Multidrug resistant Enterobacteriaeceae as a serious noscomial threat

Question 1

Discuss the nosocomial threat of enterobacteriaceae

Answer 1

70% of all UTIs
40% pneumoniase
20% of all bactaraemias
10% of endocarditis

Question 2

WHat is the most common nosocomial infection in the UK

Answer 2

E.Coli –> most are UTIs plus 15,000 Bactaraemias per year and 30% of all Surgical site infections!

Question 3

What is not far behind E.Coli in terms of nosocomial infections

Answer 3

Klebsiella Pneumonia –> less common in faeces but it is more resistant to antibiotics. Can also cause pneumonias in ICUs but isnt as important as the NFGNBs.

Question 4

Name some imporant less virulent enterbacteriaceae for nosocomial infections

Answer 4

Citrobacter and Enterbacter
Cause opportunistic infections particulalry in children/neonates
Meningitis adn brain absceses
BUt causing an increasing number of bactaraemias in the UK

Question 5

What is the definition of ESBLs

Answer 5

A bush class 2e enzyme
Molecular class A 
Hydrolyse 3rd generation cephalosporins BUT not cephamycins and are sensitive to clavulanic acid

Question 6

What used to be the most predominant cause of ESBLs and what is it now

Answer 6

Used to be TEM and SHV

Now thought to be due to CTX-M

Question 7

Where has CTX-M originiated from

Answer 7

From Kluvera species. Kluvera is an enteric bacteria hence has spread to E. Coli easily

Question 8

What species are ESBLs most common in

Answer 8

Klebsiella, K. Pneumoniae and E. Coli

Question 9

Describe the mobilisation of CTX-M

Answer 9

It is a composite transposon that uses insertion sequences to mobilise the chromosomal gene
The insertion sequence needs only a week match between IRR and IRL
Hence the transposon needs just a single copy of insertion sequence element to mobilise as the trasnpose enzyme detects the IRL but is very unspecific for IRR

Question 10

What IS and transposon has been seen in plasmics for CTX-M

Answer 10

IS26 insertion into ISEcp1B

Question 11

What CTX is predominant in humans and animasl

Answer 11

CTX-M15 humans

CTX-M14 in animals

Question 12

Are AmpC Beta lactamsases ESBLS

Answer 12

NO

Question 13

What is the definition of an AmpC Beta lactamses

Answer 13

Bush Class I Enzymes
Molecular class C enzymes
Hydrolyse all penicillins, 3rd generation cephalosporins AND cephamycins and Monobactams. Insensitive to clavulanic acid!

Question 14

What are AmpC Beta lactamases still susceptible to

Answer 14

4th generation cephalosporins

ALSO the newer beta-lactamse inhibitors of avibactam and vaborbactam have inhibitory activity against them

Question 15

How can E.Coli get carbapenemase resistance

Answer 15

Upregulation of Amp C
Normally AmpC is expressed at low levels in E. Coli due to a weak promoter and an attenuator HOWEVER mutations in either of them can increase. Need mutations in both to get high level resistance

Question 16

Describe inducible AmpC beta lactamases and how they arose

Answer 16

The increasing use of cephalosporins fuelled a rise in inducible, chromosomally encoded AmpC i.e. Citrobacter and enterobacter!
Selection of thes AmpC hyperproducing mutatns of citrobacter and enterbacter can result in resistanct

Question 17

How did AmpC mobilise

Answer 17

Mobilised onto plasmids from ACromonas and Enterbacteriaeceae species
Thought to be via ISECp, the same as CTX-M
Now present in Non-AmpC producers e.g. Salmonella and Klebsiella and also low level AmpC Producers e.g. E. COli

Question 18

What is MDR

Answer 18

Resistance to at least 3 entirely different calsses of drugs!

Question 19

What organisms do MDR plasmids generally occur in

Answer 19

Mainly in enterbacteriaceae –> mainly linekd to complex class I Integraons e.g. carrying ESBL, Qnr and aminohlycoside resistance genes

Question 20

Describe MDR ESBL plasmids and complex class I integrons

Answer 20

They are large plasmids carrying multple resistance mechanisms
Also carry resistance to things other than antibitoics e.g. heavy metals sch as silver

Question 21

What is method of produc range resistance inetnerbacteria

Answer 21

Efflux pumps e.g. AcrAB-TolC pump

Question 22

The overproduction of what pump in enterbacteriaceae conveys resistance to fluorquinolones

Answer 22

AcrAB-TolC –> also gives protection against other antimicrobials dies and disinfectants

In other bacteria e.g. Klebsiella it also gives resistance against tetracyclines

Question 23

What usually controls the expression of AcrAB-TolC

Answer 23

AcrR represses it –> but can be activated by point mutations or insertional activation with an IS element or a binding site mutations

Question 24

What else can also causes AcrAB-TolC overproduction

Answer 24

MarA –> an acivator of acrAB Expression –> however MarR usually regulates MarA level –> mutation in MarR can activate it!

Question 25

What is the relationship of Mar In Enterbacteriaceaea

Answer 25

MarA usually overpdocued in E. Coli –> also decreases susceptiblity to other antibiotics as MarA activates other RND efflux pumps and represses the production of the OmpF Porin.
MarA may also make the outer membrane more hydrophobic and repel the antibiotics

Question 26

What is the equivalent of MarA in enterbacteriaceae other than E. Coli

Answer 26

RamA

Question 27

What is the Role of MarA in Dna Repair

Answer 27

Mar A may activate genes inovlved in DNA repair –> this is particualrly imporant in conveying resistance to fluiroquinolone ressitance

Question 28

How does MarA repress the OmpF porin

Answer 28

Causes transcription of the MicF Antisesnse to ompF —> binds and prevents its translation

Question 29

Does OXA48 convey carbapenem resistance

Answer 29

It does but really needs additional mutations

Question 30

What mechanism is there for carabpenem resistance other than plasmid mediated carbapenemase

Answer 30

Porin mutants WITH hyperproduction of AmpC or a plasmid ESBL or AmpC Enzyme (mainly resistance to Ertrapenem)

These give Non-Carbapenamase mediated carbapenem resistance!!

Question 31

Is non-carbapenamse mediated carabpenem resistant a high level resistance or low level

Answer 31

It is generally resistance that is just above the breakpoint
This means that resistance may be patient specific i.e. patient in good conditions gets a good drug dosaeg at the infection site and therefore wont be resitant