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Dear All:
The Medical Letter of April 6, 2009, appears to be behind the
times in suggesting, for TDM of Vancomycin, that one should first wait
for a steady state and then monitor only trough Vancomycin serum
concentrations. They do not recommend monitoring peak levels.
I do not understand why anyone should wish to wait for a
steady state before seeing how the drug is behaving in the patient.
This places the patient needlessly at a greater risk than is
warranted. One should see how the drug is behaving in the patient and
make dosage adjustments just as soon as possible. Modern TDM software
permits that.
The view expressed in the Medical Letter appears to come from
the old modeling approach of using linear regression on the logs of
the levels. This only works in the steady state, and also only for a 1
compartment drug model. Vancomycin is clearly a 2 compartment drug. If
one only measures trough levels, one does not know if the dose (volume
of distribution) or the dose interval (elimination rate constant per
unit of creatinine clearance) needs to be adjusted. In addition, there
are the rates of equilibrium between the serum and the peripheral
compartments. The Medical Letter view in effect ignores what happens
in about the first 3-6 hours after giving the drug, during the phase
of distribution between serum and peripheral compartments. Ignoring
events during this period of distribution leads to failure to
appreciate the toxic effects of the higher serum drug levels during
that time, with essentially no greater kill then. The first 3-6 hours
are the phase that contributes most to Vancomycin toxicity.
Wysocki et al (Antimicrobial Agents and Chemotherapy, Sept
2001, p.2460-2467) have shown that continuous IV Vancomycin appears to
be as efficacious as intermittent IV administration. They also showed
that costs were significantly reduced. Vancomycin is not a
concentration-dependent drug, but a non-concentration-dependent one.
The rate of kill of an organism appears to plateau at about 6 times
the MIC of the organism. If a bug is sensitive (MIC = 1 ug/ml), since
Vanco is about 50% protein bound, a total concentration of 2 ug/ml
gives 1 free to kill. If one aims for a serum concentration of 12 ug/
ml, one is 6 times above an MIC of 1.0. A concentration of 24 (12
free) is 6 times an MIC of 2.
These higher MIC's are coming about because of the evolution
of the bugs in the current often inadequate therapeutic environment.
We want to use the drug as efficaciously as possible. The high peaks
in the first 3-6 hrs or so after a dose are not nearly as efficacious
as they are toxic, because they are so high. They contribute to
toxicity, and do little for killing. I have seen 2 patients with
agranulocytosis felt by all to be due to Vancomycin. They got it q 12 h.
The Medical Letter suggests 1000 mg Vancomycin q 12 h as the
traditional, but perhaps an inadequate dose. It also says that a dose
of 15-20 mg/kg is now recommended. If one gives 15 mg/kg to a 65 year
old man, 70 in tall, 70 kg weight, serum creatinine = 1.0, this is 15
x 70 = 1050 mg. Round this off to 1000 mg. If this dose is given to
the patient described above, using the population model for Vancomycin
in the MM-USCPACK TDM software, the first peak is about 43 ug.ml, and
rises during the first week to about 60 ug/ml. The troughs start at
less than 8, rise to 11 before the 3rd dose, and plateau at almost 18
ug/ml. The total AUC for the week is 3883 units.
How can we maximize effect and minimize toxicity? We can
minimize the total dose for the same patient, as did Wysocki, by
giving it continuously IV. If you do as Wysocki did, it was in 24 hr
IV infusions. If one selects a target trough goal of 18 ug/ml, then
the q 24 hr IV regimen is approximately 1750 mg infused over the
first day, and then 1250 mg/day thereafter. The total AUC for the week
is only 2602 units.
This saves a lot of drug and a lot of potentially toxic
exposure, as the higher peaks in the first 3-6 hrs are not there any
more. The problem Wysocki had was that he did not get the effective
serum concentrations until the end of the first 24 hours.
What can be done to get effective serum concentrations
sooner? One can develop a loading, distributional, and maintenance
infusion protocol to achieve the target value at 3 hours, for example,
and to keep it at that value thereafter. This can be done for the same
patient. again, by giving 750 mg IV for the first 3 hours, then
following this with 250 mg for the next 3 hours, and then 1250 mg over
the next 18 hrs to finish the first day. Then after that one can
simply infuse 1250 mg/day.
After the first such dose, the predicted concentrations are
almost 21 ug/ml. They then fall to 17 at about 6 hrs, rise to 19 at
the end of the first day, and settle out at about 17.5 ug/ml
thereafter. The total AUC for this regimen is 2698 units, only 69% of
the q 12 h AUC of 3883 units.
If one gives Vanco over 1 hr q 12 h, for example, then one
needs to get both peaks and troughs for TDM to evaluate the effect of
the short term (usually 1 hr) infusion on the peak, and then to get
the trough to see the effect of elimination. Otherwise you do not know
whether to adjust trhe dose or the dose interval.
On the other hand, it is simpler to monitor continuous IV
therapy well. Get a first sample at the end of the first infusion (at
3 hours), and then again after 24 hrs. Then you know everything you
really need to know. After that, simply get a sample at the end of
whatever 24 hr infusion you wish to check. If the level is 9/10 of
what you want, simply infuse 10/9 of the previous dose over the next
24 hrs, for example, and check again. Very simple. Continuous IV
appears to be the most efficient way to use a non-concentration
dependent drug, with minimal toxicity, and simpler monitoring of good
quality. Those 2 patients above who had Vancomycin toxicity may well
have had either a milder episode, or maybe even none at all, if their
therapy had been continuous IV instead of q 12 h.
Very best regards to all,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine,
Division of Geriatric Medicine,
Laboratory of Applied Pharmacokinetics,
USC Keck School of Medicine
2250 Alcazar St, Los Angeles CA 90033, USA
email= jelliffe.at.usc.edu
Our web site= http://www.lapk.org
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