E-drug: Drug pressure and emergence of drug resistance (cont)
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RE: "drug pressure" and emergence of drug resistance
Regarding the question of the relations between drug exposure and
emergence of drug resistance, a key factor is intermittency of
exposure. This aspect of, e.g., HIV, was first suggested by the
observational studies of Vanhove et al.(JAMA 276: 1955-6, 1996),
showing the correlates between multiday lapses in dosing with
protease inhibitors ('drug holidays') and PI-resistance. This theme
has been a recurring one since, and is now widely recognized in the
anti-retroviral field as an important factor in the development of
drug resistance. In the TB field, 'poor compliance' is blamed as a
source of multi-drug resistance, though the term should be defined
carefully to distinguish between, i.a., early discontinuation and
recurring drug holidays, for it would seem probable that the
on-off-on-off-on... pattern would be more likely to select for
resistance than short 'on' followed by indefinitely long 'off'. So
one might reasonably suppose, but data are preferable to speculation.
You might have a look, too, at the work that Roy Anderson, Neal
Ferguson, and their colleagues are doing at the Wellcome Trust Centre
for the Epidemiology of Infectious Diseases, at Oxford, where the
relations between drug exposure and emergence of resistance are a key
topic.
In translating to the populational level, you have the difficulty that a
population of patients prescribed an anti-microbial drug regimen will
have a spectrum of compliance (or adherence as the politically
correct want to call it) with the prescribed regimen. With the
advent of electronic monitoring methods, one can now see individual
patients' time patterns of drug intake, and identify which patients
have drug holidays, how often, for how long, etc etc. A population of
treated patients will have some more or less characteristic mix of
these patterns, and the mischief they are capable of creating. A
rough
indicator of the distribution of drug regimen compliance patterns is
the 'rule of sixes', which I described in Clin Pharmacokinet
32:345-56, 1997, but one would do better with actual data from
treated patients in the group of interest. You might have a look at
the bibliography of publications based on use of electronic
monitoring methods: www.aardex.ch
Another important variable is the prevailing microbial replication
rate -- the higher it is, the more opportunity there is for mutations
that confer drug resistance. In general, the higher the load of
infecting micro-organisms, the higher will be the replication rate.
John Urquhart, MD, FRCP(Edin)
Professor of Pharmaco-epidemiology, Maastricht University, Maastricht, NL
Chief Scientist, AARDEX Ltd/APREX Corp, Zug CH & Union City, CA, USA
Professor of Biopharmaceutical Sciences, UCSF, San Francisco
Home office: 975 Hamilton Ave, Palo Alto, CA 94301 USA
John Urquhart <urquhart@ix.netcom.com>
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