The in vitro antifungal activity and spectrum of FK463 were compared with those of amphotericin B, fluconazole, and itraconazole by using a broth microdilution method specified by National Committee for Clinical Laboratory Standards document M27-A (National Committee for Clinical Laboratory Standards, Wayne, Pa., 1997). FK463 exhibited broad-spectrum activity against clinically important pathogens including Candida species (MIC range, Ϲ0.0039 to 2 g/ml) and Aspergillus species (MIC range, Ϲ0.0039 to 0.0313 g/ml), and its MICs for such fungi were lower than those of the other antifungal agents tested. FK463 was also potently active against azole-resistant Candida albicans as well as azole-susceptible strains, and there was no cross-resistance with azoles. FK463 showed fungicidal activity against C. albicans, i.e., a 99% reduction in viability after a 24-h exposure at concentrations above 0.0156 g/ml. The minimum fungicidal concentration (MFC) assays indicated that FK463 was fungicidal against most isolates of Candida species. In contrast, the MFCs of FK463 for A. fumigatus isolates were much higher than the MICs, indicating that its action is fungistatic against this species. FK463 had no activity against Cryptococcus neoformans, Trichosporon species, or Fusarium solani. Neither the test medium (kind and pH) nor the inoculum size greatly affected the MICs of FK463, while the addition of 4% human serum albumin increased the MICs for Candida species and A. fumigatus more than 32 times. Results from preclinical in vitro evaluations performed thus far indicate that FK463 should be a potent parenteral antifungal agent.
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 (ED 50 s) 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 log 10 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 ED 50 s 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.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 broadspectrum 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 toxic...
The efficacy of FK463, a novel water-soluble lipopeptide, was evaluated in mouse models of pulmonary aspergillosis and was compared with that of amphotericin B (AMPH-B). In the pulmonary aspergillosis models induced by intranasal inoculation, FK463 exhibited good efficacy, with 50% effective doses in the range of 0.26 to 0.51 mg/kg of body weight; these values were comparable to those of AMPH-B. In an Aspergillus target organ assay with immunosuppressed mice, under conditions of constant plasma levels of FK463, using a subcutaneously implanted osmotic pressure pump, a significant reduction in viable fungal cells was observed at plasma FK463 levels of 0.55 to 0.80 g/ml or higher. We conclude that FK463 is highly effective in the treatment of pulmonary aspergillosis in this animal model. These results indicate that FK463 may be a potent parenterally administered antifungal agent for pulmonary aspergillosis.Deep-seated mycoses in immunocompromised hosts are becoming an increasingly important medicinal problem (10). Candidiasis is the most common and important fungal infection in humans, and aspergillosis is the next most common (2,8,9). Invasive aspergillosis in immunocompromised patients is associated with significant morbidity and mortality (3,4). In view of the well-known problems with the established agents, it is clear that newer antifungal therapies with improved efficacy and reduced toxicity are needed. FK463 is a new, parenterally administered antifungal drug candidate undergoing clinical development. This compound is a novel water-soluble lipopeptide derived by semisynthetic modification of FR901379, a naturally occurring cyclic hexapeptide with a fatty acyl side chain, similar in structure to echinocandins and pneumocandins (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 F141, p. 268, 1998). In mouse models of disseminated candidiasis and aspergillosis, FK463 showed good efficacy (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). In the study described in this report, the activity of FK463 was evaluated in mouse models of pulmonary aspergillosis. MATERIALS AND METHODS Compound and animals. FK463 was synthesized in Fujisawa PharmaceuticalCo., Ltd. Amphotericin B (AMPH-B) and fluconazole (FLCZ) were purchased from Bristol-Myers Squibb (Tokyo, Japan) and Pfizer (Tokyo, Japan), respectively. FK463 and AMPH-B were formulated in sterile saline and 5% glucose, respectively, for intravenous injection and injected as 10mL/kg. Male Slc-ICR strain mice (4 weeks old) were purchased from SLC Japan (Shizuoka, Japan).Organisms and media. Inocula of Aspergillus fumigatus TIMM0063, IFM40814, and IFM41209 were prepared by culturing the test organisms on potato dextrose agar. Conidia were collected in s...
FK 749 is a new parenteral cephalosporin derivative which is more active against various gram-negative bacilli, including the opportunistic pathogens such as Enterobacter, Citrobacter species, and Serratia marcescens, than cephalosporins and cephamycins such as cefotiam, cefamandole, cefuroxime, cefotaxime, and cefmetazole. FK 749 was especially active against gram-negative organisms resistant to these related antibiotics. FK 749 was more potent in bactericidal activity than the other antibiotics, and the activity was clearly enhanced in the presence of 90% defibrinated rabbit blood. The therapeutic effect of subcutaneously injected FK 749 in mice infected with various gram-negative bacilli was far superior to that of cefotiam, cefamandole, cefuroxime, and cefmetazole and was almost the same as that of cefmetazole in mice infected with Staphylococcus aureus and that of ticarcillin in mice infected with Pseudomonas aeruginosa. FK 749 has, in general, nearly the same in vitro and in vivo antibacterial activities as cefotaxime. The former had more potent bactericidal activity in the presence of the blood than the latter and showed more excellent therapeutic effect than cefotaxime against infections caused by large inoculum sizes.The cephalosporins cefazolin (4) and ceftezole (5) resulted from our drug development program. In the continuing search for new cephalosporins with even greater antibacterial activity against a wide variety of gram-positive and gram-negative organisms, including the opportunistic pathogens, FK 749, a distinctive new parenteral cephalosporin derivative, was recently developed (Fig. 1) Bacterial strains. Standard strains from the culture collection of this laboratory were used in the study. Clinical isolates of various species of bacteria were obtained from several hospitals in Japan.Antibiotic susceptibility. Minimum inhibitory concentrations (MICs) were determined by the agar dilution method using heart infusion agar (HI agar, Difco Laboratories, Detroit, Mich.), unless otherwise specified. For testing Haemophilus influenzae, Neisseria species, and streptococcal species, except Streptococcus faecalis, the medium was supplemented with 5% defibrinated horse blood. The inoculum was grown in Trypticase soy broth (BBL Microbiology Systems, Cockeysville, Md.) overnight at 37°C. The broth was supplemented with 10% Fildes enrichment (Difco) for H. influenzae and with 5% defibrinated horse blood for Neisseria species and streptococcal species. An overnight broth culture and decimal dilutions thereof were streaked or spot-inoculated onto the agar media containing graded concentrations of the test antibiotics. MICs were read after incubation at 37°C for 20 h. For testing anaerobic bacteria, incubation was performed by the GasPak method (BBL) at 37°C; GAM broth (Nissui, Tokyo) and GAM agar (Nissui) were used for the preculture and test culture, respectively.
Fig. 1.A number of penicillins and cephalosporins have long maintained clinically important status for treatment of a variety of bacterial infections. Some of the Enterobacteriaceae, however, were still out of range of their antibacterial spectra, mainly because of either intrinsic resistance or Bi-lactamase production in the organisms. Thus, it became urgent to develop antibiotics possessing therapeutic effectiveness toward such resistant bacteria (13). Research performed in this laboratory demonstrated that replacement of a sulfur atom by an oxygen atom at the 1-position of the cephem nucleus enhanced antibacterial activity to a great extent (6). This finding stimulated efforts to modify the 1-oxacephem to confer fi-lactamase stability and to extend the gram-negative spectrum; 6059-S was selected as an eligible antibiotic in this respect (T. Yoshida, Philos. Trans. R. Soc. London, in press). The aim of this paper was to evaluate the antibacterial activity of 6059-S both in vitro and in vivo against aerobic and anaerobic microorganisms, using selected penicillins, cephalosporins, and cephamycin derivatives for comparison.
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