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Antimicrobial Agents and Chemotherapy, April 1998, p. 873-878, Vol. 42, No. 4
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Efficacy of LY303366 against Amphotericin
B-Susceptible and -Resistant Aspergillus fumigatus in a
Murine Model of Invasive Aspergillosis
Paul E.
Verweij,1,*
Karen L.
Oakley,2
Jacqui
Morrissey,3
Graham
Morrissey,3 and
David
W.
Denning2,3
Department of Medical Microbiology,
University Hospital Nijmegen, Nijmegen, The
Netherlands,1 and
Department of
Medicine, Hope Hospital, Salford,2 and
University of Manchester,
Manchester,3 United Kingdom
Received 17 October 1997/Returned for modification 24 November
1997/Accepted 2 February 1998
 |
ABSTRACT |
LY303366 is a novel antifungal echinocandin with excellent in vitro
activity against Aspergillus spp. We compared four doses (1, 2.5, 10, and 25 mg/kg of body weight) of LY303366 with amphotericin B (0.5 to 5 mg/kg) in a temporarily neutropenic murine model of invasive aspergillosis against an amphotericin B-susceptible (AF210) and an amphotericin B-resistant (AF65) Aspergillus
fumigatus isolate based on in vivo response. Mice were
immunosuppressed with cyclophosphamide (200 mg/kg) and infected 3 days
later. Treatment started 18 h after infection and lasted for 10 days. LY303366 was given once daily intravenously for 10 days, and
amphotericin B (at 0.5, 2, and 5 mg/kg) was given once daily
intraperitoneally for 10 days, or only on days 1, 2, 4, and 7 (at 5 mg/kg). Kidneys and lungs from survivors were cultured on day 11. Control mice in both experiments had 90 to 100% mortality.
Amphotericin B at 0.5 mg/kg and LY303366 at 1 mg/kg yielded 10 to 20%
survival rates for mice infected with either AF210 or AF65.
Amphotericin B at 2 and 5 (both regimens) mg/kg yielded a 70 to 100%
survival rate for mice infected with AF210 but a 10 to 30% survival
rate for mice infected with AF65 (P = 0.01 to 0.04 compared with AF210). Against AF210 and AF65, LY303366 at 2.5, 10, and
25 mg/kg produced a survival rate of 70 to 80%, which was as effective
as amphotericin B for AF210, but superior to amphotericin B for AF65
(P < 0.03 to 0.0006). For AF65, LY303366 at 10 and 25 mg/kg/day was superior to amphotericin B at 2 and 5 mg/kg/day in
reducing tissue colony counts (P = 0.01 to 0.003), and
for AF210, amphotericin B at 5 mg/kg/day and at 5 mg/kg in four doses
was more effective than all four regimens of LY303366 in reducing renal
culture counts (P = 0.01 to 0.0001). The present study
shows, for the first time, that in vivo resistance of A. fumigatus to amphotericin B exists, although this could not be
detected by in vitro susceptibility assays. Furthermore, LY303366
appears to be effective against amphotericin B-susceptible and
-resistant A. fumigatus infection in this model and should be further evaluated clinically.
| |
INTRODUCTION |
Aspergillus fumigatus may
cause life-threatening infections in immunocompromised patients,
especially in those who receive treatment for hematological
malignancies. Although amphotericin B remains the standard therapy, a
successful outcome is achieved in only 34% of patients (7).
The success of treatment depends on many factors, most importantly on
the response of the underlying disease to therapy (7). The
majority of patients with invasive aspergillosis who die during
treatment with amphotericin B are persistently granulocytopenic due to
refractory underlying disease or receive a suboptimal dose due to
amphotericin B-related nephrotoxicity (11). Nevertheless,
some patients who are treated with an adequate dose of amphotericin B
and whose underlying immune deficiency is resolved fail to respond to
therapy. In these patients, treatment failure could be due to decreased
susceptibility of the fungus to amphotericin B. Since at present there
is no reproducible and meaningful in vitro assay for measuring the
susceptibility of A. fumigatus to amphotericin B, we
compared the in vivo susceptibilities of A. fumigatus
isolates cultured from patients with a clinically documented favorable
response or failure to respond to treatment with amphotericin B
desoxycholate. In addition, the efficacy of a new antifungal
echinochandin, LY303366, against these isolates was determined and
compared to that of amphotericin B. Echinocandins and pneumocandins are
a new class of drugs with antifungal activity. The drugs specifically
inhibit (1,3)-
-D-glucan synthetase, an enzyme complex
that forms glucan polymers in the fungal cell wall (5).
Fungi with (1,3)--D-glucans in their cell walls,
including Candida species, Aspergillus species,
and Pneumocystis carinii, are susceptible to echinocandins,
although the full spectrum of activity has not yet been established. In
the present study the efficacy of LY303366 was compared with that of
amphotericin B in a temporarily neutropenic murine model of invasive
aspergillosis which has been used previously to evaluate the in vivo
efficacies of antifungal agents (8, 9, 13, 18).
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MATERIALS AND METHODS |
Aspergillus isolates.
Both isolates used for the
studies were typical A. fumigatus isolates from clinical
sources. Strain AF65 was cultured from a lung biopsy from a leukemic
patient who showed no clinical improvement with therapy with
amphotericin B and whose infection subsequently recurred. Strain AF210
was cultured from the abdominal viscera from a surgical patient who
developed an Aspergillus wound infection following
laparotomy and who responded to conventional amphotericin B treatment
without change of immune status (3). These isolates have
been deposited at the National Collection of Pathogenic Fungi (Bristol,
United Kingdom) under no. NCPF 7097 (AF65) and NCPF 7101 (AF210).
In vitro studies.
A loopful of frozen stock was streaked on
a Sabouraud glucose agar plate (Lab M, Bury, United Kingdom) and
incubated at 35°C until sporulation occurred. The MIC and minimal
fungicidal concentration (MFC) of amphotericin B were determined by a
broth microdilution method using RPMI 1640 agar with 2% glucose as
previously described (6). A typical MIC end point is not
seen when LY303366 is tested against Aspergillus species.
Instead, there is a transition from a homogeneous mat of long, thin
hyphae to subspherical colonies in wells; most of the colonies are
attached to the bottom of the microtiter well. Therefore, a minimal
effective concentration (MEC), taken as the concentration in the first
well to contain the small subspherical colonies with no hyphal growth,
was used. The MEC and MFC of LY303366 were determined by the broth
microdilution method using antibiotic medium 3 (Difco, Detroit, Mich.)
and Casitone medium (Difco), since no reference medium has yet been
established for the in vitro testing of echinocandins (5).
Preparation of inocula.
The inocula were prepared by
culturing the organisms on potato glucose agar (Oxoid, Basingstoke,
United Kingdom) for 10 days at 35°C. Conidia were collected in
sterile 0.9% phosphate-buffered saline containing 0.01% Tween 80 (PBS-Tween) and were stored at 4°C. The viability of the conidial
suspension was determined by serial dilutions in PBS-Tween, and the
suspension was subcultured onto horse blood agar plates. The inoculum
was stored at 4°C until the day of infection (always a Monday).
Further adjustments to the inoculum, if necessary, were made just prior
to infection of the mice.
Drugs and therapy regimens.
Amphotericin B desoxycholate
(Fungizone; Squibb, Middlesex, United Kingdom), was given in 5%
glucose intraperitoneally. For each isolate, groups of 10 mice were
treated with 0.5, 2, or 5 mg of amphotericin B/kg of body weight/day by
once-daily injection in 0.1 ml. One group was treated with 5 mg of
amphotericin B/kg/day in four doses, one on each of days 1, 2, 4, and
7. Furthermore, groups of 10 mice were treated with 1, 2.5, 10, or 25 mg of LY303366 (Eli Lilly, Indianapolis, Ind.)/kg/day by once-daily
injection in 0.1 ml in a lateral tail vein. A solution of 2.5%
(wt/vol) Polysorbate 80, which is used as a solvent for LY303366, was
used for the controls in a concentration equal to that found in the highest concentration of LY303366 used. Intraperitoneal injections with
glucose served as controls for treatment with amphotericin B. Cages
were randomly sorted after infection, and treatment groups were
assigned by cage number. For all groups, treatment commenced 18 h
postinfection and continued for 10 days.
Mice.
Virus-free male CD-1 mice (age, 5 weeks) were
purchased from Charles River UK, Ltd. Mice were weighed on the day the
experiment commenced (range, 20.3 to 26.9 g), reassorted, and
grouped 10 to a cage. The mice were allowed food and water ad libitum.
Immunosuppression.
Mice received cyclophosphamide (C-7397;
Sigma, Dorset, United Kingdom) at 200 mg/kg administered intravenously
3 days prior to challenge as described previously (8).
Infection.
A conidial suspension of 0.1 ml of 5 × 106 conidia of AF65/ml or 1.7 × 106
conidia of AF210/ml was injected into lateral tail veins. The 90%
lethal doses (LD90) for these isolates had been determined previously in inoculum-finding studies (11a). Dilutions of
this inoculum were streaked out on horse blood agar plates and counted over 48 h of incubation at 35°C. These showed that mice infected with AF65 had received 4.4 × 106 CFU, and those given
AF210 were infected with 1.9 × 106 CFU.
Cultures.
Surviving mice were killed by cervical dislocation
on day 11. Both lungs and kidneys were removed and placed into 5 ml of sterile PBS containing penicillin (100 IU/ml) and streptomycin (100 µg/ml) and were then homogenized in a tissue grinder (Kinematica, Lucerne, Switzerland) for 15 to 30 s. Three 10-fold serial
dilutions were made, and 0.5 ml of each dilution was plated onto
Sabouraud's agar. The plates were incubated at 35°C, and colonies
were counted daily for 7 days.
Statistics.
Survival and quantitative culture were compared
by the Mann-Whitney rank sum test. Qualitative culture results were
examined by Fisher's exact test. Mice which died before day 11 were
assumed to have quantitative counts in their organs at least as high as the highest counts in the organs of any surviving mice. All analyses were performed with the computer package Minitab (Minitab Data Analysis
Software, Philadelphia, Pa.).
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RESULTS |
In vitro susceptibility.
The results of in vitro
susceptibility testing, shown in Table 1,
indicated that there was no significant difference between A. fumigatus isolates AF65 and AF210 in in vitro susceptibility to
amphotericin B or LY303366.
Treatment efficacy against isolate AF210.
An LD90
to LD100 was achieved for both intravenously and
intraperitoneally injected control mice infected with A. fumigatus isolate AF210, indicating that the model was
reproducible. There was no difference in survival or in lung and renal
colony counts between intravenously and intraperitoneally injected
control mice (Tables 2 and
3). All treatment groups showed a
significant increase in mouse survival (Table 2), although the
lowest-dosage treatment groups for amphotericin B and LY303366, i.e.,
0.5 and 1 mg/kg/day, respectively, showed no significant decrease in
tissue colony counts compared to those of control mice (Table 3).
Dosages of 2.5, 10, and 25 mg of LY303366/kg/day were as effective in improving survival as 2 and 5 mg of amphotericin B/kg/day and 5 mg of
amphotericin B/kg in four doses (Table 2). For both drugs there was no
apparent dose-response relationship. Although the three highest-dosage
regimens of amphotericin B and LY303366 significantly reduced the
tissue colony counts compared to controls, amphotericin B at 5 mg/kg in
four doses and at 5 mg/kg/day was superior to all dosage regimens of
LY303366 in reducing renal colony counts (Table
4). There was no significant difference
between the different treatment groups in the number of infected organs
(data not shown).
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TABLE 2.
Survival times for mice infected with A. fumigatus AF210 or AF65 and treated with amphotericin B
or LY303366
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TABLE 4.
Efficacy of amphotericin B compared with that of LY303366
in reducing tissue colony counts for mice infected with A. fumigatus AF210 or AF65a
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Treatment efficacy against isolate AF65.
An LD90
to LD100 of A. fumigatus AF65 was achieved for
control mice, and there was no difference in survival or in lung and renal colony counts between intravenously and intraperitoneally injected control mice (Tables 2 and 3). Mice treated with amphotericin B (all regimens) showed no improvement in survival compared to the
controls (Table 2) and no significant reduction in tissue colony counts
(Table 3). Mice treated with LY303366 at 2.5, 10, or 25 mg/kg/day
showed a significant increase in survival (Table 2), and the tissue
colony counts were significantly reduced compared to those of controls
(Table 3). LY303366 at 2.5, 10, and 25 mg/kg/day was superior to
amphotericin B therapy in improving survival (Table 2). Moreover, these
dosage regimens of LY303366 reduced tissue colony counts significantly
better than amphotericin B at 2 and 5 mg/kg/day (Table 4). There was no
significant difference among the different treatment groups in the
number of infected organs (data not shown).
Comparison of experiments.
Median survival for control mice
intravenously infected with AF210 was not significantly different from
that of those intravenously infected with AF65 (Table 2). However, the
median survival for control mice intraperitoneally infected with AF65
was longer than that for those intraperitoneally infected with AF210,
and this difference just reached statistical significance
(P < 0.05). For both groups of mice, those infected
with A. fumigatus isolate AF210 and those infected with
A. fumigatus isolate AF65, the efficacies of treatment with
amphotericin B and with LY303366 are shown in Fig.
1 and 2,
respectively. There was a statistically significant difference in
median survival between mice infected with AF210 and those infected
with AF65 for groups treated with amphotericin B at 2 and 5 mg/kg/day
and at 5 mg/kg in four doses, but not for any groups treated with
LY303366 (Table 2).
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FIG. 1.
Survival for CD-1 mice infected with isolate AF210 (A)
or AF65 (B) and treated with amphotericin B at 0.5 mg/kg/day ( ), 2 mg/kg/day ( ), 5 mg/kg given on days 1, 2, 4, and 7 ( ), or 5 mg/kg/day ( ), or given dextrose intraperitoneally (*).
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FIG. 2.
Survival for CD-1 mice infected with isolate AF210 (A)
or AF65 (B) and treated with LY303366 at 1 mg/kg/day ( ), 2.5 mg/kg/day ( ), 10 mg/kg/day ( ), or 25 mg/kg/day ( ), or given
2.5% (wt/vol) Polysorbate 80 solvent intravenously (*).
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DISCUSSION |
Although amphotericin B has been used for treating fungal
infections in humans for more than 40 years, resistance to the drug has
rarely been reported. Clinical resistance to amphotericin B has been
documented for several Candida species, including
Candida albicans (4, 14, 21), C. glabrata (21), C. tropicalis (21, 24,
30), C. lusitaniae (2, 19, 21), C. guilliermondii (10, 21), and C. krusei
(24). In some cases, in vitro susceptibility testing results
correlated with treatment outcome, but there is considerable variation
in breakpoints, which range from 0.8 to >100 µg/ml (2, 10, 19,
21, 23). C. parapsilosis has been shown to be tolerant
for amphotericin B, since the MFC was more than 32-fold higher than the
MIC (26). In some cases, resistance to amphotericin B was
shown to emerge during treatment with the drug (10, 19). The
frequency of resistance is not well known, although a recent study
found a prevalence of approximately 1% among more than 600 Candida isolates (16).
Amphotericin B resistance among fungi has been shown for clinically
resistant organisms, such as Trichosporon beigelii
(29), Fusarium species (1),
zygomycetes (12), and Pseudallescheria boydii
(17). Resistance among Aspergillus species is
very rare, although resistance to polyenes has been reported in
laboratory strains of A. nidulans (32) and
A. fennelliae (15). Amphotericin B was found to
have lost its in vitro activity against six A. fumigatus
isolates after these isolates were exposed to subfungicidal concentrations of itraconazole (25), which may be due to
antagonism between the two antifungal drugs. Our study provides, for
the first time, evidence of differential activity of amphotericin B
against two different A. fumigatus isolates examined under
highly controlled, stringent therapeutic conditions. Our murine model, with some variations, has been used extensively to evaluate the efficacy of several novel antifungal compounds (8, 9, 13, 18) and for the development of meaningful and reproducible in vitro assays for susceptibility testing of antifungal azoles
(6). The amphotericin B-resistant isolate AF65 may be less
virulent than isolate AF210, since a threefold higher inoculum of AF65 was needed to achieve comparable mortality for both isolates. Furthermore, the median survival of intraperitoneally injected control
mice infected with AF65 was longer than that for those infected with
isolate AF210 (P = 0.04). Nevertheless, amphotericin B
showed significantly reduced activity in mice infected with isolate
AF65.
The low frequency of secondary resistance of fungi to amphotericin B
has been thought to be due to the complex interaction between
amphotericin B and the plasma membrane, disruption of which would
require multiple changes (27, 28). Furthermore, membrane
alterations that can lead to decreased sensitivity to amphotericin B
may also reduce virulence (27, 28), which was also apparent
in the resistant isolate we used. However, amphotericin B resistance
among A. fumigatus isolates may be difficult to detect, since we were unable to confirm the observed in vivo resistance by use
of standard in vitro susceptibility tests. Therefore, the frequency of
resistance is unknown. It is clear that meaningful in vitro assays to
detect amphotericin B resistance among A. fumigatus isolates
need to be developed in the near future. The finding of in vivo
resistance provides the first step in developing such an assay, an
approach that has been followed successfully in developing an in vitro
assay for antifungal azoles (6).
The demonstration of resistance to amphotericin B among A. fumigatus isolates underscores the need for the development and evaluation of novel compounds with antifungal activity. In the present
study, we evaluated the efficacy of the echinocandin LY303366, which is
a member of a new class of antifungal agents active against a wide
range of fungal pathogens. The mode of action involves noncompetitive
inhibition of (1,3)--D-glucan synthase, an enzyme complex that forms glucan polymers in the fungal cell wall
(5). The compound is active against fungi which contain this
enzyme complex in their cell walls, such as Candida species,
P. carinii, and A. fumigatus, but not against
Cryptococcus neoformans, as this pathogen has little or no
(1,3)--D-glucan synthase enzyme (5). LY303366
is a compound which is derived from the echinocandin B nucleus and is
active in vitro against Candida species including C. glabrata and C. krusei, and against azole-resistant
C. albicans (20, 22, 31). The in vitro activity
of LY303366 against A. fumigatus is difficult to access by
the methods presently available, since end points are subjective and
difficult to read (18a). The efficacy of LY303366 in
increasing survival was comparable to that of amphotericin B for mice
infected with the amphotericin B-susceptible A. fumigatus
isolate AF210, although amphotericin B was superior in reducing the
fungal burden in the kidneys. However, LY303366 was superior to
amphotericin B in increasing survival and reducing tissue colony counts
in mice infected with A. fumigatus AF65. The present study
indicates that LY303366 has potentially useful activity against both
amphotericin B-susceptible and -resistant A. fumigatus
isolates in a murine model of invasive aspergillosis, and therefore
further clinical evaluation of this compound is warranted.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Medical Microbiology, University Hospital Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: 31-24-3614356. Fax: 31-24-3540216. E-mail: p.verweij{at}mmb.azn.nl.
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Antimicrobial Agents and Chemotherapy, April 1998, p. 873-878, Vol. 42, No. 4
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Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
