I wonder how these bacteria can /remain/ resistant against older antibiotics. If they mutate really fast, should not the resistance against, say penicillin, vanish after a few years when they are not exposed to the medicine?
So could we not "renew" some antibiotics by simply not using them for 5 to 10 years?
Depends. The multidrug resistant variants tend to be resistant to most everything and this resistance does not cost them enough for it to get discarded.
Moreover certain viruses cause the resistance to spread horizontally, and some bacteria do share genomes locally as well.
It is not necessary that mutation would cause the loss of a previously developed resistance.
It is not just the bacteria that grow resistant to drugs, but the human body itself starts to develop resistances. One of the major factors behind this is the presence of antibiotics in the various meats we consume. Animal antibiotics are a huge gift to the factory farming industry. But to acheive better results, many animal farmers simply (and often illegally) use the highest dose of the antibiotic they can find. A small amount of these drugs eventually make their way to human bodies. Persistent exposure to such drugs then results in increased resistance to antibiotics. So where previously a regular dose of a milder antibiotic would have sufficed, now a high dosage of a strong antibiotic is required.
Could you provide some evidence to back up your statement? As far as I am aware, antibiotics directly impact bacteria via impairing DNA, ribosomal, or cell wall synthesis. The human body does break down antibiotics via the liver, and it’s rate can be increased by numerous drugs (but not normally antibiotics) and this would not be seen as resistance.
I don’t think the concept of human resistance to antimicrobrials is consistent with conventional biological knowledge.
If you do a quick google search for “human resistance to antibiotics” you’ll find a number of good results. Any evidence I would cite would be from the more reputable sources, such as government agency websites, wiki, known scientific publications.
While I’m not a trained professional in that area to debate the specific mechanisms, I am sufficiently informed from sufficiently reliable sources about the topic.
As an example, this report from the US National Institute of Medicine titled “The Antibiotic Resistance Crisis” seems to strengthen the case the article linked by the OP of this thread is making. To quote selectively from the aforementioned report,
"The overuse of antibiotics clearly drives the evolution of resistance. Epidemiological studies have demonstrated a direct relationship between antibiotic consumption and the emergence and dissemination of resistant bacteria strains. In bacteria, genes can be inherited from relatives or can be acquired from nonrelatives on mobile genetic elements such as plasmids. This horizontal gene transfer (HGT) can allow antibiotic resistance to be transferred among different species of bacteria. Resistance can also occur spontaneously through mutation. Antibiotics remove drug-sensitive competitors, leaving resistant bacteria behind to reproduce as a result of natural selection. Despite warnings regarding overuse, antibiotics are overprescribed worldwide"
“Incorrectly prescribed antibiotics also contribute to the promotion of resistant bacteria”
"More recently, molecular detection methods have demonstrated that resistant bacteria in farm animals reach consumers through meat products. This occurs through the following sequence of events: 1) antibiotic use in food-producing animals kills or suppresses susceptible bacteria, allowing antibiotic-resistant bacteria to thrive; 2) resistant bacteria are transmitted to humans through the food supply; 3) these bacteria can cause infections in humans that may lead to adverse health consequences."
Should you wish to debate the technicalities of the topic further, I can only suggest waiting for a trained microbiologist to show up in this thread, or getting in touch with the authors of the aforementioned report and the various references linked therein (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378521/)
Perhaps I miss understand you more than anything. Thank you for the quotes and papers. I agree with you that antibiotic resistance (of bacteria) can rise due to the use in the harm industry, the part that I am sceptical is your statement that the human body itself becomes resistant to antibiotics. The sources you provided discuss bacterial resistance, which is very different from human body resistance.
It depends on how the resistance works. Some forms of resistance require active effort by the bacterium (for example efflux pumps), and you would expect that in the absence of an antibiotic they would tend to be lost by natural selection. But other forms of resistance are just minor mutations stopping the antibiotic from binding or whatever, and these probably would remain at least in some fraction of the bacterial population as they are more or less neutral.
The human immune system can deal with a huge range of things just fine. So, the metabolic weight from antibiotic resistance is inherently useful for Humans.
Antibiotic resistant bacteria do kill people, but most often as secondary infections due to a compromised immune system. Further, even if the primary infection has near total resistance suppressing secondary infections is still extremely useful.
Are you saying the adaptations bacteria make to become resistant to antibiotics causes them to be easier targets for the immune system? Do you have a link I could read more about this?
Yes, but not always, and not necessarily for long.
"While the cost of resistance is highly variable, such resistance mutations or genes often come with a fitness cost that reduces the rate of bacterial proliferation (Dahlberg & Chao, 2003; Melnyk et al, 2015)." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371735/
"The success of resistant mutants critically depends on rapid counterbalancing of the decreased fitness by acquiring compensatory mutations (Levin et al, 1997; Marciano et al, 2007), which in most cases restore normal growth while preserving resistance to the antibiotics (Marcusson et al, 2009). The number and variety of compensatory mutations required to successfully compensate fitness cost varies with organism (Palmer & Kishony, 2013, 2014; Cheng et al, 2014) and the particular environmental conditions under which compensation occurs (Testerman et al, 2006; Hoffman et al, 2010; Toprak et al, 2012; Lindsey et al, 2013)."
Basically, resistance become extremely important so anything that works get's adapted. But, after that point the search for mutations that reduce cost shows up. The second stage also depends on continuous exposure to antibiotics as reverting the mutation in a population is relatively simple.
Seems like the problem is how long it takes to lose the resistance. Probably a few decades rather than a few years. And you'd need all the world to stop, which just isn't going to happen in Asia, Africa, South America where you can just buy a couple of pills from the local pharmacist if that's all you can afford. Not an easy problem to deal with sadly.
Unfortunately, the genes developed for resistance are still present in a certain portion of the pool... so that when antibiotics are used it only takes 1 to multiply exponentially and destroy the resistance. Some of the genes cost little extra to be selected against... and even when an expensive group are selected against, it can split up into more than one survivor and then the combination will be selected for again.
Like old code... most of those once useful genes don't ever fully go away.
I asked something similar in a reddit AMA[1] with Mark Blaskovich, from Open Antimicrobial Drug Discovery. His answer wasn't super satisfying, but for what it's worth:
> The resistance genes will likely remain, but be 'switched off', so resistance would re-emerge quickly. The cycling approach could theoretically work to some extent, but the logistics on a worldwide scale would be impractical. Mark B
Counterpoint: A recent Kurzgesagt video suggests that we may be able to deploy bacteriophages (bacteria-attacking viruses) to combat superbugs. https://www.youtube.com/watch?v=YI3tsmFsrOg
Note: I'm not a doctor/biologist/etc., so I cannot comment on the details of this claim (e.g. how far away we are from a widely deployed phage-based treatment).
My extremely limited understanding is that a given bacteriophage only attacks a very specific strain, and thus that you would need to constantly evolve them to fight new strains. While perhaps not useless, that doesn't sound like a replacement for antibiotics.
In the Soviet Union, they used cocktails of bacteriophage in much the same way as broad-spectrum antibiotics are used, whenever it was impractical to identify the bacterial strain.
Bacteriophage evolve of their own accord, so phage resistance is temporary. Often the bacteriophage strain you need already exists and you just have to find it. This is much less effort than developing a new antibiotic.
Also bear in mind that as far as new strains in one patient go, unlike antibiotics they will evolve themselves to chase the new strain down, and that's useful.
Given how medicine works in the US, that's not a problem, but an opportunity.
US Medicine is for profit, and the money is in reoccuring treatment, not cures. So a never ending battle of cat-and-mouse is the type of R&D phramas would love.
A potential future scenario:
Keep going to your doctor to get a Rx for the latest strain or pay a monthly fee to a Bacteriophage-As-A-Service SV tech company to get the latest delivered right to your door you use in conjunction with a smartphone app.
The latter of which would have operated illegally until sufficiently large enough to hire insider DC lobbyists to gut the FDA.
And yet phage therapy's been successfully used under communism but not capitalism. This is because it's cheap, low tech, and there are no economic barriers to market entry.
You are correct, however with new sequencing technologies like the MinION[1] we have access to real-time sequencing in something roughly the size of a cell phone.
They are still in development and there are some technical hurdles, but before too long cheap, fast, and accurate strain typing should be ubiquitous. The next issue is then creating the specific phages, but the first stage is pretty close at hand.
And the final issue will be actually getting this in the field for non laboratory personnel. Where a GP can fashion a phage in their office and/or order one as easily as the right antibiotic.
Good luck trying to even get the bacterial sample to do it for quite a few kinds of infections. Lungs and other organs would need a good biopsy or at least really well done aspiration, handling of samples is very messy.
It is a good method to use in hospital settings perhaps where you want to sample anyway.
Reading the Wikipedia article, it sounds like we're nowhere close to being able to deploy phage therapy on a large scale, due to practical, economic, and regulatory challenges.
They were deployed on a large scale in the Soviet Union. They're not patentable, so it's difficult for private companies to make money out of them. Phage therapy could still be developed by a government-owned and run health service.
The phages are found in nature so you cant really patent them. Using them to treat patients has been done for a century or so so it's hard to patent that.
The FDA could help by letting anyone provide phage therapy without further testing given it's been proven over the decades and is pretty harmless to humans. At the moment I think you'd be blocked by regulations, unnecessary ones in my opinion.
It's unclear to me whether this is something a normal person would have access to, in the same way as antibiotics. Maybe it is, but I'm just not assuming this to be the case.
Phage therapy is as effective as antibiotics but it is not as convenient as chemotherapy.
One of the problems with phage therapy is precision. You have to know roughly what kind of bacteria is causing the infection. To know that it takes tests, and time, which cost money. Antibiotics on the other hand are broadspectrum and can be deployed without much prior knowledge (which is cheap, but also a problem that causes resistance).
The other problem is production and regulation. Antibiotics are chemical, phages are biological. It is much harder to produce a consistent safe product with a biologic compared. We don't have the infrastructure (yet) to mass produce viral phages for consumers.
Even if we did, the sampling itself would be onerous. Unless you could somehow guess the phage based on immune response or metabolic products as in blood sample. Which is extremely hard to pull off and still much harder than guessing the right antibiotic in most cases.
I Heard something controversial on the radio the other day. Don't finish your antibiotic course. Stop when you feel better.
The rational was:
Bacteria becoming resistant due to a treatment has only ever been proven for a handful of conditions( TB , HIV syphilis, and so on). The other bacteria are ether resistant or they aren't prolonging the treatment does not encourage a resistant mutation.
By prolonging your treatment with antibiotics you create an environment in which antibiotic resistant bacteria, both the good and bad kind, can replicate easier. Due to Horizontal gene transfer good bacteria can transfer their antibiotic resistance to bad bacteria.
This advice is in stark contradiction to the Fleming quote.
I heard it on the radio and can't remember the sources, but it makes sense to my non medical mind.
It only "makes sense" if you don't understand why you should finish your anti-biotics. And don't know or understand the alternative outcomes outside the reasoning you've proposed.
IE you feel better, aren't better, and risk re-infection.
It's probably much more effective overall to take the guesswork out and follow a consistent routine for each patient. If you give the patient the option to wing it, and they do and that doesn't work, they're not going to take responsibility for it. They'll blame everyone but themselves for a bad outcome.
OF coarse doctors are always going to err on the side of caution, part of the reason for the super bugs in the first place have been given as the over prescription of antibiotics. Not just over prescription in that antibiotics are not needed also the over prescription of duration.
I think the whole feel better approach will help antibiotics resistance not necessarily the patient.
Will be interesting to see the risk of "reinfection vs risk of over prescription" graph.
Horizontal gene transfer thing is what I found really interesting
Why are there so many downvotes? There is a journal article linked that questions the common wisdom that failing to complete a prescribed antibiotic course contributes to antibiotic resistance that everyone replying is parroting.
The wikipedia page about antibiotics resistance (https://en.wikipedia.org/wiki/Antimicrobial_resistance) adds some interesting points on why we are falling behind on the race for the discovery of new antibiotics.
The TLDR is it's currently not economically convenient for big pharmaceutical companies to invest in antibiotics research but several measures have been taken in order to make it better and, hopefully, will allow us to catch up on the race.
Norway seems to have a particularly enlightened approach to antibiotics.
In particular not using antibiotics as a growth stimulant (common on farms), reserving certain antibiotics for human use, and training doctors and vets on their use.
51 comments
[ 3.5 ms ] story [ 120 ms ] threadSo could we not "renew" some antibiotics by simply not using them for 5 to 10 years?
Moreover certain viruses cause the resistance to spread horizontally, and some bacteria do share genomes locally as well.
It is not just the bacteria that grow resistant to drugs, but the human body itself starts to develop resistances. One of the major factors behind this is the presence of antibiotics in the various meats we consume. Animal antibiotics are a huge gift to the factory farming industry. But to acheive better results, many animal farmers simply (and often illegally) use the highest dose of the antibiotic they can find. A small amount of these drugs eventually make their way to human bodies. Persistent exposure to such drugs then results in increased resistance to antibiotics. So where previously a regular dose of a milder antibiotic would have sufficed, now a high dosage of a strong antibiotic is required.
I don’t think the concept of human resistance to antimicrobrials is consistent with conventional biological knowledge.
https://www.google.com/search?rls=en&q=human+resistance+to+a...
While I’m not a trained professional in that area to debate the specific mechanisms, I am sufficiently informed from sufficiently reliable sources about the topic.
As an example, this report from the US National Institute of Medicine titled “The Antibiotic Resistance Crisis” seems to strengthen the case the article linked by the OP of this thread is making. To quote selectively from the aforementioned report,
"The overuse of antibiotics clearly drives the evolution of resistance. Epidemiological studies have demonstrated a direct relationship between antibiotic consumption and the emergence and dissemination of resistant bacteria strains. In bacteria, genes can be inherited from relatives or can be acquired from nonrelatives on mobile genetic elements such as plasmids. This horizontal gene transfer (HGT) can allow antibiotic resistance to be transferred among different species of bacteria. Resistance can also occur spontaneously through mutation. Antibiotics remove drug-sensitive competitors, leaving resistant bacteria behind to reproduce as a result of natural selection. Despite warnings regarding overuse, antibiotics are overprescribed worldwide"
“Incorrectly prescribed antibiotics also contribute to the promotion of resistant bacteria”
"More recently, molecular detection methods have demonstrated that resistant bacteria in farm animals reach consumers through meat products. This occurs through the following sequence of events: 1) antibiotic use in food-producing animals kills or suppresses susceptible bacteria, allowing antibiotic-resistant bacteria to thrive; 2) resistant bacteria are transmitted to humans through the food supply; 3) these bacteria can cause infections in humans that may lead to adverse health consequences."
Should you wish to debate the technicalities of the topic further, I can only suggest waiting for a trained microbiologist to show up in this thread, or getting in touch with the authors of the aforementioned report and the various references linked therein (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378521/)
Antibiotic resistant bacteria do kill people, but most often as secondary infections due to a compromised immune system. Further, even if the primary infection has near total resistance suppressing secondary infections is still extremely useful.
"While the cost of resistance is highly variable, such resistance mutations or genes often come with a fitness cost that reduces the rate of bacterial proliferation (Dahlberg & Chao, 2003; Melnyk et al, 2015)." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371735/
"The success of resistant mutants critically depends on rapid counterbalancing of the decreased fitness by acquiring compensatory mutations (Levin et al, 1997; Marciano et al, 2007), which in most cases restore normal growth while preserving resistance to the antibiotics (Marcusson et al, 2009). The number and variety of compensatory mutations required to successfully compensate fitness cost varies with organism (Palmer & Kishony, 2013, 2014; Cheng et al, 2014) and the particular environmental conditions under which compensation occurs (Testerman et al, 2006; Hoffman et al, 2010; Toprak et al, 2012; Lindsey et al, 2013)."
Basically, resistance become extremely important so anything that works get's adapted. But, after that point the search for mutations that reduce cost shows up. The second stage also depends on continuous exposure to antibiotics as reverting the mutation in a population is relatively simple.
I'm fairly sure I've come across this idea before. Oh here's an example: https://www.quora.com/What-is-antibiotic-rotation
Seems like the problem is how long it takes to lose the resistance. Probably a few decades rather than a few years. And you'd need all the world to stop, which just isn't going to happen in Asia, Africa, South America where you can just buy a couple of pills from the local pharmacist if that's all you can afford. Not an easy problem to deal with sadly.
https://www.wnycstudios.org/story/best-medicine/
They take a thousand year old recipe for some medication and test it.
Like old code... most of those once useful genes don't ever fully go away.
> The resistance genes will likely remain, but be 'switched off', so resistance would re-emerge quickly. The cycling approach could theoretically work to some extent, but the logistics on a worldwide scale would be impractical. Mark B
[1] https://www.reddit.com/r/science/comments/3k32wi/american_ch...
Note: I'm not a doctor/biologist/etc., so I cannot comment on the details of this claim (e.g. how far away we are from a widely deployed phage-based treatment).
Bacteriophage evolve of their own accord, so phage resistance is temporary. Often the bacteriophage strain you need already exists and you just have to find it. This is much less effort than developing a new antibiotic.
US Medicine is for profit, and the money is in reoccuring treatment, not cures. So a never ending battle of cat-and-mouse is the type of R&D phramas would love.
A potential future scenario:
Keep going to your doctor to get a Rx for the latest strain or pay a monthly fee to a Bacteriophage-As-A-Service SV tech company to get the latest delivered right to your door you use in conjunction with a smartphone app.
The latter of which would have operated illegally until sufficiently large enough to hire insider DC lobbyists to gut the FDA.
Please provide numbers of patients treated with phages, time to treat one and efficacy numbers.
They are still in development and there are some technical hurdles, but before too long cheap, fast, and accurate strain typing should be ubiquitous. The next issue is then creating the specific phages, but the first stage is pretty close at hand.
[1] https://nanoporetech.com/products/minion
Good luck trying to even get the bacterial sample to do it for quite a few kinds of infections. Lungs and other organs would need a good biopsy or at least really well done aspiration, handling of samples is very messy.
It is a good method to use in hospital settings perhaps where you want to sample anyway.
https://en.wikipedia.org/wiki/Phage_therapy
The FDA could help by letting anyone provide phage therapy without further testing given it's been proven over the decades and is pretty harmless to humans. At the moment I think you'd be blocked by regulations, unnecessary ones in my opinion.
You might be able to patent genetically engineered ones, or a novel process involving them.
One of the problems with phage therapy is precision. You have to know roughly what kind of bacteria is causing the infection. To know that it takes tests, and time, which cost money. Antibiotics on the other hand are broadspectrum and can be deployed without much prior knowledge (which is cheap, but also a problem that causes resistance).
The other problem is production and regulation. Antibiotics are chemical, phages are biological. It is much harder to produce a consistent safe product with a biologic compared. We don't have the infrastructure (yet) to mass produce viral phages for consumers.
The rational was: Bacteria becoming resistant due to a treatment has only ever been proven for a handful of conditions( TB , HIV syphilis, and so on). The other bacteria are ether resistant or they aren't prolonging the treatment does not encourage a resistant mutation.
By prolonging your treatment with antibiotics you create an environment in which antibiotic resistant bacteria, both the good and bad kind, can replicate easier. Due to Horizontal gene transfer good bacteria can transfer their antibiotic resistance to bad bacteria.
This advice is in stark contradiction to the Fleming quote.
I heard it on the radio and can't remember the sources, but it makes sense to my non medical mind.
*edit added sources.
Found the journal entry if anyone cares : https://www.bmj.com/content/358/bmj.j3418
Article about journal entry : https://edition.cnn.com/2017/07/27/health/antibiotics-course...
IE you feel better, aren't better, and risk re-infection.
It's probably much more effective overall to take the guesswork out and follow a consistent routine for each patient. If you give the patient the option to wing it, and they do and that doesn't work, they're not going to take responsibility for it. They'll blame everyone but themselves for a bad outcome.
I think the whole feel better approach will help antibiotics resistance not necessarily the patient.
Will be interesting to see the risk of "reinfection vs risk of over prescription" graph.
Horizontal gene transfer thing is what I found really interesting
Found the journal entry if anyone cares : https://www.bmj.com/content/358/bmj.j3418
Article about journal entry : https://edition.cnn.com/2017/07/27/health/antibiotics-course...
In particular not using antibiotics as a growth stimulant (common on farms), reserving certain antibiotics for human use, and training doctors and vets on their use.
More info at: https://www.regjeringen.no/en/aktuelt/norways-battle-against...
Same site mentioned Germany users 50x more antibiotics in their meat preparation than Norway.
https://www.regjeringen.no/en/aktuelt/norway-takes-the-lead-...
Related article on fighting "super bugs" like MSRA: http://www.spokesman.com/stories/2010/jan/03/norways-mrsa-so...