Ideally, doctors would have two bits of information available to guide antibiotic therapy: bacterial identification and antibiotic susceptibility. Not all antibiotics work on all types of bacteria. In particular, Gram-negative bacteria (those with an outer membrane covering their cell wall) are treatable with fewer and different antibiotics than Gram-positive bacteria (those with a naked cell wall). Within those two categories, optimal antibiotics vary by species.
In the era before widespread antibiotic resistance, bacterial identification was sufficient to insure appropriate antibiotic treatment in the vast majority of cases. This is no longer the case, although doctors and hospitals have been slow to recognize the new reality. Resistance rates for first-line antibiotics are now commonly 30-60%. Doctors have responded to these high levels of resistance by treating ALL infections with broad-spectrum antibiotics. One of these, vancomycin, is now the most commonly prescribed drug in US hospitals. The inevitable consequence of this behavior is to hasten the day when these antibiotics are no longer effective.
In the best-case scenario, doctors would have (and use) timely antibiotic susceptibility results in addition to identification results, so that they would prescribe broad-spectrum antibiotics only to patients whose infections are resistant to narrow-spectrum antibiotics. This would not only preserve the usefulness of broad-spectrum antibiotics, but result in better patient outcomes.
Wednesday, January 28, 2015
Tuesday, January 27, 2015
From Quora: What is it like to work in a biotech venture firm?
The intellectual skills needed in startups are very different than those needed in academia or big pharma. Academics usually succeed by learning more and more about less and less. They become the world's leading expert in a very narrowly defined field. Top-notch scientists, of course, manage to relate this focused domain knowledge to big-picture science as well. But first you have to truly master a topic, and that means narrowing your focus.
Biotech startups don't have the luxury of focusing on one problem, because there are hundreds that have to be solved in order to demonstrate the feasibility of your technology and bring it to the market. The company usually has been founded on the basis of one or two academic publications which show some promising result, and has been sold to the investors as a nearly-solved problem requiring just a few million of investment to smooth off a few rough edges and get to the clinic. As a result, most startups are undercapitalized and the scientists are under tremendous pressure to make the promises of the founders not look like bald-faced lies.
So rather than become experts in one narrow specialty, biotech scientists typically have to acquire many skills, at least to a "good enough" level, because there is simply no one else around to do the job. In my career, I've had to learn nucleotide and protein modification chemistry, conjugation chemistry, DNA and RNA sequencing and analysis, analytical and preparative HPLC, immunoassay development, in vitro protein synthesis, in vitro transcription, flow cytometry, macromolecular modeling, in vivo imaging, biodistribution and pharmacokinetics, microarray assay development, photochemistry, liposome formulation and a bunch of other things that I have forgotten about. This is not too unusual.
The other notable aspect of startup life is constant disruption. Programs are initiated, staffed and then cancelled in short order as priorities change. You will never be (nor should you be) left alone to work out all the problems that are your responsibility to solve. If you are fortunate enough to work in a company environment that fosters communication and teamwork you will need to bring problems to the attention of your team as soon as possible, so that you can get help in solving them. If you are working in a company that runs on the star system, bringing up these problems will be seen as an admission of failure, so you need to be prepared to solve them on your own.
Biotech startups don't have the luxury of focusing on one problem, because there are hundreds that have to be solved in order to demonstrate the feasibility of your technology and bring it to the market. The company usually has been founded on the basis of one or two academic publications which show some promising result, and has been sold to the investors as a nearly-solved problem requiring just a few million of investment to smooth off a few rough edges and get to the clinic. As a result, most startups are undercapitalized and the scientists are under tremendous pressure to make the promises of the founders not look like bald-faced lies.
So rather than become experts in one narrow specialty, biotech scientists typically have to acquire many skills, at least to a "good enough" level, because there is simply no one else around to do the job. In my career, I've had to learn nucleotide and protein modification chemistry, conjugation chemistry, DNA and RNA sequencing and analysis, analytical and preparative HPLC, immunoassay development, in vitro protein synthesis, in vitro transcription, flow cytometry, macromolecular modeling, in vivo imaging, biodistribution and pharmacokinetics, microarray assay development, photochemistry, liposome formulation and a bunch of other things that I have forgotten about. This is not too unusual.
The other notable aspect of startup life is constant disruption. Programs are initiated, staffed and then cancelled in short order as priorities change. You will never be (nor should you be) left alone to work out all the problems that are your responsibility to solve. If you are fortunate enough to work in a company environment that fosters communication and teamwork you will need to bring problems to the attention of your team as soon as possible, so that you can get help in solving them. If you are working in a company that runs on the star system, bringing up these problems will be seen as an admission of failure, so you need to be prepared to solve them on your own.
Monday, January 26, 2015
From Quora: Why is there no simple diagnostic test to determine if a URI is bacterial or viral?
You ask a great question. The market for such a test is huge, and the clinical impact would be enormous.
The technical challenge in developing a bacterial/viral test is substantial. Trying to detect the bacteria or the viruses directly is probably not a good approach - there are hundreds of them, and the presence of a certain bacterium or virus does not necessarily mean that it is the culprit causing the infection.
An alternative approach would be to detect not the bacteria or viruses, but the body's response to the infection. Different parts of the immune system are activated for viral vs bacterial infections. Unfortunately, there is no single biomarker that reliably distinguishes the two responses. But there have been publications that report suites of genes that discriminate viral and bacterial infection responses. Unfortunately, the technological platforms that can generate this information and return it in a reasonable amount of time - probably less than an hour - and for a reasonable cost (<$50) - don't yet exist.
The technical challenge in developing a bacterial/viral test is substantial. Trying to detect the bacteria or the viruses directly is probably not a good approach - there are hundreds of them, and the presence of a certain bacterium or virus does not necessarily mean that it is the culprit causing the infection.
An alternative approach would be to detect not the bacteria or viruses, but the body's response to the infection. Different parts of the immune system are activated for viral vs bacterial infections. Unfortunately, there is no single biomarker that reliably distinguishes the two responses. But there have been publications that report suites of genes that discriminate viral and bacterial infection responses. Unfortunately, the technological platforms that can generate this information and return it in a reasonable amount of time - probably less than an hour - and for a reasonable cost (<$50) - don't yet exist.
Friday, January 23, 2015
From Quora: When should one post negative results in powerpoint presentations of scientific research?
It depends on your audience. If they are a general audience wanting to be entertained, then your negative results can be presented as obstacles on the road to enlightenment. They are part of the hero's journey, illustrating the difficulties you had to overcome. Depicting these setbacks as frustrating and seemingly insuperable makes your final triumph all the more compelling and validates your character and intelligence to the audience. This of course assumes you have some positive results to share, thus making a good story.
If on the other hand, you are presenting to a group of colleagues trying to collectively solve a problem, you first have to assess the dynamics of your team. Most biotechs and pharmas, and all academic departments operate on the star system. That is, rewards are handed out to those who appear to unfailingly successful. If this is the case, you need to tell the hero's story, as per above.
If your team is actually focused on solving problems, rather than establishing a hierarchy of perceived merit, then presenting negative results is one of the most important and valuable things you can do. Most ideas are flawed, and fail; only a few are genuinely good. High-functioning teams try many ideas, and eliminate the failures as quickly as possible, so that they can focus on the ideas that really have a chance to succeed. Presentation of negative results is absolutely critical for this fail-fast model to function. This in turn requires group leaders who can distinguish process from results - that is, who can distinguish a negative result that proceeds from poor effort from a negative result that proceeds from a flawed underlying hypothesis. Since the group leaders usually determine which hypotheses to test, it is difficult for them to admit that the effort was good but that the premise was flawed. Count yourself lucky if you have such a leader, and try to become one yourself.
If on the other hand, you are presenting to a group of colleagues trying to collectively solve a problem, you first have to assess the dynamics of your team. Most biotechs and pharmas, and all academic departments operate on the star system. That is, rewards are handed out to those who appear to unfailingly successful. If this is the case, you need to tell the hero's story, as per above.
If your team is actually focused on solving problems, rather than establishing a hierarchy of perceived merit, then presenting negative results is one of the most important and valuable things you can do. Most ideas are flawed, and fail; only a few are genuinely good. High-functioning teams try many ideas, and eliminate the failures as quickly as possible, so that they can focus on the ideas that really have a chance to succeed. Presentation of negative results is absolutely critical for this fail-fast model to function. This in turn requires group leaders who can distinguish process from results - that is, who can distinguish a negative result that proceeds from poor effort from a negative result that proceeds from a flawed underlying hypothesis. Since the group leaders usually determine which hypotheses to test, it is difficult for them to admit that the effort was good but that the premise was flawed. Count yourself lucky if you have such a leader, and try to become one yourself.
Thursday, January 22, 2015
From Quora: Have we already lost the fight against bacterial resistance to antibiotics?
Yes, we have lost the fight, if by "lost" you mean that doctors are no longer able to prescribe antibiotics effectively based on signs and symptoms alone. This was the case for the first few decades of the antibiotic era, and we came to accept it as normal.
But the vast majority of bacteria are still susceptible to at least one antibiotic, so in that sense we haven't lost. We just have to change tactics. Rather than prescribing from a formulary or antibiogram, doctors should order - and pay attention to - lab tests that determine which antibiotics a given infection will respond to.
We have picked all the low-hanging fruit in discovering new antibiotics based on natural compounds, and squandered this bounty with imprudent and wasteful antibiotic prescribing practices. Those days are over, although far too many doctors do not realize it yet. However, prudent use of antibiotics combined with good infection control practices will allow us to manage bacterial infectious diseases in the future, despite high levels of antibiotic resistance.
But the vast majority of bacteria are still susceptible to at least one antibiotic, so in that sense we haven't lost. We just have to change tactics. Rather than prescribing from a formulary or antibiogram, doctors should order - and pay attention to - lab tests that determine which antibiotics a given infection will respond to.
We have picked all the low-hanging fruit in discovering new antibiotics based on natural compounds, and squandered this bounty with imprudent and wasteful antibiotic prescribing practices. Those days are over, although far too many doctors do not realize it yet. However, prudent use of antibiotics combined with good infection control practices will allow us to manage bacterial infectious diseases in the future, despite high levels of antibiotic resistance.
Wednesday, January 21, 2015
From Quora: How can the global community (specifically the UN) deal with antibiotic resistance?
The useful lifespan of antibiotics is usually much less than 40 years, and the development of resistant strains is inevitable. Most medically useful antibiotics are based on natural compounds that have been in the biosphere for many millions of years. As a result, bacterial resistance genes have had plenty of time to develop, and so have also been in the biosphere for many millions of years. When an antibiotic enters widespread use, it is only a matter of time until resistance genes in the biosphere find their way into pathogenic strains.
This time can be extended by the prudent use of antibiotics. This means administering antibiotics only when there is a bacterial infection (90% of upper respiratory infections are viral and will not respond to antibiotics), only for as long as necessary, and to only prescribe antibiotics to which the infecting bacterial strain is likely to be susceptible.
Unfortunately, antibiotics are misused worldwide - for growth promotion in livestock feed, as a "just in case" treatment by ER and primary physicians (egged on by patient demand), and as a panacea in many countries where they are available over the counter.
Antibiotics - more specifically, antibiotic susceptibility - should be seen as a common resource that can be depleted by overexploitation, just like fisheries or forests. Because antibiotics have few side effects and are inexpensive, it can benefit individuals to take them "just in case" they have a bacterial infection. But the collective benefit to individuals turns into a net loss to society, as the next person who gets an infection is ever slightly more likely to be infected by a resistant strain generated by antibiotic overuse.
Ideally, we would have treaties that limit antibiotic overuse. But the same can be said for many threats to common resources - forest and fishery depletion, CO2 dumping in to the atmosphere, etc. The prospects for collective action to preserve antibiotic usefulness are not good.
This time can be extended by the prudent use of antibiotics. This means administering antibiotics only when there is a bacterial infection (90% of upper respiratory infections are viral and will not respond to antibiotics), only for as long as necessary, and to only prescribe antibiotics to which the infecting bacterial strain is likely to be susceptible.
Unfortunately, antibiotics are misused worldwide - for growth promotion in livestock feed, as a "just in case" treatment by ER and primary physicians (egged on by patient demand), and as a panacea in many countries where they are available over the counter.
Antibiotics - more specifically, antibiotic susceptibility - should be seen as a common resource that can be depleted by overexploitation, just like fisheries or forests. Because antibiotics have few side effects and are inexpensive, it can benefit individuals to take them "just in case" they have a bacterial infection. But the collective benefit to individuals turns into a net loss to society, as the next person who gets an infection is ever slightly more likely to be infected by a resistant strain generated by antibiotic overuse.
Ideally, we would have treaties that limit antibiotic overuse. But the same can be said for many threats to common resources - forest and fishery depletion, CO2 dumping in to the atmosphere, etc. The prospects for collective action to preserve antibiotic usefulness are not good.
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