If we have to treat some biofilm or persistent cell population then why researchers are trying to test their killing concentrations which are far beyond the clinical achievable level. e.g. For treating S. aureus why 50-100X MIC which is nearly 25-50 ug/ml. And we knew that Cmax is not going to be above 4 ug/ml.
There are a few reasons to test antibiotics at superphysiological concentrations. The first is, as you identified, to select for persistent cell populations by rapidly depleting the sensitive majority of "normal" cells. It allows for more rapid identification of novel mechanisms of resistance or selection of populations carrying a resistance marker. Sometimes high-dose testing can be used to discriminate between low-level and high-level resistance mechanisms or constitutive and inducible expression. Finally, I'd caution against relying too much on the Cmax. While this is the pharmacokinetic value used in most literature (and is arguably the most relevant), there are some issues. It may be affected by protein binding resulting in a much lower free concentration (fCmax). The Cmax in blood may not be the Cmax at the site of infection. Finally, since most in vitro testing does not take into account clearance of the drug, it is not always straightforward to compare in vitro results to in vivo ones.
The extent to which one could wisely raise the level of antimicrobials in systemic treatment depends on the chemotherapeutic index of the agent. We should also bear in mind that the basis for clinical use of antimicrobials is “selective toxicity”. If in an attempt to destroy the pathogen we inflict significant damage to the host, then it will not be a wise course. Besides, I agree with the above contributor that in vitro testing does not fully reflect the situation at the site of infection – the pharmacokinetics and dynamics of drugs are readily affected by host factors. In vitro interaction is essentially a two- way relationship (drug –pathogen, pathogen – drug), whereas it is a 3-way relationship in vivo (drug – pathogen, pathogen – drug ; drug – host, host – drug; host – pathogen, pathogen – host).
I agree with Andrew, the use of very high antimicrobial agents can serve as a way of actively selecting the sub-populations of persister cells. Also in my opinion, it may enable the study of the mechanisms of survival by the bacteria in terms of overcoming this stress.
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