Antimicrobial Resistance Flashcards
What are the two main problems surrounding drug resistance?
Multi-drug resistance which severely limits treatment options
Cross infection which facilitates spread and transmission
List the five most commonly implicated organisms in antibiotic resistance
Methicillin resistance staphylococcus aureus (MRSA)
Vancomycin resistant enterococcci (VRE)
Carbapenemase Producing Enterobacterales (CPE)
Carbapenemase Producing Organisms (CPO)
Extended Spectrum B-lactamase Producing GNBs (ESBLs)
What does the burden of antibiotic resistance referred to?
(4)
The increased mortality rates
The increased length of hospital stays
The increased healthcare costs
All of these are at least twice as great for patients infection with resistant bacteria versus susceptible bacteria
What has WHO said about MDRO/AMR?
(2)
There is a global epidemic of AMR
It a major threat to public health, leading to mounting healthcare costs, treatment failure and deaths
Comment on the different types of MDR (multi-drug resistance)
XDR - Extensively drug resistance
PDR - Pan drug resistance
How many people die a year due to antibiotic resistant strains in the EU?
37,000 die a year
How many people are expected to die from antibiotic resistance by 2050
10 million deaths by 2050
This is expected to cost 66 trillion
What are currently the four seen trends in AMR?
(4)
- Low grade PDR Healthcare associated pathogens
- More virulent XDR healthcare associated pathogens
- MDR pathogens prevalent in Healthcare and emerging in the community
- The boundary between hospital and community pathogens is also becoming increasingly blurred, with MDR pathogens causing both hospital and community- onset infections
How do you class PDR, XDR and MDR
PDR = resistant to all classes of antibiotics
XDR = susceptible to 2 or less than 2 antibiotic classes
MDR = Resistant to 3 or more classes
Give two examples of PDR organisms
e.g. VRE
e.g. CPO-Acinetobacter
Give three examples of XDR organisms
CPE
MRSA
ESBL-GNB
Give four examples of MDROs, two in community and two in healtchare
MRSA and CPEs in the community
S. pneumoniae and N. gonorrhoeae
Comment on the emergence of resistance
(4)
There is currently resistance to all antibiotics
The emergence of resistance is a function of time and use
The extend and speed of resistance development varies with each drug
Overcome by introduction of new classes of drug but there hasn’t been any developed
What are the two ways resistance can originate
Intrinsic
Acquired
Resistance is either intrinsic or acquired, what does this mean?
Exposure to antibiotics does not make bacteria resistance
The organism already has the resistance, the use of antibiotics just selects this out
What is intrinsic/inherent resistance
Stable genetic property encoded in the chromosome and shared by all members of genus
Which form of resistance is more common
Acquired resistance
What are the two ways acquired resistance can come about?
By alteration in genotype (mutation)
By acquisition of new/’foreign’ genetic material
Selection of resistance occurs naturally, what does this mean?
(3)
A phage has come in and given a bacteria resistance genes
But the potential for resistance hasn’t been unlocked yet
The antibiotic will kill all other organisms but the resistant strains -> this will then multiply
Comment on the misuse of antibiotics and resistance
(3)
This increases the rate at which natural selection of resistant strains occurs
Indiscriminate use of 1/3 of antibiotic prescriptions given on an outpatient basis are unnecessary
Widespread antibiotic use in animal husbandry e.g. pigs need a lot of antibiotics, cattle fed antibiotic feed in america
Comment on the evolution of antibiotic resistance
(4)
Evolution of resistant strains is a natural phenomenon
It occurs when microorganisms mutate or when resistant traits are exchanged
Again, the misuse of antibiotics accelerates this emergence
Poor infection control practices, encourage the further spread of antibiotic resistance
Antibiotic activity depends on what?
(4)
Stability - must not be inactivated
Access - muse be able to reach the target
Access - must not be extruded before binding to the target
Existence of a vital target that is susceptible to the agent
How can bacteria stop antibiotic activity
By production of drug-modifying enzymes which inactivate/modify the antibiotis
How can bacteria stop antibiotic access?
(2)
Modification of cell envelope - to make it less permeable
Extrusion - expel drug from the cell
How can bacteria stop the action of antibiotics by altering the target?
Modify the target - the antibiotic will bind less avidly
Write about the production of drug-modifying enzymes
(4)
Enzymes destroy/modify the antibiotic
Bind to the antibiotic and destabilise it
e.g B-lactamase enzyme production
This is a widespread mechanism of resistance
How do B-lactamases work?
(2)
By catalysing the hydrolysis of the B-lactam ring structure
This destroys the B-lactam activity
The B-lactamase ruptures the B-lactam ring and inactivates it
Comment on B-lactamase mediated resistance
Widespread production in GN and GP bacteria
Extensively produced in Enterobacterales e.g. K. pneumonia and E. Coli
ESBL GNBs
CPEs
What are ESBLs
(2)
Extended Spectrum B-lactamase Producing GNBs
These are resistant to 3rd and 4th generation cephalosporins
What are CPEs
Carbapenemase Producing Enterobacterales
Resistant to Carbapenems and most other B-lactams
Comment on resistant brought on by modification of the cell envelope
(4)
Antibiotics are designed to be hydrophilic so they can enter the bacterial cell through porins (water-filled channels) in their outer membrane
Gram negatives have a lot of these porins
Mutations reduce porin number or alter porins to impeded drug entry and mediate resistance
Mutation is only seen in gram negatives
What organisms have porin mutations?
(2)
Pseudomonas
Enterobacterales
Porin mutations mediate resistance against which classes of antibiotics
B-lactams
Fluoroquinolones
What is extrusion of antibiotics also called
Antibiotic efflux
How does antibiotic efflux mediate resistance
(4)
Found in gram positive and negative
Involves the active extrusion of drug from the cell due to action of export protein pumps (efflux pumps)
Efflux pumps normally facilitate removal of secondary metabolites from the cell
Efflux pumps are over expressed or altered to improve pump efficiency to induce MDR
Where is efflux mediated resistance often seen
Gram positive and negative but especially in pseudomonas
Efflux mutations mediate resistance against what classes of antibtiocs
Macrolides
Fluoroquinolones
How is resistance mediated by target site modification
(4)
Seen in GP and GN but GP are better at this
Modify the antibiotic target so that is binds to antibiotic with less avidity
Very common mechanism with resistance seen against every class
Works by either altering the target that act as enzymes in the cell or alter targets that are of cell wall component
Comment on target alteration of B-lactam antibiotics
(5)
This is seen in methicillin resistance
Penicillin Binding proteins are transpeptidase enzymes that facilitate the cross-linking of peptidoglycan
PBPs are the target sites for B-lactams (antibiotic looks like the D-ala, D-ala the PBPs need to bind)
Mutation in PBP enzymes causes a loss of affinity for B-lactam drugs
This is seen in MRSA = organism makes PBP2a which won’t bind any B-lactam
Write about the target modification mediated resistance against Vancomycin
(5)
Vancomycin acts by binding to the D-ala, D-ala amino acid termini of the peptidoglycan subunits
This binding inhibits cell wall cross-linking
Acquisition of Van A or Van B genes encodes enzymes which synthesis abnormal PG subunits
These PG subunits have altered amino acid termini-reduced antibiotic affinity (D-ala, D-lac)
Seen in enterococcci VREs
Comment on the resistance seen in E. faecium
(3)
Take in Van A or Van B genes
These make D-ala, D-lactace
This stops the vancomycin from working
Antibiotic resistance is a complex process, comment on this
(4)
Individual class of drugs inactivated by more than one mechanism or resistance
Individual organisms may employ different mechanisms to generate resistance to single drug and to different classes of drugs- mechanisms interact to determine actual level of resistance
Genes that encode resistance determinants are often present on mobile genetic elements e.g. plasmids, phages
Spread of resistance between bacterial species, genera and even families
Write a note on MRSA
(5)
First real significant type of resistance the world saw - biggest setback in history of antibiotic therapy
Usually if Methicillin resistant then resistant to other B-lactams as well, often to aminoglycosides and fluoroquinolones (HA MRSA)
Used to only be seen in HAI but now seen in community
Prevalence is dropping - we are now below EU average
40% of all BSI caused by staph were MRSA
How do we investigate methicillin resistance
(4)
We use up cefoxitin disc diffusion
Incubate for 16-20 hours
Detect any colonies growing around disc or in zone of clearance
Cefoxitin can also be used in the MIC or in VITEK
Write a note on Vancomycin Resistant Enterococci (VRE)
(7)
Altered cell wall targets
Emerged in 1990s
Resistance to fluoroquinolones and aminoglycosides in 30-60% of isolates also in VRE
Linezolid and daptomycin were developed to treat VRE but there is now resistance against these - XDR
XDR moving towards PDR
Healthcare associated infection
Ireland has really high amounts versus Europe
How do we test for vancomycin resistance
(4)
Vancomycin disc diffusion for 24 hours (!!!)
Suspect resistance if zone edge is fuzzy or colonies grow within the inhibition zone
MIC or VITEK can be used
VITEK not good at detecting low levels or resistance
Write a note on ESBL producing GNBs
(4)
Arose in 1980s
B-lactamase production - ability to hydrolyse extended spectrum B-lactams i.e. cephalosporins
Predominate in K. pneumonia and E.coli but increasingly seen in other Enterobacterales
Associated with HCAI resulting from cross-infection and lapse in infection control but also emerging in the community
Comment on ESBL lab detection
(4)
Screen for ESBL production with routine cephalosporin AST
If reduced susceptibility to cefotaxime or ceftazidime observed confirm ESBL production with Combination Disc Test
CDT -> Disc diffusion with cephalosporin alone and cephalosporin plus Clavulanic acid (B-lactamase inhibitor).
If ESBL present the zone of inhibition will be 5mm smaller with the clavulanic acid as the B-lactamase enzymes are being inhibited
Comment on CPEs
(6)
Production of B-lactamases
Carbapenemase enzymes - ‘Big 5’
OXA-48 and Klebsiellella pneumonia carbapenemase most common (only really seen in Galway)
Usually resistant to many other classes of antibiotics and are virulent
Vast majority of CPEs in Ireland are just colonisation in the gut -> not invasive but this high carriage rate could cause problems later when resistance spreads
70% of CPEs in Ireland were OXA-48
How are CPEs detected in the lab?
(3)
Screen with routine Ertapenem AST
If ertapenem reduced susceptibility then confirm with Resist-5 lateral flow assay
Resist-Ab probes detection of OXA, KPC, NDM and VIM CPEs
How do we combat antimicrobial resistance
Rational drug use
Ban on OTC antibiotics
AMR committee
National Policy
Increased collaboration
New AMR programmes
Std. treatment guidelines
Hand hygiene
Infection control and prevention
Antimicrobial surveillance
Immunisation coverage
Need new novel drugs
What are the three main ways to combat antibiotic resistance
Develop new antibiotics
Antibiotic stewardship
Surveillance and infection prevention and control
Comment on how new antibiotic would control antibiotic resistance
(4)
Novel classes urgently needed for the future
Linezolid and daptomycin are active against gram-positive bacteria such as MRSA but resistance emerging
Few classes in phase II or III clinical trials
Need new drugs for CPEs and CPOs (pseudomonas and acinetobacter)
Comment on antibiotic stewardship
(3)
Judicious use of antibiotics must be promoted
Use of more appropriate drugs, shorter treatment courses and cyclic treatment regimens
Assuming comprehensive strategies are devised. continual audit must be undertaken
How does the lab play a role in antibiotic resistance?
- Labs can supress release of anti-microbial resistance results -> e.g. we put up 5 and 4 are susceptible but we only release the result on one so that the medics will only use one antibiotic – we can control the cycling of antibiotics
- Pharmacist in charge of antimicrobials can also help do this by only issuing certain antimicrobials
Comment on surveillance and infection prevention and control of antibiotic resistance
(3)
Most important options for control of resistance lie in implementation of effective surveillance and infection prevention control
Need for clinical laboratories to: provide accurate antibiotic susceptibility data, develop improved resistance detection methods, participate in local and national surveillance networks to collate resistance data
Need for Healthcare facilities to engage in IPC programmes -> patient isolation and facilities, hand hygiene and transmission-based precautions etc
The iNAP2 framework alligns with 5 strategic objectives outlines in WHO AR Global Action plan, what are these 5 objectives
Improve awareness and knowledge (stewardship)
Enhance surveillance (IPC) of antibiotic resistance and antibiotic use (Stewardship)
Reduce the spread of infection and disease (IPC)
Optimise the use of antibiotics in human and animal health (stewardship)
Promote research and investment in new medicines, diagnostic tools, vaccines and other interventions (Research)
