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Antimicrobial Agents and Chemotherapy, March 2000, p. 614-618, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Efficacy of FK463, a New Lipopeptide Antifungal
Agent, in Mouse Models of Disseminated Candidiasis and
Aspergillosis
Fumiaki
Ikeda,1,*
Yoshimi
Wakai,1
Satoru
Matsumoto,1
Katsuyuki
Maki,1
Etsuko
Watabe,1
Shuichi
Tawara,1
Toshio
Goto,1
Yuji
Watanabe,2
Fumio
Matsumoto,3 and
Shogo
Kuwahara4
Medicinal Biology Research
Laboratories1 and Research
Planning,2 Fujisawa Pharmaceutical Co., Ltd.,
Kashima, Yodogawa-ku, Osaka 532-8514, Kanagawa Prefectural
Nursing and Hygienic School Hospital, 1-6, Shiomidai, Isogo-ku,
Yokohama 235-0022,3 and Toho University
School of Medicine, Ohmori Nishi, Ohta-ku, Tokyo
143-8540,4 Japan
Received 3 May 1999/Returned for modification 26 July 1999/Accepted 10 December 1999
 |
ABSTRACT |
The efficacy of intravenous injection of FK463, a novel
water-soluble lipopeptide, was evaluated in mouse models of
disseminated candidiasis and aspergillosis and was compared with those
of fluconazole (FLCZ) and amphotericin B (AMPH-B). In the candidiasis
model, FK463 significantly prolonged the survival of intravenously
infected mice at doses of 0.125 mg/kg of body weight or higher. In
disseminated candidiasis caused by Candida species,
including FLCZ-resistant Candida albicans, FK463 exhibited
an efficacy 1.4 to 18 times inferior to that of AMPH-B, with 50%
effective doses (ED50s) ranging from 0.21 to 1.00 mg/kg and
0.06 to 0.26 mg/kg, respectively, and was much more active than FLCZ.
The protective effect of FK463 was not obviously influenced by the
fungal inoculum size, the starting time of the treatment, or the
immunosuppressed status of the host. The reduction in efficacy was less
than that observed with FLCZ or AMPH-B. The efficacy of FK463 was also
evaluated in the disseminated candidiasis target organ assay and was
compared with those of FLCZ and AMPH-B. Efficacies were evaluated on
the basis of a comparison between the mean log10 CFU in
kidneys in the groups treated with antifungal agents and that in
control group. A single dose of FK463 at 0.5 mg/kg or higher
significantly reduced the viable counts in kidneys compared with the
numbers of yeast cells before treatment, and its efficacy was
comparable to that of AMPH-B, while FLCZ at 4 mg/kg showed only a
suppressive effect on the growth of C. albicans in the
kidneys. In the disseminated aspergillosis model, FK463 given at doses
of 0.5 mg/kg or higher significantly prolonged the survival of mice
infected intravenously with Aspergillus fumigatus conidia.
The efficacy of FK463 was about 2 times inferior to that of AMPH-B,
with ED50s ranging from 0.25 to 0.50 mg/kg and 0.11 to 0.29 mg/kg, respectively. These results indicate that FK463 may be a potent
parenterally administered therapeutic agent for disseminated
candidiasis and aspergillosis.
| |
INTRODUCTION |
People who have impaired immune
systems are susceptible to fungal infections which can be
life-threatening. Immune deficiencies resulting from AIDS, aggressive
cancer treatment, the growing use of organ transplants, and other
nosocomial situations have greatly increased the incidence of serious
fungal infections (2, 3, 4, 6) and have created a critical
need for new, safe fungicidal agents that can be used to treat
disseminated infections. Systemic mycoses are not easily diagnosed, and
the patient usually has been infected for quite some time before
symptoms appear. Thus, empiric therapy needs to begin immediately, but
currently available treatments have problems with toxicity or
resistance. Amphotericin B (AMPH-B) is the first-line therapy for
systemic infections because of its broad-spectrum and fungicidal
activity. However, significant side effects limit its clinical utility
to controlled intravenous administration (16). Lipid AMPH-B
formulations have recently attracted much attention due to
significantly lower toxicity (7). The azole antifungal
agents have broad spectra of activity, are orally active, and are
considered less toxic than AMPH-B but are only fungistatic against most
major fungal pathogens. Resistance to azole antifungals has been
reported recently in several types of fungal infections worldwide
(8, 15).
FK463 is a new parenterally administered antifungal drug candidate
undergoing clinical development. FK463 is a semisynthetic derivative of
FR901379, a water-soluble cyclic hexapeptide with a fatty acyl side
chain, which is similar in structure to the echinocandin class of
antifungal agents (T. Iwamoto, N. Sakamoto, M. Yamashita, M. Ezaki, S. Hashimoto, T. Furuta, M. Okuhara, and M. Kohsaka, Prog. Abstr. 33rd
Intersci. Conf. Antimicrob. Agents Chemother., abstr. 371, 1993).
Modification of FR901379 improved antifungal potencies. FK463 has been
shown to have potent in vitro antifungal activity against
Candida and Aspergillus species (K. Maki, Y. Morishita, Y. Iguchi, E. Watabe, K. Otomo, N. Teratani, Y. Watanabe, F. Ikeda, S. Tawara, T. Goto, M. Tomishima, H. Ohki, A. Yamada, K. Kawabata, H. Takasugi, H. Tanaka, K. Sakane, F. Matsumoto, and S. Kuwahara, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother.,
abstr. F141, p. 268, 1998). FK463 is an inhibitor of synthesis of
1,3-
-D-glucan, a critical structural cell wall component
in certain pathogenic fungi (5; Maki et al., 38th ICAAC). In the study described in this report, the in vivo activity of
FK463 was evaluated in mouse models of disseminated candidiasis and aspergillosis.
| |
MATERIALS AND METHODS |
Compounds.
FK463 was synthesized by Fujisawa Pharmaceutical
Co., Ltd. AMPH-B and fluconazole (FLCZ) were purchased from
Bristol-Myers Squibb (Tokyo, Japan) and Pfizer (Tokyo, Japan),
respectively. FK463, AMPH-B, and FLCZ were formulated in sterile saline
or 5% glucose for intravenous injection and injected as 10 ml/kg of body weight.
Animals.
Male Slc-ICR mice (age, 4 weeks) were purchased
from SLC Japan (Shizuoka, Japan). Eight mice were allocated to each
dosage level.
Organisms and media.
The strains of Candida
species were cultured on Sabouraud dextrose agar (SDA). Each test
strain was suspended in sterile saline, and the inoculum was
standardized by spectrophotometer. The inocula of Aspergillus
fumigatus strains were prepared by culturing the test organisms on
potato dextrose agar. Conidia were collected in sterile saline, and the
conidium concentration was standardized by spectrophotometer. The
viable counts of test strains were confirmed by serially diluting the
cell suspension 10-fold and plating the inoculum onto SDA plates.
MICs.
The MICs of FK463, FLCZ, and AMPH-B were determined
according to guideline M27-A of the National Committee for Clinical
Laboratory Standards (NCCLS) (Maki et al., 38th ICAAC).
Systemic mouse infection.
Disseminated candidiasis and
aspergillosis were induced in ICR mice by the intravenous inoculation
of 0.2 ml of a cell suspension of each test strain via their lateral
tail veins. Cyclophosphamide (Acros Organics, Springfield, N.J.) was
administered intraperitoneally at 200 mg/kg 4 days before infection for
A. fumigatus TIMM0063; 4 days before and 1 day after
infection for the Candida albicans strains, C. tropicalis, C. krusei, C. parapsilosis, and
A. fumigatus IFM41209; and 4 days before and 1 day and 6 days after infection for C. glabrata.
For the experiment on the influence of immunosuppression on efficacy
against disseminated candidiasis, mice received either cyclophosphamide
at 200 mg/kg administered intraperitoneally 4 days before and 1 day
after infection or hydrocortisone (Nacalai Tesque, Kyoto, Japan) at 100 mg/kg administered subcutaneously 1 day before and 3 h, 1 day, and
2 days after infection to induce a continuously immunosuppressed
condition in the host. The immunosuppressed and normal mice were
challenged intravenously with a saline suspension of C. albicans FP633, containing 1.9 × 106 CFU for
normal mice, 3.1 × 104 CFU for
cyclophosphamide-treated mice, and 1.3 × 105 CFU for
hydrocortisone-treated mice.
Treatment regimens.
The antifungal agents were administered
once daily or twice daily for 4 days, starting at 1 h after
infection by intravenous injection. The regimens used for the influence
of the starting time of treatment on efficacy against disseminated
candidiasis were as follows: (i) once daily for 4 days starting at
1 h after infection and (ii) once daily for 3 days starting at
24 h after infection. The efficacies of antifungal agents were
assessed as the 50% effective doses (ED50), calculated by
probit analysis or normal probability plot based on the survival rate
at 15 days after infection.
Target organ assays.
Disseminated candidiasis was induced by
the intravenous inoculation of a 0.2-ml saline suspension containing
1.0 × 105 CFU of C. albicans FP633 into
the lateral tail veins of mice. Cyclophosphamide was administered
intraperitoneally at 200 mg/kg 4 days before infection, and the
antifungal agents were administered intravenously 1 h after
infection. The target organ assay for C. albicans monitors
the number of CFU in the kidneys at 1 day after infection. Kidneys from
sacrificed mice were removed and placed in glass vials containing 10 ml
of sterile saline. The kidneys were homogenized and were serially
diluted in saline, and aliquots were plated onto SDA plates. The plates
were incubated at 37°C for 2 days.
Statistics.
Survival was compared by the Wilcoxon rank sum
test. One-way layout analysis of variance and the Dunnet t
test were used to compare numbers of cells in the kidney for the
treatment groups and the control group.
| |
RESULTS |
Efficacy in the C. albicans and A. fumigatus disseminated infection survival models.
Survival
curves in the C. albicans disseminated infection model are
illustrated in Fig. 1. All untreated
infected control mice died within 13 days. FK463 significantly
prolonged the survival of infected mice at doses of 0.125 mg/kg or
higher. All of the infected mice could survive as long as 22 days when
treated with FK463 at 1.0 mg/kg. Survival curves in the A. fumigatus disseminated infection model are illustrated in Fig.
2. All untreated infected control mice
died within 5 days. FK463 levels at or greater than 0.5 mg/kg
significantly prolonged the survival of infected mice. All of the
infected mice treated with 1.0 mg/kg of FK463 survived at day 22 after
challenge.
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FIG. 1.
Efficacy of FK463 in disseminated C. albicans
16010 infection (intravenous challenge with 4.0 × 105
CFU/mouse) in ICR mice (cyclophosphamide was administered
intraperitoneally at 200 mg/kg 4 days before and 1 day after
infection). FK463 was administered intravenously once daily for 4 days,
starting at 1 h after infection. Symbols:  , 1.0 mg/kg;  , 0.5 mg/kg;  , 0.25 mg/kg;  , 0.125 mg/kg;  , 0.0625 mg/kg;  , sham
treatment; *, significantly different from the control (P < 0.01 by the Wilcoxon rank sum test).
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FIG. 2.
Efficacy of FK463 in disseminated A. fumigatus IFM41209 infection (intravenous challenge with 3.4 × 104 CFU/mouse) in ICR mice (cyclophosphamide was
administered intraperitoneally at 200 mg/kg 4 days before and 1 day
after infection). FK463 was administered intravenously once daily for 4 days, starting at 1 h after infection. Symbols: , 1.0 mg/kg;
, 0.5 mg/kg; , 0.25 mg/kg; , 0.125 mg/kg; , sham treatment;
*, significantly different from the control (P < 0.01 by the Wilcoxon rank sum test).
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Comparative efficacy studies in disseminated candidiasis and
aspergillosis.
The efficacy of FK463 against disseminated fungal
infection was compared with those of AMPH-B and FLCZ. The MICs of
FK463, FLCZ, and AMPH-B against the test organisms used in these
studies are presented in Table 1. Table
2 shows the ED50 calculated on the basis of the survival rate at 15 days after infection. The
ED50 of FK463 against disseminated infections with C. albicans, C. glabrata, C. tropicalis, and
C. krusei ranged from 0.14 to 0.77 mg/kg. Although the
efficacies of FK463 were 1.4 to 3.1 times inferior to those of AMPH-B
(0.09 to 0.26 mg/kg), they were 9.6 to >77 times superior to those of
FLCZ. The ED50 of FK463 against disseminated C. parapsilosis infection was 1.0 mg/kg, which was 11 times superior
to that of FLCZ (10.9 mg/kg) and 18 times inferior to that of AMPH-B
(0.06 mg/kg). The ED50 of FK463 and AMPH-B given twice
daily (BID) against C. albicans FP633 were comparable to once daily treatment (UID), but for FLCZ, twice daily treatment was
slightly superior to once daily treatment (Table 2).
FK463 showed good activity against disseminated
A. fumigatus
infection, with ED
50 in the range of 0.25 to 0.50 mg/kg.
The
efficacies of FK463 were 1.7 to 2.3 times inferior to those of
AMPH-B (0.11 to 0.29 mg/kg) and >80 times superior to those of
FLCZ.
Efficacy in immunosuppressed mouse models of disseminated
candidiasis.
Table 3 shows the
ED50 of FK463 and other antifungal agents against
disseminated C. albicans infection models using normal mice
and mice in a state of continuous immunosuppression induced by
cyclophosphamide (200 mg/kg; intraperitoneal administration) or
hydrocortisone (100 mg/kg; subcutaneous administration). Although the
efficacies of FK463 were reduced to 1/2.2 to 1/3.5 in continuously immunosuppressed mice compared to normal mice, FK463 showed good activity in both types of immunosuppressed mice, with ED50
of 0.28 to 0.45 mg/kg. The reduction in the efficacy of FK463 was less
than that observed for FLCZ (efficacy reduced to 1/2.6 to 1/9.9) and
AMPH-B (efficacy reduced to 1/3.2 to 1/5.6).
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TABLE 3.
Influence of immunosuppression and starting time of
treatment on efficacy of FK463 in mouse models of
disseminated candidiasis
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|
Influence of starting time of treatment on efficacy in mouse models
of disseminated candidiasis.
To investigate the influence of the
starting time of treatment on the efficacy of FK463 and other
antifungal agents against C. albicans disseminated
infection, compounds were administered intravenously starting at 1 or
24 h after infection (Table 3). The protective effect of FK463 was
reduced to 1/1.3 with the delay of the starting of treatment, while the
reduction of efficacy was less than that observed for FLCZ (reduced to
1/3.1) or AMPH-B (reduced to 1/3.1).
Target organ assays.
FK463 and other antifungal agents were
tested for their activities in reducing the numbers of recoverable
yeast cells from the kidneys of mice challenged intravenously with
C. albicans FP633. The antifungal agents were administered
once, at 1 h postinfection. Table 4
shows the viable counts of yeast cells in kidneys at 1 day after
infection. FK463 significantly reduced the counts of yeast cells
recovered from the kidneys when it was administered intravenously at
doses of 0.5 mg/kg or higher, and its efficacy was comparable to that
of AMPH-B. FLCZ at a dose of 4 mg/kg did not reduce the counts in the
kidneys compared with the numbers of yeast cells before treatment.
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TABLE 4.
Effect of single administration of FK463 on fungal titers
in the kidneys of mice in the disseminated C. albicans
infection model
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| |
DISCUSSION |
FK463 appears to possess a good profile as a new antifungal agent,
displaying potent activity against clinically important fungal
pathogens, good water solubility, favorable pharmacokinetic properties,
and low toxicity (J. Azuma, I. Yamamoto, M. Ogura, T. Mukai, H. Suematsu, H. Kageyama, H. Nakahara, K. Yoshida, and T. Takaya, Abstr.
38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F146, p.
269, 1998; Maki et al., 38th ICAAC; S. Matsumoto, Y. Wakai, K. Maki, E. Watabe, T. Ushitani, K. Otomo, T. Nakai, Y. Watanabe, F. Ikeda, S. Tawara, T. Goto, F. Matsumoto, and S. Kuwahara, Abstr. 38th Intersci.
Conf. Antimicrob. Agents Chemother., abstr. F142, p. 268, 1998; S. Suzuki, M. Terakawa, F. Yokobayashi, F. Fujiwara, and T. Hata, Abstr.
38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F144, p.
269, 1998; Y. Wakai, S. Matsumoto, K. Maki, E. Watabe, K. Otomo, T. Nakai, K. Hatano, Y. Watanabe, F. Ikeda, S. Tawara, T. Goto, F. Matsumoto, and S. Kuwahara, Abstr. 38th Intersci. Conf. Antimicrob.
Agents Chemother., abstr. F143, p. 268, 1998). In this study, the
efficacy of intravenous injection of FK463 and other antifungal agents
was investigated in mouse models of disseminated Candida and
Aspergillus infection, since these compounds are
administered by intravenous infusion in clinical settings.
The efficacy of FK463 in a multiple-dosage regimen against disseminated
fungal infection was compared with those of AMPH-B and FLCZ. The
efficacy of FK463 against disseminated infections with
Candida species, except C. parapsilosis, was 1.4 to 3.1 times inferior to that of AMPH-B, and it was obviously superior
to that of FLCZ. Although the efficacy of FK463 against disseminated
C. parapsilosis infection was 11 times superior to that of
FLCZ, it was 18 times inferior to that of AMPH-B. These results were correlated with the MICs of FK463 against C. parapsilosis,
which were higher than those against C. albicans (Maki et
al., 38th ICAAC).
The half-life (t1/2) and area under the
concentration-time curve (AUC) for FK463 at 1 mg/kg in mice were
5.8 h and 48 µg · h/ml (Suzuki et al., 38th ICAAC),
respectively, and the levels of FK463 in the plasma of mice were higher
than those of FLCZ and AMPH-B (10, 11). These data indicated
that the ED50 of FK463 against disseminated candidiasis in
mice, except for C. parapsilosis infection, were not related
to the in vitro MICs in comparison to those of AMPH-B. These results
suggest that high protein binding of FK463 (Suzuki et al., 38th ICAAC)
may reduce the in vivo efficacy. Once daily treatment with FLCZ in
disseminated candidiasis displayed a relative lack of efficacy in
comparison to twice daily treatment, and the best regimen for mice is
twice daily treatment, due to rapid excretion. However, our data
indicated that, due to the excellent fungicidal activities of FK463,
both once daily treatment and twice daily treatment with FK463 were obviously superior to comparable treatment with FLCZ.
The protective effect of FK463 against disseminated C. albicans infection was not obviously influenced by the starting
time of the treatment and the immunosuppressed status of the host. The
reduction in efficacy was less than that observed with FLCZ or AMPH-B.
Furthermore, the ability of a single dose of FK463 to sterilize the
kidneys of mice was superior to that of FLCZ and comparable to that of
AMPH-B. The fungicidal activity of FK463 against C. albicans
appears to contribute to this favorable in vivo activity (Maki et al.,
38th ICAAC).
LY303366 and MK0991 have been reported to inhibit the hyphal elongation
of A. fumigatus and have profound morphological effects, although they do not give MICs for Aspergillus species in a
classic broth dilution assay (9, 12, 14, 18). These
compounds have been shown to be effective in experimental disseminated
and pulmonary aspergillosis models in rodents (1, 13, 17). FK463 did not completely inhibit the growth of A. fumigatus
in the broth microdilution assay, but it showed a suppressive effect on
hyphal growth and a morphological effect (Maki et al., 38th ICAAC),
similar to pneumocandins. The efficacy of FK463 against disseminated
aspergillosis was in excellent correlation with its partial inhibitory
effect on growth at low concentrations, although it was slightly
inferior to that of AMPH-B.
In conclusion, the present data suggest that FK463 is efficacious in
the treatment of disseminated candidiasis and aspergillosis, and
further studies to evaluate the compound should be considered.
| |
ACKNOWLEDGMENT |
We are grateful to David Barrett, Medicinal Chemistry Research
Laboratories, for kind help and advice.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Infectious Diseases, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 1-6, 2-Chome, Kashima, Yodogawa-Ku, Osaka
532-8514, Japan. Phone: 81-6-6390-1158. Fax: 81-6-6304-5367. E-mail:
fumiaki_ikeda{at}po.fujisawa.co.jp.
| |
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Antimicrobial Agents and Chemotherapy, March 2000, p. 614-618, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
