The pharmacokinetics of a 2-g bolus of cefepime were measured in critically ill patients with normal renal function. Variable and low trough plasma drug concentrations were found, and 8 of 10 patients had levels below the MIC at which 50% of the isolates are inhibited for Pseudomonas aeruginosa. Computer simulations predicted that continuous infusion and shorter dosing intervals would increase trough levels

Lipman, J

Rickard, C

Wallis, SC

University of Queensland eSpace

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,
0066-4804/99/$04.0010
Oct. 1999, p. 2559–2561 Vol. 43, No. 10
Copyright © 1999, American Society for Microbiology. All Rights Reserved.
Low Plasma Cefepime Levels in Critically Ill Septic Patients:
Pharmacokinetic Modeling Indicates Improved
Troughs with Revised Dosing
J. LIPMAN,1,2* S. C. WALLIS,1 AND C. RICKARD2
Division of Anaesthesiology and Intensive Care, University of Queensland,1 and Intensive Care Facility,
Royal Brisbane Hospital,2 Brisbane, Queensland, Australia
Received 1 February 1999/Returned for modification 15 May 1999/Accepted 22 August 1999
The pharmacokinetics of a 2-g bolus of cefepime were measured in critically ill patients with normal renal
function. Variable and low trough plasma drug concentrations were found, and 8 of 10 patients had levels below
the MIC at which 50% of the isolates are inhibited for Pseudomonas aeruginosa. Computer simulations
predicted that continuous infusion and shorter dosing intervals would increase trough levels.
Cefepime (2, 17), a b-lactam antibiotic, covers most organ-
isms recovered from patients in intensive care (10, 18). As
killing of gram-negative bacilli by b-lactams is almost entirely
related to the time that levels in tissue and plasma exceed a
certain threshold (22), it is important that the dosing regimen
maintains adequate plasma drug levels for as long as possible
during the dosing interval. It is not surprising then that dosing
regimens of b-lactam antibiotics are being reevaluated to sus-
tain plasma drug levels (3, 6, 12, 15, 19).
Drug dosage regimens used for critically ill patients are
often based on data for healthy patients, who do not typically
share the characteristics of the critically ill, such as abnormal
fluid balances, different volumes of distribution, altered pro-
tein metabolism, and low albumin levels (4, 7, 8, 14, 16, 20, 21).
However, there is only sparse documentation on the pharma-
cokinetics of cefepime in critically ill patients (9).
The aim of the study was to document levels of cefepime in
plasma from critically ill patients with normal renal function.
This data was then used to develop a pharmacokinetic model,
allowing a variety of dosing regimens to be simulated to iden-
tify doses that predict sustained levels.
This study was approved by the hospital ethics committee.
Critically ill patients ranging in age from 18 to 75 years for
whom the staff intensive care specialist deemed cefepime to be
appropriate therapy were enrollable if they had an infected site
as defined by clinical suspicion with or without positive culture
results, systemic inflammatory response syndrome, and serum
creatinine level of ,0.1 mmol/liter. Enrolled patients were
considered nonevaluable if they developed renal dysfunction
(creatinine clearance, ,75 ml/min).
After informed consent had been obtained, cefepime (2 g,
diluted into 20 ml of sterile water for injection and infused over
3 min) was administered twice daily at precise 12-h intervals via
an intravenous line. Two sets of blood samples were taken over
two 12-h dosing intervals: those used to generate profile A
were collected after the first dose had been administered, and
those used to generate profile B were collected after multiple
doses (day 3, 4, 5, or 6). Samples were taken immediately prior
to dose administration (time [T] 5 0 at the start of the 3-min
infusion) and at 5, 10, 20, 30, 60, 90, 120, 240, 360, 480, and 600
min postdosing and immediately prior to the next dose (T 5
720). Blood (10 ml) was drawn into heparinized Vacutainers
from an in-situ arterial line and centrifuged at 4°C, and the
plasma was frozen at 220°C until it was stored at 280°C.
Patient plasma samples were assayed by an in-house modi-
fication of existing high-performance liquid chromatography
methods (1, 5). Briefly, sample preparation involved precipi-
tation of proteins with acetonitrile and trichloroacetic acid
containing cefadroxil (internal standard), followed by washing
with dichloromethane. Separations were performed on a re-
verse-phase C18 column with a pH 4.9 acetonitrile:20 mM
ammonium acetate mobile phase (ratio, 8:92). The assay was
linear from 1 to 200 mg/ml. The intraday and interday impre-
cision values were all under 6%, and the inaccuracy values
were under 5% at the test concentrations of 4.18, 16.7 and 83.5
mg/ml.
The trough levels C0 and C720 were those at 0 and 720 min,
respectively. Elimination half-life, area under the curve, total
body cefepime clearance, mean residence time, and volume of
distribution at steady state were determined by fitting the data
for plasma drug concentration over time for profile A to a
two-compartment pharmacokinetic model by using WinNonlin
(Scientific Consulting, Inc.). Slopes and intercepts of the biex-
ponential declines were estimated with iterative reweighting to
the inverse of the square of the predicted concentration (1/y2),
and the fit was evaluated from the standard errors of the
parametric estimates. The model parameters for each of the 10
evaluable patients were used to stimulate various cefepime
dosing regimens.
Thirteen patients (11 males) ranging from 34 to 75 years old
(mean, 55 years old) were enrolled. APACHE II scores (11)
ranged from 8 to 24 at study entry (Table 1). There was an
identifiable source of sepsis in 11 patients. In eight patients
cefepime produced a clinical cure, and in six there was a
bacteriological cure. There was one clinical and bacteriological
failure in which Pseudomonas aeruginosa was isolated (MIC of
cefepime, 6 mg/ml). Clinical and bacteriological assessments
were indeterminate (there was no change) in the other pa-
tients. Three patients were nonevaluable as they had abnormal
creatinine clearances on enrollment, even though their serum
creatinine levels were within the normal laboratory range.
The plasma cefepime concentrations of the 10 evaluable
patients after the first dose (profile A) are shown in Fig. 1.
There was a large variation in plasma drug concentrations
among patients, and a number of patients had very low plasma
* Corresponding author. Mailing address: Intensive Care Facility,
Royal Brisbane Hospital, Herston Rd. 4029, Brisbane, Queensland,
Australia. Phone: 61 7 3253-8897. Fax: 61 7 3253 3542. E-mail: jlipman
@gasbone.herston.uq.edu.au.
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drug levels (median level, 1.9 mg/ml) toward the end of the
dosing interval (Table 1). Trough levels after multiple doses
were particularly low (median levels, 1.7 and 1.8 mg/ml), with 4
of 10 evaluable patients having levels under 1 mg/ml and an-
other 4 having trough levels lower than 2.83 mg/ml, the MIC at
which 50% of the isolates are inhibited for P. aeruginosa (Table
2) (17). The consequences of these low levels could be impor-
tant if they involve inadequate bacterial killing or the devel-
opment of resistance, as has been documented to occur in vitro
(6).
Pharmacokinetic parameters for the first dose are displayed
in Table 1. Generally, cefepime was cleared in the patients
than in healthy volunteers, but overall the kinetics are similar
to those reported in the published literature (2). The large
scatter in trough levels in our study may be partly accounted
for by the variance in kidney function of our patients. The
three patients that were nonevaluable due to poor kidney func-
tion (creatinine clearances, ,75 ml/min) had high cefepime
levels, and after multiple doses the highest trough levels were
found in those with creatinine clearances of ,100 ml/min. This
is not surprising, as cefepime is largely excreted unchanged by
the kidney (2), and there was a strong relationship between
creatinine clearance and cefepime clearance revealed by our
data (r2 5 0.74).
The compartmental variables determined by the model for
the 10 evaluable patients were used to simulate alternative
dosing regimens in an attempt to identify regimens that would
maintain high trough levels. Dosing regimens were simulated,
and their predicted median trough values after 48 h were as
follows: for continuous infusions (with a 0.5-g loading dose) of
FIG. 1. Plasma cefepime concentrations for 10 intensive care unit patients
following administration of an initial dose of 2 g intravenously (over 3 min)
(profile A).
TABLE 1. Patient demographics, cefepime levels, and pharmacokinetic parameters following a 3-min infusion of 2 g of cefepime to intensive
care unit patientsa
Patient APACHEscorec
CLCR
(ml/min) C12h (mg/ml) t1/2b (h) AUC (mg z h/ml) CL (ml/min) MRT (h) VSS (liter)
1b 24 54.0 19.7 5.6 (0.3) 690 (22) 48 (2) 7.6 (0.4) 22.0 (1.0)
2 10 133.8 2.6 1.8 (0.1) 239 (12) 140 (7) 2.0 (0.1) 17.0 (1.4)
3 16 103.2 5.7 2.9 (0.1) 423 (10) 79 (2) 3.9 (0.1) 18.4 (0.6)
4b 15 67.2 9.6 4.7 (0.3) 396 (13) 84 (3) 6.2 (0.4) 31.4 (1.6)
5 11 157.2 1.1 1.5 (0.1) 226 (9) 148 (6) 1.7 (0.1) 15.0 (0.9)
6 9 153.6 1.6 2.3 (0.1) 199 (12) 167 (10) 2.6 (0.1) 26.4 (2.4)
7 9 135.6 2.1 2.5 (0.1) 241 (9) 138 (5) 3.0 (0.1) 24.6 (1.3)
8b 14 63.6 10.0 4.0 (0.2) 467 (14) 71 (2) 5.3 (0.2) 22.8 (1.1)
9 15 187.2 1.6 2.2 (0.1) 257 (8) 130 (4) 2.6 (0.1) 20.2 (0.9)
10 11 117.6 1.1 1.9 (0.1) 285 (11) 117 (4) 2.3 (0.1) 16.2 (0.8)
11 8 97.2 6.3 3.5 (0.2) 337 (12) 99 (4) 4.4 (0.2) 26.3 (1.7)
12 8 141.0 1.6 2.3 (0.1) 194 (9) 172 (8) 2.9 (0.1) 29.8 (2.0)
13 13 79.8 8.5 3.8 (0.1) 424 (10) 79 (2) 5.1 (0.2) 24.0 (0.9)
Mediand 10.5 134.7 1.9 2.5 249 134 2.8 22.1
Meand 11.0 130.6 3.2 3.0 283 127 3.1 21.8
SDd 2.8 32.0 2.6 1.2 85 33 1.1 5.1
a CLCR, creatinine clearance; C12h, cefepime concentration at 12 h postdose; t1/2b, elimination half-life; AUC, area under the plasma cefepime concentration-time
curve; CL, cefepime clearance; MRT, mean residence time; VSS, apparent volume at steady state. Values shown are estimates, and their standard errors are shown in
parentheses.
b Patient nonevaluable.
c APACHE score at time of initial cefepime dose.
d Only data for evaluable patients are included in these statistical results.
TABLE 2. Trough cefepime levels and creatinine clearance
measured after multiple 2-g doses of cefepime over 12 h (profile B),
and trough plasma cefepime concentrations at 48 h predicted by
simulated dosing regimens
Patient CLCR(ml/min)
C0h
(mg/ml)
C12h
(mg/ml)
C48h trough
a (mg/ml)
6 g/dayb 1 g/4 hc
2 128.4 2.6 2.1 29.8 9.6
3 87.6 5.4 4.0 52.9 29.5
5 127.2 ,1.0 ,1.0 28.2 7.4
6 195.6 1.4 ,1.0 24.9 10.0
7 137.4 3.0 2.8 30.1 13.5
9 146.4 ,1.0 ,1.0 32.1 13.0
10 115.8 2.0 2.2 35.7 13.2
11 118.8 ,1.0 ,1.0 42.2 24.1
12 150.6 1.4 1.4 24.3 10.9
13 74.4 6.2 7.7 53.0 33.6
Median 127.8 1.7 1.8 31.1 13.1
Mean 128.2 35.3 16.5
SD 30.5 9.7 8.3
a Predicted minimum cefepime concentration after 48 h.
b Simulated continuous infusion of 6 g of cefepime per 24 h with an initial 0.5-g
loading dose.
c Simulated 3-min infusion of 1 g of cefepime every 4 h.
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4 and 6 g/day, 20.8 and 31.1 mg/ml, respectively; and for inter-
mittent bolus dosing of 2 g 8 hourly, 5.4 mg/ml; 1.5 g 6 hourly,
8.5 mg/ml; 1 g 4 hourly, 13.1 mg/ml. The 48-h trough values
predicted for the 10 evaluable patients for the 1-g, 4 hourly
bolus and for the 6-g/day continuous infusion regimens are
shown in Table 2. The lowest 48-h trough obtained with 4
hourly boluses, 7.4 mg/ml, is almost three times the MIC at
which 50% of the isolates are inhibited for P. aeruginosa for the
entire dosing interval, whereas the lowest steady-state concen-
tration obtained with a 6-g/day continuous infusion is 24 mg/ml.
Previous modeling studies on ceftazidime given as a contin-
uous infusion to critically ill patients (23) have predicted levels
in plasma that were subsequently shown to be achievable clin-
ically (13). In spite of the interpatient variability, we propose
that the regimens of 1-g, 4 hourly bolus dosing and 6-g/day
continuous infusions would help eliminate the unpredictably
low trough cefepime levels obtained in this study.
Cefepime has a broad spectrum of activity against gram-
negative organisms (2, 10, 17) and can be used for both proven
and suspected resistant gram-negative bacterial infections (2,
18), including those with P. aeruginosa. However, the variable
and low trough levels reported here in critically ill patients may
decrease efficacy in a situation where optimal dosing is essen-
tial. Pharmacokinetic modeling suggests that shorter dosing
intervals would maintain sustained levels with higher troughs
in more patients. Our data suggests that the daily dose of
cefepime in critically ill patients with normal renal function
should be increased to 6 g/day, given preferably as 1-g, 4 hourly
doses or, alternatively, as a continuous infusion.
We thank Sue Parry-Jones and Bristol-Myers Squibb Australia Pty.
Ltd. for their financial support, for the supply of cefepime, and for the
supply of cefadroxil for the high-performance liquid chromatography
standard.
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Low plasma cefepime levels in critically ill septic patients: pharmacokinetic modelling indicates improved troughs with revised dosing

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Low plasma cefepime levels in critically ill septic patients: pharmacokinetic modelling indicates improved troughs with revised dosing

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