YouSaid · the spoken record
Dr. Maskid Barmier
- lines on the record
- 19
- first
- 2020-07-19
- most recent
- 2020-07-19
- sittings or episodes
- 1
- sources
- podcast
Every line below is reproduced as it was said and linked to the record it came from. Nothing here is summarised or generated. Directory · Search · Corrections
“The key take home message is that there is hope that by combining basic research in the lab that is really done in close proximity to what's going on in the patient, we will gain an understanding that should help direct treatment much better and even tailor the treatment to the specific bag of the specific patient.”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“Cancer cells yes. So a combination therapy of the immune system targeting therapies together with the drug that takes a load of the cancer cells down so that the immune system can do the rest of the work seems a priori as a good way to think about that. Of course, there are also anti-cancer drugs that act on non-growing cancer cells, but yeah, there are usually also much more toxic, right?”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“Like antibiotics, anti cancer drugs target fast dividing cells, and then target mechanisms that are involved in cell division. If the cells go dormant and stop dividing now, then the anti-cancer drugs aren't going to work. So there could be kind of a similar.”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“So, cancer cells, the fact that they go into phenotypic state that may be much more tolerant to the treatment is something that has been done also by many other groups. So actually we thought about cancer very early on and it was really clear to us that anti-cancer drugs were actually like using antibiotics against bacteria without the help of the immune system, right? It's a lost battle. So clearly they are the way to go was to recruit the immune system to help the drug, so to have a joint effort as we have in typical bacterial infection between the immune system and the drug. It's quite clear that the calcitrants of cancer cells treatment is really something that occurs a lot and resistant developers almost inevitably”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“Yes, so there are pathogens that have been identified already in the evolution of tolerance such as pseudomonas, slepsiella, all kind of pathogens that infect cystis fabrosy patients. So it's another case where the immune system is not active enough and therefore tolerance can evolve. It's well known also that recurrent urinary track infections develop tolerance and it would be interesting to see whether it promotes evolution of resistance in these bugs too.”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“Infections, right? And therefore, one of the first things that we'd like to do is a study linking this tolerant phenotype to clinical outcome in a supervised manner and to implement a routine detection of tolerance strains in the clinic. And for that, we develop this easy tolerance detection test. It's based on the dysfusion assay. So that actually should be able within the tools that the microbiology lab has to tell the doctors whether the bag that they are treating is actually tolerant or not.”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“So, of course, it's really very preliminary work that was done only on a very small number of patients. So clearly, it needs to be expanded to a much larger number of patients and also on other infections. But our aim is actually within the toolbox that doctors already have at their disposition, they need to pick up drug combinations. And it's really not an easy task. But within this toolbox, If you ask two different doctors, they will pick different combinations, right? So there is no clear rationale for the treatment. And what we propose is that maybe the fact that tolerance train evolves and go completely under the radar in the clinic is actually a factor to take into account that may make these choices much more clear and unified among hospitals for the same”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“As a guideline, if you have a patient that is immune or suppressed, give the combination even before tolerance ever fall, and then the combination prevents both resistant and tolerance. It's actually good for both. The other guideline is, okay, if you have a patient and you didn't catch up in time that it was immunosurprised, then now it has tolerance, this knowledge actually can guide you now to a completely different drug combination that is actually able to kill this tolerant bacteria. There are certain antibiotics, not a lot of them, but certain antibiotics that are actually able to kill bacteria even if they don't grow. So these are the combinations that you want to use.”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“And so, when we went back with this understanding to the lab, then we expanded to also other bacteria and other drug combinations. And what we see is that there are specific drug interactions that are actually very good at blocking the evolution of resistance. But once you have this mutation tolerance, it's another ballgame, right? So combination that were seemingly effective in vitro before are turning actually instead of blocking the evolution of resistance, they promote devolution of resistance, right? So it gives a new understanding. It means that in order to pick up the right combination for the patient you are treating, you need more information on the bacteria that are in the infection.”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“Having this draw combination was not helpful anymore because tolerance was messing around this drug combination. At the end of the day, the bacteria found yet another way to surprise us and to evolve resistant not to a single drug, but even when two drugs were co-administered.”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“We work in close collaboration with Dr. Maskid Barmier, who is an infectious disease doctor, and we reproduced exactly the treatment that was given to the same patient in the lab, and we could reproduce actually the evolutionary path tourize mutation and then to a resistant mutation. When the same drug regime was administered, but actually the story was more complicated. Now, what happened is that the initial drug regime was actually promoting this evolution of tolerance, right? And then afterwards, what happens is that as they saw that the Bacteria were not dying well enough, they changed the drug regime to this combination. Two drugs were co-administered in the patient. But it was too late because once tolerance has evolved under the first treatment,”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“And so, this understanding came from experiments that we did in Bakers in the lab, this dormancy imitation, which we call tolerant mutation, is actually acting as a stepping stone for the acquisition of resistant mutations. And if you take away this ability to become dormant, they would never evolve resistance. So after this first series of work in the lab and in an environment that we control completely, we wanted to know whether similar effects were going on in patients. And this is where we acquired from patients that were hospitalized under life-threatening blood infection”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“Yes, exactly. And so, you know, when we talk about antibiotics, we call them the magic bullets. But we forget that a lot of the magic is actually our immune system, right? And if you are trying to use antibiotics to eradicate infections without an immune system, you're going to lose.”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“Antibiotics can only target growing cells. The immune systems can target non-growing cells. So if you have that your immune system is working well, it doesn't matter if the bacteria are growing or not. We'll still be able to recognize and destroy them. It's in cases where people don't have a really active immune system that the bacteria are able to evade and develop this dormancy phase that's not being hit by the antibiotics and yet this stepping stone to resistance.”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“Main guess is that the important factor here is immunosuppression of the patient. So if you have a very good immune system, and even if the antibiotics are not killing all the bacteria in some of the dominant bacteria still lingering out there or slowly growing, the immune system will take care of them, aiding the antibiotics and infection should not be so long to allow this kind of evolution to occur right but in patients that are immunocompromised the conditions are actually promoting the evolution of tolerance and then of resistance and allowing all these mutations to accumulate in the bacteria within the host.”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“So at the beginning, it's counterintuitive, right? Because if you are doorman, then you replicate less. And if you replicate less, you acquire less mutations, right? But because our bags actually became dormant, the antibiotics is not acting upon them as it should act. And therefore, these bags just survive in antibiotics. They're not able to grow in the presence of antibiotics. They survive antibiotic treatment after a few hours after antibiotic treatment concentration goes down very much and then this dormibility have the ability to exit these dormances start growing again. Now they can acquire resistant mutations that are typically very rare to acquire and now the bacteria become completely resistant to the treatment.”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“Exactly. And then we found that it was more general than that. It was not only mutation, it was a behavior of bacteria that can be conferred by a mutation but can be also conferred by external condition. And this behavior of bacteria is the ability to become dormant or to grow slower. And once they enter this state of dormancy or slow growth, it turns out that they have their ability to become resistant at a much higher rate than if they don't have disability.”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“What we were asking are there other mutations that are occurring before when bacteria are exposed to antibiotics and actually promoting the fixation of resistant mutation. And this will typically go completely undetected because they don't really confer resistance, but they are making the resistant mutation fix and develop much easier.”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source
“Infection to understand the conditions that lead to multidrug resistance in a hospital setting. The work reveals how the ability of bacteria to develop tolerance, which we also refer to as dormancy or slow growth, can act as a stepping stone to resistance and can interfere with the efficacy of drug combinations. Our conversation covers what tolerance is, the conditions that promote tolerance, how it leads to resistance and impacts drug combination therapies, and lastly, integrating this new understanding into clinical microbiology protocols. Here's our conversation.”
2020-07-19 · a16z Podcast · Journal Club: A New Path to Antibiotic Resistance · IDENTIFIED FROM THE TRANSCRIPT · source