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On Wed, 29 Oct 1997 09:28:30 -0600 David Nixwrote:
>
> There are been many methods published for dosing once daily
> aminoglycosides.
Please bear in mind that all these methods are EMPIRICAL. They
have no scientific basis other than they have been tested and
appear to be effective in most patients. There is no rational
basis to justify this dosing regime or the various targets
(peaks, troughs, ratios to MIC etc). The lack of a firm
scientific basis means that there will continue to be
uncertainty about how to treat patients who are not similar to
the average.
Please note that there is nothing wrong with relying on
empiricism for typical patient management. This is the whole
ethos of evidence based medicine. What EBM lacks however is the
depth of understanding to interpolate/extrapolate beyond the
strict boundaries of the actual trials that have been performed.
For me, the central focus of PK and PD is to elucidate the
principles and develop models so that we can confidently
interpolate/extrapolate to treat individual patients.
--
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.htm
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To Nick and the group,
Re: Aminoglycoside once daily dosing.
> Please bear in mind that all these methods are EMPIRICAL. They
> have no scientific basis other than they have been tested and
> appear to be effective in most patients. There is no rational
> basis to justify this dosing regime or the various targets
> (peaks, troughs, ratios to MIC etc). The lack of a firm
> scientific basis means that there will continue to be
> uncertainty about how to treat patients who are not similar to
> the average.
I agree with Nicks comments regarding once daily dosing of aminoglycosides.
The lack of scientific basis for dosing regimens for aminoglycosides is a
significant concern when attempting to determine the optimal dosing
regimen. The AUC method which some practitioners use (including myself)
will hopefully provide the basis whereby scientific comparisons of dosing
regimens can be made. Currently all comparative trials have compared
conventional dosing (where concs are monitored to acheive specific targets)
with an empirical once daily dosing strategy, ie just give every patient
the same dose regardless! It would seem sensible to try to control for
sources of possible variability while allowing one factor to vary at a
time. So a trial that compares once daily dosing with conventional dosing
and targeting the same AUCs would be more useful. After this, then other
factors such as whether the AUC is important or not could be looked at.
Regards
Steve
=======================Steve Duffull
Christchurch
New Zealand
Ph +64 3 3815280
Fax +64 3 3640902
Email sduffull.at.clear.net.nz
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Dear Anaizi
I agree that to date we have scientific in-vitro evidence that
aminoglycosides (Ag) display dose dependent kill patterns, we also know
that they have a
post-antibiotic effect, they display adaptive resistance and they have
toxicity patterns that support low trough concentrations as safer. Data
from clinical trials, and the various meta-analyses support some of these
claims most of the time (especially reduced toxicity).
The question is not whether to once daily dose, but how to once daily dose?
What we don't know is what is the best method of dosing Ag. The claim for
a lack of scientific basis is simply that it has not yet been determined
how ODA Ag should be monitored? What targets should be employed? How
should Ags be dosed (q24h or q48h)? etc. The AUC method seems sensible in
that the highest peak concentration is achieved while constraining the
exposure to an acceptable level. The "acceptable level" has also not been
defined and is currently determined as the level of exposure that was
previously accepted as appropriate when Ag's were dosed conventionally (ie
between 70 and 100 mg/L.h).
> at the present time there is no evidence to support the need for
> AUC-based dosing. In fact he suggests that at some point we should look
> into " .. whether the AUC is important or not ...".
Currently it is not known whether the AUC is the "best" method. But it is
a method that can be used to ensure that patients are not exposed to
excessive amounts of Ag. In my experience high AUC values (> 120 mg/L.h)
for long periods of time do result in toxicity. A recent paper in Clinical
Nephrology discusses the use of a single dose of 10 mg/kg of gentamicin in
the treatment of pyelonephritis followed by ciprofloxacin PO. Perhaps a
*single* pulse (ie "hit and run") is optimal?
What seems to be needed is a prospective study that addresses the effect of
different administration regimens (eg conventional vs q24h vs a48h?) while
keeping the
total daily "exposure" the same. Hence the true validity, and advantages,
of changing administration regimens (alone) can be assessed.
Kind regards
Steve
=======================Steve Duffull
Christchurch
New Zealand
Ph +64 3 3815280
Fax +64 3 3640902
Email sduffull.-a-.clear.net.nz
Also see: http://www.cpb.uokhsc.edu/pkin/pkin.html
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On Thu, 6 Nov 1997 09:52:29 -0600 Steve Duffullwrote:
> The question is not whether to once daily dose, but how to once daily
> dose?
>
> What we don't know is what is the best method of dosing Ag. The
> claim for a lack of scientific basis is simply that it has not yet
> been determined how ODA Ag should be monitored? What targets should
> be employed? How should Ags be dosed (q24h or q48h)? etc.
None of the above have any theoretically sound basis for asserting
that aminoglycoside dosing and monitoring is optimal.
The choice of dose, infusion duration and dosing interval all
determine the profile of AG concs. What is not known is what is an
optimal profile for the antibiotic and toxic effects in humans.
A pseudo-optimum could be found empirically (as at present) by
performing many different clinical trials with different mean
profiles and trying to relate the profiles to efficacy and safety.
However, if the therapeutic and toxic effects could be predicted from
a model that explicitly includes both conc and time (i.e. the
profile) then there would be some rational (as opposed to emprical)
scientific basis for selecting a particular dosing scheme in an
individual with a particular set of AG PK parameters. This would
then permit a true optimal profile to be defined (see below for what
a true optimal profile might mean).
It should be noticed that AUC is *a priori* NOT the way to understand
this problem because by its very nature the AUC integrates time out
of the information. IMHO rational models for understanding how AG
conc profiles relate to their effects must not throw away time from
the model.
A critical distinction should also be made between understanding how
to dose AGs and the process of monitoring AG exposure. If it was
known how the AG conc profile was related to efficacy and safety then
individual treatment could (in part) be based on measuring AG concs
(at least two!) to estimate the PK parameters (at least CL and V)
which determine the profile. It would then be feasible to predict the
dosing scheme which would most closely achieve the optimum effect.
Note that the point of measuring concs is to estimate PK parameters.
It is not an end in itself.
> The AUC
> method seems sensible in that the highest peak concentration is
> achieved while constraining the exposure to an acceptable level. The
> "acceptable level" has also not been defined and is currently
> determined as the level of exposure that was previously accepted as
> appropriate when Ag's were dosed conventionally (ie between 70 and
> 100 mg/L.h).
> A
> recent paper in Clinical Nephrology discusses the use of a single
> dose of 10 mg/kg of gentamicin in the treatment of pyelonephritis
> followed by ciprofloxacin PO. Perhaps a *single* pulse (ie "hit and
> run") is optimal?
Yes indeed it might be the best one could do.
*IF* the true optimal profile was a square wave pulse lasting for 30
minutes then this could only be poorly approximated by conventional
treatment. The PK properties of AGs may preclude achieving a true
optimal profile because the half-life is constrained by V and CL. In
renal impairment, it would become increasingly difficult to approach
the true optimal profile. This might even force us to abandon the use
of AGs in renal impairment because we would realise that no amount of
fooling around with the dose could increase the therapeutic ratio. On
the other hand, development of a technique e.g. some kind of dialysis,
to enhance AG clearance would allow the conc profile to be controlled
(somewhat) independently of the patient's endogenous clearance and
perhaps allow the true optimum profile to be achieved.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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In vitro data (in broth) suggests that maximum killing occurs at
about 30 times the MIC. Aminoglycosides are probably the most active
antimicrobial agent available when comparing in vitro killing. Yet
the activity is marketed reduced when serum is added to the media.
In clinically settings, aminoglycosides are generally inferior to
beta lactams, and fluoroquinolones and are rarely used as
monotherapy. When aminoglycosides are combined with beta-lactams the
issue of adaptive resistance seems to disappear.
>
> The question is not whether to once daily dose, but how to once daily dose?
>
> What we don't know is what is the best method of dosing Ag. The claim for
> a lack of scientific basis is simply that it has not yet been determined
> how ODA Ag should be monitored? What targets should be employed? How
> should Ags be dosed (q24h or q48h)? etc. The AUC method seems sensible in
> that the highest peak concentration is achieved while constraining the
> exposure to an acceptable level. The "acceptable level" has also not been
> defined and is currently determined as the level of exposure that was
> previously accepted as appropriate when Ag's were dosed conventionally (ie
> between 70 and 100 mg/L.h).
>
There is a lot of scientific basis for pulse dosing of
aminoglycosides, but we still do not know the optimal dosing strategy
when specifics are considered.
> > at the present time there is no evidence to support the need for
> > AUC-based dosing. In fact he suggests that at some point we should look
> > into " .. whether the AUC is important or not ...".
>
> Currently it is not known whether the AUC is the "best" method. But it is
> a method that can be used to ensure that patients are not exposed to
> excessive amounts of Ag. In my experience high AUC values (> 120 mg/L.h)
> for long periods of time do result in toxicity. A recent paper in Clinical
> Nephrology discusses the use of a single dose of 10 mg/kg of gentamicin in
> the treatment of pyelonephritis followed by ciprofloxacin PO. Perhaps a
> *single* pulse (ie "hit and run") is optimal?
>
I agree with considering the AUC as a safety net to prevent greater
exposure than we have clinical data to support. Aminoglycoside
dosing evolved with safety in mind. With traditional dosing based on
peak and trough concentrations, AUC was alway less than <100-125
mg*h/L/24 hours. Why sould we allow some patients to get >200 AUC
/24 hours with pulse dosing without rigorous clinical studied to
demonstrate safety?
> What seems to be needed is a prospective study that addresses the effect of
> different administration regimens (eg conventional vs q24h vs a48h?) while
> keeping the
> total daily "exposure" the same. Hence the true validity, and advantages,
> of changing administration regimens (alone) can be assessed.
>
> Kind regards
>
> Steve
> =======================> Steve Duffull
> Christchurch
> New Zealand
> Ph +64 3 3815280
> Fax +64 3 3640902
> Email sduffull.at.clear.net.nz
>
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I find it interesting that we even call this approach to dosing once
daily. Obviously, there were always patients who needed to be dosed
once daily on aminoglycosides using conventional doses due to
diminished renal functon. These patients should definitely NOT
receive a dose once daily using the large doses associated with ODA.
The approach should be renamed something like "Large Dose - Extended
Interval (LDEI)" dosing. This would help avoid the errors that
could occur by those not taking the time to understand the basis of
this approach.
Sorry, I know you all are talking about higher level aspects of this
approach. Just wanted to get in my two cents worth on behalf of
preventing medication errors.
John E. Murphy, Pharm.D.
Professor and Head
Department of Pharmacy Practice and Science
(520) 626-5730 (P), (520) 626-7355 (FAX)
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I would like to second John E. Murphy, Pharm.D.'s e-mail about Large Dose
Extended-Interval Dosing of Aminoglycosides. The room for error by the
conventional terminology of Once Daily Dosing is great. We as pharmacists
certainly understand the concepts implied by this dosing method, whether it is
with regards to attain high MICs and post-antibiotic effects or just giving a
larger dose to attain an adequate peak serum concentration because of the
dosing interval needed for the patient's renal function. What I see are the
situations where the prescribers are not cognizant of the concept and disregard
the patient's renal function because the dosing interval "is already extended
from every 8 hours to 24 hours. Why should I give it every 36 or every 48
hours?" As one who works in a small community hospital setting, the need for
ongoing education of prescribers on not only Extended-Interval Dosing but that
conventional trough-peak monitoring with this dosing is not appropriate needs
to be undertaken.
I have also read the vast amount of discussion recently on AUC and MICs
and efficacy, etc., and that we need trials to determine these parameters. Is
there anyone out there actively conducting these trials? I have seen a few
articles on this (one in particular with q12h vs q8h aminoglycosides in CF
patients which demonstrated in a small sample size no apparent change in
efficacy but less evidence of ototoxicity in the q12h group), and was taught in
a recent pharmacy course there has been no studies demonstrating any difference
in efficacy, but apparently less toxicity and/or delayed toxicity.
Marc Semprebon, RPh, MSLS
Department of Pharmacy
APD Memorial Hospital
Lebanon, NH 03766
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