CLINICAL THERAPEUTICS”NOL. 22, NO.

1,200O

Pharmacokinetics and Pharmacodynamics of Cefepime

Administered by Intermittent and Continuous Infusion

David S. Burgess, PharmD, Rhonda W. Hastings, PharmD,

and Thomas C. Hardin, PharmD
College of Pharmacy, The University of Texas at Austin, Austin, and Department of
Pharmacology, The University of Texas Health Science Center at San Antonio, San
Antonio, Texas

ABSTRACT

Objective: This study assessed the pharmacokinetics and pharmacodynamics of cef-

epime administered by intermittent and continuous infusion against clinical isolates of
Pseudomonas aeruginosa, Enterobacter cloacae, and Staphylococcus aureus.
Background: Because beta-lactam antibiotics exhibit time-dependent bactericidal ac-
tivity and lack prolonged postantibiotic effects against many bacteria, the goal of therapy
is to maintain serum drug concentrations above the minimum inhibitory concentration
(MIC) for the relevant pathogen over most of the dosing interval. Continuous infusion is
a mode of drug administration that can provide serum drug concentrations continuously
above the MIC for most bacterial pathogens.
Methods: Twelve healthy volunteers were enrolled. Each received cefepime 2 g by in-
termittent bolus q12h and, on another day, was randomly assigned to receive 4 or 3 g ad-
ministered by continuous infusion over 24 hours.
Results: For the intermittent regimen, the mean (+ SD) pharmacokinetic findings were:
maximum serum concentration, 112.9 + 2 1.1 pg/mL; minimum serum concentration, 1.3
+ 0.5 pg/mL; and half-life, 2.6 2 0.4 hours. For the 3- and 4-g continuous infusion regi-
mens, steady-state serum concentrations (C,,) were 13.9 * 3.8 and 20.3 + 3.3 p.g/mL, re-
spectively. MICs ranged from 2 to 4, 0.125 to 8, and 2 to 8 pg/mL against P aerugi-
nosa, E cloacae, and S uureus, respectively. For the intermittent regimen, serum inhibitory
titers (SITS) at 24 hours were 2 1:2 in 46% of subjects against P aeruginosu, 48% against
E cloacae, and 2% against S aureus. For both continuous infusion regimens, SITS for each
organism were rl:2 in all subjects.
ConcHsions: The intermittent regimen maintained serum concentrations above the MIC for
P aeruginosa and E cloacae in ~92% (Ill 12) of subjects for ~70% of the dosing interval, pro-
vided the MIC was 54 pg/mL. Both continuous infusion regimens provided a Css above the
MIC for all organisms. However, the Css was s4 times the MIC only if the MIC was s2

Accepted for publication December 15, 1999.

Printed in the USA.
Reproduction in whole or part is not permitted.

66 0149.2918100/$19.00
D.S. BURGESS ET AL.
p,g/mL. Only the 4-g regimenprovided such
concentrationsagainstisolateswith an MIC
of 4 pg/mL, and neither regimenprovided
such concentrationswhen the MIC was 8
pg/mL. Thesefindings shouldbe appliedin
comparativeclinical studies.
Key words: cefepime, intermittent bo-
lus infusion, continuous infusion, beta-
lactams, pharmacodynamics, pharmaco-
kinetics. (Clin Ther. 2000;22:66-75)
INTRODUCTION
The optimal dosing strategy for many an-
timicrobials is still unknown. Although
several attempts have been made to es-
tablish optimal dosing regimens,intermit-
tent dosing continues to be the standard
of practice. l,* Intermittent dosing regi-
menshave worked reasonablywell in clin-
ical practice, but this technique does not
optimize the pharmacodynamic proper-
ties of the beta-lactams.
When beta-lactamsare administeredin
intermittent doses,their activity depends
on the length of time that serum concen-
trations exceed the minimum inhibitory
concentration (MIC) for the pathogen in
question. Against gram-negative bacteria
and streptococci, maximal activity of beta-
lactams has been observed when serum
concentrations remained above the MIC
for 70% of the dosing interval, whereas
40% was sufficient againststaphylococci.3
Becausebeta-lactamsexhibit time-depen-
dent bactericidal activity and lack a pro-
longed postantibiotic effect against many
bacteria, the goal of therapy is to maintain
serum drug concentrations at the site of
infection above the MIC for the infecting
pathogenover most of the dosing interval.
Continuous infusion is a mode of ad-
ministration that can provide such con-
centrations for most bacterial pathogens.
Several animal studies4-9comparing
continuous infusion of beta-lactamswith
intermittent bolus dosing have demon-
stratedthat continuousinfusion maximizes
the amount of time that drug concentra-
tions remain above the MIC. However, at
steady state, the desired concentration is
4 x MIC rather than the greatest amount
of time over the MIC, becausebeta-lactams
achieve the greatestbactericidal activity at
this concentration; higher concentrations
do not provide a greater rate or extent of
kill 1,6,7,10,11
Limited pharmacokinetic and pharma-
codynamic studiesof continuous infusion
of beta-lactams have been performed in
humans; most have assessedceftazidime
infusions.‘*-*l Cefepime* is an extended-
spectrumcephalosporinwith a pharmaco-
kinetic profile and spectrum of activity
similar to those of ceftazidime; however,
cefepime has improved activity against
Enterobacter speciesand Staphylococcus
aureus.lo,**
The objectives of this study were to
compare the pharmacokinetic parameters
of a continuous infusion with those of an
intermittent bolus regimen of cefepime,
and to assessthe pharmacodynamicprop-
erties of each regimen against 4 clinical
isolates of Pseudomonas aeruginosa,
Enterobacter cloacae, and methicillin-
susceptibleS aureus.
SUBJECTS AND METHODS
Subjects
To be eligible for study participation,
healthy volunteers aged B18 years had to
undergo a general physical examination;
*Trademark: Maxipime@ (Bristol-Myers Squibb,
Princeton, New Jersey).
67

have normal results on laboratory testing
(ie, blood chemistry and hematology, uri-
nalysis); and provide a medical and drug
history.
The protocol was approved by the US
Food and Drug Administration and by the
appropriate institutional review boards at
the University of Texas Health Science
Center, South Texas VeteransHealth Care
System, and Frederic C. Bartter General
Clinical Research Center, San Antonio,
Texas. All subjects provided written in-
formed consent before enrollment.
Study Design
All subjects received intravenous (IV)
cefepime 2 g over 30 minutes q12h for 2
dosesand IV cefepime 4 or 3 g as a con-
tinuous infusion over 24 hours. The se-
quenceof drug regimenswas randomized
for each subject. Regimens were sepa-
rated by a l-week washout period.
Antimicrobial Administration
Cefepime powder was reconstituted ac-
cording to the product information. The
intermittent doses were further diluted
with 100 mL of 5% dextrose in water and
administeredover 30 minutes via an infu-
sion pump. The 4- and 3-g continuous in-
fusion doseswere further diluted with 1 L
of 5% dextrose in water and administered
at a constant flow rate over 24 hours.
Blood Sampling
Blood sampleswere collected at 15 pre-
determinedtime points for the intermittent
bolus regimen and 10 predeterminedtime
points for the continuous infusion regi-
mens.For the intermittent bolus regimen,
blood was drawn before drug administra-
tion (time 0) and at 0.5, 0.75, 1, 2, 4, 6, 8,
12, 12.5, 12.75, 13, 14, 18, and 24 hours
68
CLINICAL THERAPEUTICS’
after the start of the infusion. For the con-
tinuous infusion regimen, blood was col-
lected before drug administration and at
0.5, 1, 2, 4, 6, 12, 13, 18, and 24 hours af-
ter the start of the infusion. Additional
blood sampleswere obtainedfrom all sub-
jects for each regimenat 0, 13, 18, and 24
hours for serum inhibitory titer (SIT) and
serumbactericidal titer (SBT) analyses.
All blood sampleswere collected via
an indwelling IV catheter from a forearm
vein contralateral to the arm usedfor drug
administration. Sampleswere allowed to
clot for 15 minutes at room temperature
before being centrifuged at 5000 rpm for
15 minutes. The serum was removed and
stored at -2O’C until analyzed.
Study Assessments
Analytic Methods
Cefepimeserumconcentrationswere de-
termined by high-pressureliquid chroma-
tography. 23The chromatographic equip-
ment and materials consisted of a 510
HPLC pump, 7 17 Autosampler, 486 Tun-
able Absorbance Detector, Nova-Pak C 18
column (3.9 x 150 mm), and Cl 8 Guard-
Pak (4pm) (all, Waters Corporation, Mil-
ford, Massachusetts). The mobile phase
consisted of 86% 0.0023 mol/L octane-
sulfonic acid and 14% acetonitrile, buf-
fered to pH 2.3 with 85% phosphoricacid,
at a flow rate of 1 mL/min.
Cefepime standards were prepared in
pooled human serum. Proteins were pre-
cipitated by adding 5% trichloroacetic
acid to the serum samplesin a 1: 1 ratio.
The sampleswere vortexed and then cen-
trifuged at 5000 rpm for 10 minutes. The
supematantwasextracted and injected (75
FL) in duplicate for determination of cef-
epime concentrations.The plot was linear
D.S. BURGESS ET AL.
over the concentration range of 0.5 to 200
pg/mL (? 2 0.997). The intraday and in-
terday coefficients of variation were ~5%
at all concentrations.
Pharmacokinetic Analyses
Pharmacokinetic parameters were de-
termined using standardnoncompartmen-
tal methods.Log meanconcentration-time
profiles were graphed for each subject,
and maximum, minimum, and steady-
state serum concentrations (C,,,, Cmin,
and C!,,) were calculated. For the inter-
mittent regimen, the elimination half-life
was determined using linear regression
for the last 4 data points. Areas under the
concentration-time curve (AUC) were de-
termined using the linear trapezoidal rule,
and total body clearance (TBCl) was cal-
culated as dose/AUC. For the continuous
infusion regimen, the elimination half-life
was calculated as the volume of distribu-
tion at steady state (V,,)/TBC1(0.693).
TBCl was calculated as the rate of infu-
sion (K,) divided by C,,. Vss was calcu-
lated using the equation:
V,, = ((K, x T) - (TBCl x AUC))/C,,
where T is the duration of the infusion.
TestOrganisms
Four clinical isolates of P aeruginosa,
E cloacae, and methicillin-susceptible
S aureus were used in each pharmacody-
namic analysis. The MIC and minimum
bactericidal concentration (MBC) of cef-
epime for each of the isolateswere deter-
mined in triplicate using microdilution as
describedin the guidelinesof the National
Committee for Clinical Laboratory Stan-
dards (NCCLS). 24,25 The modal MIC was
used in all data analyses.
SerumInhibitory and Bactericidal
Activity
SITSand SBTs were determinedaccord-
ing to NCCLS guidelines.26For each cef-
epimeregimen,serumsamplesat 0, 13, 18,
and24 hoursweretestedin duplicateagainst
all organisms.For the intermittent bolusreg-
imen, these times provided a maximum,
midpoint, and minimum serumconcentra-
tion; for the continuousinfusion regimens,
serumconcentrationswere at steady state.
The percentageof subjectswith SITlSBT
21:2 wasdeterminedfor eachtime point.
Pharmacodynamic Analysis
Becausetime above the MIC is the most
important pharmacodynamic parameter
with beta-lactams,the percentageof time
the serum concentration remained above
the MIC for each isolatewascalculatedfor
the intermittent bolus regimen. To deter-
mine maximal activity, the percentageof
subjectswith serum concentrationsabove
the MIC for P aeruginosa and E cloacae
isolates for 270% of the dosing interval
and the MIC for S aureusfor 240% of the
dosing interval were determined. For the
continuous infusion regimens, the per-
centageof subjectswith steady-statecon-
centrations 24 MIC for each isolate was
calculated.
Statistical Analysis
The pharmacokinetic parameters,SITS,
and SBTs were compared using analysis
of variance with the Scheffe post hoc test.
P values < 0.05 were considered statisti-
cally significant.
RESULTS
Twelve healthy volunteers (6 females, 6
males) with a mean (*SD) age of 31 f 6
69
 CLINICAL THERAPEUTICS”

years and weight of 77.4 + 15 kg were en-
rolled. All subjects completed the study.
None of the subjectshad a chronic illness
or were taking chronic medication.All sub-
jects refrained from alcohol and nicotine
useduring the study. All subjectstolerated
the cefepime infusions, and no infusion-
related adverseeffects were reported.
The pharmacokinetic parameters for
cefepime for each of the dosing regimens
are shown in Table I. The mean (&SD)
C,i, was 1.3 + 0.5 pg/mL, whereas the
C,, for the 4- and 3-g doseswas 20.3 *
3.3 and 13.9 * 3.8 p.g/mL, respectively.
With the exception of the AUC,_,,, for
the 3-g continuous infusion versus the 4-
g continuous infusion and 2-g q 12h regi-
mens (P = 0.03), no significant differ-
ences were detected between any of the
pharmacokinetic parameters.
The MICs/MBCs for each of the 4 iso-
lates are presentedin Table II. All the iso-
lates were susceptible(MIC 58 pg/mL) to
cefepime. The MICs ranged from 2 to 4,
0.125 to 8, and 2 to 8 yg/mL for P aerugin-
osa, E cloacae, and S aureus, respectively.
The median SBT for the intermittent
regimen was 1:2 for each organism at 18
hours and <1:2 at 24 hours. For the con-
tinuous infusion regimens, there were no

Table I. Pharmacokinetic parameters(mean f SD) of cefepime administeredby intermit-

tent and continuous infusion.

Continuous Infusion
Intermittent Infusion
2gq12h 4 g (n = 6) 3 g (n = 6)

C,,, (f-&W 112.9 + 21.1 NA NA

Cmi, (i-&W 1.3 * 0.5 NA NA
C,, (f.dmL) NA 20.3 + 3.3 13.9 + 3.8
G/2 00 2.6 + 0.4 2.3 + 0.7 1.9 10.8
AUC&24 (mglL/h) 357 + 95 411 k45 285 k 46*
TBCI (L/h) 12.4 r~:5.1 9.8 Y!z1.1 10.7 k 1.6

Cmax= maximum serum concentration; Cmin = minimum serum concentration; C,, = serum concentration at
steady state; t,,2 = half-life: AUC,,, = area under the curve from 0 to 24 hours; TBCl = total body clearance;
NA = not applicable
*fJ = 0.03.

Table II. In vitro activity of cefepime.

MIC/MBC (t&mL)
Isolate Pseudomonas aeruginosa Enterobacter cloacae Staphylococcus aureus

1 218 0.125/o. I 2s 212

2 214 0.5lO.5 218
3 414 4116 418
4 418 8/8 818

MIC = minimum inhibitory concentration; MBC = minimum bactericidal concentration

70
D.S. BURGESS ET AL.
differences between the 13-, 18-, and 24-
hour SITS or SBTs, and the median SBTs
for the 4- and 3-g regimens were ~1:4
and rl:2, respectively, for each organ-
ism. The percentage of subjects with
SITs/SBTs sl:2 for each cefepime regi-
men is shown in Table III. For the inter-
mittent regimen, the 13- and 18-hour SITS
were 2 112 for P aeruginosa and S aureus
for 294% of subjects. For E cloacae,
SITS were ~1:2 for 75% of subjects. At
24 hours, however, SITS were ~1:2 in
48% of subjects against E cloacae, 46%
of subjects against P aeruginosa, and 2%
against S aureus. Both continuous infu-
sion regimens maintained SITS 21:2 in
all subjects against each organism.
For the intermittent dosing regimen, the
median percentage of time that cefepime
serum concentrations remained above an
MIC of 2 pg/mL in all subjects was 97%
(range, 77% to 100%). However, with
higher MICs, median percentages of time
above the MIC decreased substantially.
For instance, the medians for MICs of 4
and 8 kg/mL were 76% and 55%, respec-
tively (ranges, 60% to 87% and 42% to
Table III. Serum inhibitory and bactericidal titers after intermittent and continuous infu-
sion of cefepime.
% of Subjects with SITs/SBTs al:2
Regimen Pseudomonas aeruginosa
Intermittentinfusion,
2 g ql2h
At 13h loo/loo
At 18h 100/81
At 24 h 46123
Continuousinfusion
4g 100/100
3g 100/89
SITS = serum inhibitory titers; SBTs = serum bactericidal
59%). Against P aeruginosa and E cloa-
cue, 2 g q12h provided serum concentra-
tions that maximized the pharmacody-
mimic parameter (ie, concentration above
the MIC for 270% of the dosing interval)
in ~92% (1 l/12) subjects, provided the
MIC was 54 pg/mL (Table IV). For iso-
lates with an MIC of 8 kg/n& no serum
concentrations were above the MIC for
70% of the dosing interval. Against S au-
reus, the intermittent regimen provided
adequate serum concentrations (ie, con-
centration above the MIC for 240% of the
dosing interval) in all subjects.
Both continuous infusion regimens pro-
vided a C,, above the MIC for each iso-
late (gram-negative and gram-positive) in
all subjects. However, the C,, was 24 MIC
for both regimens only when the MIC was
52 pg/mL. For an MIC of 4 kg/mL, the
3-g continuous infusion regimen was in-
adequate in the majority of subjects
(83%), but the 4-g regimen provided con-
centrations 24 MIC in all subjects. How-
ever, neither continuous infusion regimen
was adequate against any organism with
an MIC of 8 kg/mL.
Enterobacter cloacae Staphylococcus aureus
loo/loo 100/98
15l.50 94111
48125 212
10017 1 100/100
1OOl57 100196
titers.
71
 CLINICAL THERAPEUTICS”

Table IV. Pharmacokinetic/pharmacodynamicrelationshipsfor cefepime administeredby

intermittent and continuous infusion.

% of SubjectsMeeting
Parameter,Basedon MIC
Phatmacodynamic
Regimen Parameter 52 pg/mL 4 M/d 8 pg/mL

Intermittentinfusion,2g q12h
(n = 12) C ZMIC for 240%T 100 100 100
C >MIC for 270%T 100 92 0
Continuousinfusion
4 g (n = 6) C,, 24 MIC 100 100 0
3 g (n = 6) C,, 24 MIC 100 17 0

MIC = minimum
inhibitory concentration; C = serum concentration; T = dosing interval; CSs = concentration at
steady state.

DISCUSSION AND CONCLUSIONS 240% of the dosing interval3 Altema-

An ideal therapeutic plan for treating an
infection must considersuch factors as the
etiology and location of the infectious
process; patients’ immune status and or-
gan function; and drug properties (eg,
spectrum and pattern of activity, pharma-
cokinetic and pharmacodynamic charac-
teristics). There are approved dosing regi-
mensthat work reasonablywell; however,
such regimensoften fail to optimize phar-
macokinetic and pharmacodynamic inter-
relationshipsthat would maximize the ac-
tivity of the antimicrobial agent.
Data from in vitro models and animal
studies have shown that when using in-
termittent dosing of beta-lactams,there is
a correlation between the amount of time
drug concentrations are maintained above
the MIC against the organism at the site
of infection and activity. Against gram-
negative infections, concentrations should
remain above the MIC for 270% of the
dosing interval; against staphylococci,
they should remain above the MIC for
tively, with continuous infusion, maximal
activity is achieved when drug serumcon-
centrations are 24 MIC.‘7~27~28
In the present study, we found that cef-
epime serumconcentrationsfor all 3 regi-
mens satisfied the aforementioned goals,
provided the MIC was 52 pg/mL. How-
ever, only the 4-g total daily dose(2 g q12h
or 4-g continuous infusion) continued to
provide serum concentrations that opti-
mized the respectivepharmacodynamicpa-
rameter given an MIC of 4 kg/ml. If the
MIC is 8 pg/mL, then even the 4-g total
daily dose is no longer adequateto maxi-
mize the pharmacodynamic relationship
againstgram-negativebacteria. On the ba-
sis of the pharmacokinetic parametersin
this study population, a 6-g continuousin-
fusion should provide a serumconcentra-
tion of 32 pg/mL (ie, 4 x MIC of 8 pg/mL).
Likewise, an intermittent dose of 2 g q8h
should provide concentrations above the
MIC for 270% of the dosing interval.
The number of human studies assess-
ing continuous infusion of beta-lactamsis

72
D.S. BURGESS ET AL.
limited; however, ceftazidime has been
the most extensively studied. Nicolau et
all9 evaluated ceftazidime administered
by intermittent dosing and continuous in-
fusion in healthy volunteers. They re-
ported that the C,, for 3- and 2-g contin-
uous infusions was 18.2 and 12.8 pg/mL,
respectively, and suggestedthat the 2-g
continuous infusion regimen provided
bactericidal activity equivalent to that of
the l-g q8h regimen. This would be true
with MICs 52 pg/mL, but for MICs >2
pg/mL, continuous infusion would not
maximize activity, since the C,, would be
54 MIC. When one considers organisms
with MICs 52 pg/mL from a pharmaco-
dynamic standpoint, 1 g q12h rather than
q8h should suffice.
Recently, 3 studiescompared intermit-
tent dosing with continuous infusion of
ceftazidime in critically ill patients. Al-
though Benko et a129did not assessclini-
cal outcomes, time above the MIC and
SBTs were the samefor each regimen, al-
though the continuous infusion used half
the total daily dose. However, on the ba-
sis of the pharmacokinetic parametersfor
the study population, it may be estimated
that adjusting the intermittent regimen to
1 g q8h would provide an amount of time
above the MIC similar to that with the
2-g q8h regimen.
Nicolau et a130reported similar phar-
macodynamic parametersand clinical and
microbiologic outcomes in patients with
nosocomial pneumonia who were treated
with 2 g q8h or a 3-g continuous infusion
plus once-daily tobramycin, which could
have confounded the comparisonbetween
intermittent and continuous administra-
tion of the beta-lactam. In contrast, Hanes
et a13tsuggestedthat continuous infusion
of ceftazidime may be clinically and mi-
crobiologically inferior to intermittent
dosing in the samepatient population, al-
though the pharmacodynamic parameters
(ie, time above the MIC) were similar.
Clinically, there is a trend toward using
continuous infusion of beta-lactams as a
way of maintaining serumdrug concentra-
tions above the MIC. Dosesused in con-
tinuous infusion often are the sameas or
half the total daily doseusedin intermittent
dosing;however, resulting serumdrug con-
centrations do not necessarily maximize
drug activity (ie, concentrationsZZ~MIC).
In our study, we found that a total daily
doseof cefepime 4 g (continuousinfusion
or 2 g q12h) failed to provide optimal phar-
macodynamicserumconcentrationsagainst
organismshaving an MIC >4 pg/mL. Just
as clinicians have identified how long
serumconcentrationsshouldremain above
the MIC to effectively treat bacterial infec-
tions by intermittent dosing, they should
target a C,, that maximizes the activity of
beta-lactams administered by continuous
infusion. Consequently, comparisonsare
necessarybetween the outcomeswith in-
termittent andcontinuousinfusionregimens
designedto apply pharmacodynamicprin-
ciples of beta-lactamadministration.
ACKNOWLEDGMENTS
This study was supported by an un-
restricted research grant from Bristol-
Myers Squibb, Princeton, New Jersey,and
National Institutes of Health Grant RR-
01346. The results were presentedat the
International Congresson Clinical Phar-
macology in Orlando, Florida, on April
12, 1998.
The authors acknowledge the nursing
and dietetic care provided by the staff of
the Frederic C. Bartter GeneralClinical Re-
searchCenter at the South Texas Veterans
Health CareSystem in SanAntonio, Texas.
73

Address correspondence to: David S.
Burgess, PharmD, Clinical Pharmacy
Programs, The University of Texas Health
Science Center, 7703 Floyd Curl Drive,
San Antonio, TX 78284-6220.
REFERENCES
1. Craig WA, Ebert SC. Continuous infusion
of p-lactam antimicrobials. Antimicrob
Agents Chemother. 1992;36:2577-2583.
2. Schentag JJ. Pharmacokinetics and phar-
macodynamics of beta-lactam antibiotics.
Infect Med. 1992;9(Suppl B): 10-12.
3. Craig WA. Interrelationship between phar-
macokinetics and pharmacodynamics in
determining dosage regimens for broad-
spectrum cephalosporins. Diagn Micro-
biol Infect Dis. 1995;22:89-96.
4. Fluckinger U, Segessenmann C, Gerber
AU. Integration of phatmacokinetics and
pharmacodynamics of imipenem in a hu-
man-adapted mouse model. Antimicrob
Agents Chemother. 1991;35:1905-1910.
5. Gengo FM, Mannion TW, Nightingale CH,
Schentag JJ. Integration of pharmacoki-
netics and pharmacodynamics of methi-
cillin in curative treatment of experimen-
tal endocarditis. J Antimicrob Chemother.
1984;14:619-631.
6. Leggett JE, Ebert S, Fantin B, Craig WA.
Comparative dose-effect relations at sev-
eral dosing intervals for beta-lactam,
aminoglycoside, and quinolone antibiotics
against gram-negative bacilli in murine
thigh-infection and pneumonitis models.
Stand .I Infect Dis. 1991;74:179-184.
7. Leggett JE, Fantin B, Ebert S, et al. Com-
parative antibiotic dose-effect relations at
several dosing intervals in murine pneu-
monitis and thigh-infection models. J fn-
feet Dis. 1989;159:281-292.
8. Roosendaal R, Bakker-Woudenberg IA,
Van den Berg JC, Michel ME Therapeutic
74
CLINICAL THERAPEUTICS”
efficacy of continuous versus intermittent
administration of ceftazidime in an exper-
imental Klebsiella pneumoniae pneumo-
nia in rats. J Infect Dis. 1985; 152:373-378.
9. Roosendaal R, Bakker-Woudenberg IA,
van den Berghe-van Raffe M, Michel ME
Continuous versus intermittent adminis-
tration of ceftazidime in experimental
Klebsiella pneumoniae pneumonia in nor-
mal and leukopenic rats. Antimicrob
Agents Chemother. 1986;30:403-408.
10. Chong Y, Lee K, Kwon OH. In-vitro activ-
ities of cefepime against Enterobacter cloa-
cae. Serratia marcescens, Pseudomonas
aeruginosa and other aerobic Gram-nega-
tive bacilli. J Antimicrob Chemother.
1993;32(Suppl B):21-30.
11. McGrath BJ, Bailey EM, Lamp KC, Ry-
bak MJ. Pharmacodynamics of once-daily
amikacin in various combinations with
cefepime, aztreonam, and ceftazidime
against Pseudomonas aeruginosa in an in
vitro infection model. Antimicrob Agents
Chemother. 1992;36:2741-2746.
12. Bodey GP, Ketchel SJ, Rodriguez V. A
randomized study of carbenicillin plus
cefamandole or tobramycin in the treat-
ment of febrile episodes in cancer patients.
Am J Med. 1979;67:608-616.
13. Castela N, Taburet AM, Carlet J, et al.
Pharmacokinetics of ceftazidime during
continuous infusion in intensive care pa-
tients. Presented at 34th Interscience Con-
ference on Antimicrobial Agents and
Chemotherapy; October 4-7, 1994; Wash-
ington, DC.
14. Daenen S, de Vries-Hospers H. Cure of
Pseudomonas aeruginosa infection in neu-
tropenic patients by continuous infusion of
ceftazidime. Lancer. 1988;i: 1454. Letter
15. Lagast H, Meunier-Carpentier F, Klaster-
sky J. Treatment of gram-negative bacil-
lary septicemia with cefoperazone. f&r /
Clin Microbial Infect Dis. 1983;2:554-558.
D.S. BURGESS ET AL.
16. Lemmen S, Kropec A, Engels I, et al.
Serum bactericidal activity after adminis-
tration of four cephalosporins in healthy
volunteers. Eur J Clin Microbial Infect
Dis. 1993;12:856-860.
17. Mouton JW, Horrevorts AM, Mulder
PGH, et al. Pharmacokinetics of ceftazi-
dime in serum and suction blister fluid
during continuous and intermittent infu-
sions in healthy volunteers. Antimicrob
Agents Chemother. 1990;34:2307-23 11.
18. Mouton JW, Michel ME Pharmacokinet-
its of meropenem in serum and suction
blister fluid during continuous and inter-
mittent infusion. J Antimicrob Chemother
1991;28:911-918.
19. Nicolau DP, Nightingale CH, Banevicius
MA, et al. Serum bactericidal activity of
ceftazidime: Continuous infusion versus
intermittent injections. Antimicrob Agents
Chemother 1996;40:61-64.
20. Rio Y, Leroy F, Humbert G, Didion J.
Comparative ceftazidime serum concen-
trations during continuous infusion in
healthy subjects and severe burn patients.
Presented at 38th Interscience Conference
on Antimicrobial Agents and Chemother-
apy; September 24-27, 1998; San Diego,
Calif.
21. Zeisler JA, McCarthy JD, Richelieu WA,
Nichol MB. Cefuroxime by continuous
infusion: A new standard of care? Infect
Med. 1992;11:54-60.
22. Thomsberry C, Brown SD, Yee YC, et al.
In-vitro activity of cefepime and other an-
timicrobials: Survey of European isolates.
J Antimicrob Chemother. 1993;32(Suppl
B):31-53.
23. Barbahaiya RG, Forgue ST, Shyu WC, et
al. High-pressure liquid chromatographic
analysis of BMY-28142 in plasma and
urine. Antimicrob Agents Chemother 1987;
31:55-59.
24. Methods for Determining Bactericidal Ac-
tivity of Antimicrobial Agents. Tentative
Guidelines M26-T Villanova, Pa: National
Committee for Clinical Laboratory Stan-
dards; 1992.
25. Methods for Dilution Antimicrobial Sus-
ceptibility Tests for Bacteria That Grow
Aerobically. 4th ed. M7-A4. Villanova,
Pa: National Committee for Clinical Lab-
oratory Standards; 1997.
26. Methodology for the Serum Bactericidal
Tests. Tentative Guidelines M21-T. Vil-
lanova, Pa: National Committee for Clin-
ical Laboratory Standards; 1992.
27. Cappelletty DM, Kang SL, Palmer SM,
Rybak MJ. Pharmacodynamics of ceftaz-
dime administered as continuous infusion
or intermittent bolus alone and in combi-
nation with single daily-dose amikacin
against Pseudomonas aeruginosa in an in
vitro infection model. Antimicrob Agents
Chemother 1995;39:1797-1801.
28. Manduru M, Mihm LB, White RL, et al.
In vitro pharmacodynamics of ceftazidime
against Pseudomonas aeruginosa isolates
from cystic fibrosis patients. Antimicrob
Agents Chemother 1997;41:2053-2056.
29. Benko AS, Cappelletty DM, Druse JA,
Rybak MJ. Continuous infusion versus in-
termittent administration ceftazidime in
critically ill patients with suspected gram-
negative infections. Antimicrob Agents
Chemother. 1996;40:691-695.
30. Nicolau DP, Lacy MK, McNabb JC, et al.
Continuous versus intermittent adminis-
tration of ceftazidime in intensive care
unit patients with nosocomial pneumonia.
Presented at 38th Interscience Conference
on Antimicrobial Agents and Chemother-
apy; September 24-27, 1998; San Diego,
Calif.
31. Hanes SD, Wood GC, Croce MA, et al.
Continuous vs intermittent infusion cefta-
zidime for the treatment of gram-negative
nosocomial pneumonia. Pharmacother-
apy. 1999;19:491. Abstract.
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