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Our hospital has been using od aminoglycosides for several months. The
dosage range is 5-7mg/kg/day (for gent and tobra).
Comparison studies with conventional q8h administration found similar
efficacy /c no greater toxicity. (This stuff is on MEDLINE.)
The putative clinical advantage relies on a sequence of events when
susceptible bacteria are exposed to an aminoglycoside. Since the drug
has an intracellular mechanism, it requires some sort of transport
into a bacterium. A conventional trough concentration appears to be high
enough to downregulate this transport, making bacteria less susceptible.
Allowing the concentration to drop over 8 half-lives (effectively to
zero), which is what a dose/24h amounts to, allows bacteria to "recover"
the transport mechanism. In addition, some drug binds to extra-membrane
bacterial structures, and as extra-bacterial drug concentration drops,
bound drug becomes unbound (it's a reversible binding event with a
low enough affinity constant to make this possible). This unbound drug
is then taken up by bacteria to effect a kill. This last bit is also
an explanation proposed for the 'post-antibiotic effect' exhibited by
the aminoglycosides.
Even if there doesn't turn out to be a greater clinical effectivness
with od dosing, there are other advantages. We now see more patients
being treated on an out-patient basis in our ER, since they only have to
come in once a day. There's also the reduced cost of administration
for in-patients, with nurses preparing and hanging one dose a day rather
than three, plus no more gent assays. After all, what would you be
measuring--that there's nothing there after 24 hours? The assay that
*is* done is serum Cr, just so you know how the patient's kidneys are
holding up, and if their renal function is such that you can assume
a normal half-life. If their Cr is high, give the gent every 36 or
48 hours.
********************************
Randy Trinkle, BScPharm, BA
Dept. of Pharmacy
Dawson Creek & District Hospital
Dawson Creek, BC
rtrinkle.-at-.pris.bc.ca
********************************
"Every now and then when your life gets complicated . . ."
HST
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I have just recently seen a posting to this group referring to ODA. There
seemed some concern over the references and pharmacists that use
this protocol. The definitative article describing this practice was written
by Hartford Hospital and is available in several journals. At the hospital I
work at the pharmacists monitor the aminoglycoside therapy for patients
on the ODA protocol. Those pharmacists have demonstrated their
capability by passing a strigent pharmacokinteic examination and
demonstrating the clinical ability. In short the ODA protocol is as follows.
Gent or Tobra are doses as 7 mg / kg on ideal body weight(given over 1
hr)( ideal weight = 50kg + 2.3kg x height in inches over 5 foot for males
(females are 45kg + 2.3kg/inch > 5foot))obese individuals( 30% > ideal
wt) are dosed as ideal body weight + 0.4 x excess wt over ideal). After
this initial dose a random level is obtained from 6 - 14 hrs after the start
of the infusion. This level is plotted on the aminoglycoside nomogram to
determine the dosing frequency (q24 , q36, or q48 hrs). This level is
repeated in 5 days or if clinically necessary. Some patients are excluded
from the protocol ie pregnancy, renal diaylsis, burn patients, severe
ascites, cystic fibrosis, and endocarditis. Some of the doses I have seen
are from 280mg to 680mg ivb q24 hrs. The reasoning behind the protocol
is to have the trough level fall below 0.4mcg/ml about 4 hrs before the
next dose. (remember aminoglycosides exhibit a post antibiotic effect)
Clinical experience shows that the aminoglycoside level that provides
poor outcomes is the trough level > 2.0 mcg/ml. The higher peak levels
allow for aminoglycosides to acheive a better antimicrobal effect than
traditional dosing. Pseudmonas infections can be treated with this
regimen. Hope this helps
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>
> PharmPK - Discussions about Pharmacokinetics, Pharmacodynamics and related
> topics
> Our hospital has been using od aminoglycosides for several months. The
> dosage range is 5-7mg/kg/day (for gent and tobra).
>
> Comparison studies with conventional q8h administration found similar
> efficacy /c no greater toxicity. (This stuff is on MEDLINE.)
>
> The putative clinical advantage relies on a sequence of events when
> susceptible bacteria are exposed to an aminoglycoside. Since the drug
> has an intracellular mechanism, it requires some sort of transport
> into a bacterium. A conventional trough concentration appears to be high
> enough to downregulate this transport, making bacteria less susceptible.
> Allowing the concentration to drop over 8 half-lives (effectively to
> zero), which is what a dose/24h amounts to, allows bacteria to "recover"
> the transport mechanism.
> In addition, some drug binds to extra-membrane
> bacterial structures, and as extra-bacterial drug concentration drops,
> bound drug becomes unbound (it's a reversible binding event with a
> low enough affinity constant to make this possible). This unbound drug
> is then taken up by bacteria to effect a kill.
What is an extra-membrane bacterial stucture? Is this part of the
bacterium? Those hairy bits that some bacteria have?
So are you saying that the kinetics of unbound drug close to the effect site are
determined by binding to the bacterium itself? Is there any direct exptl
support for this or is hypothesis only?
>... plus no more gent assays. After all, what would you be
> measuring--that there's nothing there after 24 hours? The assay that
> *is* done is serum Cr, just so you know how the patient's kidneys are
> holding up, and if their renal function is such that you can assume
> a normal half-life. If their Cr is high, give the gent every 36 or
> 48 hours.
Nothing like closing the stable door after the horse has bolted!
PLEASE consider measuring the gent concs. They are a more sensitive
marker of renal function changes (Thalf of gent is half that of
creatinine). Plus you can use the gent concs to adjust the dose BEFORE
the patient's renal function deteriorates.
Measuring gent concs at 1 and 8 hours after the od dose will give
readily measurable concs and if your lab is up to scratch you will have
the results back before the next dose is due.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.html
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I'd like to respond and echo some of Nick's comments re: ODA.
Actually three meta-analyses have been published- one in Lancet (BMJ?),
another in Ann Intern Med, and another in J Antimicrob Chemother. What is
interesting is that the papers all have slightly different conclusions.
The "definitive paper" written by the Hartford group is largely anecdotal,
i.e., "this is what we did, and it seemed to work". The mean duration of
therapy was 2-3 days. The authors cannot, when prompted, defend the
method(s) used to determine the serum concentration nomogram used. Others
who have adopted this method have had problems with toxicity. 7 mg/kg dose
is designed to achieve higher peak:MIC for Pseudomonas---why not use tobramycin?
Integration of concentration-effect (bactericidal rate) relationship for
aminoglycosides implies that net kill should reflect AUC, not peak. This is
why most studies show no difference (the Prins paper was not a randomized
study). ODA will likely be more effective if only bacteria with high (>2
mcg/mL) MICs are included.
I agree one serum concentration would be appropriate in patients who would
trationally be dosed q 8-12h. We use a 5 hr post dose to estimate AUC
(least biased time point based on optimal sampling theory). In patients
with poor renal function, we obtain peak/trough as traditionally is done.
We rarely used ODA outside of ICU and home/ambulatory patients. We stratify
maximal daily dose (3-6 mg/kg/d) by estimated CrCl and disease severity. On
the other hand, we do not use 8h interval, but instead go right to q 12h.
We average 0.7 serum concentrations/course (mean 5d) and out nephrotoxicity
rate is 2.8%.
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