Antibiotic resistance Flashcards
What is antibiotic resistance?
- The ability of bacteria to survive treatment by certain antibiotics.
- Bacteria which are resistant to multiple antibiotics are called multi-drug resistant (MDR strains)
XDR-Resistant to most antibotics (extensively drug resistant bacteria)
TDR- totally drug resistant to antibiotics
Why is the problem of AMR so bad?
What can be used to differentiate between viral and bacterial infections?
What can GP’s do?
Antibiotic use in humans
- People not taking complete courses of antibiotics
- Inappropriate prescriptions or over-prescription of antibiotics
- CRP test: A c-reactive protein test measures the level of c-reactive protein (CRP) in your blood. CRP is a protein made by your liver. It’s sent into your bloodstream in response to inflammation.
- high infammatory response in bacterial infection, not so high in viral infection (very expensive and turn around time not quick enough)
- GP’s are instead doing delayed prescriptions, they prescribe antibiotics but you are told to wait 2 or 3 days to see if you feel worse, if so take and finish the course of antibiotics
Why is the problem of AMR so bad?
Non-therapeutic uses of antibiotics
•To treat sick animals:
Solution: use different classes of antibiotics for animals than for humans
•As growth promoters in agriculture (Not in the EU!)
Still have meat imported from outside the EU
•Biocide use
Triclosan (stops bacteria and fungal growth in soaps, body washes, toothpastes and some cosmetics) shown to increase antibiotic resistance
- Brewing
- Aquaculture
Feeding antibiotics to fish them eating the fish
•Anti-fouling (industrial, ships)
Prevent build up of algal bloom on shipping equipment
Survival of the fittest
•Selection of bacteria with (an) advantageous physiological trait(s) that enables survival in the presence of an antimicrobial
Do not have quality control mechanisms that eukaryotes have within their DNA replication processes which often gives rise to mutations
If selective pressure is maintained, those organisms grow and transfer the resistance (horizontal gene transfer) to other bacteria
•Darwinian evolution
How does this work in people?
Why should you always complete the full course of antibiotics?
- When you have an infection the bacterial population is high, causes a large inflammatory response
- Inflmation presses on the nerves and causes pain
- Start taking antibiotics, imflammation reduced, bacterial load reduced pain alleviated (80% reduction of bacteria in the first 24-48 hours of taking the antibiotics)
- Stop taking antibiotics prematurely
- Causes selection for persista population which can grow back and recolonise and reinitiate the inflammation and pain so you require another (different course of antibiotics)
Why is the problem of AMR so bad? No new antibiotics!
- Novel therapeutics are now needed to combat antibiotic resistant infections
- 14 classes of antibiotics were introduced for human use between 1935 and 1968; since then, only 5 have been introduced.
- Pheotypic strategy adopted in early 2000
The future of antibiotic resistance
Forecasted future for antibiotic resistance
700,000 deaths- 10 million deaths (by 2050)
Economic impact also forecasted
How do bacteria become resistant to antibiotics?
- Make enzymes which alter or destroy the antibiotic (Beta lactomase can hydrolyse beta lactam very efficiently)
- Alteration of target site (can mutate the target, this means that the antibiotic can no longer bind to the target but the enzyme can continue to function)
- Prevent antibiotics getting into the cell (e.g. change hydrophobicity of cell wall, downregulate outer membrane porins this means less things can get into the bacterial cell)
- Pump (efflux) the antibiotic out of the cell (maintains sublethal concentration inside the cell)
- Temporarily change their metabolism (dormancy) (e.g. adapt carbon source, temporarily shut down core metabolic pathways e.g. stop the process of glycolysis, stop dividing
Inhibition of Transpeptidase by β-Lactam Antibiotics
β-lactam antibiotics inhibit the transpeptidase (similar structure to D-alanyl D-alanine in the peptide chain)
competitive inhibition; irreversible binding
Types of β-Lactam Antibiotics: Cephalosporin
Third generation
- Cefalexin
- Cefuroxime
- Cefotaxime
- Ceftriaxone
Types of β-Lactam Antibiotics: Carbapenem
Second generation
Meropenem
Imipenem
Doripenem
Ertapenem
Types of β-Lactam Antibiotics: Penicillin
- Narrow Spectrum:
Benzylpenicillin (Penicillin G)
Phenoxymethylpenicillin (Pen V)
Flucloxacillin
- Broad Spectrum:
Amoxicillin/Co-amoxiclav
Ampicillin
Piperacillin with Tazobactam (Tazocin)
Enzymes which alter or destroy the antibiotic
First generation *
- Can be encoded in their genome or on plasmids (ca be transferred horizontally)
- The β-lactamases (penicillinases)
- Adaptive resistance mechanism
- Hydrolyse the β-lactam ring to produce inactive metabolites so it is no longer functional
- Broad spectrum resistance mechanism for a variety of β-lactams
- Gram –ve β-lactamases excreted and β-lactams can be hydrolysed in their local environment as well as inside the cell
From the diagram:
Reduction in zone of inhibition
Enzymes which alter or destroy the antibiotic
- Extended spectrum β-lactamases (ESBLs)
Inhibit a huge variety of β-lactams
Discovered in 1980s
Plasmid-encoded
Confer multi-resistance
- Inhibit a wide range of β-lactams
Resistance to penicillins and extended-spectrum cephalosporins
Carbapenems can be used (but resistance reported)
- ESBL are found in: 90% E. coli resistance. Also H. influenzae, K. pneumoniae, N. gonorrhoeae
β-Lactamase inhibitors
- Combinations with β-lactam antibiotics
- First was co-amoxiclav (aka. Augmentin or clavulin) which is clavulanic acid (contains the β-lactam ring but has a much higher affinity for the β-lactamase enzyme than for the PBP’s)in 1985 (by GSK-Beecham)
- Combination of amoxicillin and clavulanic acid that (Co-amoxiclav)
- Competitive suicide inhibition (irreversible):
- Clavulanic acid has a high affinity for and binds to β-lactamase rendering it ineffecative. This means that amoxicillin can inhibit PBP’s and cause lysis
- Broad spectrum - U/LRTI (respiratory tract infections), skin, sinus etc.
- Latest: Piperacillin with Tazobactam ( produced by MSD) these are non-competitive so dont bind to the enzymes active site; they bind elsewhere
Clavulanic acid - Mode of action (MOA)
*
- β-lactam goes into the bacterial cell and inhibits the bacteria by binding to the PBP but β-lactamase produces a hydrolysed β-lactam that doesnt bind the PBP anymore
- Add Clavulanic acid 1 in every 1000 molecules will covalently bind to β-lactamase and brings about suiside inhibition of that enzyme
- This frees up antibiotic amoxicillin to block the PBP’s and the bacteria dies as a result
The spread of AMR: The big picture
Describe the chain of infection
How can we break the chain of infection and stop the spread of microorganisms?
- Environmental resovoirs of antibiotic resistance in animals
- Impacts the farms and the environments they live in
- People consume the meat products therefore ingest the antibiotics
- There are antibiotic resistant infections in hospitals; a hospital-acquired infection (HAI), also known as a nosocomial infection
- Patients go home and spread these resistant infections into the community
- Hygiene:
- Wash your hand after you go to the toilet
- Wash your hand after using public transport
- Wash your hand before you eat
- Cover your mouth and nose when you sneeze/cough
