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Antimicrobial Agents and Chemotherapy, December 1999, p. 2848-2854, Vol. 43, No. 12
Anti-Infective Research Laboratory, College
of Pharmacy,1 and the Department of
Surgery, College of Medicine,2 Medical
University of South Carolina, Charleston, South Carolina
Received 25 January 1999/Returned for modification 17 May
1999/Accepted 23 August 1999
The pharmacokinetics of cefepime following administration of a
single 2-g dose were evaluated for 12 adult patients with thermal burn
injury and suspected or documented infection. Serial blood and urine
samples for cefepime concentration determination were obtained for
24 h following drug administration. Serum and urine cefepime
concentrations were determined by high-performance liquid chromatography and serum concentrations were fit to a two-compartment pharmacokinetic model. Mean (standard deviation [SD]) age, actual body weight (ABW), percent total body surface area burned, and days
postburn at the time of study were 41 (13) years, 84 (22) kg, 36 (17)%, and 9 (3) days, respectively. Mean (SD) measured creatinine
clearance (CLCR), total clearance (CLT), renal
clearance (CLR), alpha phase half-life, beta phase
half-life, and volume of distribution at steady state
(VSS) were 135 (31) ml/min, 8.8 (2.4) liters/h,
8.1 (2.0) liters/h, 0.33 (0.14) h, 2.8 (0.6) h, and 0.43 (0.10)
liters/kg ABW, respectively. Cefepime CLT and CLR in burn patients were similar to previously
reported values for healthy volunteers when normalized by
CLCR. Stepwise multiple regression was used to associate
CLT with CLCR and days postburn (r2 = 0.861), CLR
with CLCR and days postburn
(r2 = 0.773), nonrenal clearance
with percent third-degree (% 3°) burn and albumin concentration
(r2 = 0.550), and
VSS only with % 3° burn
(r2 = 0.624). Simulated
steady-state serum concentrations obtained by using the patients'
pharmacokinetic parameters exceeded the susceptibility interpretive
standard (breakpoint) of cefepime for at least 60% of the
dosing interval with dosing regimens of 1 g every 8 h (q8h),
2 g q8h, and 2 g q12h. Despite differences in pharmacokinetic
parameters between our patients and healthy volunteers, it appears that
these dosing regimens may be adequate in similar burn patients.
Numerous pathophysiological changes
occur as a result of burn injury, and these changes may alter the
pharmacokinetic characteristics and effectiveness of antimicrobial
agents administered to burn patients (9, 21, 26). Several
reports have demonstrated the necessity of larger and/or more
frequently administered doses for antimicrobials which are primarily
renally eliminated (2, 10, 11, 16, 17, 23, 28, 35, 37).
Major reasons for this include increased renal elimination of drugs
resulting from burn-induced increased glomerular filtration rate,
alterations in fluid balance (affecting apparent distribution volume),
increased metabolic rate, and altered protein binding (21,
24). Therefore, it is important to rigorously evaluate
antimicrobials to determine what effect burn injury may have on
the pharmacokinetic disposition and resultant dosing requirements
in these patients.
Cefepime is a newer cephalosporin antibiotic possessing a wider
spectrum of antibacterial activity and greater potency than most
earlier cephalosporins (29). Its spectrum of activity
includes pathogens such as Pseudomonas aeruginosa and
Staphylococcus aureus, making it a potential candidate
for treatment of bacterial infections in this population. Because
of known alterations of drug disposition with other (This study was presented in part at the American College of Clinical
Pharmacy Spring Practice and Research Forum, Palm Springs, Calif.,
April 1998.)
Patients.
All patients aged 18 to 80 years admitted to the
Medical University of South Carolina Burn Unit with thermal burn injury
having a percent total body surface area burned (% TBSAB) Patient data.
Information collected for all patients
included age, sex, weight on day of study, height, date of burn, date
of study, % TBSAB, percent second-degree burn (% 2° burn), percent
third-degree burn (% 3° burn), review of systems and physical
findings pertinent to the evaluation of liver and renal function, pre-
and poststudy urinalysis, blood chemistry (SMA-7, SMA-25), and complete
blood count with differential, dosage, schedule, and route of
administration of concurrent medications, and fluid intake and output.
Drug administration and sample collection.
All patients
received 2 g of cefepime (lot D6V89A; expiration date January
1999; Bristol-Myers Squibb Company, Princeton, N.J.). Cefepime was
reconstituted as directed by the manufacturer and added to a 100-ml
0.9% saline minibag. A sample was frozen at
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Pharmacokinetics of Cefepime in Patients with Thermal Burn
Injury
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-lactams and its
potential usage in this patient population, the objective of this study
was to characterize the pharmacokinetics of cefepime following a
single dose in burn patients requiring antibiotics for suspected or
documented infection.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
15%
(excluding first-degree burns) and requiring antimicrobial therapy
(either suspected or documented infection) were eligible for study
enrollment. The study was approved by the institutional review board,
and written informed consent was obtained for all patients. Patients excluded from the study were the following: patients with a history of
allergy to cefepime or cephalosporins or penicillins, patients with
reduced renal function (estimated prestudy creatinine clearance [CLCR] < 30 ml/min calculated by the method of Cockroft
and Gault [12]), patients with hepatic impairment
(serum bilirubin and alanine aminotransferase levels above the normal
upper limit by factors of 2 and 4, respectively), or those
undergoing any type of dialysis. All patients were studied following
completion of fluid resuscitation and monitored in accordance with
standard burn patient care at our institution.
70°C within 1 h
of preparation for subsequent cefepime concentration determination.
The contents of the cefepime minibag were infused intravenously
over 30 min with a programmable pump, and the actual volume delivered
was recorded. Immediately following the end of the infusion, the
administration line was flushed with 0.9% saline. The calculation of
the actual amount of drug administered was based on the assayed
concentration of cefepime in the minibag and the volume delivered.
The actual amount of drug administered was used for all subsequent
pharmacokinetic calculations. Blood samples were collected at the
following times: predose, and 30, 40, 50, and 60 min and 2, 3, 4, 6, 8, 10, 12, 18, and 24 h after the start of the infusion. Each sample
was collected with an additive-free VACUTAINER tube (Becton Dickinson,
Franklin Lakes, N.J.) either through a central or peripheral line. At
each sample point, 5 ml of blood was drawn through the line and placed
in a separate container prior to collecting the sample. Samples were
obtained by peripheral venipuncture only when an intravenous catheter
was not available. Following collection, all blood samples were
immediately placed on ice until they could be centrifuged at 2,000 × g (Centra-8R; IEC, Needham Heights, Mass.) for 6 min. The
serum was removed and placed into polypropylene containers and frozen
at 70°C. Serum samples were assayed within 7 months.
70°C until the time of cefepime assay.
Urine samples were assayed within 10 months of collection. Preliminary
studies indicated that cefepime in serum and urine samples was
stable (retention of 91% of the original concentration) during the
period of frozen storage (unpublished data).
Cefepime serum assay. Cefepime serum and urine samples were analyzed by a modification of the method described by Barbhaiya et al. (3). High-performance liquid chromatography (HPLC) equipment used for the cefepime serum and urine assays consisted of a pump (model 510; Waters, Milford, Mass.), sample injector (715 Ultra WISP; Waters), UV light absorbance detector (Lambda-Max model 481; Waters), and an integrator (Chromatopac C-R3A; Shimadzu, Kyoto, Japan). Chromatographic separation was performed with a reverse-phase HPLC column (Nova-Pak C-18; 3.9 by 150 mm; Waters). The mobile phase consisted of an 86% 0.0023 M 1-octanesulfonic acid sodium salt in HPLC-grade water and 14% (vol/vol) acetonitrile adjusted to pH 2.3 with 85% phosphoric acid. Dissolved gases were removed from the final product by filtration through a 0.45-µm-pore-size nylon membrane filter (Whatman, Maldstone, England) while the sample was stirred under vacuum. The mobile-phase flow rate was 1 ml/min, the setting for full-scale absorbance units was 0.05, and the detection wavelength was 280 nm.
Patient serum samples were allowed to thaw at room temperature prior to analysis. When necessary, samples were diluted with pooled human serum into the range of the assay. Protein precipitation was accomplished by adding an equal volume of 5% trichloroacetic acid to all patient samples as well as standards, vortexing for 20 s, and centrifuging at 3,000 × g (IEC Centra-8R) for 10 min. Samples were injected in duplicate with an injection volume of 75 µl. The retention time of cefepime was approximately 10 min, and no interfering peaks were observed. Serum standards were prepared from laboratory grade cefepime (batch CCB4V0189, lot 189; Bristol-Myers Squibb Company, Syracuse, N.Y.). Standards were prepared with pooled human serum (Abbott Laboratories, North Chicago, Ill.) to produce concentrations of 0.5, 1, 5, 8, 10, 25, 35, 50, and 75 µg/ml. Quality control samples had concentrations ranging from 0.5 to 75 µg/ml. Two standard curves were used to accommodate the wide range of anticipated concentrations while assuring linearity. They ranged from 0.5 to 10 µg/ml (r2 0.998) and from 10 to 75 µg/ml (r2 0.999). The
intraday coefficients of variation were 
7 and 1% for the low- and
high-concentration standard-curve quality control samples,
respectively; the corresponding interday coefficients of variation were
8 and 5%, respectively. A standard curve was considered acceptable
if the quality control samples were within 15% of the nominal concentration.
Cefepime urine assay. The HPLC equipment used for the cefepime urine assay was the same as that listed above. Chromatographic separation was performed with a reverse-phase HPLC column (Partisil 5 ODS-3 C18; 4.6 by 100 mm; Whatman). The mobile phase consisted of 49.7% HPLC grade methyl alcohol, 40.4% of a 0.01 M sodium dodecyl sulfate solution (pH 3; adjusted with glacial acetic acid), 5.3% tetrahydrofuran, 3.9% of a 5% trichloroacetic acid solution, and 0.7% of a 2.49 M (vol/vol) phosphoric acid solution. The mobile phase was filtered through a 0.45-µm-pore-size nylon membrane filter (Whatman) while the sample was stirred under vacuum to remove dissolved gases. The mobile-phase flow rate was 2.8 ml/min, the detection wavelength was 280 nm, and the settings for full-scale absorbance units were 0.02 and 0.05 for the low-concentration and high-concentration standard curves, respectively.
Patient urine samples were allowed to thaw at room temperature prior to analysis. They were diluted with an equal volume of 0.2 M sodium acetate buffer into the range of the assay when necessary. Samples were injected in duplicate, and the injection volume was 10 µl. The retention time of cefepime was approximately 10 min. Urine standards were prepared from laboratory grade cefepime powder (batch CCB4V0189, lot 189; Bristol-Myers Squibb Company). Standards were prepared in 0.2 M sodium acetate buffer (pH 4.25) to produce concentrations of 1.6, 3.1, 6.3, 12.5, 25, 50, 100, 200, 400, 600, and 800 µg/ml. Quality control samples had concentrations ranging from 1.6 to 800 µg/ml. Two standard curves were used for the urine assay to assure linearity over the wide range of concentrations to be measured. The low-concentration standard curve ranged from 1.6 to 12.5 µg/ml (r2 0.999), and the
high-concentration standard curve ranged from 12.5 to 800 µg/ml
(r2 0.999). The intraday
coefficients of variation were 2 and 3% for the low- and
high-concentration standard-curve quality control samples,
respectively; the corresponding interday coefficients of variation were
4 and 8%, respectively. A standard curve was considered acceptable
if the quality control samples were within 15% of the nominal concentration.
Pharmacokinetic analysis.
The serum concentration-time
profile for each patient was fit to a two-compartment model with a
weighting selection of 1/y2 (where
y is the observed concentration) by using RSTRIP
(15). Determination of the optimal compartmental model was
based on visual inspection of the concentration-time curves,
minimization of the residual sum of squares, and the model selection
criterion obtained from RSTRIP, which is an adaptation of the Akaike
information criterion (34). Pharmacokinetic parameters
included the area under the concentration-time curve (AUC) from 0 h to the last measured serum concentration
(AUC0-t), AUC from 0 h to infinity
(AUC0-
), alpha phase rate constant (
), and beta
phase rate constant (). was also calculated as the negative
slope of the terminal elimination phase by linear least-squares
regression of at least four points. The alpha phase half-life was
calculated as t1/2
= 0.693/, and the
beta phase half-life was calculated as
t1/2
= 0.693/. The AUC was calculated
by the linear trapezoidal method and extrapolated to infinity as
follows: AUC0- = AUC0-t + Clast/ where Clast is
the last measured serum concentration. In addition, a noncompartmental
analysis was performed. The area under the first moment of the
concentration-time curve and the volume of distribution at steady state
(VSS) were calculated with standard
pharmacokinetic equations (18). Total clearance
(CLT), renal clearance (CLR), and nonrenal
clearance (CLNR) were calculated as follows:
CLT = (actual dose
administered)/AUC0-, CLR = (amount of
cefepime recovered in urine during 0 to 8 h)/AUC from 0 to
8 h, and CLNR = CLT CLR. CLT, CLR, CLNR,
CLCR, and VSS were divided by actual
body weight (ABW), lean body weight (LBW), a formula for corrected body
weight that accounts for obesity (LBW + 0.4 [ABW LBW]),
and body surface area to normalize these parameters for differences in
body weight among the patients studied. By least-squares analysis, the
normalization factor that provided the strongest relationship between a
pharmacokinetic parameter and the patient demographic factors was
identified, and then this factor was used in subsequent analyses.
Urinary excretion of cefepime as a percent of the dose recovered in
24 h was calculated as (amount of cefepime recovered in the
urine/actual dose administered) × 100.
Pharmacodynamic analysis.
We assessed the time the serum
concentration exceeded the MIC (T > MIC). The
steady-state serum concentration-time profile for each patient was
simulated assuming a one-compartment open model with a 0.5-h infusion
time by using patient-specific t1/2 and
VSS. Theoretical regimens simulated consisted of
1 g every 8 h (q8h), 2 g q8h, 1 g q12h, and 2 g q12h. The percentage of a dosing interval that the serum
concentrations remained above a given MIC (%T > MIC)
was calculated as [(T > MIC) × 100]/dosing interval. MICs utilized in this analysis were 8 (National Committee for
Clinical Laboratory Standards susceptibility interpretive standard for
cefepime), 4, 2, and 1 µg/ml (25). All calculations were verified by visual inspection of the serum concentration-time profiles.
Statistical analysis.
Descriptive statistics were used to
summarize the pharmacokinetic parameters. Simple and stepwise multiple
linear regression, by the method of least squares, was used to describe
the relationships between pharmacokinetic parameters and demographic
characteristics of interest (i.e., measured CLCR, % 2°
burn, % 3° burn, age, days post-burn-injury, and albumin
concentration [in grams per deciliter]). These relationships were
analyzed with the StatView statistical software package, version 4.51 (Abacus Concepts, Inc., Berkeley, Calif.). A P value 0.05
was considered to be statistically significant.
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RESULTS |
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Introduction
Materials and Methods
Results
Discussion
References
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Thirteen adult patients (10 male and 3 female) were enrolled. One
patient was excluded from the study when venous access was lost. The
analysis is based on the remaining twelve patients. Patient
demographics are displayed in Table 1.
All patients were studied following completion of fluid resuscitation
and within 14 days of burn injury. The severity of the burn injury
varied widely among patients with % 2° burn ranging from 0 to 50%
and % 3° burn ranging from 0 to 70%. The mean (standard deviation [SD]) dose of cefepime administered was 1,844 (55) mg.
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The pharmacokinetic parameters for all patients are shown in Table
2. Serum concentration-time data were
best fit to a two-compartment model with a weighting factor of
1/y2 except for two patients (patients
4 and 9). In these patients, the phase was better described by a
weighting factor of 1/y. For patient 9, we were unable to
characterize the phase due to incomplete sample collection
immediately following cefepime administration. We were unable to
measure CLCR and to calculate CLR for one
patient due to incomplete urine collection. In the remaining patients,
the 24-h mean (SD) percent urinary excretion was 90 (12)%.
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In the analysis of the relationships between pharmacokinetic parameters and patient demographics, CLT, CLR, CLNR, and CLCR were normalized by LBW whereas VSS was normalized by ABW. CLT was significantly associated with CLCR by simple linear regression (r2 = 0.575; P = 0.0068). This is depicted in Fig. 1. With stepwise multiple regression, the inclusion of days postburn in addition to CLCR enhanced the explanation of variability in CLT (r2 = 0.861; P = 0.0004). CLR was significantly associated with CLCR (r2 = 0.519; P = 0.0124). With stepwise multiple regression, inclusion of days postburn in addition to CLCR helped explain the variability in CLR (r2 = 0.773; P = 0.0026). CLNR was significantly associated with % 3° burn (r2 = 0.376; P = 0.0448) by simple linear regression. With stepwise multiple regression, the inclusion of albumin concentration in addition to % 3° burn better explained the variability in CLNR (r2 = 0.550; P = 0.0411). By simple linear regression and stepwise multiple regression, only % 3° burn was significantly associated with VSS (r2 = 0.624; P = 0.0022). Patient demographics included in each stepwise multiple-regression relationship were individually statistically significant with the exception of albumin concentration, which was included in the CLNR relationship because it contributed considerably to the explanation of variability for this parameter.
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The fitted serum concentration-time profiles for the patients are shown in Fig. 2. The mean (SD) observed serum concentration at the end of the infusion was 110 (23) µg/ml, whereas the observed concentrations at 8 and 12 h after the start of the infusion (SD) were 5.5 (2.6) µg/ml and 2.3 (1.6) µg/ml, respectively. The estimated %T > MIC values for dosing regimens consisting of 1 g q8h, 2 g q8h, 1 g q12h, and 2 g q12h administered over 0.5 h, obtained by using patient-specific pharmacokinetic parameters, are shown in Table 3. Simulated steady-state serum concentration-time profiles based on mean pharmacokinetic parameters with the same dosing regimens are shown in Fig. 3. In each panel, the x axis represents the time after the start of the infusion. All dosing regimens except 1 g q12h maintained a %T > MIC of at least 60% throughout the dosing interval for all MICs at or below 8 µg/ml, a susceptibility interpretive guideline for cefepime (25).
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DISCUSSION |
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Materials and Methods
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Burn injury results in numerous pathological changes in the body
that can affect the disposition of antimicrobials (9, 21,
26). Since infection is a common complication of burn injury and
since drug disposition may be altered in these patients, it is
important to examine newer agents used in this patient population. Most
of the published information regarding drug disposition in burn
patients has been limited to aminoglycosides (7, 19, 20, 23, 27,
30, 35-37) and vancomycin (2, 11, 17, 28). Few
studies have focused on the drug disposition of -lactams in burn
patients (1, 8, 10, 16, 32, 33). Consistent throughout these
reports is the fact that drug disposition is influenced in this patient
population. Similarly, we found cefepime pharmacokinetics to be
altered in our burn patients.
Overall, the two cefepime pharmacokinetic parameters that appear to be most affected in burn patients are clearance and volume of distribution. The CLT and CLR for the study patients were approximately 10 and 20 to 30% higher, respectively, than those previously reported for healthy volunteers (4, 6). The patients in our study population also demonstrated an above-normal CLCR with a mean (range) of 153 (104 to 191) ml/min. Similarly, Loirat et al. (23) demonstrated a significant increase in CLCR among patients between the 4th and 35th days following burn injury compared to that for healthy controls. However, when normalized by CLCR, the ratios of CLT/CLCR and CLR/CLCR in our study were found to be similar to ratios calculated from a study of healthy volunteers (5). Thus, it appears that the increased CLT we observed was likely due to an elevated glomerular filtration rate in our patient population. Not all burn patients will have a CLCR elevated above normal. Patients with preexisting renal impairment may experience an increase in the glomerular filtration rate over their baseline, although their increased renal function may still be below normal levels.
As is expected with a drug that is eliminated primarily by glomerular filtration, we found a statistically significant association between CLT or CLR and CLCR by simple linear regression. When analyzed by stepwise multiple regression, days post-burn-injury also helped explain the variability in CLT and CLR. An inverse relationship between CLT or CLR and days post-burn-injury was found. Perhaps wound healing results in decreased drug clearance. CLNR was positively associated with both % 3° burn and albumin concentration. Because the mechanisms of CLNR were not assessed, we are unable to physiologically explain this finding. Lastly, the association between VSS and % 3° burn that we found may be related to the physiological effects resulting from thermal burn injury, an effect directly related to the medical interventions, or some combination of the above.
We found a strong relationship between CLCR and
CLT with cefepime in this population. Other authors
have found strong relationships between CLCR and
CLT with other -lactam antibiotics in burn patients. Boucher et al. (8) observed a significant relationship
between CLCR and CLT with imipenem
(r2 = 0.60; P = 0.0001) and Friedrich et al. (16) noted a similar significant relationship with aztreonam in burn patients
(r = 0.95; P = 0.0018). In a study of
the pharmacokinetics of piperacillin-tazobactam in burn patients,
Bourget et al. (10) found a significant relationship between the CLT of piperacillin-tazobactam and
CLCR (r = 0.83, P = 0.03),
and Shikuma et al. (32) found a relationship between the
CLT of piperacillin and CLCR (r = 0.49). In contrast to the findings of the previous authors, Walstad
et al. (33) failed to find a relationship between
CLCR and CLT of ceftazidime (r = 0.13), although a significant correlation between CLCR
and CLR was found (r = 0.96). The authors
report that this finding may be explained by an elevated
CLNR in patients with large burns. Therefore, the
CLT of -lactams is variable in burn patients but appears
to be associated with CLCR. Although the CLCR
range observed in the patients we studied was limited (104 to 191 ml/min), the ratio of CLT/CLCR we observed in
our study patients was consistent with that reported for healthy
volunteers (5).
Although the calculated CLR for patient 6 appears to exceed the CLT, this is unlikely to occur physiologically and may be explained by experimental error, especially in the case of a drug for which the CLR approaches the CLT. In contrast, the low CLR relative to the CLT we observed for patient 12 may be related to the % 3° burn, which was the highest among all patients. This, coupled with the needed debridement surgery during the study, may explain an increased CLNR due to an associated increase in insensible fluid loss.
Similar to other investigators who noted an increase in the
VSS of -lactams, we noted an increase in the
VSS of cefepime in burn patients. The
VSS in our burn patient population (0.43 liters/kg) was approximately twice that previously reported for volunteers (0.18 to 0.24 liters/kg) with or without renal impairment (5, 6, 14). Walstad et al. (33) observed an
increase in the VSS of ceftazidime in burn
patients compared to that in other patients. The increase was almost
twice that seen with ceftazidime in healthy volunteers (22).
Bourget et al. (10), Boucher et al. (8),
Friedrich et al. (16), and Adam et al. (1)
reported similar increases in VSS with
piperacillin-tazobactam, imipenem, aztreonam, and
ticarcillin-clavulanate, respectively, in burn patients. Shikuma et al.
(32) described approximately a threefold increase in
VSS of piperacillin in burn patients compared to
that in healthy subjects. Thus, it appears that the
VSS of cefepime is increased, as has been
previously described for other -lactams. The increase in the
VSS of cefepime may also be partially
attributed to alterations in protein binding; other studies have shown
changes in plasma protein levels and drug binding following burn injury (24). Plasma albumin levels in our patients were sometimes
low, ranging from 1.7 to 3.4 g/dl. However, because the protein binding of cefepime is less than 20% (3), it is unlikely to
explain the observed increase in VSS.
The %T > MIC for -lactams has been associated with
outcome in both animal infection models (13) and humans
(31). Using a neutropenic-mouse thigh infection model,
researchers have previously demonstrated, with cephalosporins against
gram-negative organisms, that maintaining drug concentrations above the
MIC for 60 to 70% of the dosing interval may be necessary to maximize
bactericidal activity (13). Therefore, it is reasonable to
design cephalosporin dosing regimens for humans based on this
pharmacodynamic parameter. According to our pharmacokinetic simulations
with MICs 8 µg/ml, a %T > MIC of at least 60%
was accomplished with all assessed dosing regimens except 1 g
q12h. It should also be noted that the 1-g-q8h regimen produced a
%T > MIC similar to that produced by the 2-g-q12h regimen and
represents a reduction in the total daily dose.
In conclusion, the CLT and VSS of cefepime were increased in our study population compared to those for healthy volunteers. The CLT may be explained by an increase in the glomerular filtration rate, whereas VSS is associated with the burn severity. Nonetheless, it appears that the dose does not need to be adjusted in similarly affected burn patients and that 1 g q8h and 2 g q12h provide similar %T > MIC, while the 1-g-q8h regimen allows a reduction in the daily dose.
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ACKNOWLEDGMENTS |
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This work was supported, in part, by a grant from Bristol Myers Squibb Company, Princeton, N.J.
We acknowledge Linda B. Mihm for her contribution to the study and Archie J. Taylor for his expertise and assistance with HPLC. In addition, we are indebted to the entire Burn Unit staff, without whom this project would not have been possible.
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FOOTNOTES |
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* Corresponding author. Mailing address: Anti-Infective Research Laboratory, Medical University of South Carolina, College of Pharmacy, 280 Calhoun St., P.O. Box 250140, Charleston, SC 29425. Phone: (843) 792-8501. Fax: (843) 792-1617. E-mail: bossoja{at}musc.edu.
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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