If bacterial resistance randomly occur, then why limit broad-spectrum antibiotic use?

Question

If there is importance to study some discipline, then one of the main matters is its applications, so besides the primary goal of knowing the truth of the matter regarding what that discipline is investigating, applicability or usefulness of that study in other fields or in the field itself is a very important matter. I'll direct my attention here to Evolution, and its mechanisms. So accordingly if something that I personally want to come up with is application of that knowledge to the field of my work.

In reality we don't study evolution extensively at college level in medicine, since it doesn't have a direct clinical impact on the diagnosis and treatment of patients in most of the cases. However, one possible area of interaction is "bacterial resistance to antibiotics", since this is related to "mutations", and generally viewed as a mechanism whereby the bacterium adapts to its environment.

Now all of my life in medicine from college through specialty and academic teaching, we've never ceased being reminded about not dispensing antibiotics liberally, and the main concern outlined is "emergence of resistant strains of bacteria" due to this liberal use of antibiotics itself. There are other reasons of course, like side effects and cost, but they are not the main concern most of the times.

During my recent review of Evolution, looking at the introductory courses that were cited to me by many participants here, in particular this page of Evo101 titled "Mutations are Random" I was really shocked to know that even the mutations that resulted in bacterial resistance were not "directed mutations", i.e. it is not the case that the exposure to the antibiotic caused the bacteria to have that mutation in the first place, actually the page mentions Esther and Joshua Lederberg experiments showing that those resistant bacteria were already there before the population was exposed to the antibiotics?

So why have we been always reminded by bacteriologists of limiting our antibiotic usage if emergence of drug resistance is not due to exposure to it?

Actually, its not only that, many lectures we attend, which are pretty much delivered by official bodies, does mention of emergence of antibiotic resistance as a DIRECTED mutation response to exposure to the particular antibiotic, that almost most of us we clinicians became to think that this is a fact. For example hospital bacteria are of the most resistant ones, especially those in intensive care facilities. The association between exposure to antibiotics and emergence of drug resistant bacteria to them is almost hammered in our brains, that to discover that the mutation was already there before exposure to the antibiotic seems quite shocking, at least to me in person.

My question here is the following:

Is it a scientific fact that emergence of bacterial resistance through mutations is always random, i.e. in the sense that it is not a directed response to exposure of the population to that antibiotic?

For instance this seems to be a counter-example.

If that is the case then why bother about liberal use of broad-spectrum antibiotics? I mean as far as emergence of bacterial resistance is concerned!

I mean its not the case that I'm going to eradicate the "useful bacterial" that could rival the pathogenic resistant bacteria, by that liberal use of broad-spectrum antibiotics. If that happens temporarily we can in principle replace them back, like with the use of probiotics.

During my surfing of the web I found that page addressing the same point, but the responses are not that explicit, and far from being convincing?

Answer 1

You're correct, this is extremely relevant, and it's unfortunate that your medical education didn't include good instruction about evolution.

You point to some very useful and interesting studies. I'm particularly fond of the studies that demonstrate the early existence of antibacterial resistance genes, e.g., in ancient permafrost.

Now to your question

Is it a scientific fact that emergence of bacterial resistance through mutations is always random, i.e. in the sense that it is not a directed response to exposure of the population to that antibiotic?

I think the issue here is a conflation of two separate concepts. Mutation is one mechanism for producing variation. Mutation can be understood as a stochastic process, causing changes in the genome of an individual by chance.

Evolution occurs because of existing variation. Evolution is not a stochastic process. It is a biased process, a change in the distribution of existing variation.

The emergence of antibacterial resistance is evolution that results from selection acting on existing variation. Emergence here refers to emergence of a resistant variant within a population. Selective pressure (application of antibiotics) causes a predictable change in the frequency of genes that would allow reproduction in that environment, the frequency of existing resistance genes increases in the bacterial population.

Though there is evidence for important antibacterial resistance mutations pre-dating the use of antibiotics, this does not rule out the occurrence of spontaneous mutations, as demonstrated in the article you linked. The production of genetic variation by random mutation can be followed by a rapid increase in the frequency of a new genetic variation that is selected for in a given environment. This can be particularly likely in organisms with high error rates, short generation times, and large numbers of individuals. The spontaneous mutation isn't directed, as you say. It is random. The selection of that particular random mutation is directed, though. Once the random mutation occured, then we can say the variation exists. Then selective pressure acts on existing variation, allowing evolution, a change in the frequency of the, in this case, gene for resistance.

Goodman & Gilman, one of my go to pharmacology references, actually has an excellent discussion of these concepts as they relate to antibacterial resistance, in Ch. 48, under the subsection EMERGENCE. There is a good discussion of the various mechanisms of emergence, but this general statement is helpful:

Mutations are not caused by drug exposure per se. They are random events that confer a survival advantage when drug is present. Any large population of drug susceptible bacteria is likely to contain rare mutants that are only slightly less susceptible than the parent. However, suboptimal dosing strategies lead to selective kill of the more susceptible population, which leaves the resistant isolates to flourish.

Answer 2

The mutations are random, the survival and spread of bacteria with said mutations is NOT random.

Evolution and selection are situational.

The careless use of antibiotics causes those mutations and bacteria to spread because they out compete others without resistance. However, often these will not outcompete without antibiotics being present. Often mutations that produce resistance are detrimental when antibiotics are not present, or more precisely the downsides of the mutation are more than offset by the benefits of resistance when antibiotics are present. Meaning even when they occur mutations the produce resistance die out quickly without antibiotics.

Even when they offer no advantage of disadvantage without the presence of antibiotics normal genetic drift can eliminate them, but when antibiotics are present and a mutation occurs the mutation then offers an advantage and spreads. That means a person is more likely to catch a strain that is resistant than if their was no antibiotics present in the bacteria's environment.

Note the "environment" can be anything from the greater ecosphere down to an individual patient. and population can be the population inside an individual or the population of bacteria across the globe.

lets try a pair of scenarios

In each the mutation for resistance occured in 1% of the population of bacteria.

Scenario 1 no antibiotics. You have a 1% chance of catching a resistant strain.

Scenario 2 Antibiotics present. Now selective pressures quickly change the population so that resistant strains now make up the majority (we'll say 75%). Now you have a 75% chance of catching a resistant strain, and worse those resistant strains now have a high chance of meeting other strains with other resistances or of having another resistant mutation occur (now 1% of 75% instead of 1% of 1%) this means the population becomes even more resistant and it does so rather quickly until no antibiotics work.

So emergence, AKA exposure of humans to resistant strains, IS due to use of antibiotics.

Careless use of antibiotics include.

1. Use of antibiotics on people/animals/things who do not need it.

2. Disposal of antibiotics in the environment.

3. Incomplete courses of antibiotics.

But there is a hidden forth and fifth concern, that is the one your paper is concerned with. Patients and doctors are humans and each of these things will inevitably happen, patients fail to take drugs, or impure drugs are improperly disposed of or a hundred other errors expose bacteria population to antibiotics. So a further concern about having useful antibiotics, by limiting which antibiotics we use, that is by only using common ones unless absolutely necessary, we are minimizing the chances of resistance to those less used antibiotics so we have something that works when we run across a resistant strain.

Lastly people already have bacteria present in their system so these microbes can be exposed to antibiotics targeted at other unrelated infections, thus encouraging resistance. Some are even protected by natural barriers that reduce exposure to antibiotics used to treat other things, like bacteria on the outside of the skin for internal antibiotics. Worse, bacteria can transfer resistance horizontally so these microbes can then share resistance with later infections. So even using antibiotic A correctly on a patient to kill microbe X can lead to microbe Z developing resistance just because the treatment for X is not enough to kill all Z. Staph is particularly prone to this since it is everywhere. So even if you use antibiotics correctly you can still produce resistant strains of other bacteria.

As a side note some confusion is caused by is a quirk of language and terminology in the study of evolution. If X produces an environment in which a mutation that produces trait Z is favored causing that mutation and thus Z to spread in a population often scientists will just say X caused Z, just to save time. humans are lazy and typing out "X produces an environment in which a mutation that produces trait Z is favored causing said mutation to spread in the population and thus Z to spread in a population." takes much longer and uses more space than "X causes Z to spread" or just X causes Z. Other evolutionary scientists know what they mean but it can be confusing for everyone else. It is not a great practice but jargon creeps into all science.

As a personal note it has always been a concern for me that medical schools don't require an understanding of evolution at least for research fields; infection, cancer, and a million other weird quirks of anatomy and physiology are caused by evolution or evolutionary baggage. Heck infection and cancer ARE evolutionary competitions, and some of the most predictable ones.