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The following message was posted to: PharmPK
Does anybody have any opinions on using continuous infusion beta-lactams
(or carbapenems) in the treatment of Pseudomonal endocarditis? At
steady-state I would assume that the concentration in the vegetation
should be constant and that if above the MIC of the organism that this
may be better than intermittent infusions.
Bill Murray Pharm.D.
Children's Hospital San Diego
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[Two replies - db]
From: GLDrusano.-at-.aol.com
Date: Wed, 13 Feb 2002 08:53:48 EST
To: david.-at-.boomer.org
Subject: Re: PharmPK Continuous infusion beta-lactams
HI!
That is one option and, given the vagaries of penetration into the
vegetation into the clot, may be near optimal. Given that carbapenems
optimize their cell kill at approximately 40% Time of Free Drug > MIC,
we (our group at Albany Medical Center - myself, Ben Lomaestro, Arnold
Louie and Mike Miller) have been giving carbapenems (meropenem in our
case) as a 3 hour infusion every 8 hours. Some 3-4 hour infusion may
actually be slightly nearer optimal than continuous infusion.
Do you really have a case of Pseudomonas endocarditis? If so, good luck.
As an aside, I would use high dose meropenem (2 gms IV Q8h as a
prolonged infusion or 250 mg/hr as a continuous infusion) and also give
high dose, extended interval aminoglycosides for at least two weeks and
four weeks, if the patient can tolerate it. I would NOT give a
concurrent fluoroquinolone as this upregulates the MexAB system and can
lead to cross resistance for BOTH fluoroquinolone and carbapenem.
All the best,
George Drusano
---
From: "Kavanagh, Ronald E"Date: Wed, 13 Feb
2002 09:53:07 -0500
To: david.-at-.boomer.org
Subject: RE: PharmPK Continuous infusion beta-lactams
The following message was posted to: PharmPK
I would agree with your assumption regarding steady-state. However, the
rate of transfer into and out of the vegetation may be so slow that the
concentration fluctuation within the vegetation may be minimal even with
intermittent dosing.
It may be possible to do an experiment measuring time to steady-state
within a vegetation in vitro. This would demonstrate the net effect of
the transfer rates. You could then simulate the two administration
designs to see if there's really much difference. I would do this before
progressing to a clinical experiment.
Ron Kavanagh
The opinions are my own and do not represent the FDA.
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The following message was posted to: PharmPK
Here is a start thanks to our friend Dr. Ronchera
http://www.boomer.org/pkin/consensus/bl.html
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Dear Bill:
About continuous infusion models and therapy with beta lactams. We have
had a 1 compartment population model of Ticarcillin in the USC*PACK
programs, but have not had much call to use it. However, our colleagues
Pascal Maire, in Lyon, France, and Donald Crowell, at Harbor - UCLA,
have determined diffusion coefficients from measured concentrations of
drug in aortic vegetations in experimentally produced endocarditis, in
rabbits, I think. Using this data, if one wanted to achieve a serum
concentration of 100 ug/ml in a series of 12 hour infusions proceeding
continuously, and if this was for a 65 year old man, 70 in tall, 70 kg,
serum creatinine 1.0, one might give 6700 mg ticar q 12 h, as a series
of continuous 12 hour infusions. With this model, serum concentrations
should be about 90 ug/ml at 12 hours, and 100 after that.
Now, using a model of diffusion into porous spherical objects such as
endocardial vegetations, and the diffusion coefficients obtained by
Crowell et al, the concentrations in the center of a 1.0 cm vegetation
might be about 3 ug/ml at 6 hours, 28 at 12 hrs, 75 at 24 hrs, 95 at 48
hrs, and 100 after that.
If you plug this concentration profile into the Zhi - Nightingale model
of bactericidal effect made by Maire et al, for Pseudomonas with
Ticarcillin, and if you start with 1 relative unit of an inoculum (such
as 1 million bugs, and an assumed MIC of 16 ug/ml, then the number of
bugs should first increase to about 130 relative units (like 130 million
bugs) at about 10 hours into the regimen, after which the MIC is reached
and the number of bugs decreases, falling to about zero at 24 hours, and
staying there thereafter.
So, it is likely you are right, and that such a regimen may well be
effective clinically. If you would like to see our work, or examine this
model under other conditions, you can download a demo version of the
USC*PACK software from our web site, which is www.lapk.org. The default
installation is to a C drive, in the directory USCPACK.
There is also more information on these models and approaches on our web
site, under teaching topics.
Very best regards,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine, USC USC Laboratory of
Applied Pharmacokinetics 2250 Alcazar St, Los Angeles CA 90033, USA
email= jelliffe.aaa.hsc.usc.edu Our
web site= http://www.usc.edu/hsc/lab_apk
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Dear Bill:
Based on the pharmacodynamics of the beta-lactams continuous infusion
would be the preferred method of administration. Targeting the
concentration in the vegitation is more difficult though. There have
been a few diffusion models described in the literature, e.g., by Pascal
Maire and part of the USCPACK collection of programs. Our group did some
initial work developing diffusion models for beta-lactams in sputum of
cystic fibrosis patients based on published in vitro diffusion
coefficients. Unpublished work but described in my PhD thesis. Pleas
feel free to contact me for a copy. Some useful references:
1. Mouton JW, Vinks AA. Is continuous infusion of beta-lactam
antibiotics worthwhile?--efficacy and pharmacokinetic considerations. J
Antimicrob Chemother 1996;38(1):5-15.
2. Maire P, Barbaut X, Vergnaud JM, el Brouzi M, Confesson MA, Pivot C,
et al. Computation of drug concentrations in endocardial vegetations in
patients during antibiotic therapy. Int J Biomed Comput
1994;36(1-2):77-85.
3. Bolister N, Basker M, Hodges NA, Marriott C. The diffusion of
beta-lactam antibiotics through mixed gels of cystic fibrosis-derived
mucin and Pseudomonas aeruginosa alginate. J Antimicrob Chemother
1991;27(3):285-93.
Alexander A. Vinks, PharmD, PhD,
Research Professor of Pediatrics
Cincinnati Children's Hospital and Medical Center Pharmacology Research
Center & Clinical Trials Office CHFR 6506, MLC 7025
3333 Burnet Avenue
Cincinnati, Ohio 45229-3039
CHMCC email: sander.vinks.aaa.chmcc.org
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