-Drug Resistant Non-Fermenting Gram-Negative Bacilli

Question 1

What is the size cut off for nutrient access in porins

Answer 1

Generalls about 600Da

Many antibiotics are larger than this

Question 2

How can porins convey resistance

Answer 2

Some bacteria ntaurally have less porins or may lose/downregulate them e.g. in Klebsiella
NFGNBs are an example of this

Question 3

Why are NFGNBs intrinically resistant to lots of antibiotics

Answer 3

They are environmental organisms which are relatively impermeable due to the harsh environmental conditions
But his also decreases nutrient uptake hence are slow growing

They are generally etherefore will only affect immunocompromised for there to be an infection

Question 4

What are the A-D types of antibiotic efflux pumps

Answer 4

A- porins
B - Single component pumps i.e. SMR, MFS, ABC or MATE type
C - Tripartite RND Pump
D - Tripartite transports, MFS or ABC type

Question 5

Name antibiotics that need to be in the cytoplasm to work

Answer 5

Aminoglycosides

Fluoroquinolones

Question 6

What type of pump is the AcrAB-TolC Pump

Answer 6

An RND transported

The wings in the AcrA allows substrates to be pumped from the periplasm as well as the cytplasm

Question 7

What is the main mechanism of MDR in P. Aeurginosa

Answer 7

MexAB-OprM Pump

Question 8

What does the MexAB-OprM Pump convey resistance to

Answer 8

Quinolones
Trimethoprim
Triclosan
Chloramphonical
Beta lacktams

Question 9

What are the 3 main regulators of the MexAB-OprM pump

Answer 9

MexR, NalD, NalC

Question 10

Action of MexR

Answer 10

Transcriptional repressor of MexAB-OprM

Inactivated by point mutation or insertional inactivation with an IS element of binding site mutations

Question 11

Action of NalD

Answer 11

NalD is another rpressor of MexABoprM –> need inactivation of both MexR and NalD to give high levels of resistance

Question 12

Action of NalC

Answer 12

NalC transcriptionally suppresses PA3719/20

PA3719/20 enocodes a protein that can bind and sequester MexR

Question 13

Why are there so many mechanisms that can regulate mexABoprM pump expression

Answer 13

As the pump is so broad spectrum it has to be able to respond to many different chemicals and signals

Question 14

Why are NFGNBs worrying for HCAIs

Answer 14

As they have high intrinsic resistance, and the ability to gain lots of resistance

Question 15

What do NFGNBs predominantly cause

Answer 15

Bacteraemia or resp infection

Wound infections depending on the skin

Question 16

What predisposes you to NFGNBs

Answer 16

Prior antibiotic therapy and prolonged hospital stay

However they are usually unable to colonise patients

Question 17

What are the resistance levelss if NDGNBs

Answer 17

They are generally variable –> this is due to high genetic variability with unique strains that aren’t generally transmissible hence it is hard to predict the reponse to treatment.

Question 18

What is the most common NFGNB in HCAI

Answer 18

P. Aeruginosa –> causes 3000 bactaraemias per year in england and wales

Question 19

What is the most virulent NFGNB

Answer 19

P. aeurginosa –> produces signifcant virulence factors e.g. elastase and can form biolfilms

Patient to patient transmission has also be seen

Question 20

What is resistance like in P. Aeurginosa

Answer 20

25% of HCAI strains shown to be MDR
Pan resistance has emerged –> colisitn is last line but colisitn is also emerging

Resistance has arisen throguh a combination of increase efflux, intrinsic ezymes, decreased permeability and acquired enzymes e.g. VIM and IMP_

Question 21

What does Acinobacter generally cause

Answer 21

More wound infections than P. Aeruginosa and also problematic

Question 22

What is the genetic variability like in acinobacter

Answer 22

Highly genetically variable but some cloens are emrging in the UK i.e. OXA-23 mediated carbapenemase resistance !

Question 23

Where does acinobacter survive well

Answer 23

Highly tolerant of disinfectant and tolerant of dessication

Caused lots of problems in the Gulf war

Question 24

What is MDR like in acinobacter

Answer 24

MDR is generally less of a problem as less intrinsic resistance (less efflux and more permisability)

But still resistant to carbapenems, aminoglycosides and fluoroquinolones

Question 25

What disease do strenotrophomonas Maltophilia cause

Answer 25

Mainly bactaraemia and respiratory infections | Up to 50% mortality rates

Question 26

Is What is the genetic variability l ike in strenotrophomonas maltophilia lke

Answer 26

Highly genetically variable | Patient to patient spread is rare

Question 27

What generally causes transmission of strenotrophomonas maltophilia

Answer 27

Contaminated water supply

Question 28

what is stenotrophomonnas maltophilia resistance like

Answer 28

THE MOST INTRINISCALLY RESISTANT OF ANY HUMAN CAUSING ORGANISM! Particularly to beta lactams, aminoglycosides and macrolides

Question 29

What is the treatment of strenotrophomonas maltpphilia

Answer 29

Trimethoprim/Sulphamethoxazole --> resistance is rare BUT this bone marrow suppressive. Problematic as most of the patients are immunocompromised

Question 30

Why is CF carrier status so high

Answer 30

As one copy of the allele decreases susceptibility to certain bacteria adhering to the gut wall e.g. cholera

Question 31

What do mutations in CFTR cause

Answer 31

Defective CFTR Processing so CFTR doesnt reach the apical membrane of epithelial cells --> impairs chloride transport across the epithelial cells

Question 32

Why do aiways become infected repeatedly in CF

Answer 32

Increaesd GM-1 in cells --> increases pseudomonas binding to it Decreased Cl- secretion and Increased Na+ and water reabsoprtion, this leaves less water in airways, decreased depth of the ASL and hence bacteria become trapped in the mucus Also mutant CFTR = less NO which is a primary innate repsonse to bacterial contamination

Question 33

What organisms commonly infect young CF patients

Answer 33

S. aureus - in first year. cotinues for life in 30% of patients H. Influenzae - closely follows Staph Aureus but then mostly cleared by 10 years

Question 34

What organisms commonly infect older teens CF patients

Answer 34

P. Aeruginosa --> colonises 70% of patients. Burkholderia Cepacia --> also a NFGNB and is very serious ! causes a rapid decline in lung function Stenotrophomonas Maltophilia --> 30% serious if it colonises children and in adults if co-colonising with P. Aeurginosa Achromobacter Xylosidas

Question 35

What organisms commonly infect patients in later life

Answer 35

Non-tuberculous ycobacteria | Aspergillus

Question 36

Why is p. aeurginosa hypermutable in CF

Answer 36

Ozygen free radicals are generated in the inflammatory response Oxygen free radicaly cause DSB and mutations causing hypermutability This hypermutability can activate efflux and aliginiate production --> ALIGINATE MAKES THE CELLS GLOOBY AND GET BIOFILM FORMATION

Question 37

what stage do we try and keep patient in with CF

Answer 37

In transient colonisation

Question 38

What is the Liverpool strains

Answer 38

LIverpool strain is a MDR strain of P. Aureginosa that has increasing clonal spread Capable of causing super infection and replacing infection in the host of non-epidemic P. Aeurginosa strains. Clinical state can worse when P. Aeurginosa infection becomes established

Question 39

What is cepacia syndrome

Answer 39

A fatal decline over short period when infected with BCC

Question 40

Is BCC antibitoic resistance

Answer 40

High levels --> not as high as P. Aeruginosa BUT if co-colonise with p. aeruginosa than the biofilm can protect it

Question 41

What are the 2 main types of BCC

Answer 41

B. multivorans and B. cenocepacia

Question 42

What makes B Cenocepacia particularly transmissible

Answer 42

Has the cbl gene which encodes the major structural subunit of unique cable pili This mediates binding to mucin components and respiratory epithelial cells This also possessses the B Cepacia epidemic strain marker

Question 43

What is the difference between B multivorans and B Cenocepacia

Answer 43

B multiborans has less of a clnical impact as less stransmissionle, less likely to cause chornic colinisation and lower morbidity and mortality

Question 44

Which si there more clonal spread of b multivorans or cenocepacia

Answer 44

Cenocepacia | In one manchester study all multivorans straisn were unique but 88% of cenocepacia were a single strains

Question 45

What is the treatment of NFGNBs

Answer 45

Respiratory quinolones - levofloxacin Beta lactams with betalactams inhibitors - piperacillin with tazobactam Trimethorpim/sulphamethoxazole New tetracycline derivatives e.g. tigecycline! infection control measures are important to try and rpeven the transmission of MDR organisms

Question 46

Why is hard to test NFGNBs in vitro

Answer 46

As they dont grow well in agar | Also clnical response often doesnt correlate to in vitro studies

Question 47

What may be important in the future treatment of NFGNBs

Answer 47

Efflux Pump Inhibitors Antimicriobial peptides New Beta Lactamase Inhibitors