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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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June 27, 2011

The Evolution of Resistance: Are We Doing It Wrong?

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Posted by Derek

Here's a paper in PNAS that says that we're probably treating infectious disease the wrong way - and perhaps cancer as well. The authors go over the currently accepted doctrines: multiple-mechanism therapies, when possible, and restricted use to patients who really need antibiotics. But there's a third assumption that they say is causing trouble:

A third practice thought to be an effective resistant management strategy is the use of drugs to clear all target pathogens from a patient as fast as possible. We hereafter refer to this practice as “radical pathogen cure.” For a wide variety of infectious diseases, recommended drug doses, interdose intervals, and treatment durations (which together constitute “patient treatment regimens”) are designed to achieve complete pathogen elimination as fast as possible. This is often the basis for physicians exhorting their patients to finish a drug course long after they feel better (long-course chemotherapy). Our claim is that aggressive chemotherapy cannot be assumed to be an effective resistance management strategy a priori. This is because radical pathogen cure necessarily confers the strongest possible evolutionary advantage on the very pathogens that cause drugs to fail.

The harder you hit a population of infectious disease organisms, the harder you're selecting for resistance. The key, they say, is that in many cases there's genetic diversity among these organisms even inside single patients. So you can start off with a population of bacteria, say, that could be managed by less aggressive therapy and the patient's own immune system. But then aggressive treatment ends up killing off the great majority of the bacterial population, which you'd think would be a step forward. But what you're left with are the genotypes that are hardest to kill with antibiotics. They were in a minority, and might well have died out under competition from their less-genetically-burdened cohorts. But killing those off gives the resistant organisms an open field to work in.

The other problem here is a public-heath one. You want to cure the individual patient, and you want to keep their disease from spreading, and you want to keep from encouraging resistance among the infectious organisms. Optimizing for all three at once is probably not possible.

The paper goes into detail with the example of malaria, pointing out that it may well be the norm for people to be infected with several different lineages of malaria parasites at the same time. They seem to be in there competing for nutrients and for red blood cells, and some of them appear to be keeping the others in check. Antimalarial drugs alter the cost/benefit ratio (for the parasites) of carrying resistance genes.

So what should we do? The problem is, they say, that there are probably no general rules that can be recommended:

Thus, aggressive chemotherapy is a double-edged sword for resistance management. It can reduce the chances of high-level resistance arising de novo in an infection. But when an infection does contain resistant parasites, either from de novo mutation or acquired by transmission from other hosts, it gives those parasites the greatest possible evolutionary advantage both within individual hosts and in the population as a whole. How do the opposing evolutionary pressures generated by radical cure combine in different circumstances to determine the useful life span of a drug? There will be circumstances when overwhelming chemical force retards evolution and other times when it drives things very rapidly. We contend that for no infectious disease do we have sufficient theory and empiricism to determine which outcome is more important. It seems unlikely that any general rule will apply even for a single disease, let alone across disease systems.

For more on such ideas as applied to bacterial infections, see here and here. But near the end of this paper, the authors apply similar reasoning to cancer. (That analogy has come up around here before, I should note).

An analogous situation also occurs in cancer therapy, where cell lineages within a tumor compete for access to space and nutrients. There, the argument has recently been made that less aggressive chemotherapy might sustain life better than overwhelming drug treatment, which simply removes the competitively more able susceptible cell lineages, allowing drug-resistant lineages to kill the host. Mouse experiments support this: Conventionally treated mice died of drug-resistant tumors, but less aggressively treated mice survived (95).

So maybe too many of us have been thinking about these questions the wrong way. If we switch over to favoring whatever strategy minimizes resistance, both in individual patients and thus across the population, we could be in better shape. . .

Comments (21) + TrackBacks (0) | Category: Cancer | Infectious Diseases


1. anon on June 27, 2011 9:43 AM writes...

Improved public health resources (education and convenient prophylactics) should do wonders in preventing infectious disease. As far as cancer goes, I agree with the authors that we may be too quick to subject patients to radio- and chemotherapy. My recently-deceased acquaintance had a recurrent, small-cell lung cancer that was initially slow-growing. After going through a buffet of small-molecule drugs over the past year, the cancer metastasized to his spine and brain...he was pretty much a goner at that point. Perhaps more efforts should be devoted to patient screening algorithms, which could minimize the chances of wasting time and money on ineffective therapies.

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2. simpl on June 27, 2011 10:31 AM writes...

The most resistent bugs may not be the most agressive or fastest growing. Thus, when you stop a course of antibiotics, other organisms should then displace any survivors in the gut. This probiotic approach can be treated for e.g. freeze-dried E Coli in a capsule.

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3. anchor on June 27, 2011 10:39 AM writes...

Derek : Who knows where this is all headed? How does one deal with nasty pathogen such as MRSA? Aggressive therapy can defeat the pathogen or else you are going to meet the fate of those German's who died because of those endo-toxins released by E.coli.

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4. Anon on June 27, 2011 10:50 AM writes...

There are many reasons for development of resistence. as well as contributing to health-care cost to individuals & society. The clinical use of antibiotics remains overused and abused, for example, given out when there is no reason to suspect bacterial infection, but provided when the patient is insistent. Elderly are often given antibiotics prophylactically, "just in case", but all to frequently resulting in other more serious issues such as development of resistence infections (my elderly father was one of the very unlucky who did not survive the events). So, there's lot's of places that anibiotics can be cut back for the benefit of individuals as well as society overall.

application, just because or

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5. daen on June 27, 2011 12:01 PM writes...

And this is why teaching evolution to chemists and doctors is so important. When I started studying med chem in 2002, I'd just finished a course on evolution, which made me think about the acquisition of cisplatin resistance by certain cancers very much in terms of adaptation and natural selection, and made me wonder if the "go-in-with-all-guns-blazing" approach to treating cancer was really the optimal one.

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6. CMCguy on June 27, 2011 2:09 PM writes...

This sounds like arguments coming from the personalized medicine promotions which in principle would lead to better outcomes when treatments can be tailored to what works for an individual. Attractive yes however are the diagnostic tools of sufficient refinement available for infections and cancers and more so once have identified the differences are the right drugs/treatments on hand to handle the variations? Would be great to achieve all this yet wonder about the cost requirements that would accompany implementation verses the direction of tolerance for the funding development and pricing these days.

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7. MoMo on June 27, 2011 2:15 PM writes...

The authors are sure jumping around from bacteria to parasites to mammalian cells and their statement "The guiding principle should be to impose no more selection than is absolutely necessary" is a lofty goal for medicine to acheive.
When is the imposition on infection enough? When the patient survives? You don't impose enough, though, guess what? The patient dies! Try that in a Phase II study. I can see it now in the study design-we are only going to give you enough not to impose resistance-Good Luck, here's a lucky rabbit's foot for you!

I am not sure of the point of this paper, but theoretical ramblings like this from biologists/clinicians are cheap, poignant thoughts of real meaning and actionable items in resistance chemotherapy expensive.

On a scale of 1 to 10 on the use of this paper in real infectious diseases/treatment this scores a Fluffy -4.

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8. barry on June 27, 2011 2:43 PM writes...

what we (or some of us) have learned from CML is that--if left untreated--it progresses to lethal "blast crisis" but if treated early (when there's just the single mutation) with a BcrAbl inhibitor, it can be stopped. At least for this cancer, the analogy to bacterial infection is probably meaningless. Many putative cancer therapeutics fail to change mortality because they kill only some of the cancer cells but fail to eradicate the line.

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9. lynn on June 27, 2011 3:24 PM writes...

@7 Momo, I agree that this theoretical stuff lumping bacterial, malaria and cancer is a bit much - but don't lump all biologists together! In the bacterial area, what could be done - but which is not done yet in a serious way - is to model resistance development (at least for mutations that occur in the pathogen) to established and novel antibacterials in stringent, standardized animal models to test these ideas. As a microbial geneticist, I have ideas about what constitutes "selective pressure" - but it's hard to quantify the amount of selective pressure in any given situation. More experiments - with more chemicals [at least in the systems that can be experimentally manipulated] is called for. IMVHO, of course.

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10. David Young MD on June 27, 2011 3:26 PM writes...

The sure fire way to fail at curing a 20 year old of advanced testicular cancer is to withhold the heavy duty chemotherapy. Give moderate dose and notice the drug resistance develop and the young man dies. Same thing for high grade lymphoma and Hodgkins lymphoma. What is said may apply to lung cancer or colon cancer, but certainly not to cancers considered curable by chemotherapy.

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11. Dr. Manhattan on June 27, 2011 4:38 PM writes...

Lynn above has made an excellent point about our limited understanding of selective pressure. I suggest that those with interest in this area look at the papers of researchers such as Bruce Levin (Emory Univ), whose is making serious efforts to model resistance development. But more work is needed to really solidify these concepts. The idea that resistant organisms are at some sort of fitness disadvantage is not new, but there is also the issue of compensatory mutations that can restore fitness to a resistant organism and thereby preserve resistance. So the statement that "...they were in a minority, and might well have died out under competition from their less-genetically-burdened cohorts", is really a conjecture.

I should also point out that while the idea may sound fine in the abstract, the FDA is extremely unlikely to support sub-optimal dosing trials of antibiotics to test resistance selection theories!! When things "go south" in a serious infection, there is little time to spare (hours at most) in hitting the organisms as hard as possibel to reduce the infection burden to a point where eyou hope it can be cleared. Those of us left in antibiotic research (the few, the proud, the survivors..) know that there are a set of PK-PD values that must be achieved, and these are based on clinical isolate population studies of the target pathogen(s)with the compound in question. These populations include resistant organisms, and you must demonstrate target attainment against those resistant organisms.

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12. Matt on June 27, 2011 5:58 PM writes...

An alternative solution is spectrum targeting. Rather than radical treatment with one antibiotic or chemotherapeutic, use multiple drugs with different modes of action. There is a much lower probability of resistance mutations occurring in multiple genes simultaneously.

This is a common approach in agrochemical resistance management. Fungi are so promiscuous that any single-fungicide approach is usually overcome quickly. Of course not all therapeutic areas have this luxury.

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13. barry on June 27, 2011 6:19 PM writes...

re Matt (#12)
people in the oncology field are pursuing two strategies along these lines. Hitting a cancer by blockade of two different pathways can give synergetic effects. Blockading two paths on the same pathway won't give synergy, but can defeat resistant mutants. In either case, the goal is still eradication rather than just killing off the weak ones.

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14. Jose on June 27, 2011 6:31 PM writes...

Just to clarify, the situation with malaria is FAR more complex than as stated above. There are four (or five, or six, depending on who's counting) different *species* all of which have sexual reproduction cycles. So, within a single patient, you can have multiple genetic populations of the same species, multiple populations of different species, or both together (infection with multiple parasites is fairly common).
Add the dynamics within human populations, and well.... no-one has a clue.

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15. provocateur on June 27, 2011 9:11 PM writes...

This is bunkum!In cancer as well as infectious disease, you have to kill all of them with some prevention/education.Why I say this...because it worked for polio,small pox etc.This is out of the box thinking is some liberal idiots having too little to do and thinking too much to hv a paper!

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16. cliffintokyo on June 28, 2011 4:25 AM writes...

This is all very well, but the patient needs to get back to work in three days, (not next month), otherwise he will be terminated.
Harsh economic reality triumphs over common sense, as usual.

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17. simpl on June 28, 2011 6:57 AM writes...

@ Matt
You are right - the spectrum therapy concept that you mention is used in two combinations fot leprosy, for example: The site also discusses side-effects and resistance.

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18. Mark B on June 28, 2011 7:41 AM writes...

Rock, Paper, Scissors and survival of the "least fit"?

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19. Rick on June 28, 2011 8:31 AM writes...

On the other side of the story, you have strong evidence, in vitro and in vivo, that too low, or irregular dosing is the IDEAL way to induce resistance, period. Sounds like we have a Goldilocks and the 3 Bears situation. Not too much, not too little, just right.

Another thing to bear in mind - and this may only apply to bacterial infections - is that selective use of antibiotics for only more severe cases has been shown to significantly reduce resistance prevalence in a large population.On a large population basis, it's not too high of a dose, but too many unecessary prescriptions that's the problem. Of course, that would be an inconvenient answer for pharma marketing, so it must be wrong.

Overall, a provocative hypothesis, but if I have a kid with streptococcal meningitis, I'll still take my chances with the all-out antibiotic assault.

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20. Epoetker on June 28, 2011 2:17 PM writes...

Didn't...Michael Behe...the ID guy...actually address these very problems in The Edge of Evolution when talking about malarial resistance? Specifically when calculating the probability of a two-mutation evolutionary event versus a one-mutation event?

And did he mention some things on how due to the fact that certain mutations appear in widely disparate malarial victims when dosed with chloroquine, that we could effectively say we had exhausted the mutational possibilities of wild-type malaria against that particular drug?

What's really needed for effective treatment of these infections is the notion of "Every Man an Ecosystem." Then we could at least tailor our destructive extinctionary impulses with much greater sharpness.

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21. MoMo on June 29, 2011 12:31 PM writes...

1000 pardons Lynn! i dont lump all you biologists together, unless you are publishing fluffy papers which I can spot a mile away!

All of you, open a book on cellular resistance once in a while and you can see its complexity. When mere mortals try to describe it mathematically using generalities is when I move on back to reality.

And synergy testing has been studied for decades, with companies coming and going, and currently gone.

What ever happened to CombinatorX?

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