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ABSTRACT
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D.S. BURGESS ET AL.
67
CLINICAL THERAPEUTICS’
have normal results on laboratory testing after the start of the infusion. For the con-
(ie, blood chemistry and hematology, uri- tinuous infusion regimen, blood was col-
nalysis); and provide a medical and drug lected before drug administration and at
history. 0.5, 1, 2, 4, 6, 12, 13, 18, and 24 hours af-
The protocol was approved by the US ter the start of the infusion. Additional
Food and Drug Administration and by the blood sampleswere obtainedfrom all sub-
appropriate institutional review boards at jects for each regimenat 0, 13, 18, and 24
the University of Texas Health Science hours for serum inhibitory titer (SIT) and
Center, South Texas VeteransHealth Care serumbactericidal titer (SBT) analyses.
System, and Frederic C. Bartter General All blood sampleswere collected via
Clinical Research Center, San Antonio, an indwelling IV catheter from a forearm
Texas. All subjects provided written in- vein contralateral to the arm usedfor drug
formed consent before enrollment. administration. Sampleswere allowed to
clot for 15 minutes at room temperature
before being centrifuged at 5000 rpm for
Study Design
15 minutes. The serum was removed and
All subjects received intravenous (IV) stored at -2O’C until analyzed.
cefepime 2 g over 30 minutes q12h for 2
dosesand IV cefepime 4 or 3 g as a con-
Study Assessments
tinuous infusion over 24 hours. The se-
quenceof drug regimenswas randomized
for each subject. Regimens were sepa- Analytic Methods
rated by a l-week washout period. Cefepimeserumconcentrationswere de-
termined by high-pressureliquid chroma-
Antimicrobial Administration tography. 23The chromatographic equip-
Cefepime powder was reconstituted ac- ment and materials consisted of a 510
cording to the product information. The HPLC pump, 7 17 Autosampler, 486 Tun-
intermittent doses were further diluted able Absorbance Detector, Nova-Pak C 18
with 100 mL of 5% dextrose in water and column (3.9 x 150 mm), and Cl 8 Guard-
administeredover 30 minutes via an infu- Pak (4pm) (all, Waters Corporation, Mil-
sion pump. The 4- and 3-g continuous in- ford, Massachusetts). The mobile phase
fusion doseswere further diluted with 1 L consisted of 86% 0.0023 mol/L octane-
of 5% dextrose in water and administered sulfonic acid and 14% acetonitrile, buf-
at a constant flow rate over 24 hours. fered to pH 2.3 with 85% phosphoricacid,
at a flow rate of 1 mL/min.
Blood Sampling Cefepime standards were prepared in
Blood sampleswere collected at 15 pre- pooled human serum. Proteins were pre-
determinedtime points for the intermittent cipitated by adding 5% trichloroacetic
bolus regimen and 10 predeterminedtime acid to the serum samplesin a 1: 1 ratio.
points for the continuous infusion regi- The sampleswere vortexed and then cen-
mens.For the intermittent bolus regimen, trifuged at 5000 rpm for 10 minutes. The
blood was drawn before drug administra- supematantwasextracted and injected (75
tion (time 0) and at 0.5, 0.75, 1, 2, 4, 6, 8, FL) in duplicate for determination of cef-
12, 12.5, 12.75, 13, 14, 18, and 24 hours epime concentrations.The plot was linear
68
D.S. BURGESS ET AL.
TestOrganisms
Statistical Analysis
Four clinical isolates of P aeruginosa,
E cloacae, and methicillin-susceptible The pharmacokinetic parameters,SITS,
S aureus were used in each pharmacody- and SBTs were compared using analysis
namic analysis. The MIC and minimum of variance with the Scheffe post hoc test.
bactericidal concentration (MBC) of cef- P values < 0.05 were considered statisti-
epime for each of the isolateswere deter- cally significant.
mined in triplicate using microdilution as
describedin the guidelinesof the National
RESULTS
Committee for Clinical Laboratory Stan-
dards (NCCLS). 24,25 The modal MIC was Twelve healthy volunteers (6 females, 6
used in all data analyses. males) with a mean (*SD) age of 31 f 6
69
CLINICAL THERAPEUTICS”
years and weight of 77.4 + 15 kg were en- the 3-g continuous infusion versus the 4-
rolled. All subjects completed the study. g continuous infusion and 2-g q 12h regi-
None of the subjectshad a chronic illness mens (P = 0.03), no significant differ-
or were taking chronic medication.All sub- ences were detected between any of the
jects refrained from alcohol and nicotine pharmacokinetic parameters.
useduring the study. All subjectstolerated The MICs/MBCs for each of the 4 iso-
the cefepime infusions, and no infusion- lates are presentedin Table II. All the iso-
related adverseeffects were reported. lates were susceptible(MIC 58 pg/mL) to
The pharmacokinetic parameters for cefepime. The MICs ranged from 2 to 4,
cefepime for each of the dosing regimens 0.125 to 8, and 2 to 8 yg/mL for P aerugin-
are shown in Table I. The mean (&SD) osa, E cloacae, and S aureus, respectively.
C,i, was 1.3 + 0.5 pg/mL, whereas the The median SBT for the intermittent
C,, for the 4- and 3-g doseswas 20.3 * regimen was 1:2 for each organism at 18
3.3 and 13.9 * 3.8 p.g/mL, respectively. hours and <1:2 at 24 hours. For the con-
With the exception of the AUC,_,,, for tinuous infusion regimens, there were no
Continuous Infusion
Intermittent Infusion
2gq12h 4 g (n = 6) 3 g (n = 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.
MIC/MBC (t&mL)
Isolate Pseudomonas aeruginosa Enterobacter cloacae Staphylococcus aureus
70
D.S. BURGESS ET AL.
differences between the 13-, 18-, and 24- 59%). Against P aeruginosa and E cloa-
hour SITS or SBTs, and the median SBTs cue, 2 g q12h provided serum concentra-
for the 4- and 3-g regimens were ~1:4 tions that maximized the pharmacody-
and rl:2, respectively, for each organ- mimic parameter (ie, concentration above
ism. The percentage of subjects with the MIC for 270% of the dosing interval)
SITs/SBTs sl:2 for each cefepime regi- in ~92% (1 l/12) subjects, provided the
men is shown in Table III. For the inter- MIC was 54 pg/mL (Table IV). For iso-
mittent regimen, the 13- and 18-hour SITS lates with an MIC of 8 kg/n& no serum
were 2 112 for P aeruginosa and S aureus concentrations were above the MIC for
for 294% of subjects. For E cloacae, 70% of the dosing interval. Against S au-
SITS were ~1:2 for 75% of subjects. At reus, the intermittent regimen provided
24 hours, however, SITS were ~1:2 in adequate serum concentrations (ie, con-
48% of subjects against E cloacae, 46% centration above the MIC for 240% of the
of subjects against P aeruginosa, and 2% dosing interval) in all subjects.
against S aureus. Both continuous infu- Both continuous infusion regimens pro-
sion regimens maintained SITS 21:2 in vided a C,, above the MIC for each iso-
all subjects against each organism. late (gram-negative and gram-positive) in
For the intermittent dosing regimen, the all subjects. However, the C,, was 24 MIC
median percentage of time that cefepime for both regimens only when the MIC was
serum concentrations remained above an 52 pg/mL. For an MIC of 4 kg/mL, the
MIC of 2 pg/mL in all subjects was 97% 3-g continuous infusion regimen was in-
(range, 77% to 100%). However, with adequate in the majority of subjects
higher MICs, median percentages of time (83%), but the 4-g regimen provided con-
above the MIC decreased substantially. centrations 24 MIC in all subjects. How-
For instance, the medians for MICs of 4 ever, neither continuous infusion regimen
and 8 kg/mL were 76% and 55%, respec- was adequate against any organism with
tively (ranges, 60% to 87% and 42% to an MIC of 8 kg/mL.
Table III. Serum inhibitory and bactericidal titers after intermittent and continuous infu-
sion of cefepime.
Intermittentinfusion,
2 g ql2h
At 13h loo/loo loo/loo 100/98
At 18h 100/81 15l.50 94111
At 24 h 46123 48125 212
Continuousinfusion
4g 100/100 10017 1 100/100
3g 100/89 1OOl57 100196
71
CLINICAL THERAPEUTICS”
% 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.
72
D.S. BURGESS ET AL.
limited; however, ceftazidime has been dosing in the samepatient population, al-
the most extensively studied. Nicolau et though the pharmacodynamic parameters
all9 evaluated ceftazidime administered (ie, time above the MIC) were similar.
by intermittent dosing and continuous in- Clinically, there is a trend toward using
fusion in healthy volunteers. They re- continuous infusion of beta-lactams as a
ported that the C,, for 3- and 2-g contin- way of maintaining serumdrug concentra-
uous infusions was 18.2 and 12.8 pg/mL, tions above the MIC. Dosesused in con-
respectively, and suggestedthat the 2-g tinuous infusion often are the sameas or
continuous infusion regimen provided half the total daily doseusedin intermittent
bactericidal activity equivalent to that of dosing;however, resulting serumdrug con-
the l-g q8h regimen. This would be true centrations do not necessarily maximize
with MICs 52 pg/mL, but for MICs >2 drug activity (ie, concentrationsZZ~MIC).
pg/mL, continuous infusion would not In our study, we found that a total daily
maximize activity, since the C,, would be doseof cefepime 4 g (continuousinfusion
54 MIC. When one considers organisms or 2 g q12h) failed to provide optimal phar-
with MICs 52 pg/mL from a pharmaco- macodynamicserumconcentrationsagainst
dynamic standpoint, 1 g q12h rather than organismshaving an MIC >4 pg/mL. Just
q8h should suffice. as clinicians have identified how long
Recently, 3 studiescompared intermit- serumconcentrationsshouldremain above
tent dosing with continuous infusion of the MIC to effectively treat bacterial infec-
ceftazidime in critically ill patients. Al- tions by intermittent dosing, they should
though Benko et a129did not assessclini- target a C,, that maximizes the activity of
cal outcomes, time above the MIC and beta-lactams administered by continuous
SBTs were the samefor each regimen, al- infusion. Consequently, comparisonsare
though the continuous infusion used half necessarybetween the outcomeswith in-
the total daily dose. However, on the ba- termittent andcontinuousinfusionregimens
sis of the pharmacokinetic parametersfor designedto apply pharmacodynamicprin-
the study population, it may be estimated ciples of beta-lactamadministration.
that adjusting the intermittent regimen to
1 g q8h would provide an amount of time
ACKNOWLEDGMENTS
above the MIC similar to that with the
2-g q8h regimen. This study was supported by an un-
Nicolau et a130reported similar phar- restricted research grant from Bristol-
macodynamic parametersand clinical and Myers Squibb, Princeton, New Jersey,and
microbiologic outcomes in patients with National Institutes of Health Grant RR-
nosocomial pneumonia who were treated 01346. The results were presentedat the
with 2 g q8h or a 3-g continuous infusion International Congresson Clinical Phar-
plus once-daily tobramycin, which could macology in Orlando, Florida, on April
have confounded the comparisonbetween 12, 1998.
intermittent and continuous administra- The authors acknowledge the nursing
tion of the beta-lactam. In contrast, Hanes and dietetic care provided by the staff of
et a13tsuggestedthat continuous infusion the Frederic C. Bartter GeneralClinical Re-
of ceftazidime may be clinically and mi- searchCenter at the South Texas Veterans
crobiologically inferior to intermittent Health CareSystem in SanAntonio, Texas.
73
CLINICAL THERAPEUTICS”
74
D.S. BURGESS ET AL.
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75