The rise of Multi-Drug Resistant Non-Fermenting Gram-Negative Bacilli Flashcards
What is the size cut off for nutrient access in porins
Generalls about 600Da
Many antibiotics are larger than this
How can porins convey resistance
Some bacteria ntaurally have less porins or may lose/downregulate them e.g. in Klebsiella
NFGNBs are an example of this
Why are NFGNBs intrinically resistant to lots of antibiotics
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
What are the A-D types of antibiotic efflux pumps
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
Name antibiotics that need to be in the cytoplasm to work
Aminoglycosides
Fluoroquinolones
What type of pump is the AcrAB-TolC Pump
An RND transported
The wings in the AcrA allows substrates to be pumped from the periplasm as well as the cytplasm
What is the main mechanism of MDR in P. Aeurginosa
MexAB-OprM Pump
What does the MexAB-OprM Pump convey resistance to
Quinolones Trimethoprim Triclosan Chloramphonical Beta lacktams
What are the 3 main regulators of the MexAB-OprM pump
MexR, NalD, NalC
Action of MexR
Transcriptional repressor of MexAB-OprM
Inactivated by point mutation or insertional inactivation with an IS element of binding site mutations
Action of NalD
NalD is another rpressor of MexABoprM –> need inactivation of both MexR and NalD to give high levels of resistance
Action of NalC
NalC transcriptionally suppresses PA3719/20
PA3719/20 enocodes a protein that can bind and sequester MexR
Why are there so many mechanisms that can regulate mexABoprM pump expression
As the pump is so broad spectrum it has to be able to respond to many different chemicals and signals
Why are NFGNBs worrying for HCAIs
As they have high intrinsic resistance, and the ability to gain lots of resistance
What do NFGNBs predominantly cause
Bacteraemia or resp infection
Wound infections depending on the skin
What predisposes you to NFGNBs
Prior antibiotic therapy and prolonged hospital stay
However they are usually unable to colonise patients
What are the resistance levelss if NDGNBs
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.
What is the most common NFGNB in HCAI
P. Aeruginosa –> causes 3000 bactaraemias per year in england and wales
What is the most virulent NFGNB
P. aeurginosa –> produces signifcant virulence factors e.g. elastase and can form biolfilms
Patient to patient transmission has also be seen
What is resistance like in P. Aeurginosa
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_
What does Acinobacter generally cause
More wound infections than P. Aeruginosa and also problematic
What is the genetic variability like in acinobacter
Highly genetically variable but some cloens are emrging in the UK i.e. OXA-23 mediated carbapenemase resistance !
Where does acinobacter survive well
Highly tolerant of disinfectant and tolerant of dessication
Caused lots of problems in the Gulf war
What is MDR like in acinobacter
MDR is generally less of a problem as less intrinsic resistance (less efflux and more permisability)
But still resistant to carbapenems, aminoglycosides and fluoroquinolones
What disease do strenotrophomonas Maltophilia cause
Mainly bactaraemia and respiratory infections
Up to 50% mortality rates
Is What is the genetic variability l ike in strenotrophomonas maltophilia lke
Highly genetically variable
Patient to patient spread is rare
What generally causes transmission of strenotrophomonas maltophilia
Contaminated water supply
what is stenotrophomonnas maltophilia resistance like
THE MOST INTRINISCALLY RESISTANT OF ANY HUMAN CAUSING ORGANISM!
Particularly to beta lactams, aminoglycosides and macrolides
What is the treatment of strenotrophomonas maltpphilia
Trimethoprim/Sulphamethoxazole –> resistance is rare BUT this bone marrow suppressive. Problematic as most of the patients are immunocompromised
Why is CF carrier status so high
As one copy of the allele decreases susceptibility to certain bacteria adhering to the gut wall e.g. cholera
What do mutations in CFTR cause
Defective CFTR Processing so CFTR doesnt reach the apical membrane of epithelial cells –> impairs chloride transport across the epithelial cells
Why do aiways become infected repeatedly in CF
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
What organisms commonly infect young CF patients
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
What organisms commonly infect older teens CF patients
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
What organisms commonly infect patients in later life
Non-tuberculous ycobacteria
Aspergillus
Why is p. aeurginosa hypermutable in CF
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
what stage do we try and keep patient in with CF
In transient colonisation
What is the Liverpool strains
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
What is cepacia syndrome
A fatal decline over short period when infected with BCC
Is BCC antibitoic resistance
High levels –> not as high as P. Aeruginosa BUT if co-colonise with p. aeruginosa than the biofilm can protect it
What are the 2 main types of BCC
B. multivorans and B. cenocepacia
What makes B Cenocepacia particularly transmissible
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
What is the difference between B multivorans and B Cenocepacia
B multiborans has less of a clnical impact as less stransmissionle, less likely to cause chornic colinisation and lower morbidity and mortality
Which si there more clonal spread of b multivorans or cenocepacia
Cenocepacia
In one manchester study all multivorans straisn were unique but 88% of cenocepacia were a single strains
What is the treatment of NFGNBs
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
Why is hard to test NFGNBs in vitro
As they dont grow well in agar
Also clnical response often doesnt correlate to in vitro studies
What may be important in the future treatment of NFGNBs
Efflux Pump Inhibitors
Antimicriobial peptides
New Beta Lactamase Inhibitors
