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Antimicrobial Agents and Chemotherapy, March 2001, p. 922-926, Vol. 45, No. 3
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.3.922-926.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Pharmacodynamics of Amphotericin B in a
Neutropenic-Mouse Disseminated-Candidiasis Model
D.
Andes,1,*
T.
Stamsted,2 and
R.
Conklin2
Section of Infectious Diseases, Department of
Medicine, University of Wisconsin School of
Medicine,1 and Section of Clinical
Pharmacology, Department of Medicine, William S. Middleton VA
Hospital,2 Madison, Wisconsin
Received 13 June 2000/Returned for modification 21 October
2000/Accepted 27 November 2000
 |
ABSTRACT |
In vivo pharmacodynamic parameters have been described for a
variety of antibacterials. These parameters have been studied in
correlation with in vivo outcomes in order to determine which dosing
parameter is predictive of outcome and the magnitude of that parameter
associated with efficacy. Very little is known about pharmacodynamics
for antifungal agents. We utilized a neutropenic mouse model of
disseminated candidiasis to correlate pharmacodynamic parameters
(percent time above MIC [T > MIC], area under the
concentration time curve [AUC]/MIC ratio, and peak serum level/MIC
ratio) for amphotericin B in vivo with efficacy, as measured by
organism number in homogenized kidney cultures after 72 h of
therapy. Amphotericin B was administered by the intraperitoneal route.
Drug kinetics for amphotericin B in infected mice were nonlinear. Serum
half-lives ranged from 13 to 27 h. Infection was achieved by
intravenous inoculation with 106 CFU of yeast cells per ml
via the lateral tail vein of neutropenic mice. Groups of mice were
treated with fourfold escalating total doses of amphotericin B ranging
from 0.08 to 20 mg/kg of body weight divided into 1, 3, or 6 doses over
72 h. Increasing doses produced concentration-dependent killing,
ranging from 0 to 2 log10 CFU/kidney compared to the
organism number at the start of therapy. Amphotericin B also produced
prolonged dose-dependent suppression of growth after serum levels had
fallen below the MIC. Nonlinear regression analysis was used to
determine which pharmacodynamic parameter best correlated with
efficacy. Peak serum level in relation to the MIC (peak serum level/MIC
ratio) was the parameter best predictive of outcome, while the AUC/MIC ratio and T > MIC were only slightly less predictive
(peak serum level/MIC ratio, coefficient of determination
[R2] = 90 to 93%; AUC/MIC ratio,
R2 = 49 to 69%; T > MIC, R2 = 67 to 85%). The total amount of
drug necessary to achieve various microbiological outcomes over the
treatment period was 4.8- to 7.6-fold smaller when the dosing schedule
called for large single doses than when the same amount of total drug
was administered in 2 to 6 doses. Given the narrow therapeutic window
of amphotericin B and frequent treatment failures, these results
suggest the need for a reevaluation of current dosing regimens.
| |
INTRODUCTION |
The incidence of nosocomial candida
infections has risen sharply, representing nearly 10% of
hospital-acquired bloodstream infections (4).
Currently available therapies result in unacceptably high failure rates
(25). In addition, available antifungal therapies often
produce significant toxicities (12). Although the
discovery of new antifungal agents is promising, approaches to optimize efficacy and limit toxicity of currently available agents through rational pharmacodynamic dosing may offer more immediate impact (9, 11).
Amphotericin B is an intravenously administered polyene antibiotic that
has been available for clinical use for more than 40 years. Studies in
both experimental infection models and clinical trials have
demonstrated the potency of amphotericin B against a variety of yeasts
(2, 3, 10, 12, 14, 17, 24). In a recent consensus
publication on the therapy of candidemia, nearly all of the
participants would include amphotericin B for therapy of candidemia for
patients with life-threatening illness (10). Despite the
potency of this drug, many clinicians have grown reluctant to use
amphotericin B because of the relatively narrow therapeutic or toxic
window (12).
Pharmacodynamic characterization of amphotericin B should
maximize dosing efficacy and perhaps limit toxicity. In the present experiments we have characterized the pharmacodynamic parameter predictive of efficacy of amphotericin B monotherapy in a neutropenic mouse model of disseminated candidiasis.
(Part of this work was presented at the 39th Interscience Conference on
Antimicrobial Agents and Chemotherapy, San Francisco, Calif., 26 to 29 September 1999.)
| |
MATERIALS AND METHODS |
Organisms.
Three clinical isolates of Candida
albicans (K-1, 98-17, and 98-234) and single clinical isolates of
Candida krusei 5810 and Candida dubliniensis 3588 were used in the experiments. Each Candida strain was a
bloodstream isolate, with the exception of C. dubliniensis, which was an oropharyngeal isolate. The organisms were maintained, grown, subcultured, and quantified on Sabouraud dextrose agar (SDA)
slants (Difco Laboratories, Detroit, Mich.). Twenty-four hours prior to
study, organisms were subcultured at 35°C.
Antifungal.
Amphotericin B desoxycholate was obtained as a
powder from Bristol-Myers Squibb (Princeton, N.J.). The powder was
stored at 
70°C. Drug solutions were prepared on the day of study by
dissolving the powder in sterile H2O. Subsequent drug
dilutions were obtained with D5W.
In vitro susceptibility testing.
MICs were determined using
a microbroth modification of the NCCLS M27-A method with both RPMI
buffered with 0.165 M morpholine propanesulfonic acid and antibiotic
medium 3 (16, 19). Determinations were performed in
duplicate on at least two separate occasions. Final results are
expressed as the geometric means of these results.
Animals.
Six-week-old ICR/Swiss specific-pathogen-free
female mice weighing 23 to 27 g were used for all studies (Harlan
Sprague Dawley, Madison, Wis.). All animal studies were approved by the
Animal Research Committee of the William S. Middleton Memorial VA Hospital.
Infection model.
Mice were rendered neutropenic (<100
polymorphonuclear leukocytes per mm3) by injection with
cyclophosphamide (Mead Johnson Pharmaceuticals, Evansville, Ind.)
intraperitoneally 4 days (150 mg/kg of body weight) and 1 day (100 mg/kg) before infection.
Organisms were subcultured on SDA 24 h prior to infection.
Inoculum was prepared by placing six colonies into 5 ml of sterile pyrogen-free 0.9% saline warmed to 35°C. Fungal counts of the inoculum determined by viable counts on SDA were 106
CFU/ml.
Disseminated infection with the
Candida organisms was
achieved by injection of 0.1 ml of inoculum via the lateral tail vein
2 h prior to the start of drug therapy. At the end of the study
period, animals were sacrificed by CO
2 asphyxiation. After
sacrifice,
the kidneys of each mouse were immediately removed and
placed
in sterile 0.9% saline at 4°C. The homogenate was then
serially
diluted 1:10, and aliquots were plated on SDA for viable
fungal
colony counts after incubation for 24 h at 35°C. The lower
limit
of detection was 100 CFU/ml. Results were expressed as the mean
CFU per kidney for two mice (four
kidneys).
Pharmacokinetics.
Single-dose pharmacokinetics of
amphotericin B were determined in individual neutropenic-infected
ICR/Swiss mice following intraperitoneal doses of 0.625, 2.5, 5.0, 10.0, and 20 mg/kg administered in 0.2-ml volumes. At each dose
examined, groups of three mice under light halothane anesthesia were
sampled three or four times by retro-orbital puncture. Samples were
collected in heparinized capillary tubes (Fisher Scientific,
Pittsburgh, Pa.) at 5- to 18-h intervals. Tubes were centrifuged (model
MB; International Equipment Co.) at 10,000 × g for 5 min. The serum was subsequently removed, and drug levels were
determined by standard drug diffusion bioassay using Paecilomyces
variotii as the assay organism in antibiotic medium 12 (20). Assays of serum samples and standard curves prepared
for mouse serum were performed on the same day. Intraday coefficient of
variation ranged from 2.3 to 9.6%. The lower level of detection for
this assay was 0.15 mg/liter. Pharmacokinetic constants, including
elimination half-life and the concentration of drug in serum at time
zero (C0), were calculated via nonlinear least-squares techniques (MINSQ; MicroMath, Inc., Salt Lake City, Utah). The area under the concentration-time curve (AUC) was calculated by the trapezoidal rule. For doses that had no kinetics determined, pharmacokinetic parameters were extrapolated from the values obtained in the actual studies.
In vivo PAE.
Infection in neutropenic mice was produced as
described above. Two hours after infection with C. albicans
K-1, mice were treated with single intraperitoneal doses of
amphotericin B (0.25, 1.0, and 4.0 mg/kg). Groups of two treated and
control mice were sacrificed at each sampling time interval, ranging
from 2 to 12 h. Control growth was determined over 24 h at five
sampling times. The treated groups were sampled six to eight times over
56 h. Kidneys were removed at each time point and processed
immediately for CFU determination, as outlined above. The time that
levels of amphotericin B in serum remained above the MIC
(T > MIC) for the organism following the three doses
was calculated from the pharmacokinetic data. The postantibiotic effect
(PAE) was calculated by determining the time it took for controls to
increase 1 log10 CFU/kidney (C) and subtracting
this from the amount of time it took organisms from the treated animals
to grow 1 log10 CFU/kidney (T) after serum levels fell below the MIC for the organism (PAE = T C) (22).
Pharmacodynamic parameter determination.
Neutropenic mice
were infected with each of the Candida species 2 h prior to
the start of therapy. Fifteen dosing regimens were chosen to minimize
the interdependence among the three pharmacodynamic parameters studied
and also to describe the complete dose-response relationship. Groups of
two mice were treated for 72 h with dosing regimens of
amphotericin B using fourfold increasing total doses administered at
12-, 24-, or 72-h dosing intervals. Total doses ranged from 0.078 to 20 mg/kg/72 h. The drug was administered in 0.2-ml volumes. Mice were
sacrificed after 72 h of therapy, and kidneys were removed for CFU
determination as described above. Untreated control mice were
sacrificed just before treatment and at the end of the experiment.
Efficacy was defined as the change in log10 CFU/kidney over
the 72-h treatment period and was calculated by subtracting the mean
log10 CFU/kidney in untreated control mice after 72 h
from the mean number of CFU from kidneys of two mice at the end of therapy.
Data analysis.
A sigmoid dose-effect model was used to
measure the in vivo potency of amphotericin B. The model is derived
from the Hill equation: E = (Emax × DN)/(ED50N + DN), where E is the observed effect
(change in log10 CFU/kidney compared with untreated
controls at 72 h), D is the cumulative 72-h dose,
Emax is the maximum effect, ED50 is
the dose required to achieve 50% of Emax, and
N is the slope of the dose-effect relationship. The
correlation between efficacy and each of the three parameters studied
was determined by nonlinear least-squares multivariate regression
analysis (Sigma Stat; Jandel Scientific Software, San Rafael, Calif.).
The coefficient of determination (R2) was used
to estimate the percent variance in the change of log10 CFU/kidney over the treatment period for the different dosing regimens
that could be attributed to each of the pharmacodynamic parameters.
To allow a more meaningful comparison of potency among the dosing
regimens studied, we calculated the dose required to produce
a
fungistatic dose or no net growth over 72 h and the dose required
to achieve a 1 log
10 reduction in colony counts compared to
numbers
at the start of therapy. If the doses needed to achieve these
benchmarks increased significantly as the dosing interval was
lengthened from every 12 h to every 72 h,
T > MIC was
the parameter
predictive of efficacy. On the other hand, if the doses
necessary
to reach these outcomes decreased with the lengthening of the
dosing interval, then the parameter associated with these outcomes
would be the peak serum level. If the doses remained similar
independent
of changes in the dosing interval, then the AUC would be
predictive
of
efficacy.
| |
RESULTS |
In vitro susceptibility testing.
There was no difference in
MICs determined with both the accepted M27 methodology and
antibiotic medium 3. MICs of amphotericin B for the
Candida species were 0.25 mg/liter for each of the organisms tested, with the exception of C. dubliniensis, for which the
MIC of amphotericin B was 0.5 mg/liter.
Pharmacokinetics.
The time courses of amphotericin B in serum
of infected neutropenic mice following intraperitoneal doses of 0.625, 2.5, 5.0, 10.0, and 20 mg/kg are shown in Fig.
1. Peak serum levels and the AUC did not
increase in a linear fashion with dose escalation. Peak levels were
achieved within 6 h for each of the doses and ranged from
2.51 ± 0.40 to 0.28 ± 0.03 mg/liter. The elimination half-life ranged from 13.7 to 27 h, similar to that previously described in a murine model (13). The AUC, as determined
by the trapezoidal rule, ranged from 10 to 83 mg · h/liter with
the lowest and highest doses, respectively.
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FIG. 1.
Concentrations of amphotericin B in serum after
subcutaneous doses of 20, 10, 5, 2.5, and 0.625 mg/kg in neutropenic
infected mice. Each symbol represents the geometric mean ± standard deviation of serum levels from three mice.
|
|
In vivo PAE.
Following tail vein inoculation of
106 CFU/ml, growth of Candida organisms in the
kidneys of untreated mice increased (3.31 ± 0.20)
log10 CFU/kidney over 24 h. Control growth of 1 log10 CFU/kidney in untreated mice was achieved in 5.2 h.
No drug carryover was observed in treatment groups. Based upon the
above pharmacokinetics, the three doses of amphotericin B studied
(0.25, 1.0, and 4.0 mg/kg) would produce serum levels above the MIC for
the Candida organism (0.25 mg/liter) for 0, 14, and 46 h, respectively. Only treatment with the highest single dose resulted
in any significant reduction in colony counts compared with numbers at
the start of therapy. Growth curves for both the control group and
experimental groups following the single doses of amphotericin B are
shown in Fig. 2. Amphotericin B
suppressed regrowth of organisms at each of the three doses studied in
a dose-dependent fashion. PAEs increased from 23 to 30 h with
escalation of dosage from 0.25 to 1.0 mg/kg. We were unable to
calculate a PAE for the highest dose studied, as organisms did not
regrow during the period of study. The growth suppression due to the
0.25 mg/kg dose was due entirely to sub-MIC effects, as the peak
concentration with this dose never reached the MIC of amphotericin B
for the organism.
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FIG. 2.
In vivo PAE of amphotericin B at doses of 4, 1, and 0.25 mg/kg against C. albicans in neutropenic mice. Each symbol
represents the mean ± standard deviation from two mice (four
kidneys).
|
|
Pharmacodynamic parameter determination.
At the start of
therapy, each kidney had (3.81 ± 0.12) log10 CFU.
After 72 h, the organisms grew (3.11 ± 0.39) log10
CFU/kidney in untreated mice and resulted in the death of each of the
control mice. Drug carryover was not observed in any of the samples.
Escalating doses of amphotericin B produced significant net killing
compared to the inoculum in control animals at the start of therapy.
Highest total doses for the different regimens resulted in a mean
reduction in colony count compared with numbers at the start of therapy of (1.84 ± 0.26) log10 CFU/kidney for the 72-h dosing
interval and (0.69 ± 0.84) log10 CFU/kidney with the
shortest dosing interval (Fig. 3).
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FIG. 3.
Relationship between the 24-h total dose for three
lengthening dosing intervals and log10 CFU/kidney in a
neutropenic mouse model of disseminated candidiasis. Each symbol
represents data from two mice (four kidneys).
|
|
Examples of the relationship between microbiological effect and each of
the pharmacodynamic parameters, including
T > MIC,
the
AUC/MIC ratio, and the peak serum level/MIC ratio, are shown
in Fig.
4. As shown in Table
1,
the peak level in relation to
the MIC had the strongest relationship
with each of the organisms
studied.
T > MIC appeared
more important than the AUC in relation
to the MIC. That the
time-dependent parameter was important in
this model is likely a
reflection of the prolonged dosing intervals.
As dosing intervals are
lengthened,
T > MIC eventually becomes
the most
important parameter for any drug or drug class.
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FIG. 4.
(A) Relationship between T > MIC and
log10 CFU/kidney after 72 h of therapy. Each symbol
represents data from two mice (four kidneys). (B) Relationship between
the 72-h AUC/MIC ratio and log10 CFU/kidney after 72 h of
therapy. Each symbol represents data from two mice (four kidneys). (C)
Relationship between the peak serum level/MIC ratio and
log10 CFU/kidney after 72 h of therapy. Each symbol
represents data from two mice (four kidneys).
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TABLE 1.
Relationship between the pharmacodynamic parameters and
efficacy of amphotericin B against Candida organisms
|
|
The doses of amphotericin required to achieve a net fungistatic effect
and a 1 log
10 reduction in CFU/kidney compared to numbers
at the start of therapy over the 72-h period with each of the
three
dosing intervals and the various organisms studied are shown
in Table
2. The static dose increased
7.60-fold ± 5.65-fold (range,
2.4-fold to 16.6-fold) when the
dosing interval was shortened
from 72 to 12 h. Similarly, the dose
required to produce a 1 log
10 reduction in CFU/kidney
increased 4.86-fold ± 2.33-fold (range,
3.3-fold to 7.1-fold).
| |
DISCUSSION |
The time course of antimicrobial activity can be determined by two
characteristics: the effect of increasing drug concentrations on the
extent of organism killing and the presence or absence of antimicrobial
effects which persist after serum levels have fallen below the MIC
(9). For example, demonstration of concentration-dependent killing and prolonged PAE with the aminoglycoside class has provided the basis for once-daily dosing of these drugs (8, 9).
This regimen optimizes the concentration-dependent parameters, the peak
serum level/MIC and AUC/MIC ratios, which have been shown to predict
efficacy, limit toxicity, and reduce the development of organism
resistance (6, 15).
Previous in vitro time-kill and PAE studies with amphotericin B have
demonstrated concentration-dependent activity and significant PAEs
against a variety of yeasts (14, 21). The magnitude of the
PAE in vitro was dependent upon the concentration of amphotericin B and
the duration of exposure, ranging from 0.5 to 10 h (21). The PAEs we demonstrated in vivo were much longer than those found in
vitro (8). This discrepancy in PAE duration is similar to that observed with several classes of antimicrobials (9).
These in vivo studies are unable to determine what degree of growth suppression could be due to the antimicrobial effect of concentrations that are below the MIC with the two other doses. Previous studies have
demonstrated a variety of sub-MIC effects on both C. albicans and Cryptococcus neoformans (1, 14, 18,
21). In addition, although serum drug concentrations have been
shown to be a relatively good surrogate of tissue concentrations, the
magnitude of the PAE in these experiments may have been different if we
were able to accurately measure amphotericin B concentrations at the
site of infection (the kidney). The duration of the PAE induced by amphotericin B may be related to the time necessary for yeast cell wall
damage to be repaired and subsequent organism multiplication to resume.
Previous animal infection models have demonstrated the potency of
amphotericin B against several Candida species (2,
3). In addition, several studies have demonstrated the
concordance between in vitro susceptibility and in vivo endpoints
(2, 17). These studies have, however, utilized only a
single dosing interval, limiting one's ability to determine which
pharmacodynamic parameter best predicts efficacy. With only a single
dosing interval, escalating doses increase all three parameters. The
interdependence between the parameters with single-dosing-interval
studies is too great to determine if one is more important than another.
Our in vivo studies demonstrated concentration-dependent activity in
neutropenic animals with doses that covered a 250-fold range in total
doses and an effect that varied by more than 3 log10. These
studies demonstrated that the peak serum level/MIC ratio was the
pharmacokinetic and pharmacodynamic parameter that most strongly
correlated with the outcome of amphotericin B. When the same total
amount of drug was given over the 72-h treatment period, less
total drug was needed to achieve a given effect (static dose or 1 log10) when larger doses were administered infrequently, maximizing the concentration-dependent parameter, the peak serum level/MIC ratio. More than fivefold more drug was required to produce a
net static effect when administered using the most frequent dosing in
this model, compared to only a single dose during the 72-h study. Thus,
these data suggest that high, infrequent doses of amphotericin B can be
as effective as lower-dose, more frequently administered regimens of
amphotericin B.
The most frequently recommended amphotericin B dosing, every 24 h at
doses ranging from 0.5 to 1.0 mg/kg, often results in unacceptable
toxicities. If one were able to administer the drug to maximize peak
serum levels but decrease the frequency of administrations to every 48 or even 72 h, not only might the efficacy of the drug be
equivalent or improved, but toxicities may also be less likely. Very
few studies have compared the kinetics of amphotericin B in humans
using varying dosing intervals. Bindschadler and Bennett (5) demonstrated that higher peak serum levels
were achieved when twice the daily dose was administered every other
day than when administered daily. This dosing schedule was often
recommended in earlier antifungal dosing guidelines but has been
replaced more recently by daily dosing. These studies would support
clinical studies reexamining administration of larger doses given less frequently, perhaps only two or three times per week. Future in vivo
studies and clinical trials should attempt to correlate these pharmacodynamic parameters with efficacy and toxicity.
| |
ACKNOWLEDGMENT |
We thank Jacque Meis for kindly providing the C. krusei and C. dubliniensis isolates.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Section of
Infectious Diseases, Department of Medicine, University of Wisconsin
School of Medicine, Room H4/570, 600 Highland Ave., Madison, WI 53792. Phone: (608) 263-1545. Fax: (608) 263-4464. E-mail:
drandes{at}facstaff.wisc.edu.
| |
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Antimicrobial Agents and Chemotherapy, March 2001, p. 922-926, Vol. 45, No. 3
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.3.922-926.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
