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Antimicrobial Agents and Chemotherapy, December 2001, p. 3322-3327, Vol. 45, No. 12
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.12.3322-3327.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Compartmental Pharmacokinetics and Tissue
Distribution of the Antifungal Echinocandin Lipopeptide Micafungin
(FK463) in Rabbits
Andreas H.
Groll,1
Diana
Mickiene,1
Vidmantas
Petraitis,1
Ruta
Petraitiene,1
Khalid H.
Ibrahim,2
Stephen C.
Piscitelli,2
Ihor
Bekersky,3 and
Thomas J.
Walsh1,*
Immunocompromised Host Section, Pediatric
Oncology Branch National Cancer Institute,1 and
Pharmacokinetics Research Laboratory, Pharmacy Department,
Warren Grant Magnuson Clinical Center,2 National
Institutes of Health, Bethesda, Maryland, and Fujisawa
Healthcare USA, Deerfield, Illinois3
Received 20 February 2001/Returned for modification 21 July
2001/Accepted 20 September 2001
 |
ABSTRACT |
The plasma pharmacokinetics and tissue distribution of the novel
antifungal echinocandin-like lipopeptide micafungin (FK463) were
investigated in healthy rabbits. Cohorts of three animals each received
micafungin at 0.5, 1, and 2 mg/kg of body weight intravenously once
daily for a total of 8 days. Serial plasma samples were collected on
days 1 and 7, and tissue samples were obtained 30 min after the eighth
dose. Drug concentrations were determined by validated high-performance
liquid chromatographic methods. Plasma drug concentration data were fit
to a two-compartment pharmacokinetic model, and pharmacokinetic
parameters were estimated using weighted nonlinear least-square
regression analysis. Micafungin demonstrated linear plasma
pharmacokinetics without changes in total clearance and dose-normalized
area under the concentration-time curve from 0 h to infinity.
After administration of single doses to the rabbits, mean peak plasma
drug concentrations ranged from 7.62 µg/ml at 0.5 mg/kg to 16.8 µg/ml at 2 mg/kg, the area under the concentration-time curve from 0 to 24 h ranged from 5.66 to 21.79 µg · h/ml, the apparent
volume of distribution at steady state ranged from 0.296 to 0.343 liter/kg, and the elimination half-life ranged from 2.97 to 3.20 h, respectively. No significant changes in pharmacokinetic parameters
and no accumulation was noted after multiple dosing. Mean tissue
micafungin concentrations 30 min after the last of eight daily doses
were highest in the lung (2.26 to 11.76 µg/g), liver (2.05 to 8.82 µg/g), spleen (1.87 to 9.05 µg/g), and kidney (1.40 to 6.12 µg/g). While micafungin was not detectable in cerebrospinal fluid,
the concentration in brain tissue ranged from 0.08 to 0.18 µg/g.
These findings indicate linear disposition of micafungin at dosages of
0.5 to 2 mg/kg and achievement of potentially therapeutic drug
concentrations in plasma and tissues that are common sites of invasive
fungal infections.
| |
INTRODUCTION |
Micafungin (FK463) is a novel,
semisynthetic antifungal echinocandin-like lipopeptide that inhibits
the synthesis on 1,3
-glucan, an essential polymeric polysaccharide
in the cell wall of many pathogenic fungi (12, 24). As a
class, the echinocandins lack mechanism-based toxicity and have an
extended spectrum of antifungal activity without cross-resistance to
existing antifungal agents (4, 5, 9, 15, 18). In vitro,
micafungin has demonstrated potent and broad-spectrum fungicidal
activity against clinically relevant Candida spp. and potent
inhibitory activity against Aspergillus spp. (21, 23,
25). The compound displayed promising antifungal efficacy in
murine models of disseminated candidiasis as well as disseminated and
pulmonary aspergillosis (16, 19, 20) and is currently in
advanced stages of clinical development (12).
Little is still known, however, about the disposition of micafungin in
plasma and tissues. Therefore, the purpose of this study was to assess
the compartmental plasma pharmacokinetics and tissue distribution of
micafungin at potentially therapeutic dosages in healthy laboratory
animals. The information derived from this study will assist to further
explore the relationships between concentration and effect of
micafungin in pharmacodynamic models of disseminated candidiasis and
invasive pulmonary aspergillosis in persistently neutropenic animals of
the same species.
(A preliminary report of this work has been presented previously
[A. H. Groll, D. Mickiene, V. Petraitis, R. Petraitiene, R. Alfaro, K. H. Ibrahim, A. Kalim, I. Bekersky, S. C. Piscitelli, and T. J. Walsh, Abstr. 40th Intersci. Conf.
Antimicrob. Agents Chemother., abstr. 1688, p. 388, 2000].)
| |
MATERIALS AND METHODS |
Experimental design. (i) Study drug.
Micafungin (FK463;
Fujisawa USA, Inc. Deerfield, Ill.) was provided as a 10-mg/ml solution
for injection and maintained at room temperature protected from light.
Prior to use, the drug was freshly diluted with sterile normal saline
to a 1-mg/ml solution. Micafungin was administered at ambient
temperature as a slow intravenous (IV) bolus over 4 min through the
indwelling catheter.
(ii) Animals.
Healthy female New Zealand White rabbits
(Hazleton, Denver, Pa.) weighing 2.8 to 3.2 kg were used in all
experiments. They were individually housed and maintained with water
and standard rabbit feed ad libitum according to the National
Institutes of Health Guidelines for Laboratory Animal Care
(2) and in fulfillment of American Association for
Accreditation of Laboratory Animal Care criteria. Vascular access was
established in each rabbit 
72 h prior to experimentation by the
surgical placement of a subcutaneous silastic central venous catheter
as previously described (27).
(iii) Single-dose plasma pharmacokinetics.
Three groups of
three animals each were studied. Animals received micafungin at 0.5, 1, or 2 mg/kg of body weight as a steady IV bolus over 4 min. Plasma
samples (2.0 ml of blood) were drawn immediately before administration
of the drug and then at 0.1 (maximum concentration of drug in plasma
[Cmax]), 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, and
24 h after the start of the IV bolus.
(iv) Multiple-dose plasma pharmacokinetics.
After completion
of single-dose pharmacokinetics, the identical three groups of three
animals each continued to receive micafungin at either 0.5, 1, or 2 mg/kg of body weight once daily as a steady IV bolus over 4 min for a
total of 7 days. On day 7, plasma samples (2.0 ml of blood) were drawn
immediately before administration of the drug and then at 0.1 (Cmax), 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, and
24 h after the start of the IV bolus.
(v) Tissue distribution studies.
For the assessment of
tissue micafungin concentrations near peak plasma micafungin levels
after multiple doses, animals received one more dose of the assigned
regimen on day 8. All animals were sacrificed 30 min after dosing by IV
pentobarbital and brain tissue, cerebrospinal fluid (CSF), choroid,
vitreous humor, aqueous humor, lung, liver, spleen, and kidney were
obtained at autopsy for analysis of drug concentrations.
(vi) Assessment of tolerance.
All animals were evaluated
clinically each day. Biochemical parameters of hepatic and renal
toxicities were monitored in plasma samples obtained on the last day of
the experiment. Values were compared to reference values established in
healthy rabbits naive to prior drug exposure.
Processing of samples and analytical assay. (i) Processing of
blood and tissues.
Blood samples were collected in heparinized
syringes, and plasma was separated by centrifugation. All plasma, body
fluid, and tissue samples were stored at 
80°C until assay.
Micafungin was extracted from acidified heparinized plasma by
liquid/liquid extraction with acetonitrile-based organic solvents and
diluted with phosphate buffer prior to injection. Tissue specimens were
thoroughly rinsed with phosphate-buffered saline and blotted to dryness
with Micro Wipes (Scott Paper Company, Philadelphia, Pa.). Specimens
were then weighed and homogenized twice for 30 s each time with
ice-cold phosphate-buffered saline (pH 7.4) (1:4 [wt/wt]) using a
high-speed tissue homogenizer (Ultra-Turrax; Tekmar, Cincinnati, Ohio)
with a 10N head and placement of the sample in an ice bucket.
The homogenates were incubated for 30 min at 4°C and centrifuged at
2,000 × g for 10 min. Micafungin was extracted from
tissue homogenates and all other body fluids by solid-phase extraction
using acetonitrile-ammonium acetate-based solvents and C8
bonded phase extraction cartridges (Varian Inc., Harbor City, Calif.)
as previously described (14). Standards and quality
control samples were similarly prepared by adding known amounts of
micafungin to either healthy rabbit plasma (for serum and choroid;
Gibco Laboratories, Grand Islands, N.Y.), commercially available CSF
standards (Instrumentation Laboratories, Lexington, Mass.), Hanks'
balanced salt solution (for vitreous and aqueous humor; Mediatech,
Herndon, Va.), or healthy rabbit tissue homogenates. Blank samples of
all matrices also were extracted to ensure the absence of interfering peaks.
(ii) Analytical assay.
Concentrations of micafungin were
determined using reversed-phase high-performance liquid chromatography.
For plasma, the mobile phase consisted of 20 mM
KH2PO4-acetonitrile (59:41 [vol/vol]), delivered at 1 ml/min. Samples were maintained in the autosampler at
room temperature in amber glass vials. The injection volume was 75 µl. Micafungin eluted at 10.3 to 13.8 min, using a 5-µm TSK-GEL silica-based analytical column (ODS80TM [150 by 4.6 mm]; TosoHaas, Montgomeryville, Pa.) maintained at 50°C in conjunction with a precolumn filter containing a 5-µm insert and
fluorimetric detection (excitation wavelength, 273 nm excitation;
emission wavelength 464 nm). For nonplasma body fluids and tissue
homogenates, the mobile phase consisted of acetonitrile-50 mM ammonium
acetate (pH 4.0) (45:55 [vol/vol]), delivered at 0.75 ml/min. Samples were maintained in the autosampler at room temperature in amber glass
vials. The injection volume was 75 µl. Micafungin eluted at circa 8 min, using a 5-µm C8 analytical column (Alltech
Inertsil [150 by 4.6 mm]; Alltech, Deerfield, Ill.) maintained at
room temperature, and UV detection at a wavelength of 273 nm.
Quantification was based on the peak height of micafungin and the
nonweighted concentration response of the external calibration
standard. Eight- to ten-point standard curves (range, 0.05 to
25 µg/ml for plasma; 0.05 to 5 µg/ml for all other matrices) were
linear with
r2 values greater than 0.987. The
lower limit of quantification
(LLQ) in plasma was 0.100 µg/ml, and
the LLQ in all other body
fluids and tissue homogenates was 0.05 µg/ml. The methods were
sensitive to at least 0.010 µg/ml.
Accuracies in plasma were within
1.7 to 12.8%, and intra- and interday
variability ranged from
1.2 to 6.8% (0.4 to 13% for tissues and 0.99 to 8.44% for nonplasma
body
fluids).
Pharmacokinetic data analysis. (i) Pharmacokinetic modeling.
Pharmacokinetic parameters for micafungin were determined using
compartmental analysis. Experimental plasma micafungin
concentration-versus-time profiles were fitted to a two-compartment
open model with IV bolus input and linear first-order elimination from
the central compartment using iterative weighted nonlinear
least-squares regression with the ADAPT II computer program
(3). Model selection was guided by visual inspection of
the plasma drug profiles and Akaike's information criterion
(28). The model fit the data well, with r2 values for the individual fits ranging from
0.954 to 1.000 (mean, 0.977). The regression lines through the plot of
observed concentrations versus estimated concentrations did not differ
from the line of identity, and no bias was observed.
Cmaxs were determined as model-estimated concentrations 6 min after the start of the IV bolus, and the minimum
concentrations of drug in plasma (Cmins) were determined as
model-estimated concentrations 24 h postdosing, respectively. Area
under the concentration-time curve from 0 h to infinity
(AUC0-
) was calculated from estimated 24-h plasma drug
concentration profiles using the trapezoidal rule and extrapolation to
infinity by standard techniques (8). Dose linearity after
single and multiple doses was determined by comparison of the
dose-normalized AUC0- across dosage levels by analysis
of variance (ANOVA) and linear regression analysis. Accumulation was
assessed for each dosage level by comparing the mean AUC between doses
after multiple doses as an approximation of AUC between doses at steady
state with the mean AUC0- after single doses.
Distribution and clearance terms were normalized to body weight to
allow for comparison across species.
(ii) Statistical analysis.
All values are presented as
means ± standard errors of the means for three animals in each
group. Differences between the means of pharmacokinetic parameters
across dosage levels were evaluated by ANOVA. A two-tailed P
value of <0.05 was considered statistically significant.
| |
RESULTS |
Single-dose studies.
The estimated plasma drug
concentration-versus-time curves following single-dose administration
of micafungin are shown in Fig. 1A, and
the corresponding mean compartmental pharmacokinetic parameters are
listed in Table 1. IV bolus
administration of micafungin at dosages of 0.5 to 2 mg/kg resulted in
mean peak plasma drug levels that ranged from 7.67 ± 1.49 to
16.08 ± 1.72 µg/ml. Plasma drug concentration profiles showed a
rapid initial distributive phase, followed by a slower elimination
phase with an estimated elimination half-life of approximately 3 h. Mean plasma drug levels fell below the LLQ (0.1 µg/ml) in a
dose-dependent manner 8, 12, and 18 h after dosing. Consistent
with dose-independent, linear plasma pharmacokinetics, total plasma
clearance (CLt) and dose-normalized AUC0-
were not different across the investigated dosage range. Similarly, the
apparent volume of distribution at steady state
(VSS) did not change with the dosage.
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FIG. 1.
Concentration-versus-time profiles in plasma after IV
bolus administration of micafungin over 4 min. (A) Single-dose profiles
after administration of 0.5, 1, and 2 mg/kg. (B) Profiles after
administration of 0.5, 1, and 2 mg/kg over 7 days. Each point is the
mean ± SEM for three rabbits at that time point. The LLQ was
0.100 µg/ml.
|
|
Multiple-dose studies.
The estimated plasma micafungin
concentration-versus-time profiles following multiple once-daily doses
of the compound for 7 days are shown in Fig. 1B, and the corresponding
mean compartmental pharmacokinetic parameters are listed in Table
2. At all three dosage levels, plasma
drug concentrations immediately prior to dosing were below the LLQ.
Peak plasma drug concentrations immediately after dosing were not
significantly different from those observed after administration of a
single dose. Similar to single-dose administration, mean plasma drug
levels fell below LLQ in a dose-dependent manner 8, 12, and 18 h
postdosing. There were no significant differences in AUC (Fig.
2A), VSS,
CLt, and half-life compared to the values after single
doses. No differences in dose-normalized AUC0- across
the investigated dosages were noted by ANOVA and linear regression
(Fig. 2B), indicating dose-independent plasma pharmacokinetics of
micafungin also after multiple doses.
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FIG. 2.
(A) AUC0- at the three investigated
dosage levels (0.5, 1, and 2 mg) after administration of single and
multiple doses of micafungin (FK). Each bar represents the mean ± SEM of three rabbits. Note the absence of drug accumulation in plasma
over time after multiple once-daily doses. (B) Plot of dose-normalized
AUC after multiple once-daily doses with micafungin over 7 days versus
dosage. The values for individual animals (squares) and the
corresponding means (triangles) ± SEM are shown. The slope of the
regression line is not significantly different from zero, indicating
linear disposition in plasma over the investigated dosage range.
|
|
Tissue distribution.
Mean tissue drug concentrations near peak
plasma drug concentrations 30 min after the last of eight daily doses
of micafungin are shown in Table 3. At
this time point of the dosing interval, the highest concentrations were
detected in the lung, followed by the liver, spleen, and kidney. Drug
concentrations in these organs increased proportionally to the dosage
and ranged from 2.26 ± 0.10 to 11.76 ± 1.40 µg/g in the
lung to 1.40 ± 0.08 to 6.12 ± 0.17 in the kidney. Although
micafungin was undetectable in CSF, it was detectable in brain tissue
in all animals at mean concentrations ranging from 0.08 ± 0.01 to
0.18 ± 0.02 µg/g. Similar drug concentrations were measured in
the choroidal layer of the eye. Concentrations of micafungin in
vitreous humor were comparatively low, and the compound was
undetectable in aqueous humor.
Toxicity.
Abnormal elevations in the mean blood urea nitrogen,
serum creatinine, plasma potassium, magnesium, bilirubin, alkaline
phosphatase, and hepatic transaminase levels were not observed in
samples determined after 8 days of treatment. Throughout the
pharmacokinetic study, no apparent infusion-related toxicities or other
clinical abnormalities were observed and no abnormal weight changes
were noted.
| |
DISCUSSION |
The results of this study demonstrate linear plasma
pharmacokinetics of micafungin across the investigated dosage range of 0.5 and 2 mg/kg as evidenced by dose-independent plasma clearance and
dose-proportional increases in AUC0- with increasing dosage. Plasma drug concentration data fit best to a two-compartment open pharmacokinetic model that revealed an apparent elimination half-life of approximately 3 h. Micafungin achieved sustained plasma
drug concentrations that were multiple times in excess of MICs reported
for opportunistic fungi known to be susceptible to the compound. No
significant differences in pharmacokinetic parameters were noted
between single-dose and multiple-dose administration. Tissue drug
concentrations near the completion of the initial distributive phase of
micafungin in plasma showed substantial disposition in lung, liver,
spleen, and kidney with achievement of potentially therapeutic
concentrations at these sites. Micafungin was undetectable in CSF but
was found in low concentrations in brain and eye tissues of all
animals. The compound was well tolerated in rabbits without evidence
for clinical or laboratory toxicities.
The favorable pharmacokinetic profile of micafungin is in principle
shared by caspofungin and anidulafungin, structurally and functionally
similar echinocandin-like lipopeptides that are currently in clinical
development. Using a dosage of 1 mg/kg for comparison, the plasma
pharmacokinetics of micafungin and caspofungin in healthy rabbits
appear virtually identical. After multiple once-daily doses of
caspofungin over 7 days, mean Cmax,
AUC0-, VSS, and CLt
values were 16.01 ± 0.61 µg/ml, 13.15 ± 2.37 µg · h/ml, 0.299 ± 0.01 liter/kg, and 0.086 ± 0.01 liter/h/kg,
respectively, and were thus not different from the values observed for
micafungin following the identical dosing schedule (11).
In contrast, at similar dosages and dosing schedules, anidulafungin
exhibited an approximately sixfold-lower mean
Cmax, a twofold-faster CLt, a
twofold-lower AUC0- but a fourfold-larger
VSS in comparison to the values for micafungin
and caspofungin (14). Whether these differences in plasma
pharmacokinetics are associated with differences in pharmacodynamics
remains to be investigated.
The plasma pharmacokinetics of micafungin in rabbits after single doses
were similar to those obtained in mice, rats, and dogs. In these
species, after a single IV bolus of 1 mg/kg, the mean
AUC0-24 ranged from 11.9 to 21.2 µg · h/ml, the
mean VSS ranged from 0.25 to 0.56 liter/kg, the
mean CLt ranged from 0.079 to 0.046 liter/h/kg, and the
half-life ranged from 4.57 to 5.34 h, (S. Suzuki, M. Terakawa, F. Yokobayashi, F. Fujiwara, and T. Hata, Abstr. 38th Intersci. Conf.
Antimicrob. Agents Chemother., abstr. F144, 1998). In healthy male
human volunteers, at dosages ranging from 12.5 to 50 mg given as a 2-h
infusion by the IV route, micafungin exhibited linear pharmacokinetics
with mean Cmaxs ranging from 0.94 to 3.36 µg/ml and mean AUC0- values of 17.11 to 60.93 µg · h/ml. The mean VSS was between
0.237 and 0.242 liter/kg, and the terminal half-life was approximately
15 h. While mean peak plasma drug concentrations in humans were
four- to 13-fold lower than after bolus administration in rabbits,
AUC0- values were similar at the 12.5-mg dosage level
(approximately 0.25 mg/kg) and four- to fivefold higher at comparable
dosages (J. Azuma, I. Yamamoto, M. Ogura, T. Mukai, H. Suematsu, H. Kageyama, K. Nakahara, K. Yoshida, and T. Takaya, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F146, 1998).
Notwithstanding the different modes of drug administration, the plasma
clearance of micafungin was approximately six- to sevenfold less in
humans than that in rabbits. As a consequence of the different modes of
administration (i.e., bolus versus 2-h infusion), direct scaling of
therapeutically effective dosages from rabbits to humans would be best
accomplished by formal pharmacodynamic models that link dosage,
concentrations over time, and antifungal effects.
Despite the fact that tissue drug concentrations represent a mixture of
drug concentrations in the intravascular, interstitial, and
intracellular compartments (1), information on these
concentrations is of potential utility in the selection of antifungal
therapies (14). Cognizant of the fact that different
equilibria may prevail during the dosing interval, assessment of tissue
concentrations of micafungin after the administration of multiple
once-daily doses for 8 days revealed potentially therapeutic drug
concentrations in lung, liver, spleen, and kidneys near the completion
of the initial distributive phase in plasma. Similar to amphotericin B
(13), micafungin was undetectable in CSF and achieved
relatively low levels in brain tissue compared to other sites. However,
therapeutically effective levels of micafungin in brain tissue may be
achieved in the state of tissue inflammation and/or necrosis, as
evidenced by the effective clearance of Candida albicans
from the central nervous system in our persistently neutropenic rabbit
model of subacute disseminated candidiasis (V. Petraitis, R. Petraitiene, A. H. Groll, T. Sein, R. L. Schaufele, J. Bacher, and T. J. Walsh, Abstr. 40th Intersci. Conf. Antimicrob.
Agents Chemother., abstr. 1684, 2000).
Micafungin achieved plasma and tissue drug concentrations that were
severalfold in excess of the MICs at which 90% of the Candida and Aspergillus isolates tested are
inhibited (21, 23, 25). In plasma, concentrations above
these values were maintained in a dose-dependent manner for up to
18 h. Similar to cilofungin (26), caspofungin
(7), and anidulafungin (10, 17, 22), micafungin exhibits predominantly concentration-dependent fungicidal activities against Candida spp. in vitro (Petraitis et al.,
40th ICAAC). Concentration-dependent activity also was demonstrated in
a Candida thigh infection model, where the ratio between
tissue concentrations and MIC was found to be highly predictive for
therapeutic efficacy of micafungin (S. Matsumoto, E. Warabe, Y. Wakai,
Y. Koide, T. Ushitani, N. Teratani, K. Ohtomo, K. Hatano, F. Ikeda, T. Goto, F. Matsumoto, and S. Kuwahara, Abstr. 40th Intersci. Conf.
Antimicrob. Agents Chemother., abstr. 1687, 2000). Pharmacokinetic and
pharmacodynamic modeling of anidulafungin in our neutropenic rabbit
model of disseminated candidiasis revealed that, apart from
drug-specific threshold values for Cmax,
AUC0-24, and tissue concentrations, maintenance of plasma
drug concentrations above the minimum fungicidal concentration of the
experimental isolate for 12 h was associated with 100% efficacy
(14). These findings and the documentation of a
concentration-dependent, prolonged postantifungal effect of up to
12 h and longer for caspofungin and anidulafungin
(6) suggest that once-daily dosing regimens are also
appropriate for micafungin. Nevertheless, pharmacodynamic studies
comparing single- versus split-dose regimens are needed for a
pharmacodynamically founded determination of the optimal dosing regimen.
In conclusion, micafungin displayed linear plasma pharmacokinetics that
were best described by a two-compartment pharmacokinetic model. The
drug achieved and maintained potentially therapeutic plasma drug
concentrations exceeding the MICs of susceptible opportunistic fungi
and distributed into tissues that are common sites of deeply invasive
infections. The compound was well tolerated without evidence of
clinical or laboratory toxicity. The characterization of the pharmacokinetics of micafungin in the rabbit will be of help for the
design of pharmacodynamic animal models investigating the concentration-response relationships of this novel echinocandin-like lipopeptide. The findings from such studies are anticipated to support
the determination of optimal dosing regimens in patients.
| |
ACKNOWLEDGMENTS |
We thank Azhar Kalim at MDS Harris, Lincoln, Nebr., for
assistance with the analytical assay of micafungin in plasma and our colleagues Myrna Candelario and Aida Field-Ridley for expert technical support in conducting these experiments.
| |
FOOTNOTES |
*
Corresponding author. Mailing address:
Immunocompromised Host Section, Pediatric Oncology Branch, National
Cancer Institute, National Institutes of Health, Building 10, Rm.
13N240, 10, Center Dr., Bethesda, MD 20892. Phone: (301) 402-0023. Fax:
(301) 402-0575. E-mail: walsht{at}mail.nih.gov.
| |
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Antimicrobial Agents and Chemotherapy, December 2001, p. 3322-3327, Vol. 45, No. 12
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.12.3322-3327.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
