Drug resistance Flashcards
Where does drug resistance come from?
- overuse of anibiotics in clinical settings
- After WWII we needed food! Research into supplements lead to the “accidental” discovery that feeding animals antibiotics increased weight gain.
By 1951 deliberate use of penicillin, aureomycin, bacitracin, streptomycin, and terramycin as growth promoters
By 1969 the UK noted 168 tonnes of antibiotics being fed to animals - direct infection - for example in petting zoos you have all these wash stations so you don’t come in contact with the pathogens that have resistance and you don’t promote spillover
-transfer of ressistance genes - not necessarily the disease has spilled over but the resistance has been transfered from one bacterium to another
Hoc could you decrease the drug resistance?
Decrease antibiotic use in animals
Motivate drug companies to make new generation anti-biotics
New antibioitics in pharmaceutical pipeline are limited because they can’t recover the development sots when new antibioitics are required by populations that can’t afford them- new schemes for motivating these companies
From a biological point of view where does resistance come from?
- From a human perspective microbial drug resistance is the process by which pathogens evolve defences against pharmalogical compounds used to treat infections
- Clinical anti-biotics are frequently isolated from microbes that exist in the natural world and in that natural world deploy secondary metabolites in order to compete.
In their natural state, a majority of microorganisms produce antibiotics in nonlethal trace amounts - Every function metagenomics screen of microbial populations has found evidence for novel resistance genes
If these resistance genes confer a fitness advantage they will be selected for even at sub clinical levels.
What is the correlation between heave metal tolerance and drug resistance and why does it exist?
That correlation exists because bacteria who are good at pumping out heavy metals are also quite good at pumping out antibiotics
What is mixing and what is the purpose?
- multiple distinct antibiotic regimes are prescribed to different patients to create a “spatial mosaic”
- aims to increase heterogeneity of selection pressure so resistant bugs can’t readily spread from patient to patient
When is mixing the most beneficial?
- only beneficial when initial resistance frequencies are low
- best results when several drugs used
- network is important- how big and who it contains
What is cycling?
- a particular class of antibiotics is useful preferentially for a period of time followed by a different class
- relies on resistance imposing a fitness cost in the absence of antibiotic selection and assumes resistance will decline when antibiotic use is suspended
What is combination therapy?
- simulations use of more than one drug in an individual - simultaneous occurence of multiple resistance mutations in a cell is very unlikely
- need drugs with similar level of persistance and efficacy
What can happen when drugs work synergistically and antagonistically?
if drugs work synergistically (increased efficacy together) single mutation can confer resistance to one drug and cancel out the synergetic benefit other and increase the fitness benefit of resistance
if drugs work antagonistically this can protect from resistance because resistance to one drug will provide limited benefits
How can concentration and duration of doses affect drug resistance?
- high doses impose intense selection for resistance
- one solution is to decrease the concentration to the lowest required to get treatment effect (you feel better) to slow the spread of resistance
- however, danger that reducing the dose will increase mutation supply
- shorter duration can provide benefits of the low dose regime with less selection on commensals and environmental bacteria and less increase of mutations supply
Do drug-susceptible parasites help control the spread of drug resistant parasites?
- in normal conditions you have a mouse with parasites and the non resistent parasites almost always outcompete the resistent parasites
- when you trat your mouse with drugs then you are only left with the resistent parasites which are then released from the competition and are now able to grow much more
-Most of the mosquitos that now feed on the resistant mice are now also resistant
What does WHO recommend to for fighting drug resistance?
- The WHO recommends that once more than 10% of patients
are failing to respond to treatment with a particular drug, that
drug be withdrawn from front-line use by national authorities [4].
One way to prevent the spread of parasites with resistance levels
high enough to render a drug insufficiently efficacious for clinical
use is to preemptively kill sensitive or semi-resistant parasites with
drugs, since dead parasites cannot mutate to the drug-threatening
high-level resistance. This is the resistance management justification
for designing treatment regimens aimed at removing all
parasites as fast as possible from a patient [4]. This strategy can be
an important weapon in the fight against drug resistance, but our
data clearly demonstrate the unavoidable downside of this strategy
[42]: it confers exceedingly strong evolutionary advantages on any
high-level resistance that is already present in an infection.
It can, by killing parasites, control the
probability that de novo mutants will occur in a patient in the first
place, but only at the cost of imposing very strong selection for any
that are already there.
What happens when an organism requires a resource and their competitior doesn’t
when an organism requires more of a limiting resource to survive than it’s competitior , depleting the resource will tip the competitive scales in favour of the organisms competitor
