Week 4 - Evolution of drug resistance Flashcards
What is drug resistance?
It describes the ability of pathogens and parasites to overcome pharmalogical control efforts by developing new mechanisms of evasion
What are the different forms of resistance?
Drug resistance, fungicide resistance, resistance to vaccines (marek’s virus in chickens) and diagnostic resistance (p.falciparum)
What are some genetic mechanisms that lead to drug resistance?
- point mutations e.g. mutations in specific genes can alter parasite functuining like transporter proteings, efflux, folate metabolism to evade drugs
- adaptive copy numbers e.g increased copy number of gch gene increases resiatnce against Fansidar in plasmodium
- Genetic recomination to create new combinations of mutations e.g. HIV and influenza
- Horizontal gene transfer
What are some moelcular mehcnisms of resistance?
alteration, circumvention of target protein, overexpression of target protein, degredation of drug, efflux pumps and changing permeability
Does evolution of resistance always occur?
Not always but highly likely - while evolutionary theory predicts that resisance will occur it cannot predict when or how and there is a limit to the theory. For example penicilli is the antibiotic against syphillis but there is no record of resisance against it despite evidence of it developing reisstance against newer antibiotics
How do parasites evolve resistance?
This is modelled through the Emergence, Establishment, Increase and Equillibrium (EEIE) model
1. Emergence is the first appearance of the resistant genotype in a population, This is done through a stochastic process which depends on mutation rates, immigration rate and population size
2. Establishment is the rise of the resistant genotype beyond the danger of immediate extinction. It depends on the selection coefficient and population size. The smaller the selective advantage and the smaller the population the more chance of the mutation perishing
3. Increase in the resistant genotype to high levels in the population is achieved though a deterministic process, It depends on the selection coefficient
4. Equilibrium is either when the resistant genotype co-exists with the wild type strain or the wild type becomes exctinct.
How is resistance acquired?
The first time a parasite evolves resistace it arises de novo. However later it may be acquired through transmission of the resistant strain to other hosts. The degree to which transmission evolved de novo over and over again or is acquired through transmission varies. For example, resistance often arises de novo for HIV and TB but is commonly acquired through transmission for malaria. This distinction is important for control efforts as acquired resistance offers additional option to prevent and manage resistance through the minimisation of transmition from treated patients
Can we stop the evolution of drug resistance?
No, but we can slow it down by using science to “evolution-proof” control programmes. There are four main factors we can control that influence the emergence, establishment, increase and equilibrium model of resistance:
1. Reduce population size (emergence, establishment)
2. Reduce selection coefficient (establishment, increase)
3. Reduce intensity of selection (Increase)
4. Reduce transmission (increase)
How do you reduce the intensity of selection?
The less drugs are used then the lower the intensity of selection. This can be done through mixing and cycling of drugs. When using different drugs against the same parasite the insenity of each drug is reduced. Cycling includes changing the schedule of the predominant first-line drugs for treatment. Mixing includes alternate assignment of drugs to consecutive patient
How can you reduce population size?
The likelihood of beneficial mutants arising is proportional to the population size, therefore reducing the population size fast can slow down the evolution of drug resistance. This can be done with a high dose of an effective drug and by controlling transmission to target existing infections and prevent new ones - element of speed is crucial. Sub-optimal drug doses won’t work and non-adherance can also promote further evolution by not completely clearing the infection.
How can you reduce the selection coefficient?
Combination therapy of two or more drugs decreases the probability of de-novo resistance because the pathogen with two or more appropriate mutations is unlikely to exist or spontaneously arise. Through combination therapy, clearance of the infection is more likely and this is already recommended for HIV, TB and malaria.
How can you reduce transmission?
For diseases where drug resistance is acquired, like malaria, reducing transmission slows down the spread of resistant genotypes. Reducing transmission can be done through multiple interventions depending on the route of transmission e.g. hygienic measures for waterborne, condoms for STIs, vector control products for vectorborne.
