Tuesday, December 29, 2009

Myth and fact in antibiotic resistant bacteria

Following the big expose on drug resistant bacteria posted by MSNBC today, I'd like to outline the probable distribution of causes of resistant strain evolution between the broad categories of physician over-prescription, informal antibiotic use by individuals, and agricultural feed-mixing. The most serious form of resistance is the multiple antibiotic resistance, which generally means the infection is untreatable. Individual drug resistances, though dangerous, are not so serious, and so the causes of the two types should be distinguished.

Resistance arises through the presence of random genetic mutants. Typically the mutant genes confer resistance by encoding for a slightly different enzyme shape for an enzyme needed in the absorption of the antibiotic. Resistance is conferred between different strains of bacteria through the processes of plasmid exchange and bacterial transformation. Generally, this leads to an evolutionary selection process for bacteria where the possibility of genetic exchange with similar bacteria moderates the factors influencing individual, genetically identical colonies.

Before venturing further into this topic, let us refine the parameters by which resistance is measured, to dispell some common misperceptions. The natural selection model implies that bacteria do not respond to antibiotics by reactively evolving defenses, but rather have these defenses before exposure (and are therefore selected for) or do not have such defenses (and are therefore selected against). Furthermore, bacteria face constant pressure from immune systems when invading a host. Therefore, the antibiotics don't need to (and most certainly aren't) completely effective in the sense of killing all the bacteria. All the antibiotics need to do to be effective is kill off a large enough percentage of the bacteria to allow the body's immune system to gain the upper hand.

When people take antibiotics as prescribed, they suddenly introduce them in large quantities. There simply is not enough time for the entire evolutionary process to occur. It follows that the evolutionary process can't realistically happen during a particular infection in a person. Thus, there are two scenarios where a person can suffer from an antibiotic resistant infection.

1. The person is infected with a strain that is entirely resistant to the given antibiotic
2. The person is infected with a strain where the resistance is not prevalent, but has a similar, begnin strain posessing accessible resistance-conferring DNA. This DNA is assimilated into the infecting strain in significant quantities prior to the application of antibiotics.

This second scenario is unlikely for two reasons. First, though the bacteria that cause infections are similar to bacteria found on the human body, they generally occupy different parts of the body. Thus, they will not come into frequent contact. Secondly, there is no selection pressure in the individual to lead begnin strains to have such resistance meaning that the resistance must by chance be given by a mutant and that the mutant will have some other mechanism that propagated the DNA across the colony. This same mechanism would then need to be effective at introducing the resistance DNA into the invader.

If antibiotics are taken in an irresponsible manner, it is possible for them to be introduced in insufficient quantities to constitute a spike, or to be taken frequently enough to represent a more regular selection pressure.

In these cases, the majority of individuals do not end up in the hospital, dying. So we can reasonably assume that they have recovered from their infections. It is likely that the infection has been passed on in some cases, but passing the infection on after antibiotic use is not altogether too likely, because even improper antibiotic use does dramatically reduce the incidence of bacteria, making a person much less contagious. Even though such an event is rare, it is feasible for it to promote one or another particular mutants. But, unless multiple antibiotic resistance is conferred by a single mutation, it could only occur through a long series of such improper exposures, something that seems impossible, considering that even when exposure occurs it does not guarantee that resistance genes are present.

However, if antibiotics are applied in constant, low doses to an entire population of creatures, this is tantamount to effecting an environmental change. Populations of bacteria are continuously being introduced to an environment where antibiotics are present, and the selection pressure is in the "just right" range where it overrides the force of random mutations but is not strong enough to destroy entire populations before adaptation can occur.

In particular, the constant presence of the antibiotics makes it more likely that transferrable resistances are developed. Various strains may each have one or two antibiotic resistances, but multiple resistance would represent several mutations that would surely compromise the viability of the bacteria in the absence of the antibiotics. Though I have read nothing that supports this idea experimentally, I believe that Multiple Resistances are in fact expressed as plasmids or some other transferrable DNA that is exchanged through bacteria populations as a cooperative survival strategy. In this way, no members of the populace must exhibit all the resistances at any one time, but all the various genetic material is associated with every resistance in aggregate, guaranteeing the survival of the genes against the antibiotics.

Regardless of the characteristics of multiple resistance, it is agreed and established that there must be constant selection pressure for bacteria to maintain resistance over the long term, especially multiple resistances, because it reduces their viability when antibiotics are absent. Multiple resistance can only be the result of a constant regime of multiple antibiotics, either simultaneously or in series, something done only in agriculture.

For each multiply resistant strain, there are many less broadly resistant strains that constitute the genetic pool from which the multiply resistant strains develop. Multiple resistance must arise in a combination of the following ways:

1. Series mutation of strains, with each mutation conferring additional resistance.
2. DNA exchange through environmental cohabitation of different strains
3. Bacteria that becomes supersaiyan

The temporal requirements of the first case are only met in an agricultural environment with constant antibiotic use. The second case is less likely in humans (who have relatively good hygeine) than it is in animals, particularly ones raised in filthy conditions. Open sores, lack of space in which to engage in instinctive cleaning, and a maximally fattening, hormone enhanced diet all combine to compromise the immune system and blur the line between environment and host. This is an ideal breeding environment for all types of infectious bacteria. It is also a decidedly unnatural environment where many selection pressures are reduced, replaced by antibiotics.

The final question is how often and in what way are resistant strains passed from animals to people. This is a much more empirical question, requiring knowledge of the sanitary practice of slaughterhouses and the like. But even in our enlightened society we know that there are people all around us that work with raw meat on a regular basis. If the plasmids or other transferrable DNA is preserved in the meat that we eat, these resistances could pass into us, waiting for the unlikely exchange with a nonresistant strain, leading to a random and otherwise difficult to explain pattern of resistance appearing.

It is also possible that small amounts of the antibiotics are simply passed into people who eat meat, making us each a walking training camp for bacterial resistance. This would mean that over and above all the analysis provided thus far, agricultural use of antibiotics creates a selection pressure in individual meat eaters that requires no exposure to the resistant strains that develop in livestock.

The amount of antibiotics used in agriculture is very large. The amount of meat eaten by Americans is equally large. On the basis of the description of these mechanisms alone, it seems likely that Agricultural use of antibiotics is the dominant cause of all antibiotic resistances. The comparable possibility of prescription and informal antibiotic use causing any resistance to develop is very low, given the mechanisms involved.

Why is it then that first there was a long and vigorous campaign to get people to use fewer antibiotics, before any attention was paid to the agricultural practices? Is the industrial capture of biological science simply this far progressed?

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