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A physican friend asked me the following question:
The dose of Zinacef (cefuroxine) is about 750 mg BID when given IV or IM.
However the dose is 250 mg BID when administered orally. Why the dose given IV
is higher? I could not come up with a satisfactory answer. I have not verified
if the PDR has this dose recommendation. Does any body know the reason for
this difference?
Dyal Garg
561-737-3954
E-mail: Dgarg8838.-a-.aol.com
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Dyal,
Possibility of first pass lung metabolism?
Masood Bhatti
Madison
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[Quite a few replies - it looks like different indications is the winner
:-) - db]
From: "Touw, DJ."
To: "'PharmPK.aaa.pharm.cpb.uokhsc.edu'"
Subject: RE: PharmPK Different IV and oral doses for Cefuroxine
Date: Tue, 27 Oct 1998 15:43:38 +0100
MIME-Version: 1.0
zinacef iv is licensed for totally other indications and infections as
zinacef po. You may not change from iv to po in case of a severe infection!!
dr. D.J. Touw
university hospital vrije universiteit
Amsterdam
---
Date: Tue, 27 Oct 1998 13:46:24 -0500 (EST)
From: VINCENT EARL PEARSON
To: PharmPK.at.pharm.cpb.uokhsc.edu
cc: Multiple recipients of PharmPK - Sent by
Subject: Re: PharmPK Different IV and oral doses for Cefuroxine
MIME-Version: 1.0
Greetings!
I had reviewed cefuroxime axetil for our hospital. This compound is
niched as a "step down" agent for completing antibiotic therapy after a
5-7 day course of parenteral antibiotics. Therefore, the infection is
presumably eradicated and not as much drug is needed to complete the full
course. I have more complete data if it is needed.
I hope this information proves useful.
With best regards,
Vince Pearson, Pharm.D., BCPS
Clinical Coordinator, Drug Information
The Johns Hopkins Hospital
Baltimore, Maryland USA
---
Date: Tue, 27 Oct 1998 13:38:16 -0700
From: "David Nix, Pharm D."
Organization: College of Pharmacy
MIME-Version: 1.0
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK Different IV and oral doses for Cefuroxine
Having higher IV doses for cephalosporins and penicillins is quite
common. The reason has more to do with GI tolerance after oral dosing
than with pharmacokinetics. However, most beta-lactam drugs show some
saturable absorption and bioavailability is lower with higher doses. In
addition, a greater fraction of the dose may be presented to the lower
intestine (e.g. ampicillin) resulting in further alteration of bacterial
flora and increased incidence of antibiotic associated diarrhea.
David Nix
---
Date: Tue, 27 Oct 1998 15:52:07 -0500
From: Joan Korth-Bradley
To: PharmPK.at.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK Different IV and oral doses for Cefuroxine
Mime-Version: 1.0
I haven't worked with this product, but in the PDR, Ceftin (oral) and
Zinacef (IV) do indeed have different dosing recommendations. I suspect
that the differences may come from the indications for each. Ceftin is
indicated for infections that are more minor in nature and so lower
concentrations are adequate while Zinacef is indicated for more serious
infections in potentially more complicated patients and so a higher
concentration is preferred.
You find something similar for ampicillin. The usual dose recommended for
IV infusion is 1.5 to 3 g every 6 hours (see Unasyn), while the oral dose
recommended is 250 to 500 mg every 6 hours (see Omnipen).
Joan K-B
Wyeth-Ayerst Research
---
Date: Tue, 27 Oct 1998 14:07:29 -0800
From: bmurray.-a-.chsd.org (Bill Murray)
MIME-Version: 1.0
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
CC: Multiple recipients of PharmPK - Sent by
Subject: Re: PharmPK Different IV and oral doses for Cefuroxine
With po cefuroxime the bioavailability is incomplete. There is a high
incidence
of diarrhea and other GI complaints even with the low doses used orally.
Bill Murray Pharm.D.
Childrens' Hospital San Diego
---
From: "Jones, Jim - Pharm Tox"
To: "'PharmPK.at.pharm.cpb.uokhsc.edu'"
Subject: RE: PharmPK Different IV and oral doses for Cefuroxine -Reply
Date: Tue, 27 Oct 1998 17:58:00 -0500
X-Priority: 3
MIME-Version: 1.0
Intravenous cefuroxime is the sodium salt where oral cefuroxime is
axetil and is a prodrug with a longer half-life than the sodium salt
Jim Jones
Cols OH Children's
---
Sender: acy62.aaa.pop.dial.pipex.com
Subject: Re: PharmPK Different IV and oral doses for Cefuroxine -Reply
Date: Wed, 28 Oct 98 08:28:35 +0000
x-sender: acy62.aaa.pop.dial.pipex.com
From: Andrew Sutton
To: "Pharm PK"
Mime-Version: 1.0
but what about the aim of an IV dose being to achieve higher
concentrations in order to kill more resistant bacteria or eliminate a
potentially overwhelming infection. When medics use the IV route in
preference to IM or SC that is often the intention.
Andrew Sutton
Guildford Clinical Pharmacology,
Guildford, UK.
Andrew Sutton
ASutton.at.gcpl.co.uk
Guildford Clinical Pharmacology
Telephone +44 (0) 1483 406886
---
Date: Wed, 28 Oct 1998 05:27:30 -0500
From: Joachim Gruber <73064.3320.-a-.compuserve.com>
Subject: PharmPK Different IV and oral doses for Cefuroxime
Sender: Joachim Gruber <73064.3320.aaa.compuserve.com>
To: "INTERNET:PharmPK.at.pharm.cpb.uokhsc.edu"
MIME-Version: 1.0
my comment:
(1) Oral cefuroxime
====================
Oral dosing has to be checked by lab determination of the resulting
concentrations in plasma. I don't know whether physicians usually do that
regularly also for i.v. (I do not think so).
To help with the dosage of oral cefuroxime , Glaxo Wellcome, the
manufacturer of cefuroxime axetil tablets (and powder), gives statistical
averages gained from 12 healthy adults in Product Information 4081487.
The following values are copied from that info. They pertain to cefuroxime
axetil tablets. The dose is expressed in gram cefuroxime equivalent, the
drug is administered immediately after a meal. The peak plasma
concentration is given in the units mg/L. The following table has the
structure:
{{dose, peak plasma conc}, {dose, peak plasma conc}, ...}
{{0.125 g, 2.1 mg/L}, {0.25 g, 4.1 mg/L}, {0.5 g, 7.0 mg/L}, {1.0 g, 13.6
mg/L}}
Address of Glaxom Wellcome:
Glaxo Wellcome Inc.
Research Triangle Park, NC 27709, USA
We used larger doses of cefuroxime axetil tablets and measured the peak
plasma concentrations 2.5 hours after tablet intake:
{{2.0 g, 21.9 mg/L}, {3.0 g, 28.1 mg/L}, {5.0 g, 58.9 mg/L}}
We also measured peak plasma concentrations when the tablets were taken
without a prior meal. The peak plasma concentrations were a factor of 2.7
lower:
{{2.0 g, 8.1 mg/L}, {3.0 g, 10.4 mg/L}, {5.0 g, 21.8 mg/L}}.
For an intake of 2 g cefuroxime equivalent we determined the entire plasma
concentration time curve. It can be found at
http://www.Lymenet.de/symptoms/cycles/pkcefu.gif
(2) i.v. cefuroxime
===================
I think 250 mg p.o. cannot be equivalent to 750 mg i.v. Goodman and
Gilman's The Pharmacological Basis of Therapeutics, 9th edition gives the
folling data:
CEFUROXIME (Chapter 45)
AVAILABILITY (ORAL) (%): 68a
URINARY EXCRETION (%): 96 +/- 10
BOUND IN PLASMA (%): 33 +/- 6
CLEARANCE (ml * min-1 * kg-1): CL = 0.94 CLcr + 0.28
VOL. DIST. (liters/kg): 0.20 +/- 0.04;
HALF-LIFE (hours): 1.7 +/- 0.6;
EFFECTIVE CONCENTRATIONS: See Chapter 45
TOXIC CONCENTRATIONS: --
a Cefuroxime axetil, prodrug of cefuroxime.
Reference: Emmerson, A.M. Cefuroxime axetil. J. Antimicrob. Chemother.,
1988, 22:101-104.
I hope this helped.
Joachim Gruber
(Joachim_Gruber.-at-.Compuserve.com)
---
Date: Wed, 28 Oct 1998 07:18:42 -0500
From: Steven Gelone
Reply-To: sgelone.at.thunder.ocis.temple.edu
X-Accept-Language: en
MIME-Version: 1.0
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK Different IV and oral doses for Cefuroxine -Reply
Dyal,
Much of the dosing of IV antibiotics (especially with regard to higher
doses given IV as compared to oral) has to do with the idea that "more
is better". The assumption is that the patient requiring IV therapy is
"sicker" and therefore requires "more" drug.
Steven Gelone
Temple University School of Pharmacy
Section of Infectious Disease, School of Medicine
Philadelphia, PA
---
From: Varun Garg
To: "'PharmPK.-a-.pharm.cpb.uokhsc.edu'"
Subject: RE: PharmPK Different IV and oral doses for Cefuroxine
Date: Wed, 28 Oct 1998 09:06:34 -0600
X-Priority: 3
MIME-Version: 1.0
The 2 formulations - oral and parenteral - are for
different indications. a 250 mg oral dose produces a Cmax
of 4.1 mcg/mL, whereas a 750 mg IV produces a Cmax of 27 mcg/mL.
(Source - PDR 98, pages 1008 and 1131).
Hope this helps.
~~~~~~~~~~~~~~~~~
Varun Garg, Ph.D.
Aronex Pharmaceuticals, Inc.
8707 Technology Forest Place
The Woodlands, TX 77381-1191
Tel: 281-367-1666 x317
Fax: 281-367-1676
email: vgarg.at.aronex-pharm.com
~~~~~~~~~~~~~~~~
---
Reply-To: Dr Les White
To: PharmPK.at.pharm.cpb.uokhsc.edu
Date: Wed, 28 Oct 1998 10:16:43
Subject: Re: PharmPK Different IV and oral doses for Cefuroxine
From: lesassays.aaa.ukneqasaa.win-uk.net (Dr Les White)
Its horses for courses
IV cefuroxime would be used in an hospital environment to treat
serious life-threatening infections.
Oral cefuroxime would probably be prescribed for a GP for
something less dramatic
The difference is therefore more to do with
microbiology/infectious disease issues than anything else.
BUT NO IT IS NOT BRCAUSE OF 300% BIOAVAILABILITY!
The UK NEQAS for Antibiotic Assays is provided by:
Department of Microbiology, Southmead Health Services NHS Trust
Bristol BS10 5NB, UK.
Tel INT+UK+117 9595653 Fax INT+UK+117 9593217
http://www.ukneqasaa.win-uk.net
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[A few more replies - db]
Date: Wed, 28 Oct 1998 18:58:20 +0100
From: harald.-at-.mertes.inka.de
MIME-Version: 1.0
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
CC:
Multiple recipients of PharmPK - Sent by
Subject: Re: PharmPK Different IV and oral doses for Cefuroxine -Reply
> Possibility of first pass lung metabolism?
>
> Masood Bhatti
> Madison
Do you mean first pass LIVER metabolism?
--
Harald Mertes, MD
Anaesthesiologist
Rastatt/Germany
mailto:harald.-at-.mertes.inka.de
http://sites.inka.de/sites/mertes/index.html
---
Date: Wed, 28 Oct 98 14:16:13 EDT
X-Sender: apo.aaa.198.252.186.133
Date: Wed, 28 Oct 1998 14:17:18
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
From: "Andy O'Connor"
Subject: Re: PharmPK Different IV and oral doses for Cefuroxine
Mime-Version: 1.0
I believe that Zinacef is cefuroxime sodium and that the oral form of
cefuroxime is cefuroxime axetil, which is not the same molecule.
Andy O'Connor
aoconnor.at.inolex.com
---
Comments: Authenticated sender is
From: "Randy Trinkle"
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
Date: Wed, 28 Oct 1998 16:25:43 -0700
MIME-Version: 1.0
Subject: Re: PharmPK Different IV and oral doses for Cefuroxine
Priority: normal
> The dose of Zinacef (cefuroxine) is about 750 mg BID when given IV or IM.
> However the dose is 250 mg BID when administered orally. Why the dose
>given IV
> is higher? I could not come up with a satisfactory answer. I have not
>verified
> if the PDR has this dose recommendation. Does any body know the reason for
> this difference?
We give cefuroxime IV q8h at 750 mg. Oral dosages range from
250-500 mg bid. Oral bid dosing at these dosages obviously
won't give concentrations as high as those given IV. They're
used for less serious infections. The drug can be given orally
bid because of the length of time for absorption from the gut
--about three hours.
*****************
Randy Trinkle, BScPharm, BA
Pharmacy Department
Prince Rupert Regional Hospital
mailto:rtrinkle.at.mail.citytel.net
Health Science links:
http://www.rupert.net/~rtrinkle
******************
Back to the Top
[A few replies - db]
Date: Thu, 29 Oct 1998 13:39:16 -0600
From: "Masood Bhatti"
To: harald.at.mertes.inka.de, PharmPK.at.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK Different IV and oral doses for Cefuroxine -Reply
-Reply
I don't know if it is metabolized by LUNG or not, but if the IV dose
is higher than Po then there might be a possibility of first pass
LUNG metabolism.
Masood Bhatti
Madison
---
From: Olof.Borga.at.draco.se.astra.com
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Subject: Comments on "Different IV and oral doses for Cefuroxime"
Date: Fri, 30 Oct 1998 10:40:15 +0100
Mime-Version: 1.0
I would like to offer the following comments in this discussion which
is getting a bit confused:
1) Different indications often require different dosages as pointed out by
Randy Trinkle in his comment. Once a regimen has been proven in clinical
trials to work, doctors will not and should not change the dose.
2) The intravenous and oral formulations use different salts of cefuroxime
as pointed out in one comment. The "molecules" are not different however;
the active component is the same. The number of milligrams indicating the
strength also refers to the equivalent amount (in milligrams) of the active
component, not the number of milligrams of the salt.
3) The latter confusion could be avoided altogether if doses were to be
given in molar amounts. Plasma concentrations should also be given in molar
terms, e.g. mmoles/L. That should put an end to the nonsense discussion of
whether to use gravimetric or molar units for plasma concentrations. People
educated in chemistry should be able to handle the molar concept.
Olof Borg=E5, Ph.D.
Pharmacokinetic Expert
Kinetics and Metabolism
Preclinical R&D
Astra Draco AB, P.O. Box 34, S-221 00 Lund, Sweden
e-mail: olof.borga.-at-.draco.se.astra.com
---
Date: Fri, 30 Oct 98 09:16:51 -0700
From: "Mike Jones"
To:
Subject: Re: PharmPK Different IV and oral doses for Cefuroxine
MIME-Version: 1.0
The lower oral dose is to prevent or lessen gastrointestinal side
effects. The lower oral dose also result in lower serum
concentrations, therefore the indications for oral therapy are
different than IV/IM therapy.
Hope this helps.
Mike Jones, Pharm.D.
Medical Editor
Micromedex, Inc
---
Date: Fri, 30 Oct 1998 18:32:35 +0100
From: harald.-at-.mertes.inka.de
MIME-Version: 1.0
To: Masood Bhatti
CC: PharmPK.at.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK Different IV and oral doses for Cefuroxine -Reply
-Reply
There is no relevant metabolism of the lungs known. Oral cephalosporines
are not so important in clinical practice as parenteral perparations.
Oral dosage may be sufficient for common illness at low dosage whereas
parenteral high dosage is dayly rotine for critical ill patients more
focusing on being a little under the toxic threshold as the clinical
often unknown MIC-value of a likewise often unknown bacteria tribe.
--
Harald Mertes, MD
Anaesthesiologist
Rastatt/Germany
mailto:harald.at.mertes.inka.de
http://sites.inka.de/sites/mertes/index.html
Back to the Top
[Two replies - db]
Date: Fri, 30 Oct 1998 22:24:52 -0200
From: Luis Fernando Marques-Santos
MIME-Version: 1.0
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK Re: Different IV and oral doses for Cefuroxine
Sorry, but for a drug to be metabolized in the lung at such extent it
would be necessary a high Cytochome P 3A 450 (CYP3A) expression on lung
cells, what I don't know at the moment if it occurs. But, you can be sure
that this is an interesting fact. There are two reasons for this: a) There
is a high expression of Cytochome P on lung cells; or/and b) There is
another unknown metabolic way for this drug on lung cells, what could be
interesting, once this way could be common for others substances. This fact
is very, very important. It could let us to understand lung metabolism, for
a while...
Yours sincerely,
Luis Fernando Marques-Santos
Lab. Imunologia Tumoral
Depto. Bioqu=EDmica M=E9dica
Universidade Federal do Rio de Janeiro
Rio de Janeiro - Brasil
tel: 55 21 560 8895 r. 151
fax: 55 21 270 8647
e-mail : fagioli.-a-.olimpo.com.br
=20
---
From: "Stephen Duffull"
To:
Subject: Re: PharmPK Re: Different IV and oral doses for Cefuroxine
Date: Mon, 2 Nov 1998 09:26:11 -0000
MIME-Version: 1.0
X-Priority: 3
I would like to add that I agree with almost all of Olof's summary of the
cefuroxime saga. However I would like to comment on one point:
>1) Different indications often require different dosages as pointed out by
>Randy Trinkle in his comment. Once a regimen has been proven in clinical
>trials to work, doctors will not and should not change the dose.
This last sentence seems counter-intuitive to me. Clinical trials are
essential to determine dose ranges appropriate for treating a population.
Prescribers are essential in interpreting this information in light of their
patient's clinical status and individualising this recommendation for their
patient. Hence prescribers should and do change doses.
Regards
Steve
Stephen Duffull
School of Pharmacy
University of Manchester
M13 9PL, Manchester, UK
Ph +44 161 275 2355
Fax +44 161 275 2396
Email sduffull.-at-.fs1.pa.man.ac.uk
Back to the Top
I have recently come across a similar problem. A highly lipophilic material
given either iv (Emulphor suspension) or by oral gavage gives different
kinetics by the two routes. The oral dose reaches Cmax in 5 min., and the
optimal metabolic parameters is in reasonable agreement with in vitro
measurements. PK parameters which reproduce these kinetics predict much too
rapid clearance of the iv dose. In particular, the distributional phase is
predicted to be extremely fast although the phase limited by metabolic
clearance is much slower. Does anyone have any idea why the kinetics for these
two routes differ so drastically?
--
Michael C. Kohn
Laboratory of Computational Biology and Risk Analysis
National Institute of Environmental Health Sciences
P.O. Box 12233, Mail Drop A3-06
Research Triangle Park, NC 27709-2233
Telephone:
919-541-4929 (voice)
919-541-1479 (fax)
e-mail:
kohn.-a-.valiant.niehs.nih.gov
Web site:
http://valiant.niehs.nih.gov
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[Three replies - some of these replies may warrent a new subject line ;-) - db]
From: "BRUNO LOUIS"
To:,
"Multiple recipients of PharmPK - Sent by"
Subject: Re: PharmPK Re: Different IV and oral doses for Cefuroxine
Date: Wed, 4 Nov 1998 22:00:17 +0400
X-Priority: 3
MIME-Version: 1.0
From
Bruno Louis
Univesity Hospital
Po.Box 38, Al Khod Muscat
OMAN
Urinary clearance of Cefuroxime sodium (95%)is more compared to Cefuroxime
axetil(52%)
---
X-Sender: st005899.-at-.brandywine.otago.ac.nz
Mime-Version: 1.0
Date: Thu, 5 Nov 1998 10:42:22 +1300
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
From: Robert Purves
Subject: Re: PharmPK Re: Different IV and oral doses for Cefuroxine
Did you determine PK parameters from the two compartment model with
first-order absorption? If so, there is a long list of pitfalls in
parameter estimation, one of which could have given you Wrong Answers. A
relevant paper:- Purves RD (1996) Multiple solutions, illegal parameter
values, local minima of the sum of squares, and anomalous parameter
estimates in least-squares fitting of the two-compartment model with
absorption. J Pharmacokin Biopharm 24 79-101.
Robert Purves
MailTo:robert.purves.-a-.stonebow.otago.ac.nz
---
Date: Thu, 05 Nov 1998 08:04:43 -0500
From: Nabil B. Darwazeh
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
Subject: PharmPK Re: Different IV and oral doses for Cefuroxine
Mime-Version: 1.0
are the dosage forms (i.v. vs oral) have the same form of the drug molecule
( free base, salt , prodrug......)?
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