Download Pharmacokinetics of a 3 mg/kg Body Weight

Pharmacokinetics
of a 3 mg/kg Body
Weight Loading Dose of Gentamicin
or
Tobramycin
in Critically Ill Patients*
L. Chelluri,
M.D.,
F.C.C.P;tJonathan
Michael
S. Jastremski,
M.D.
Warren,
M.D.,
F.C.C.P;
and
We evaluated
the pharmacokinetics
and adequacy
of gentamicin
or tobramycin
after administration
of a loading
dose of3 mg/kg body weight
in 14 critically
ill patients
with
presumed
sepsis.
Therapeutic
blood levels after loading
dose were obtained
in 13 of the 14 patients.
Measured
volume
ofdistribution,
serum half-life,
and elimination
rate
constant
were significantly
different
from values calculated
by using standard
formulae.
All the patients
tolerated
the
dose well without significant
deterioration
in renal function.
Based on the present
study, we conclude
that administration
of 3 mgfkg body weight
loading
dose of gentamicin
or
tobramycin
in critically
ill patients
with sepsis would result
in earlier
therapeutic
drug levels.
(Chest
1989; 95:1295-97)
G
ICU
ram-negative
pneumonia
nificant
morbidity
and
have shown
that 50 percent
Gram-negative
hours.
Craven
creased
bacteremia
occur
et al2 demonstrated
survival
for
with
the adult
Gram-negative
of therapy
for
resuscitation,
and removal
that
ules
often
previously
glycoside
This
critically
also
these
critically
doses
and
ill
and
0
we
loading
summarizes
with
have
now
dose
routinely
weight
in a
presumed
loading
group
of
Gram-negative
thermia
all
broad
tobramycin
modification
of
distribution
(Vd),
were
derived
and
serum
Additional
so as to avoid
Three
and
trough)
for
a mathematical
curve
as described
were
measured
coefficient
value
of4
p.g/dl,
value
of4
p.g/dl.
Net
fluid
mined
dose,
when
as
increase
initial
value
consecutive
patients
Department
ofCritical
in
our
general
in
was
death
was
less
than
3 mg/dl
or hospital
an
or greater.
2.8
levels
The
percent
with
a control
percent
with
a control
admission
was
deter-
of the
loading
was
defined
if initial
serum
function
mg/dl
increase
Renal
Ke
immunoassay.
of 0.5
or
and
elimination
Aminoglycoside
in renal
3 mI/di
admin-
T112,
to administration
creatinine
times
midcycle,
Vd,
to hospital
Deterioration
serum
peak
respec-
after
exponential
Zaske.)2
prior
of 1 mg/dI,
function
was
if the
monitored
discharge.
data
are
for
paired
samples
was
values;
p<O.05
was
measured
Fourteen
period
expected
1 .cgIml,
obtained
was 4.3
as compared
(Ke)
to calculate
postinfusing,
polarization
for gentamicin
constant
at different
of the
and
of
aminoglycoside.
were
for tobramycin
day
the
and
a
volume
used
that
minutes
fluorescence
weight
Using
of
rate
of “measured”
by Sawchuk
two
was
(30
calculation
and
body
infusion.
administered
with
of aminoglycoside
available.
creatinine
were
interaction
after
a gentamicin
in turn,
such
In
and
empirically
estimates
8 p.gfml
reconstruction
balance
for the
an
interval
were
ofvariation
employed,
elimination
levels
by
were
adjusted
were,
dosing
the
using
and
These
dose
this
evi-
of infection.
received
Ng,”
and
loading
in
of hyper-
focus
begun
mgfkg
drug
levels
of the
3
(T1/2),
antibiotics
described
presence
as a continuous
of
patient.
potential
blood
istration
of
hour
methods
half-life
was
All patients
dose
the
dose
trough
tively.
therapy
one-half
for each
a maintenance
identifiable
measures
cultures.
loading
over
the
(T<35#{176}C), tachycardia,
an
antibiotic
appropriate
intravenously
t-test
METHODS
hypothermia
and
are
required
resuscitation
spectrum
All
AND
or
standard
sepsis
of sepsis
(T>38.5#{176}C)
cases,
or
Gram-negative
diagnosis
of hypoperfusion,
until
infection.
MATERIALS
presumed
The
dence
in these
the pharmacokinetic
a 3 mg/kg
body
or tobramycin
ill patients
We
body weight
aminoachieve
therapeutic
aminoglycoside
report
ill patients.8
dosing
sched-
levels.
that a 2 mg/kg
dose
fails to
observed
after
of gentamicin
of
outcome.5
Evidence
of distribution
for
in subtherapeutic
a 3 mg/kg
levels
infec-
result
utilize
adequate
Gram-negative
in most
loading
in critically
and
with
increased
standard
levels
data
dose
early
with
summary.
obtaining
patients
adequate
antibiotic
therapy,
of infection,
if possible.
It is
influences
the volume
shown
loading
patients.
ventilated
distress
syndrome
when
developed.
The mainstay
sepsis
includes
fluid
in patients
tions positively
suggests
that
drugs
is
Therefore,
and
focus
achieving
aminoglycoside
in the initial 24 to 48
a significantly
de-
mechanically
respiratory
pneumonia
Gram-negative
early
of the
recognized
and/or
sepsis
cause
sigmortality.
Kreger
et al’
of deaths
secondary
to
expressed
as mean
±
used
considered
SD.
for
The
two-tailed
comparing
statistically
Student’s
estimated
and
significant.
medical/surgical
RESULTS
*From
the
Care
and
Emergency
Medicine,
SUNY
Health
Science
Center,
Syracuse,
NY.
tPresently
at Department
of Anesthesiology,
Division
of Critical
Care Medicine,
Presbyterian-University
Hospital,
Pittsburgh.
Presented
in part at the 53rd Annual
Meeting
of the American
College
of Chest
Physicians
at Atlanta,
Georgia,
1987. Winner
of
Winthrop-Breon
Young Investigator
Award.
Manuscript
received
July 15; revision
accepted
October24.
General
Table
1
suspected
men and
Accurate
.
patient
characteristics
are summarized
in
Lung,
with
or without
other
sites,
was the
site of infection
in 12 patients,
with abdokidney
fluid
suspected
in the other
two patients.
balance
was obtained
in eight
of 14
CHEST
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I 95 I 6 I JUNE,
1989
1295
1 -Characteristics
Table
ofPatient
Population
of
distribution
(0.32
Range
Mean±SD
Age,
yr
63±
Male
body
37-87
15
Female
weight,
kg
Total
loading
dose,
Serum
59
mg/dl
,
c..learance*
Actual
ml/,nin
±
*51
47
±
20
of infectiont
*Creatinine
clearance
calculated
by
0.9-2.8
12
Other
8
patients
had
of infections
more
patients.
4.3
(
than
Seven
L), and
-
niultiple
0.8
L).
method
of Cockroft
aminoglycoside
dose
were
dose
number
remia
resulting
fluid
within
±
serum
levels obtained
the therapeutic
balance
(mean
The
measured
Vd,
Zaske,’2
values”
values
obtained
by
for aminoglycoside
method
differed
significantly
(Table
2). Specifically,
of
0.24
value
constant
was
poor
(mean
and
greater
vs
mI/nin
Serum
Level,
1
20
39
3
56
7
4
70
9
5
49
4.4
6
91
8.4
7
63
9.5
8
22
14.1
9
30
8.8
10
41
12.6
11
20
12
esti-
Ke,
have
shown
blood
levels
Others
have
aminoglycoside
with
in
into
ofthe
in
and
bacteremia.
in infected
were mdi-
pneumonia
drug
into
lung
dose.
critically
ill
is crucial
shown
body
of
tissue.3”5
Since
in limiting
may
and
mor-
that
the standard
weight
results
in
serum
ammnoglycoside
An expanded
volume
patients
in
because
of deaths
secondary
to Gram-negative
occur
in the first 24 to 48 hours,
early
subtherapeutic
this loading
T1/2,
that
achieving
improves
out-
recommended
achieving
levels
of 8 to 10 p.g/ml
Gram-negative
penetration
bacte-
in the hospital
be
levels following
of distribution
the
reason
inadequacy
of this standard
loading
dose.6’8”6
present
study,
measured
volume
of distribution
the
ammnoglycoside
was
significantly
greater
for
the
In
the
for
than
Pharmacokinetics
2-A.minoglycoside
Measured
Trough
Seruni
p.g/ml
2
the
and
mortality
Estimated
CrC1,*
1.8
0.133±0.5
pneumonia
and
adequate
antibiotic
therapy
bidity
and mortality.’
We and others9”#{176} have
loading
dose
of 2 mg/kg
± 0.44
Sawchuk
Table
Patient
±
measured
than
hours-’
11kg
half-life
4.29
the
in Gram-negative
pneumonia
and
et al’ reported
improved
survival
patients
when
dosages
of gentamicin
a majority
bacteremia
from
the estimated
the measured
volume
Peak
values
0.005
±
drug
p<0.05);
Moore
et
aminoglycoside
patients
after the loading
range
in 13 of 14
in any patient
entered
or hospital
discharge.
the
hours,
morbidity
vidualized.
higher
peak
2.8 p.g/ml,
range
4.4 to 15 i.g/ml).
obtained
prior
to the first maintenance
renal
function
was noted
this study prior to death
and
come
Zaske
burn
fluid balance
at the time
were
well within
the safe range
(1.06
range
0.5 to 1 .6 p.g/ml).
No deterioration
iWIfll,
estimated
2.3
Gram-negative
increase
setting.
adequate
is, number
of patients.
in positive
measured
value
(0.86±0.07
p<O.O5).’
Nosocomial
and
the study,
using the method
of Cockroft
varied
from
20 to 91 mI/mm.
Peak
(9.8
levels
Trough
were
of infection
one patient
was in negative
Creatinine
clearance
calculated
of entry
into
and
Gault,’3
patients
the
sites
the
the
rate
published
vs.
DIscussIoN
Gault.#{176}
tSonie
±
than
weight
20-91
Lung
the
than
vs 5.89
mated
hours’,
greater
body
p<O.O5);
elimination
38-87
115-240
1 .4
or suspected
site(s)
13
176±36
ing
creatiniiie,
Creatii,ine
±
less
hours
5
Body
weight,
was
9
was
0. 1 11kg
±
Level,
g/ml
(11kg)
(Hours)
1)
Ke
)
(Hours
1112
Vd
(Hours)
(L/kg
10.7
.25
.09
7.37
.31
.11
6.6
.25
.18
3.95
.19
0.6
.16
4.3
.24
.26
2.7
.48
1.5
.18
3.8
.24
.16
4.26
.31
.14
4.8
.24
.33
2.09
.56
1.0
.25
2.8
.24
.3
2.28
.31
1.0
.17
4
.24
.19
3.67
.32
.07
9.3
.25
.19
3.7
.19
.11
6.2
.24
.13
5.28
.33
NA
.11
6.2
.25
.24
2.89
.21
10.1
NA
.08
9
.24
.16
4.25
.27
56
6.8
NA
.15
4.5
.24
.08
8.39
.42
13
67
11.8
1.4
.13
5.4
.24
.16
4.43
.24
14
37
10.4
0.9
.14
4.8
.24
.14
4.85
.33
Mean±SD
47±20
9.8±2.8
.133±05
5.89±2.3
.24±.005
.186t
4.29t
.321’
±0.07
±1.8
creatinine
clearance,
1.6
Vd
T1J2
-
.06
*CrC1,
9.1
Ke
(Hours
15
calculated
NA
<0.5
<0.5
1.6
1.06±44
by method
of Cockroft
and
Gault’;
Ke,
elimination
rate
constant;
T1/2,
serum
in CritiCally
III Patients
half-life;
±.1
Vd,
volume
of distribution.
tp<0.05.
1296
Gentamicin,
Tobramycin
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21595/ on 05/13/2017
(Chelluri,
Warren,
Jastremski)
previously
standard
published
weight
vs 0.24
Dasta
et
pharmacokinetics
11kg
body
values”
weight,
shown
that
ill patients
and need
to be directly
measured,
rather
than estimated,
for appropriate
dosing.
In the present
study,
the estimated
serum
half-life
was significantly
greater
than
the
nation
actual
actual
rate
value.
resulted
value.
Further,
in adequate
four
were
therapeutic
high
the
(>10
ratios
ofvolume
depletion.
levels
volume
trough
patients,
creatinine
decreased
Based
estimated
constant
was significantly
A loading
dose of 3 mg/kg
patient
in whom
the
high. All had non-toxic
In
the
g/ml).
prior
All
to fluid
This
drug
increased
resuscitation,
might
the
volume
of distribution
for these
on our data, we recommend
giving
glycoside
loading
patients
dose
suspected
of 3 mg/kg
of having
and
may
side
from
remia:
IV Re-evaluation
patienta
2 Craven
BJ,
Respir
3 Noone
Davies
Am
DE,
McCabe
patients
DE,
J
Med
BUN!
9 Summer
BM,
1986;
features
and
10
factors
continuous
for
V, Lichtenberg
pneumonia
mechanical
and
ventilation.
11
WR,
Chelluri
D. Experience
TMC,
in monitoring
JR,
Slack
gentamicin
RCB,
therapy
Effect
levels
of altered
in
volume
patients
in
of
surgical
122:207-12
J,
DK.
Bertino
JS.
acute
Gentamicin
pancreatitis.
Variability
dosing
Surgery
1988;
in aminoglycoside
ill surgical
JR.
patients.
Care
MS.
doses
JJ.
Lipsky
ill. Crit
L, Jastremski
Ng
PK.
phar-
Crit
Initial
Med
Care
Med
aminoglycoside
1983;
11:948-50
of standard
Inadequacy
in acutely
Determining
ill patients.
Crit
aminoglycoside
a programmable
12
Sawchuk
which
calculator.
13
RJ, Zaske
utilize
J Pharm
Cockcroft
DW,
from
serum
Zaske
DE,
Am
aminogly-
Care
Med
dosage
and
J
Pharm
Hosp
fatality
in
Rev
17
Surgery
1982;
Garfield-
Gault
1987;
blood
levels
1980;
37:
1982;
PL,
dosage
patients
(abstract).
sepsis.
Clin
Fuhs
of creatinine
1976;
LB.
clearance
16:31-41
Strate
individualized
J,
Shod
secretion
HJ,
in burn
RG.
Increased
dosages
of
burn
gentamicin.
91:142-49
MR.
Dis
Prediction
Solem
regimens
gentamicin
4:183-94
Nephron
JL,
of dosing
infusions:
1976;
MH.
with
kinetics,
Mann
Biopharm
Bootman
survival
Bronchial
Maid
Pharmacokinetics
intravenous
creatinine.
patient
Respir
DE.
multiple
patients.
aminoglycoside
Pattison
of aminoglycoin gram-negative
225-31
133:792-96
Parsons
Association
CF.
with
Michael
loading
using
in 612
Am
gram-
149:443-48
15:1143-45
bacte-
DA,
with
77;657-62
1987;
in critically
in the critically
coside
septic
treatment
Surg
of amino-
association
outcome
Miller
Bordley
Armstrong
16 Townsend
Kilinsky
1:477-
16:327-30
levels
to
Gram-negative
PS.
1984;
in patients
JF,
1988;
68:344-85
LM,
Risk
receiving
Dis
WR.
ofclinical
1980;
Kunches
WR.
McCabe
1974;
in patients
therapeutic
MD,
SP,
The
1984;
Lietman
Med
Arch
Dick
15 Alexander
Craven
Dis
aminoglycoside
care.
macokinetics
14
BE,
J
Allo
requirements
pneumo-
outcome
with
on
MR.
levels
weight
CR,
Am
intensive
REFERENCES
1 Kreger
Br MedJ
mortality
J Infect
levels
PW,
PS.
with
Smith
pneumonia.
Lietman
levels
bacteremia.
RD,
7 Carr
CR,
Smith
plasma
8 Dasta
patients.
an amino-
Gram-negative
improve
sepsis.
103:533-37
nia or bacteremia,
especially
in the critically
ill patient
or in the patient
who has received
intravenous
fluid
resuscitation.
This
will result
in earlier
therapeutic
drug
levels
episodes.
gram-negative
plasma
5 Moore
one
relatively
body
RD,
negative
indicative
explain
Moore
glycoside
distribution
was very
(<2 p.g/ml).
dose
had
elimi-
in all but
4
6 Niemiec
less than
the
body weight
of distribution
drug levels
postloading
ofserious
81
and
Mann
et al’ have
are variable
in critically
al8
treatment
11kg body
(0.32
p<O.O5).
Hicklin
G,
concentrations
Kasik
of
JE,
Coleman
tobramycin.
D.
Am
Rev
125:208-15
Fink
ME
Stein
KL.
requirements,
Crit
DW,
Care
Med
Awang
1987;
pharmaco-
nephrotoxicity
1987;
R, Ndemo
pharmacokinetics
Pharmacol
Aminoglycoside
and
in
trauma
15:430
FA,
in critically
Cerra
FB.
ill patients
Altered
with
6:148-53
during
CHEST
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1989
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