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Antimicrobial Agents and Chemotherapy, June 2000, p. 1624-1629, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Comparison of Nikkomycin Z with Amphotericin B and Itraconazole
for Treatment of Histoplasmosis in a Murine Model
Janet
Goldberg,1,2
Patricia
Connolly,1,2
Carol
Schnizlein-Bick,1
Michelle
Durkin,1,2
Stephen
Kohler,2,3
Melinda
Smedema,1,2
Edward
Brizendine,1
Richard
Hector,4 and
Joseph
Wheat1,2,3,5,*
Departments of
Medicine1 and
Pathology,5 Indiana University School of
Medicine, Department of Veterans' Affairs
Hospital,3 and Histoplasmosis Reference
Laboratory,2 Indianapolis, Indiana, and
Shaman Pharmaceuticals, South San Francisco,
California4
Received 22 September 1999/Returned for modification 31 January
2000/Accepted 26 March 2000
 |
ABSTRACT |
Nikkomycin Z was tested both in vitro and in vivo for efficacy
against Histoplasma capsulatum. Twenty clinical isolates
were tested for susceptibility to nikkomycin Z in comparison to
amphotericin B and itraconazole. The median MIC was 8 µg/ml with a
range of 4 to 64 µg/ml for nikkomycin Z, 0.56 µg/ml with a range of
0.5 to 1.0 µg/ml for amphotericin B, and 
0.019 µg/ml for
itraconazole. Primary studies were carried out by using a clinical
isolate of H. capsulatum for which the MIC of nikkomycin Z
was greater than or equal to 64 µg/ml. In survival experiments, mice
treated with amphotericin B at 2.0 mg/kg/dose every other day (QOD)
itraconazole at 75 mg/kg/dose twice daily (BID), and nikkomycin Z at
100 mg/kg/dose BID survived to day 14, while 70% of mice receiving
nikkomycin Z at 20 mg/kg/dose BID and none of the mice receiving
nikkomycin Z at 5 mg/kg/dose BID survived to day 14. All vehicle
control mice died by day 12. Fungal burden was assessed on survivors. Mice treated with nikkomycin Z at 20 and 100 mg/kg/dose BID had significantly higher CFUs per gram of organ weight in quantitative cultures and higher levels of Histoplasma antigen in lung
and spleen homogenates than mice treated with amphotericin B at 2.0 mg/kg/dose QOD or itraconazole at 75 mg/kg/dose BID. Studies also were
carried out with a clinical isolate for which the MIC of nikkomycin Z
was 4 µg/ml. All mice treated with amphotericin B at 2.0 mg/kg/dose
QOD; itraconazole at 75 mg/kg/dose BID; and nikkomycin Z at 100, 20, and 5 mg/kg/dose BID survived until the end of the study at day 17 postinfection, while 30% of the untreated vehicle control mice
survived. Fungal burden assessed on survivors showed similar levels of
Histoplasma antigen in lung and spleen homogenates of mice
treated with amphotericin B at 2.0 mg/kg/dose QOD; itraconazole at 75 mg/kg/dose BID; and nikkomycin Z at 100, 20, and 5 mg/kg/dose BID. The
three surviving vehicle control mice had significantly higher antigen
levels in lung and spleen than other groups (P < 0.05). The efficacy of nikkomycin Z at preventing mortality and
reducing fungal burden correlates with in vitro susceptibility.
| |
INTRODUCTION |
Nikkomycin Z is an experimental
compound that has been shown to exhibit antifungal properties (1,
8, 10). The nikkomycins are nucleoside analogs of
UDP-N-acetylglucosamine. They act as competitive inhibitors
of the fungal enzyme chitin synthase that polymerizes
N-acetyl-glucosamine to form chitin, a structural fungal
cell wall component (4). Three chitin synthase isozymes have
been described extensively in Saccharomyces cerevisiae, each with a different role in cell wall synthesis (4, 7, 12). The
susceptibility of an organism to nikkomycin Z would depend on both the
chitin content and the difference in distribution and function of each
of these chitin synthases (12). Nikkomycin Z in vitro has
been shown to be active against dimorphic fungi such as
Coccidioides immitis and Blastomyces dermatitidis
(10). It has limited to no inhibition with true yeasts such
as Cryptococcus neoformans, Candida albicans, and
Candida tropicalis and is inactive against filamentous fungi
such as Aspergillus fumigatus (4, 10; M. Flores and R. F. Hector, Abstr. 36th Intersci. Conf. Antimicrob.
Agents Chemother., abstr. F-190, 1996).
Studies of experimentally induced histoplasmosis in animals have been
useful in identifying antifungal agents for trials in humans (2,
13). In this report, we describe experiments evaluating the in
vitro and in vivo activity of nikkomycin Z in histoplasmosis.
| |
MATERIALS AND METHODS |
Antifungal susceptibility testing.
Isolates of
Histoplasma capsulatum var. capsulatum (yeast
phase) were grown for 4 days on brain heart infusion agar containing 5% sheep blood at 37°C. Yeasts were suspended in sterile saline and
were adjusted to a McFarland standard of 5 at 530 nm. Each suspension
was diluted in RPMI 1640 medium and was added to the drug dilutions.
Itraconazole (Janssen Pharmaceutica, Inc., Titusville, N.J.) was
dissolved in polyethylene glycol (molecular weight of 200), nikkomycin
Z (Shaman Pharmaceuticals, South San Francisco, Calif.) was diluted in
5% dextrose, and amphotericin B (Bristol-Myers Squibb, Princeton,
N.J.) was diluted in dimethyl sulfoxide. Macrobroth suspensions were
incubated at 37°C and read at 120 to 144 h by visual inspection.
Candida parapsilosis ATCC 90018 was used as a control to
ensure that the drug activity of the dilutions fell in the expected
range. The MIC was defined as the dilution at which the turbidity was
equal to or less than that of an 80% dilution of the no drug control
for nikkomycin Z and itraconazole or the dilution which contained no
observable growth for amphotericin B as recommended by the National
Committee for Clinical Laboratory Standards (14).
Lethal dose determination.
Isolate 1 is a clinical isolate
maintained by this laboratory for use specifically in animal models.
The isolate is from an Indiana case of histoplasmosis in a pediatric
cancer patient. The lethal dose for this isolate has been previously
determined to be 105 in B6C3F1 mice
(2). Isolate 2 was chosen for the second study based on
differences in nikkomycin Z MICs for isolates 1 and 2 (>64 and 4 µg/ml, respectively). In comparison, isolate 2 is from an Indiana
case of histoplasmosis in an adult AIDS patient. A lethal dose was
determined for this isolate by infecting groups of mice with 1 × 105, 5 × 105, 1 × 106,
or 5 × 106 yeasts and monitoring for mortality over a
19-day period.
Preparation of H. capsulatum yeast inoculum.
The
yeast phase of H. capsulatum was grown in HMM medium
(16) at 37°C with shaking at 150 rpm for 48 h. The
yeast culture was centrifuged and washed with Hank's balanced salt
solution containing 20 mM HEPES. The inoculum was adjusted by using a
hemacytometer. For survival studies, isolate 1 was administered at a
dose of 105 yeasts/mouse, and isolate 2 was administered at
a dose of 5 × 105 yeasts/mouse.
Intratracheal mouse inoculation model.
Six-week-old
B6C3F1 mice (Harlan Sprague-Dawley) were anesthetized with
4.5% halothane at an oxygen flow rate of 0.9 liters per min. A
20-gauge, 1-1/4-in. angiocath (Becton Dickinson) was passed through the
mouth into the trachea, and 25 µl of the H. capsulatum
inoculum was administered by stylet passed to the bifurcation of the
trachea (6, 11).
Survival studies.
Mice received a lethal inoculum
intratracheally. Treatment began 4 days after infection and continued
for 10 days. Mice received amphotericin B (Fungizone) at 2.0 mg/kg/dose
intraperitoneally every other day (QOD). Itraconazole (10 mg/ml of
solution in hydroxypropyl-
-cyclodextrin [gift of Janssen
Pharmaceutica]) was given twice daily (BID) by gavage at 75 mg/kg/dose. Nikkomycin Z was diluted in 5% dextrose and given
by gavage at 100, 20, and 5 mg/kg/dose BID. Control mice were
treated by gavage with 5% dextrose alone. Ten mice were studied in
each treatment group. Mice were held for 14 to 17 days, at which time
survivors were sacrificed for fungal burden analysis.
Fungal burden assessment of survivors.
Surviving mice were
sacrificed, and lungs and spleens were removed aseptically. Organs were
weighed and then ground in Ten Broeck tissue grinders containing 2.0 ml
of RPMI 1640 medium. Homogenates were diluted and plated on brain heart
infusion agar containing 10% sheep blood. Plates were incubated for 10 to 14 days at 30°C, and colony counts were determined. Undiluted
organ homogenates of 0.1 ml or 1/20 of the total organ were cultured, representing a detection limit of 20 CFU/organ. Quantitative culture data were expressed as CFU/gram by dividing the CFU/organ by the organ
weights, ranging from about 0.169 to 0.503 g for lungs and 0.073 to
0.312 g for spleens for treated versus untreated mice, respectively. A
detection limit of 67 CFU/gram of organ weight for the lungs and 200 CFU/gram of organ weight for the spleen can be determined by using a
mean organ weight of 0.3 and 0.1 g for the lung and spleen,
respectively. Any values less than the detection limit were considered
to represent 0 CFU/organ in these experiments.
Histoplasma antigen was measured in organ homogenates by
enzyme immunoassay (EIA) (
5). Dilutions of the organ
homogenates
(1:10 for spleen and 1:100 for lung) were made to fall
within
the working range of the assay. The EIA results are expressed
as
EIA units (EU) by dividing the mean value obtained for each
organ
homogenate by 1.5 times the mean value of the negative controls.
Results of greater than or equal to 1.0 were considered
positive.
Statistical analysis.
A Wilcoxon test for survival analysis
was used to compare the survival times for the different treatments of
each isolate. An analysis of variance was performed on the ranks of the
antigen and quantitative cultures (3). Tukey's multiple
comparison adjustment was used for making pair-wise comparisons among
the treatment groups. An overall significance level of 
= 0.05 was used to test all hypotheses.
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RESULTS |
Antifungal susceptibility.
The MICs of nikkomycin Z,
itraconazole, and amphotericin B were determined by testing 20 patient
isolates of H. capsulatum following the National Committee
for Clinical Laboratory Standards guidelines for yeasts with
modifications made in our laboratory for H. capsulatum (Fig.
1). MICs for nikkomycin Z ranged from 4 to 
64 µg/ml, with a mean of 18.8 µg/ml, a median of 8 µg/ml, and a MIC at which 90% of the isolates tested are inhibited
(MIC90) of 64 µg/ml. In comparison, amphotericin B MICs
had a range of 0.5 to 1.0 µg/ml with a mean of 0.55 µg/ml, a median
of 0.50 µg/ml, and a MIC90 of 0.5 µg/ml. MICs to
itraconazole were 0.019 µg/ml for every isolate.
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FIG. 1.
MICs of amphotericin B, itraconazole, and nikkomycin Z
for the yeast phase organisms of 20 clinical isolates of H. capsulatum. The lowest concentrations tested for the antifungal
agents were as follows: amphotericin B, 0.031 µg/ml; itraconazole,
0.019 µg/ml; and nikkomycin Z, 0.125 µg/ml.
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Survival following an infection with isolate 1.
Survival
studies used an inoculum of 105 yeasts (Fig.
2). All mice treated with amphotericin B
at 2.0 mg/kg/dose QOD, itraconazole at 75 mg/kg/dose BID, and
nikkomycin Z at 100 mg/kg/dose BID survived to day 14. Thirty percent
of the mice treated with nikkomycin Z at 20 mg/kg/dose BID died between
days 12 and 14, with the remaining 70% surviving to day 14. Mice
treated with nikkomycin Z at 5 mg/kg/dose BID all died between days 11 and 14. All of the untreated control mice died between days 11 and 12. Log-rank test for survival analysis showed that there was a significant
difference among these survival curves (P = 0.0001).
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FIG. 2.
Survival following intratracheal infection with
105 H. capsulatum yeasts of isolate 1 (nikkomycin Z MIC, >64). Therapy was given from days 4 to 13. The no
drug control group received gavage BID with 5% dextrose used to dilute
nikkomycin Z. There were 10 animals in each group. Survivors were
sacrificed at day 14.
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Fungal burden analysis of survivors of infection with isolate
1.
Mice that survived the infection were sacrificed on day 17. Fungal burden was determined by comparing quantitative cultures from
spleen and lung homogenates (Fig. 3).
Treatment of mice infected with an inoculum of 105 yeasts
with nikkomycin Z at 100 and 20 mg/kg/dose BID was unable to reduce the
fungal burden in the lungs and spleen as effectively as treatment with
amphotericin B at 2.0 mg/kg/dose QOD or itraconazole at 75 mg/kg/dose
BID, P < 0.05 (Table 1).
There are no data for untreated animals since all died by day 12.
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FIG. 3.
Quantitative culture results of lung and spleen tissue
from mice surviving to day 14 following infection with 105
H. capsulatum yeasts of isolate 1 (nikkomycin Z MIC, >64).
Each triangle represents one animal, and the circles represent the
means of each group. There were 7 to 10 mice in each study group. None
of the nikkomycin Z 5-mg/kg/dose-BID mice survived to day 14. The
minimum detection limit was 20 CFU/organ, representing 67 to 200 CFU/g
of tissue. Individual platings for the nikkomycin Z
20-mg/kg/dose-BID group were too numerous to count. Animals from this
group were assigned a colony count of 400 per plate, based on
the highest number of colonies which were individually counted
per plate. After conversion to CFU per gram of organ weight, results
were used for graphing and statistical analysis.
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TABLE 1.
Fungal burden in the lungs and spleen of mice that
survived to day 14 after infection with 105 CFU of
H. capsulatum (isolate 1; nikkomycin Z MIC,
64 µg/ml)
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Antigen testing was performed on organ homogenates for surviving mice
and produced results comparable to the culture data.
In summary,
antigen levels were higher in the nikkomycin Z 100-
and
20-mg/kg/dose-BID-treated groups than in the amphotericin
B and
itraconazole 75-mg/kg/dose-BID-treated group,
P < 0.05
for
lung and spleen homogenates (Table
1).
Survival following an infection with isolate 2.
In preparation
to assess the effectiveness of nikkomycin Z for an isolate for which
the agent had lower MIC (4 µg/ml), a series of inocula were tested to
define the lethal dose. Survival was monitored over a 19-day period in
mice infected with an inoculum of 1 × 105, 5 × 105, 1 × 106, or 5 × 106 yeasts. All mice survived until day 10, when 90% of
mice receiving the highest inoculum died. Mice receiving 5 × 105 yeasts died between days 11 and 13. Mice receiving
106 yeasts died between days 10 and 13, while mice
receiving the lowest dose of 105 yeasts died between days
13 and 17. There was a significant difference between survival curves
for the four inocula (P = 0.00070).
An inoculum of 5 × 10
5 was chosen to evaluate
antifungal therapy of mice infected with isolate 2. All mice that
received amphotericin
B at 2.0 mg/kg/dose QOD; itraconazole at 75 mg/kg/dose BID; or
nikkomycin Z at 100, 20, or 5 mg/kg/dose BID
survived until the
end of the study at day 17 postinfection (Fig.
4). However, the
mice in the nikkomycin Z
5-mg/kg/dose-BID group had lost weight,
appeared dehydrated, groomed
poorly, and were presumed to be near
death. Most untreated control mice
died between days 11 and 14,
but 30% survived to the completion of the
study. Survival was
significantly better in the treated mice than in
the control mice
(
P = 0.0001).
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FIG. 4.
Survival following intratracheal infection with 5 × 105 H. capsulatum yeasts of isolate 2 (nikkomycin Z MIC, 4). Therapy was given from days 4 to 13. The no drug control group received gavage BID with 5% dextrose used to
dilute nikkomycin Z. There were 10 animals in each group.
Survivors were sacrificed at day 17.
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Fungal burden analysis of survivors of infection with isolate
2.
Fungal burden was determined on mice that survived to day 17 of
infection. Three untreated control animals survived to day 17 and
appeared to be recovering from the infection. Thus, they were
sacrificed for fungal burden determination (Fig. 4). Based on the
results with isolate 1, higher CFU were anticipated for this study. Due
to restrictions on the number of dilutions which can be done for
quantitative culture, we chose dilutions of 1/103,
1/104, 1/105, and 1/106 for the
untreated controls. The results of the 1/103 dilution were
negative for the spleen; this dilution would have required a CFU of
greater than or equal to 8.6 × 104/g of organ weight
to yield a positive result. Lung tissue of the three surviving control
mice contained a median of 9.0 × 105 CFU/g of organ
weight. Culture data was fully evaluated for the amphotericin B
2.0-mg/kg/dose-QOD and itraconazole 75-mg/kg/dose-BID treatment groups (Table 1). Bacterial contamination of culture plates prevented evaluation of all organ homogenates for the
nikkomycin Z 100- and 20-mg/kg/dose-BID treatment groups. Two
mice were evaluable for lung homogenates and four mice were evaluable
for the spleen homogenates of the nikkomycin Z
20-mg/kg/dose-BID treatment group. Five mice that were evaluable in the
nikkomycin Z 100-mg/kg/dose-BID treatment group had median
quantitative cultures of 0 CFU/g in the spleen (Table
2). The results of the 1/10 dilution for
the lung homogenates were negative. To yield a positive result, this dilution would have required a minimum CFU of greater than or equal to
1.2 × 103/g. The nikkomycin Z
5-mg/kg/dose-BID treatment group was not evaluated due to overdilution
of the homogenates. The results of the 1/102 dilution for
lung and spleen were negative. At this dilution, a minimum CFU of
greater than or equal to 9.1 × 103/g for the lung and
greater than or equal to 1.9 × 104/g for the spleen
would have been required to yield a positive result. Reduction in
fungal burden was not as effective in the itraconazole
75-mg/kg/dose-BID and nikkomycin Z 20-mg/kg/dose-BID treatment groups as in the group treated with amphotericin B at 2.0 mg/kg/dose QOD (P < 0.05).
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TABLE 2.
Fungal burden in the lungs and spleen of mice that
survived to day 17 after infection with 5 × 105
CFU of H. capsulatum (isolate 2; nikkomycin Z
MIC, 4 µg/ml)
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|
Antigen levels were determined for all treatment groups (Table
2).
Untreated controls had a median antigen level of 13.6
EU in the lung
and 13.4 EU in the spleen. Similar results were
seen with the
itraconazole 75-mg/kg/dose-BID and nikkomycin Z
100- and
20-mg/kg/dose-BID treatment groups. Antigen levels in
the
nikkomycin Z 5-mg/kg/dose-BID treatment group were not
significantly
different than untreated controls with median antigen
levels in
the lung and spleen of 3.8 and 2.5 EU, respectively. Fungal
burden
studies showed that nikkomycin Z at 100 and 20 mg/kg/dose BID
and amphotericin B at 2.0 mg/kg/dose QD significantly
reduced
fungal burden in lung and spleen tissues as measured by
Histoplasma antigen levels in comparison to untreated
controls (
P < 0.05)
(Table
2).
| |
DISCUSSION |
By intratracheally infecting mice, this model imitates the
infectious process seen in humans after inhalation of H. capsulatum conidia. This route of inoculation results in diffuse
pulmonary infiltrates and subsequent dissemination to the liver and
spleen (6). The severity of infection in this model is
related to inoculum size and the immune status of the host (C. Schnizlein-Bick, M. Durkin, P. Connolly, S. Kohler, and J. Wheat, Program Abstr. 34th Ann. Meet. Infect. Dis. Soc. Am. 1996, abstr. 207, p. 74, 1996). H. capsulatum causes a
self-limited infection in immunocompetent animals exposed to a
lesser inoculum but a progressive fatal infection in mice administered
higher inocula or in those that are immunosuppressed (6, 9).
Similar features are seen in humans with histoplasmosis (15).
Nikkomycin Z was less active in vitro than amphotericin B or
itraconazole against H. capsulatum, with MICs ranging from 4 to 64 µg/ml. When studies were performed with isolate 1 (MIC, 64 µg/ml), nikkomycin Z at 100 mg/kg/dose BID was as
effective at preventing death as amphotericin B at 2.0 mg/kg/dose QOD
and itraconazole at 75 mg/kg/dose BID with 100% survival at day 14. However, nikkomycin Z at 100 mg/kg/dose BID was less
effective at reducing fungal burden in the lungs and spleen than either amphotericin B or itraconazole (Table 3).
Lower doses of nikkomycin Z were less effective at
preventing death or reducing fungal burden.
Studies with a second isolate which was more susceptible
(nikkomycin Z MIC, 4 µg/ml) showed nikkomycin
Z at all doses to be as effective as amphotericin B and itraconazole at
preventing mortality (Table 4). Antigens
in tissues of mice infected with isolate 2 showed a statistically
significant reduction in fungal burden for amphotericin B and
nikkomycin Z at 100 and 20 mg/kg/dose BID as compared to
the untreated controls, supporting the increased efficacy of
nikkomycin Z for this isolate (Table 2). Culture data could
not be fully evaluated for all treatment groups due to either
overdilution of organ homogenates or bacterial contamination of culture
plates. Culture data showed that nikkomycin Z at 100 mg/kg/dose BID in the spleen was as effective as amphotericin B at
reducing fungal burden. No culture data was available for the
nikkomycin Z 5-mg/kg/dose-BID treatment group. In earlier studies, we have shown that antigen detection yields results which approximate those obtained by culture, supporting the validity of the
data obtained in this experiment (2).
Two previous murine studies evaluating nikkomycin Z for
treatment of histoplasmosis yielded somewhat different results than those obtained in our study (8, 10). In contrast to our
model, these studies utilized an intravenous infection route, different laboratory isolates of H. capsulatum, and a treatment
protocol beginning on day-2 postinfection. Hector et al. showed that 5 mg/kg/dose of nikkomycin Z increased survival rates after
infection with 5 × 106 yeasts (MICs were not
reported). Fungal burden studies showed that nikkomycin Z
at 20 mg/kg/dose reduced CFU per gram in liver or spleen to levels
similar to those seen after treatment with fluconazole (10).
However, in unpublished studies in our laboratory, fluconazole was less
active than amphotericin B or itraconazole at reducing fungal burden. A
second study by Graybill et al, using an isolate for which the MIC of
nikkomycin Z was 0.5 µg/ml, showed a significant increase
in survival with nikkomycin Z administered at greater than
2.5 mg/kg/dose BID as compared to untreated controls (8).
Fungal burden studies showed nikkomycin Z at 2.5 mg/kg/dose BID to significantly reduce quantitative counts in liver and spleen tissue. These findings are consistent with our observations using the
more sensitive isolate.
In conclusion, nikkomycin Z at higher doses was as
effective as amphotericin B or itraconazole for the treatment of mice
infected with more-susceptible strains of H. capsulatum.
Susceptibility to nikkomycin Z, however, was highly
variable, with MICs for the agent of 16 µg/ml and higher in 40% of
the isolates.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Histoplasmosis
Reference Laboratory, 1001 W. Tenth Street, OPW 430, Indianapolis, IN 46202. Phone: (317) 630-6262. Fax: (317) 630-7522. E-mail:
lwheat{at}iupui.edu.
| |
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Abstract
Introduction
