Size matters when it comes to antimicrobial resistance…
I am talking here about the size of the antimicrobial dose that is given to the patient.
If a small dose is given to the patient then the drug levels at the site of infection may be at or just above the MIC of the drug to that particular micro-organism. This may allow mutants with slightly higher MIC breakpoints to be selected out in the presence of the antibiotic thus increasing anti-microbial resistance.
If a large dose is given to the patient, then the chances are much lower of any mutant strains having MICs higher than the antimicrobial level at the site of infection and thus surviving.
Dosing recommendations for adults are still very much in a one size fits all type category with a relatively small range recommended by the manufacturers and prescribed by the clinicians.
For the reasons above I always advise antimicrobial doses that are at the upper end of the recommended range. Unfortunately this does not always happen as doctors have a natural inclination to start off with a low dose and then increase if the anti-microbial is not working.
Michael
Antimicrobial dosing also has implications for the laboratory and the murky world of in-vitro versus in-vivo susceptibility. Our breakpoints essentially assume that every patient gets the same dose of antibiotic. Is there a better way?
There has been a lot of coverage in recent years on the topic of “Bad Bugs, No Drugs”, along with some concerted pressure on governments to fund greater research into the development of new and original antimicrobials.
The focus on this as an absolute priority sits a little uneasily with me…. The idea that when we have “prescribed to death” one broad spectrum antimicrobial, another one (even broader spectrum) will just fill its place seems to me a little short-sighted, and I think does little to support good anti-microbial stewardship.
I would like to think that there is not subtle pressure for such lobbying from pharmaceutical giants.
Bacteria are not stupid. For many reasons, they are the masters of adaptation and survival. They were amongst the first living organisms on the planet, and I am sure they will be among the last.
You can be sure that bacteria will quickly acquire a means to counteract any new antimicrobial agent. (Interestingly though generally not all bacteria in the population will become resistant. This is likely due to open systems and equilibriums which I will discuss in a later article.)
I am not saying there should be no further Research and Development of new anti-microbials. Of course there should. I am just saying that I think the focus should very much be on making the best use of our currently available agents, not relying on new ones to magically come along at regular intervals.
The primary aim should be to “tame the dragon”, not to hunt it…
Bacteria are masters of survival, but they are also very efficient.They generally will not expend energy on something unless they have to, and that includes energy required for antimicrobial resistance. Bacteria best avoid becoming resistant to a particular antimicrobial if they can avoid exposure ( i.e. hide) to that anti-microbial (or a similar one). Antimicrobial exposure selects out resistant mutants of the bacterium.
Those that know me will be aware that I do not foresee a doomsday scenario in which all bacteria will be resistant to all antibiotics. This is mainly due to the fact that most bacterial populations exist in open systems (more about this in a later article).
Gram stain N. gonorrhoeae
However I do have some concerns about Neisseria gonorrhoeae, and in particular its susceptibility to ceftriaxone. This is simply because it is not very good at “hiding”, for the reasons below:
N. gonorrhoeae usually only found in human flora: Other bacteria may be found both in human and environmental niches. The environmental niche may be a hiding place for bacteria from antibacterials manufactured in high dose for human consumption. (In the “pre-human antibiotic era”, bacteria that were confined solely to human flora did not need to be resistant, as they were to a large degree protected from naturally occurring antibacterial substances in the environment.)
When N. gonorrhoeae found in humans, it usually causes symptoms rather than just colonising. Apart from a portion of females, most people who harbour Neisseria gonorrhoeae have symptoms. This usually triggers a visit to the doctors and ensuing antibiotic exposure. (Bacteria that mainly colonise can hide to some extent from antimicrobial pressure.)
When “found”, the bacteria are usually exposed to ceftriaxone. The recent introduction of molecular testing has meant that more and more Neisseria gonorrhoeae is being diagnosed without antimicrobial susceptibility testing being performed. This means the majority of people are being exposed to ceftriaxone the only real empiric antibiotic that is available (at the moment). The bacteria are unable to “hide” from ceftriaxone by being exposed to another antibiotic.
There are already reports of Neisseria gonorrhoeae isolates that are becoming resistant to ceftriaxone. Given the points above, I fear that this is going to become more likely. (Click here for a presentation on multi-drug resistant gonorrhoea)
and the answer…Difficult to see an answer here. I think we have a genuine problem. Higher dosing with ceftriaxone may reduce the chances of ceftriaxone resistant mutants being selected out. It may be that as resistance to ceftriaxone gradually increases, we will be forced back into universal susceptibility testing for Neisseria gonorrhoeae.
Michael
Note that Streptococcus pyogenes is another organism that might fall into that “No hiding place” category of bacteria, in that it is confined to the niche of human flora, it usually infects rather than colonises, and is predominantly treated with one antibiotic, ie penicillin. Fortunately, Strep pyogenes is still exquisitely susceptible to beta-lactams so it may be some time (decades) before the resistance appears.
Click here for a few MCQs on Neisseria gonorrhoeae.
