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> In reaction to the antibiotic resistance problem and with treatment options dwindling, public health officials attempted to control antibiotic usage as a mean

> In reaction to the antibiotic resistance problem and with treatment options dwindling, public health officials attempted to control antibiotic usage as a means of controlling resistance (20). The expectation was that rates of resistance would diminish as antibiotic usage dropped. However, resistance persisted even in the face of such drug management practices on both small and large scales (20–23). This makes perfect sense to me. Why did this not work? The article continues with an explanation of "the ecological fallacy" but I don't understand how the two are supposed to be connected.

christkv 5y ago
There are so many exiting old antibiotics that might be possible to repurpose however no money or willingness to qualify them https://www.sciencedirect.com/science/article/pii/S1198743X15006205 https://www.sciencedirect.com/science/article/pii/S1198743X1... I guess there is no money in requalifying an out of patent antibiotic.
Fomite 5y ago
The problem is that there was a very compelling "just so" story that antibiotic-resistant bacteria are inherently at a competitive disadvantage vs. susceptible bacteria absent selective pressure. Take the antibiotics away, and the resistant bacteria will follow. Unfortunately, microbial ecology is much more complex than that, and it hasn't panned out that way. Often because resistance plasmids also carry other helpful genes. For example, I'm currently working on a study where there's high levels of antibiotic resistance to an antibiotic that isn't used in that population because there's other things hanging out on the same plasmid. Also note: That's not what most people mean when they say "ecological fallacy", which is a statistics term.
- jessriedel 5y ago
  Not all proposed evolutionary mechaniams that turn out to be false, much less merely incomplete, are just-so stories. The fact that the hypothesis was simple makes it more reasonable.
  - Fomite 5y ago
    Yeah, but this was very much a just so story.
    - jessriedel 5y ago
      Huh, how? It takes scarce resources for the bacteria to produce many of the structures that protect it from antibiotics. Structures that are unused but require resources are selected against, or at the least decay through mutation. This is an extremely common and simple evolutionary effect. Are you using "just so" as a synonym for "suspiciously convenient"? That's not what it means.
      - Fomite 5y ago
        No, I'm using it to mean an untestable (or in this case untested) narrative explanation for a biological phenomenon. There are several prevalent narratives around the evolution of microbes that are taken to be true because they tell a nice narrative story with very little empirical backing, and even less information on things like time frames. "Structures that are unused but require resources are selected against" for example, is something that feels correct, but isn't necessarily true because resistance genes don't exist in isolation. "Community MRSA will lose out to MSSA because of an absence of selective pressure" kept being trotted out because it fit narratively well beyond when it was becoming apparent that wasn't true.
        jessriedel 5y ago
        I can't find a way to interpret your use of "narrative" that makes your argument work.
- quotemstr 5y ago
  The explanatory gap you're seeing is the difference between equilibrium and dynamic analysis. As time goes to infinity, the probability of an organism retaining genes not useful to it declines to zero. Given enough time, that resistance gene, if not directly beneficial by side effect, will be pruned. But evolution takes time. If the resistance gene is on a stable plasmid, if the plasmid confers other fitness advantages, and if the resistance gene itself only infinitesimally reduced fitness, then evolution can take a very long time indeed to reconfigure that plasmid and optimize away the resistance gene. Both camps are right here.
  - Fomite 5y ago
    The problem is one of those camps was relying on an equilibrium condition and pretending like it was on a clinically relevant time scale.
wonnage 5y ago
The hypothesis was that resistance mutations would negatively impact fitness (as mutations usually do), so natural selection would prefer no-resistance once the antibiotics are stopped. But instead it looks like once resistance has evolved it doesn’t go away, suggesting that it comes at no cost to reproductive fitness.
- brazzy 5y ago
  Not necessarily at no cost - but not at a cost greater than the advantage of having the resistance, which is still massive since the use of antibiotics is not in fact stopped, just reduced.
rudyfink 5y ago
From "The Demon Under the Microscope" by Hager--an interesting read on the history of Sulfonamides (the drug that kicks off the "golden age of antibiotics on the chart)--usage was entirely uncontrolled and people did not complete drug regimes. Generally (and I'll probably get this very wrong), that antibiotic worked by blocking uptake of external energy sources. The drug was tremendously effective and widespread. The book made it sound like all of the strains that did not evolve a solution to that antibiotic were completely wiped out by the evolutionary pressure of the antibiotic. I'd imagine (just guessing) that even if the antibiotic was stopped, the organisms would not have anything like the evolutionary pressure to change back (and the consequence of getting wiped out by the drug if they did). They probably get along "good enough" or the drift back is slow. In other words, the pressure to change was one of, essentially, absolute survival, while the change back is one of risky convenience.

christkv 5y ago

There are so many exiting old antibiotics that might be possible to repurpose however no money or willingness to qualify them https://www.sciencedirect.com/science/article/pii/S1198743X15006205 https://www.sciencedirect.com/science/article/pii/S1198743X1... I guess there is no money in requalifying an out of patent antibiotic.

Fomite 5y ago

The problem is that there was a very compelling "just so" story that antibiotic-resistant bacteria are inherently at a competitive disadvantage vs. susceptible bacteria absent selective pressure. Take the antibiotics away, and the resistant bacteria will follow. Unfortunately, microbial ecology is much more complex than that, and it hasn't panned out that way. Often because resistance plasmids also carry other helpful genes. For example, I'm currently working on a study where there's high levels of antibiotic resistance to an antibiotic that isn't used in that population because there's other things hanging out on the same plasmid. Also note: That's not what most people mean when they say "ecological fallacy", which is a statistics term.

jessriedel 5y ago
Not all proposed evolutionary mechaniams that turn out to be false, much less merely incomplete, are just-so stories. The fact that the hypothesis was simple makes it more reasonable.
- Fomite 5y ago
  Yeah, but this was very much a just so story.
  - jessriedel 5y ago
    Huh, how? It takes scarce resources for the bacteria to produce many of the structures that protect it from antibiotics. Structures that are unused but require resources are selected against, or at the least decay through mutation. This is an extremely common and simple evolutionary effect. Are you using "just so" as a synonym for "suspiciously convenient"? That's not what it means.
    - Fomite 5y ago
      No, I'm using it to mean an untestable (or in this case untested) narrative explanation for a biological phenomenon. There are several prevalent narratives around the evolution of microbes that are taken to be true because they tell a nice narrative story with very little empirical backing, and even less information on things like time frames. "Structures that are unused but require resources are selected against" for example, is something that feels correct, but isn't necessarily true because resistance genes don't exist in isolation. "Community MRSA will lose out to MSSA because of an absence of selective pressure" kept being trotted out because it fit narratively well beyond when it was becoming apparent that wasn't true.
      - jessriedel 5y ago
        I can't find a way to interpret your use of "narrative" that makes your argument work.
quotemstr 5y ago
The explanatory gap you're seeing is the difference between equilibrium and dynamic analysis. As time goes to infinity, the probability of an organism retaining genes not useful to it declines to zero. Given enough time, that resistance gene, if not directly beneficial by side effect, will be pruned. But evolution takes time. If the resistance gene is on a stable plasmid, if the plasmid confers other fitness advantages, and if the resistance gene itself only infinitesimally reduced fitness, then evolution can take a very long time indeed to reconfigure that plasmid and optimize away the resistance gene. Both camps are right here.
- Fomite 5y ago
  The problem is one of those camps was relying on an equilibrium condition and pretending like it was on a clinically relevant time scale.

wonnage 5y ago

The hypothesis was that resistance mutations would negatively impact fitness (as mutations usually do), so natural selection would prefer no-resistance once the antibiotics are stopped. But instead it looks like once resistance has evolved it doesn’t go away, suggesting that it comes at no cost to reproductive fitness.

brazzy 5y ago
Not necessarily at no cost - but not at a cost greater than the advantage of having the resistance, which is still massive since the use of antibiotics is not in fact stopped, just reduced.

rudyfink 5y ago

From "The Demon Under the Microscope" by Hager--an interesting read on the history of Sulfonamides (the drug that kicks off the "golden age of antibiotics on the chart)--usage was entirely uncontrolled and people did not complete drug regimes. Generally (and I'll probably get this very wrong), that antibiotic worked by blocking uptake of external energy sources. The drug was tremendously effective and widespread. The book made it sound like all of the strains that did not evolve a solution to that antibiotic were completely wiped out by the evolutionary pressure of the antibiotic. I'd imagine (just guessing) that even if the antibiotic was stopped, the organisms would not have anything like the evolutionary pressure to change back (and the consequence of getting wiped out by the drug if they did). They probably get along "good enough" or the drift back is slow. In other words, the pressure to change was one of, essentially, absolute survival, while the change back is one of risky convenience.