Mechanisms of antibiotic resistance

[sarjasy]

Maybe a little off topic, but would like to hear from any of you micro buffs or others that have a good grasp on this.

I am constantly hearing and reading about drug resistance related to failure to comply with therapies, “overuse” of antibiotics, etc. I’ve yet, however, to find anyone that can explain the exact mechanism of how this occurs. Explanations just don’t seem to add up.

The first idea is that antibiotic therapies where the patient is noncompliant and/or fails to complete therapy selects for resistant strains. How does it select exactly? Some kind of selective pressure? If so, has this been demonstrated in studies?

The second idea is that in noncompliant and/or failure to complete patients, random mutation pops out a critter that eats antibiotics for breakfast. This makes the least sense to me. Let’s say it is 1965 and George has a nasty boil. Culture shows S. aureaus. He gets his penicillin, takes it for a few days and notices the boil looks better and quits the meds. Let’s say, hypothetically, the penicillin knocked out 50% of all staph cells. What exactly now happens to the remaining 50% that has given us the modern day gift of MRSA? Seems to me a random mutation could occur at any point during therapy or with no therapy at all and the introduction of penicillin is irrelevant. How, exactly, does therapy and/or failure to comply with it increase the odds of a resistant mutation? Cannot a resistant mutant emerge completely randomly in the absence of treatment?

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[The right Path]

One mechanism is that bacteria can transfer plasmids that contain genes that code for enzymes that inactivate antibiotics: such as the gene for beta lactamase.

If a patient that has a staph infection (mostly penicillin sensitive) is treated with penicillin appropriately, the antibiotic would be effective against most of the bacteria and the patient's immune system will take care of the rest. If it is inadequtely treated, both sensitive and resistant strains continue to exist and the resistant strain has a greater opportunity to pass on its resistant genes.

 

[sarjasy]

One mechanism is that bacteria can transfer plasmids that contain genes that code for enzymes that inactivate antibiotics: such as the gene for beta lactamase.

Right, and if I'm not mistaken, that gene has been found in bacteria living in mummified remains, interestingly enough, so it does not exist as a result of selective pressure (at least from "synthetic" antibiotics). Not arguing with you, BTW, just throwing that out there.

If it is inadequtely treated, both sensitive and resistant strains continue to exist and the resistant strain has a greater opportunity to pass on its resistant genes.

But sensitive and insensitive strains would continue to exist without treatment as well. How does treatment itself increase the probability? I understand how the susceptible bacteria and normal microbiota can inhibit growth of the resistant strain and that treatment can wipe them out, allowing the resistant bugs free reign to multiply and pass on their genes. But again, not treating allows the resistant bugs to live on, which seems to me would give them more time to pass on their super powers to their sensitive buddies and possibly the normal flora as well (I think plasmids can even be passed between species).

 

[Paseo Del Norte]

But sensitive and insensitive strains would continue to exist without treatment as well. How does treatment itself increase the probability? I understand how the susceptible bacteria and normal microbiota can inhibit growth of the resistant strain and that treatment can wipe them out, allowing the resistant bugs free reign to multiply and pass on their genes. But again, not treating allows the resistant bugs to live on, which seems to me would give them more time to pass on their super powers to their sensitive buddies and possibly the normal flora as well (I think plasmids can even be passed between species).

Look at it more in terms of natural selection. By killing off sensitive bacteria, you in essence create a situation where bacteria with resistance can flourish without any competition. Do not look at bacteria as having "buddies," bacteria are very much in competition and the widespread use of antibiotics has led to a situation that favours these resistant strains. They have always been around, but now they have no competition and can flourish.

In my mind, it really seems a very intuitive outcome.

 

[nlax30]

PDF (2006 American Journal of Medicine) Mechanisms of Antimicrobial Resistance in Bacteria

Just found this. Talks briefly about the different ways that resistance occurs and gives a few case studies/examples of resistant bugs.

 

[Frozen]

Look at it more in terms of natural selection. By killing off sensitive bacteria, you in essence create a situation where bacteria with resistance can flourish without any competition. Do not look at bacteria as having "buddies," bacteria are very much in competition and the widespread use of antibiotics has led to a situation that favours these resistant strains. They have always been around, but now they have no competition and can flourish.

In my mind, it really seems a very intuitive outcome.

This. Plus there are many gradients of resistance. (Highly resistant to slightly resistant).

Patients who do not complete their meds provide a constant cycle of selecting for more resistant strains of critters (especially in recurrent infections).

Their is also the aspect of stress induced mutations: increased stress on many bacteria results in higher rates of mutations. If a population of bacteria are not sufficiently destroyed by appropriately long antibiotics, those that are left behind will be damaged and often with mutations which can lead to increased genetic diversity (and thus more likely to have mutated antibiotic target proteins--> resistance).

 

[Paseo Del Norte]

This. Plus there are many gradients of resistance. (Highly resistant to slightly resistant).

Patients who do not complete their meds provide a constant cycle of selecting for more resistant strains of critters (especially in recurrent infections).

Their is also the aspect of stress induced mutations: increased stress on many bacteria results in higher rates of mutations. If a population of bacteria are not sufficiently destroyed by appropriately long antibiotics, those that are left behind will be damaged and often with mutations which can lead to increased genetic diversity (and thus more likely to have mutated antibiotic target proteins--> resistance).

Agreed. You can have a strain that may be "weakly" resistant that would have been eliminated if a full course was taken and adequate concentrations antibiotics were achieved. Instead, you have a bacteria that is resistant to some extent left without any competition.

Also, a generation in the evolutionary/genetic sense is nothing but a G thang for a prokaryotic organism. So, even with good antibiotic use, I still think resistance would eventually be a problem.

Thanks for the stress comments as well.

 

[nlax30]

Also some evidence that actually shortening the course of antibiotics may actually decrease rates of resistance.

So it gets tricky.... do you need that 14 day treatment or is 7 ok? We don't want to undertreat, but you also don't want to "overtreat" and increase the amount of exposure.

 

[sarjasy]

This. Plus there are many gradients of resistance. (Highly resistant to slightly resistant).

Patients who do not complete their meds provide a constant cycle of selecting for more resistant strains of critters (especially in recurrent infections).

Their is also the aspect of stress induced mutations: increased stress on many bacteria results in higher rates of mutations. If a population of bacteria are not sufficiently destroyed by appropriately long antibiotics, those that are left behind will be damaged and often with mutations which can lead to increased genetic diversity (and thus more likely to have mutated antibiotic target proteins--> resistance).

OK, but as I mentioned earlier, NOT treating also allows the resistant/mildly resistant to continue on as well, albeit inhibited by whatever other bugs are present around it. Seems to me increased resistance could very well occur in the absence of treatment, just at a slower rate.

Would it be correct to say that improper use/overuse of antibiotics accelerates or increases the odds of resistance rather than causes resistance? After all, it appears resistance occurs anyway, e.g. beta lactamase being found in ancient bacteria before "man-made" penicillin was ever used.

 

[pamac]

there certainly are studies that demonstrate what you are asking about. its pretty basic.

heres a way to look at the random mutation issue and how it plays out on a practical level...

you have a population of bacteria in a patient that is pathogenic... its all descended from the initial infection. random mutations are taking place in all the descendents. now you start antibiotics. the first individual bacteria that start to die are the ones that have genetic code that leave them vulnerable to the antibiotic. ones that had genetic mutations that provided varying degree's of resistance are starting to survive. i liked what frozen said about the increased likelyhood of damage taking place on the survivors dna. i havent come across that as a mechanism (so if its out there that that takes place, that would be an interesting notion to consider as well). in the case of antibiotics taking out bacteria, often its a case of dosage being the answer. if the patient doesnt give time for the dosage to hit the bacteria with the lethal dose, then you just have selected for bacteria that are resistant. the following generations offspring carry the genes that make them more resistant. any bacteria that is shed carries more resistance than the original ones that were wiped out.

given enough time, the antibiotic would probably have overwhelmed the pathogen population and left no survivors, but when we stop prematurely we really do cause resistance. the random mutations that are angry and formidable do have the possibility of emerging randomly on thier own, but its a numbers game that we sped up by making the bacteria with the mutation the star of the show.

so if you dont treat, the patient gets overwhelmed by the original pathogen (weaklings and all). if you treat incompletely, you farmed up bacteria that are more formidable, and did the job of weeding the garden of the weaklings. when you said that increased resistance still would occur, but at a slower rate, you are correct. not treating it only means that the bacteria from the original infection (all strains... resistant or otherwise) have an unchecked opportunity to overwhelm the host, and no one mutation goes to the forefront of the infection, because they all are equally deadly when left unchecked.

any of the bacteria that do spread are in the same raios that they were in originally, and the random 1 in a billion mutation is spread along with the countless other bacteria that dont have the supermutation. but if you treat with antibiotic and kill off 999, 999, 990, and the one in a billion mutation made it with 9 of his siblings, and they then infect, you have a 1 in 10 chance that if that colony infects someone, the bacteria that thrive will will have your enhanced mutation. and originally, your bacteria only had a 1 in 1 billion chance of being the bacteria. you just sped up time and amplifyed the resistance. very quickly, that mutation is in most or all of the bacteria, and any new infected patient is then given a round of antibiotic... another 1 in a billion mutation pops up that makes the bacteria a little more resistant... the antibiotics kill 999,999,990 (with the new mutation among the survivors)... it spreads.... you get more resistance. you make it easier for the bacteria to rack up traits that make it meaner and meaner. thats your mechanism.