Antibiotics Resistance Flashcards
Why is antibiotic resistance a global concern?
~ 25,000 people die every year across Europe because of infections related to Antimicrobial Resistance (AMR)
In USA, MDR infections cost the health-care system ~20 billion US$ annually and generate more than 8 million additional hospital days.
What does antibiotic resistance do?
- increases mortality
- challenges control of infectious diseases
- threatens a return to the pre-antibiotic era
- increases the costs of health care
- jeopardizes health-care gains to society
What is a common misconception about superbugs?
Drug resistant bacteria are NOT MORE pathogenic.
We just have fewer antibiotic options for treatment, so they are more difficult to treat.
List the mechanisms of antibiotic resistance.
DRUG INACTIVATION: The bacteria acquires enzymes that destroy the active component of the antibiotics, rendering them useless.
ALTERED OR NEW TARGET: If the component on the bacteria that the antibiotic targets mutates and becomes unrecognisable, the bacteria has effectively become resistant.
The components don’t only need to mutate, the bacteria can acquire a new one. This is what happened with MRSA; it acquired a new PBP (PBP2A).
EFFLUX: The bacteria can upregulate proteins that produce efflux pumps, or acquire new efflux pumps. They pump out antibiotics, or anything that the bacteria doesn’t want intracellularly.
INTRINSIC IMPERMEABILITY: The membranes are so impermeable that the antibiotic cannot access them.
OVERPRODUCTION OF TARGET: In terms of folic acid inhibitors, bacteria can overcome their effects by overproducing the target, so they upregulate the genes that produce those enzymes.
METABOLIC BY-PASS: Taking the example of Vacomycin, bacteria that are resistant to it have acquired a set of genes that encode a new biosynthetic pathway, so instead of generating a D-ala D-ala terminal, it makes a D-ala D-lac terminal. The Vancomycin can no longer bind to it, making the bacteria resistant.
What are the three types of mechanisms of resistance?
- natural resistance
- genetic mechanisms (acquired)
- non-genetic mechanisms (growth phases)
Describe natural mechanims of resistance.
Natural Resistance (as opposed to acquired):
The drug must be able to reach the target (overcoming natural barriers, porins, export pumps, etc.).
Gram positive peptidoglycan is highly porous, so there is no barrier to diffusion for the antibiotic.
With Gram negative bacteria, the outer membrane is a barrier to antibiotics, so it gives it a resistance advantage.
Describe genetic mechanisms of resistance.
CHROMOSOME-MEDIATED:
These occurs due to spontaneous mutation:
- in the target molecule
- in the drug uptake system
The mutants are selected, not induced.
PLASMID-MEDIATED:
- common in Gram-negative rods
- transferred via conjugation
- multidrug resistance
What are the three mechanisms by which bacteria exchange genetic information?
1) Transformation: The uptake of naked DNA from a bacteria that has just been lysed by another bacteria.
2) Transduction: When a bacteriophage infects a bacterium, it normally takes with it a piece of host cell DNA and takes it over to the next bacterial host.
3) Conjugation: Two bacteria form pili through which DNA is exchanged, either chromosomal or plasmid.
List the mechanisms by which bacteria become resistant to penicillin.
- produce penicillinases/ β-lactamases that cleave the β-lactam ring = penicillin is inactivated
- acquire alternative forms of/ or mutations in penicillin binding proteins (PBPs) = penicillin can’t bind
- acquire alternative forms of/ mutations in porins = penicillin cannot get into cell
- acquire alternative forms of/ mutations in efflux pumps = penicillins are pumped out faster
How can we overcome resistance due to β-lactamase?
There is a medication combination that is quite common nowadays used to overcome it.
In it, it contains a β-lactam antibiotic (called Amoxicillin) and Clavulanic acid, an inhibitor of β-lactamase enzymes.
With Clavulanic acid blocking the β-lactamase enzyme, it allows the broad-spectrum Amoxicillin to work.
There are many different combinations, designed to block the enzyme that the bacteria have acquired to overcome the antibiotic. Once the enzyme is degraded, the antibiotic can work.
Unfortunately, organisms are now acquiring extended-β-lactamases that are not inhibited by Clavulanic acid. Those bacteria still remain resistant.
Describe how a bacterium can become Vancomycin resistant?
The van operon is a set of genes that regulate the biosynthesis of D-ala D-lac instead of D-ala D-ala.
It’s acquisition gives bacteria resistance to Vacomycin, as it cannot recognise the new sequence.
Describe non-genetic mechanisms of resistance.
INACCESSIBILITY TO DRUGS:
For some parts of the body, it’s difficult to get the drug to concentration that we need.
(e.g., abscess, TB lesion)
STATIONARY PHASE/ VEGETATIONS AND BIOFILMS:
For other parts of the body, bacteria sit and create biofilms, which are very difficult to treat. The bacteria are not resistant, they have just form this muco-polysaccharide surface structure to the biofilm, and the antibiotics can’t get through.
(non-susceptible to inhibitors of cell wall synthesis)
Briefly, how would we conduct an antibiotics resistance test?
Every bacteria that comes through the lab is normally tested for antibiotic resistance.
We do that on these blood agar plates, where we have discs containing antibiotics that diffuse into the agar and stop the bacteria from growing.
We can tell if the bacteria is affected by the zone of inhibition around the disc; if there is no zone, the bacteria is resistant to that particular antibiotic.
What are some ways in which we can prevent/ overcome antibiotic resistance?
CONTROL USE:
- not use them in animal feeds
- complete their course
- prescribe appropriately
NEW OR MODIFIED DRUGS: there have only been a few in the past 25 years
COMBINATION THERAPY:
- medications go for different targets
- they overcome mutation rates
INFECTION CONTROL: can be of the individual, ward or society
Briefly, go through the war of drug resistance with gonorrhoea.
In the 1950s-60s, gonorrhoea could be completely cleared simply with a single dose of penicillin. After a few years, the resistance rate crept up to about 15%.
After that, we switched to Ciprofloxacin (a DNA Gyrase inhibitor). You could use it once at a high dose, and it would clear the infection. However, yet again, the Ciprofloxacin resistance rates crept up.
A new cephalosporin was used called Cefixime; again, all it needed was a single oral dose. Again, resistance rates increase.
Now, the treatment guidelines outline a combination therapy of Ceftriaxone, a 3rd generation cephalosporin, and Azithromycin. This has been used for the last 2/3 years to treat gonorrhoea, but we can see a gradual increase in resistance.
