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The following message was posted to: PharmPK
I am a victim of gentamicin poisoning. I have less than 5%
of my vestibular function left because of 7 weeks of gent
therapy IV. My weight at the time of dosing was 48kg. I was
given 160mg q12 for 13 days. The dose was then dropped to
120q12 for 7 more days, then dropped to 80mgq12 for the
duration of 51 days total. The infection was never cured.
(enterrococcus gram neg). I have had a rotational chair test
done . I am not alone in this outrage. My life has been
ruined. I was a healthy, active woman. Working for a
living. I am now on SS, can't drive, can't ride my horse,
can't walk without a cane. You get the picture. If there is
no safe dosage for gentamicin concerning vestibular damage,
no way to effectively monitor this drug for ototoxicity, why
not stick to the safest dosages and minimal duration of
therapy? Why not talk about bedside monitoring for
ototoxicity? Why not stick to the labeling of the
C J Petersen
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[Two repiles - db]
From: "Gamal Hussein"
Date: Wed, 7 Feb 2001 20:27:13 +0300
Subject: Re: PharmPK
The following message was posted to: PharmPK
THIS RESPONSE REFLECTS MY FEELINGS AND PERSONAL OPINION, NOT THAT OF THE
MY OPINION IS LIMITED BY THE VERY LIMITED KNOWLEDGE OF THE CASE.
I am very very sorry to know what you have been through. Everyone in
this list is working so hard, exchanging experiences, and communicating with
others on how to get the best out of medications and how to minimize
"eliminate if you can" dose-related adverse effects. However, if you read
the messages that were posted with regard to gentamicin dosing you will see
that optimizing drug therapy is not a simple process. In the clinical
setting, it is only executable when more than one person are working
together; physicians, nurses, laboratory techs, and of course pharmacists.
To add to the complexity, and to be frank with you, recommendations from
pharmaceutical companies are not the best and even information in textbooks
may be misleading and must be interpretted carfuly. The idea of giving
larger doses less frequent was proposed to minimize toxicity and maximize
benefits, I personally not convinced by it, but again monitoring blood
levels and patient response were recommended, so as long as this is done, it
is fine with me.
I do not know how to best answer you with limited information about your
case or about knowing other medications that were given or conditions that
you may have had, without getting into legal troubles. You also know the
limitation by the low, on providing incomplete assessment in cases like
yours. However, I will try to clarify some points which may help, partially,
answer some of the questions you have raised:
"why not stick to the safest dosages and minimal duration of therapy? "
Each therapeutic intervention has a risk, the real questions are "Does the
expected benefit outweighs the expected "potential" risk? or what
therapeutic alternative does the physician have that may pose less risk?
These may be best answered by the knowledge of the prognosis and the
alternative therapy at the time. These issues may have been already ansered
by your physician.
"Why not talk about bedside monitoring for ototoxicity?" We have been
taking about this for years, and teaching it for years. The issue is well
known and guidelines are almost established, it is not a mystery; you want
to give a drug, here are the best doses to achieve your goal of levels which
may provide a cure "again the magic word is may", then get more levels,
correlate it with response, adjust doses, evaluate patient, and start all
over again. Deviation from this may occur by misleading results, drug
interactions, or misunderstanding of drug behavior as well as
bacteriological cure/clinical response. Now you get there and try to do
these simple process, all what you find is imperfect world; too many
patients with complicated diseases to take care of, reduction in insurance
money which pays for tests, etc. These are not execuses, I know, but this is
reality, you know!
Why not stick to the labeling of the drug? we should, but the real question
is how much respect the current labeling has to individual variations? How
much pressure do we have, on pharmaceutical companies, to provide best
support for research and evaluation to find best dosage and monitoring?
Let me ask you this, How often do you think companies update their inserts?
and what makes them do that, and what information do they have, by low, to
update? In a study we did evaluating drug effects on nursing babies, we
faced the sad reality that the labeling of many drugs indicate "unknown
data", the print is on for tens of years, and still that way, while data
were published with exact drug concentration on mothers milk and were also
corrlated with side effects on the babies!!!!!
I am very sorry to take the time from everyone in the list to read this long
response, but I felt that I have to.
Gamal Hussein, Pharm.D.
Director of Clinical Pharmacy, Touro Infirmary
Adjunct Clinical Associate Professor of Neurology, LSU
From: Roger Jelliffe
Date: Wed, 07 Feb 2001 19:04:11 -0800
Subject: Re: PharmPK Once Daily Dosing of gentamicin
Dear Ms. Petersen:
Thank you so much for sharing all this with us. I might say
that as physicians, we probably do not ask or test patients
vigorously enough about their hearing and vestibular function when we
use aminoglycosides. I know of one physician who had a transient high
tone deafness for about 3 days after a single 80 mg dose of
gentamicin back about 1980. I also know of a 7 year old girl back in
the late 60's who by mistake received 10 times the prescribed dose
twice. She also had a high tone deafness for about 3 days. I get the
impression that if one asks about hearing and vestibular function and
can catch it early, it may often be reversible. I also know of
another case in which there was permanent deafness with chronic
irrigation of a draining wound with neomycin, again, back in the 70's.
People in dialysis centers, I think, see considerably more
such toxicity. After the usual doses, the peak serum concentrations
in patients with really poor renal function persist much longer and
decrease much more slowly than in patients with normal renal
function. Because of this, It is probably useful to dialyse patients
about 3 hours AFTER the dose than to give the dose after dialysis, as
is the usual custom. This will decrease the total exposure to the
drug, and make the serum concentration profile somewhat more similar
to that seen in patients with better renal function.
I think it is probably also easier for us to ask patients
about their hearing than it is to inquire about their vestibular
function, especially when they are bedridden at the time. I will
certainly pay much more attention to this in the future.
I have tried to analyze some of your data using our USC*PACK
software, which has been available in various forms since 1973. I
think it is very important to monitor the concentrations of
aminoglycosides, both peak and trough concentrations, to help
understand what is going on with the drug in the patient. I wish this
practice would become more common. The concepts behind this approach
are, in my experience, very poorly taught to medical and even to
pharmacy students, so that it is really not the fault of the
physicians that they don't do this, but of our educational systems.
Curriculum committees are not interested in teaching students how to
use drugs well or precisely. They say there is not enough time
available in the schedule to do this, and that it is too complicated.
Students, many of them, say the same. This is a big problem that I
have been working to overcome for over 30 years. Basically, most
people who go into medicine have a very great resistance to dealing
with quantitative concepts. Put an equation on the board and they
turn right off. This, I believe, is true of the great majority of
people in the medical culture, and has been a very real problem in
getting them to accept, understand, and use such approaches. Sharing
your experiences this way hopefully will help in this regard. We need
to learn how to give drugs to hit desired target goals precisely,
instead of simply following some general guidelines, not even
adjusted to a patient's body weight (your case), and renal function.
The Physicians Desk Reference for 1998, and similar sources
in other countries, say exactly what you say - that patients should
be monitored for renal, auditory, and vestibular dysfunction, and
that serum concentrations, "when feasible" should be monitored. It is
almost always feasible, in my experience. Various guidelines are also
given to lengthen the dose interval when renal function is decreased.
The key in all this is the serum concentrations, peak and
trough, that are achieved on the various dosage regimens, and their
relevance, or lack of it, to the needs on each individual patient.
That is why some of us strongly believe that specific target serum
concentrations should be thoughtfully selected for each patient,
based on that patient's perceived need for the drug, and that a
dosage regimen then be developed, using a model of the behavior of
the drug, to most precisely hit the desired targets. This is
"Model-Based, Goal-Oriented" drug therapy. There is a very good
article by van Lent Evers, et al in Therapeutic Drug Monitoring, 21:
63-73, 1999. It describes the use of these approaches with
aminoglycoside therapy in patients with cystic fibrosis. It is a good
illustration of what can be done with this general approach. It shows
the utility of combining the use of serum concentration monitoring
with available software to make individualized models of the behavior
of the drug in each patient, and to compare the behavior of the
patient's model with the patient's clinical behavior. In this way one
can evaluate whether or not the initial target goal was well selected
or not, and it provides the structure for developing any adjustment
of the dosage to best suit the perceived needs of the patient. The
article not only showed improved outcome, but also improved
I have tried to analyze your situation from some of the data
you have provided.You do not state your age, your height, or your
renal function. I have used an age of 45 years, a height of 65 in,
and a serum creatinine of 1.0 mg/dL in these analyses. Based on this,
and on the doses you say you received, it is likely, using the 2
compartment deep tissue model in our collection, based on the work of
Schentag, that on the 160 mg every 12 hours for 13 days, that you
were having peak serum concentrations of about 17 and troughs of 1.6
ug/ml, then falling to about 13 and 1.4 on 120 mg every 12 hours, and
then to 9 and 0.9 ug/ml on the 80 mg every 12 hours. The peaks of 16
are probably too high for twice daily administration, but are usually
OK for once daily administration. Those of 13 are in between, and
those of 9 are common target concentrations for twice daily dosage.
The concentrations in the peripheral compartment are about twice what
we usually see. I have had the impression that these peripheral
concentrations may well correlate with the incidence of renal
toxicity and ototoxicity.
One can also use not unreasonable models of the relationship
of the serum concentration profiles and the ability to kill bacteria.
Based on these, it is likely that the minimum inhibitory
concentration of your organism was about 4 ug/ml, which would put it
in the range of moderate sensitivity or resistant. It is therefore
likely that your organism may have become resistant, or might have
been resistant shortly after beginning therapy. An any rate, one can
use models of this type to study the behavior of drugs and their
effects based on various dosage regimens in various types of
patients, and to see better just what is actually going on during
their therapy. Further, it is easy now to develop dosage regimens
that are individualized for each patient and his/her perceived need
for the drug, to hit selected target goals. Our software has been
around in various forms since 1967. If you wish, you can get more
information from our web site given below. It is used in teaching in
some schools of pharmacy, but I do not know of its use, or any real
use of these general approaches, in medical schools. A pity.
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