Efficacy of FK463, a (1,3)-beta-D-glucan synthase inhibitor, in disseminated azole-resistant candida albicans infection in mice

The efficacy of FK463, a new (1,3)-beta-D-glucan synthase inhibitor, against azole-resistant Candida albicans strains has been studied. The MIC of FK463 was lower than those of azoles and amphotericin B against CDR1-expressing C26 and CaMDR-expressing C40 strains. All mice treated with FK463 (1 mg/kg) survived disseminated murine candidiasis. The fungal burden in the kidney after 6 days was markedly reduced after therapy with FK463 and amphotericin B sodium deoxycholate, and plasma (1,3)-beta-D-glucan concentration was found to be lower in FK463-treated mice. In our study, FK463 was found to be a potent antifungal agent against disseminated infection with azole-resistant C. albicans.     

Effects of the Hematoregulatory Peptide SK&F 107647 Alone and in Combination with Amphotericin B against Disseminated Candidiasis in Persistently Neutropenic Rabbits

The effects of the hematoregulatory peptide SK&F 107647 were examined in a persistently and profoundly neutropenic rabbit model of disseminated candidiasis in order to determine its potential to enhance resistance against infection and its role as an adjunct to conventional antifungal chemotherapy. In healthy animals, SK&F 107647 elicited a time-dependent increase in CD11b-positive monocytes and neutrophils. When administered to neutropenic rabbits infected with Candida albicans, no significant differences in the number of CFU per gram in any of the tissues tested compared with the number in untreated control rabbits were detected. However, when SK&F 107647 was administered in combination with low doses of amphotericin B, there was a significant reduction in organism burden in the lungs, liver, spleen, and kidneys compared with the burdens in the organs of untreated control animals and in the lungs and kidneys compared with the burdens in the lungs and kidneys of animals treated with amphotericin B alone. These data suggest a potential role for this peptide as adjunctive therapy in combination with conventional antifungal agents in the treatment of disseminated candidiasis in the setting of profound and persistent neutropenia.     

Efficacy of oral E1210, a new broad-spectrum antifungal with a novel mechanism of action, in murine models of candidiasis, aspergillosis, and fusariosis

E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action-inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. Oral E1210 demonstrated dose-dependent efficacy in infections caused by Candida species, Aspergillus spp., and Fusarium solani. In the treatment of oropharyngeal candidiasis, E1210 and fluconazole each caused a significantly greater reduction in the number of oral CFU than the control treatment (P < 0.05). In the disseminated candidiasis model, mice treated with E1210, fluconazole, caspofungin, or liposomal amphotericin B showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also highly effective in treating disseminated candidiasis caused by azole-resistant Candida albicans or Candida tropicalis. A 24-h delay in treatment onset minimally affected the efficacy outcome of E1210 in the treatment of disseminated candidiasis. In the Aspergillus flavus pulmonary aspergillosis model, mice treated with E1210, voriconazole, or caspofungin showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also effective in the treatment of Aspergillus fumigatus pulmonary aspergillosis. In contrast to many antifungals, E1210 was also effective against disseminated fusariosis caused by F. solani. In conclusion, E1210 demonstrated consistent efficacy in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. These data suggest that further studies to determine E1210's potential for the treatment of disseminated fungal infections are indicated.     

Comparative antifungal activities and plasma pharmacokinetics of micafungin (FK463) against disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits

Micafungin (FK463) is an echinocandin that demonstrates potent in vitro antifungal activities against Candida and Aspergillus species. However, little is known about its comparative antifungal activities in persistently neutropenic hosts. We therefore investigated the plasma micafungin pharmacokinetics and antifungal activities of micafungin against experimental disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits. The groups with disseminated candidiasis studied consisted of untreated controls (UCs); rabbits treated with desoxycholate amphotericin B (DAMB) at 1 mg/kg of body weight/day; or rabbits treated with micafungin at 0.25, 0.5, 1, and 2 mg/kg/day intravenously. Compared with the UCs, rabbits treated with micafungin or DAMB showed significant dosage-dependent clearance of Candida albicans from the liver, spleen, kidney, brain, eye, lung, and vena cava. These in vivo findings correlated with the results of in vitro time-kill assays that demonstrated that micafungin has concentration-dependent fungicidal activity. The groups with invasive pulmonary aspergillosis studied consisted of UCs; rabbits treated with DAMB; rabbits treated with liposomal amphotericin B (LAMB) at 5 mg/kg/day; and rabbits treated with micafungin at 0.5, 1, and 2 mg/kg/day. In comparison to the significant micafungin dosage-dependent reduction of the residual burden (in log CFU per gram) of C. albicans in tissue, micafungin-treated rabbits with invasive pulmonary aspergillosis had no reduction in the concentration of Aspergillus fumigatus in tissue. DAMB and LAMB significantly reduced the burdens of C. albicans and A. fumigatus in tissues (P < 0.01). Persistent galactomannan antigenemia in micafungin-treated rabbits correlated with the presence of an elevated burden of A. fumigatus in pulmonary tissue. By comparison, DAMB- and LAMB-treated animals had significantly reduced circulating galactomannan antigen levels. Despite a lack of clearance of A. fumigatus from the lungs, there was a significant improvement in the rate of survival (P < 0.001) and a reduction in the level of pulmonary infarction (P < 0.05) in micafungin-treated rabbits. In summary, micafungin demonstrated concentration-dependent and dosage-dependent clearance of C. albicans from persistently neutropenic rabbits with disseminated candidiasis but not of A. fumigatus from persistently neutropenic rabbits with invasive pulmonary aspergillosis.     

Efficacy of caspofungin in a juvenile mouse model of central nervous system candidiasis

Neonatal candidiasis is an increasingly common occurrence causing significant morbidity and mortality and a higher risk of dissemination to the central nervous system (CNS) than that seen with older patients. The current understanding of optimal antifungal therapy in this setting is limited. We have developed a model of disseminated candidiasis with CNS involvement in juvenile mice to assess the efficacy of the echinocandin caspofungin relative to amphotericin B (AmB). Juvenile mice were inoculated intravenously with 5.64 × 10(4) CFU of Candida albicans MY1055. Treatment with caspofungin at 1, 2, 4, and 8 mg/kg of body weight/day, AmB at 1 mg/kg/day, or a vehicle control (VC) was initiated 30 h after infection and continued for 7 days. Pharmacokinetic parameters for caspofungin were also determined. Culture and histology showed evidence of disseminated candidiasis with multifocal encephalitis at the start of antifungal therapy. Survival was 100% in all treated groups, while mortality was 100% in the VC by day 11 after infection. By day 5, all mice in the caspofungin treatment (four doses) groups showed reductions in kidney and brain burden relative to the VC, while AmB treatment reduced kidney burden but gave no reduction of brain fungal burden. Systemic levels of caspofungin were similar in infected and uninfected mice, while brain levels were higher in infected animals. In this juvenile mouse model, caspofungin demonstrated dose-dependent activity, equivalent to or better than that of AmB at 1 mg/kg, against disseminated candidiasis with CNS involvement.     

Effect of attachment of anticandidal antibody to the surfaces of liposomes encapsulating amphotericin B in the treatment of murine candidiasis.

The effect produced by antibody specific to Candida albicans when attached to liposomes containing amphotericin B was studied in vivo. Liposomal amphotericin B bearing specific immunoglobulin (LAMB-Ab) was compared with the unencapsulated drug (fAMB) and other liposomal amphotericin B formulations in the short-term survival (21 days) of mice with disseminated candidiasis. Both the treatment and prophylaxis of the murine model of candidiasis were explored in these trials. LAMB-Ab increased survival rates in the model more than other liposomal preparations containing amphotericin B. Liposomal amphotericin B compounds as a group prolonged survival over fAMB. Liposomal preparations used for comparison included liposomes with attached nonspecific antibody (LAMB-Ab-), liposomes without antibody (LAMB), and liposomes with unattached specific antibody (LAMB+).     

Therapeutic efficacy of human macrophage colony-stimulating factor, used alone and in combination with antifungal agents, in mice with systemic Candida albicans infection

We examined the in vivo activity of human macrophage colony-stimulating factor (hM-CSF) against lethal Candida albicans infection in mice. In C. albicans-infected mice which had been immunosuppressed with cyclophosphamide, treatment with hM-CSF at a daily dose of 8 x 10(5) units/kg of body weight or greater slightly but significantly prolonged survival. Furthermore, the therapeutic efficacy of amphotericin B (AMPH-B) in infected mice was enhanced by its combined use with hM-CSF, while that of fluconazole (FLCZ) was not. The activities of peritoneal macrophages and neutrophils from mice administered hM-CSF plus AMPH-B in combination for inhibition of hyphal growth of C. albicans cells and intracellular phagocytosis and killing of the cells were greater than those of comparable phagocytic cells from control mice to which hM-CSF plus AMPH-B was not administered. These results suggest that intravenous administration of hM-CSF augments the efficacy of AMPH-B by enhancing the antifungal activities of macrophages and neutrophils. Therefore, it is expected that therapy with the combination AMPH-B and hM-CSF could improve the efficacy of AMPH-B and reduce the therapeutic dose of the antifungal drug that is required.     

Fluconazole (UK-49,858) treatment of candidiasis in normal and diabetic rats.

Fluconazole (UK-49,858), a new oral bistriazole antifungal agent, was compared with amphotericin B in the treatment of established systemic infection with Candida albicans in normal and diabetic rats. In normal rats, oral fluconazole at 10 mg/kg per day for 7 days reduced Candida colony counts in the kidneys and livers as well as amphotericin B did and was nearly as effective as amphotericin B in a 21-day treatment trial. There was no further reduction in Candida colony counts when normal rats were treated with fluconazole at 40 mg/kg twice a day for 7 days. In streptozotocin-induced diabetic rats, fluconazole at 20 mg/kg per day for either 7 or 21 days compared favorably with amphotericin B in efficacy. Results of our study suggest that oral fluconazole may be useful in the treatment of established disseminated candidiasis in normal as well as diabetic hosts.     

Prophylaxis of Candida albicans infection in neutropenic mice with liposome-encapsulated amphotericin B

The efficacy of liposome-encapsulated amphotericin B in the prophylaxis of disseminated Candida albicans infections in neutropenic mice was studied. The administration of liposome-encapsulated amphotericin B was associated with protection against infection with C. albicans when used at doses of greater than or equal to 2 mg of amphotericin B per kg of body weight. Neither empty liposomes nor free amphotericin B showed prophylactic efficacy.     

Effectiveness of quinolone antibiotics in modulating the effects of antifungal drugs.

Quinolone antibacterial drugs inhibit DNA gyrase, a type 2 topoisomerase. Since topoisomerases are present in eukaryotic cells, it was of interest to evaluate the antifungal activities of two clinically available quinolones, ciprofloxacin and trovafloxacin, alone and in combination with amphotericin B or fluconazole, in vitro against Candida albicans and in a murine model of invasive candidiasis. The in vitro activity of trovafloxacin was also tested against other yeasts and molds. In vitro, trovafloxacin exhibited no antifungal activity against any of the fungi (MIC, >250 microg/ml). There was also no effect of the quinolone on the in vitro activity of either antifungal drug. Marked antifungal effects were seen, however, in the murine model of candidiasis. In all experiments, control mice infected intravenously with C. albicans were dead by day 24. While either quinolone had minimal effects on survival of mice when used alone in oral doses of up to 40 mg/kg twice daily, the combination of the quinolone with fluconazole (40 or 80 mg/kg given twice daily by oral gavage) was more effective in prolonging survival than was fluconazole alone. Colony counts of kidneys on days 12 and 30 showed similar reductions in C. albicans recovered from mice treated with fluconazole with or without trovafloxacin or amphotericin B with or without trovafloxacin. Survival of mice treated with a suboptimal dose of amphotericin B (0.2 mg/kg/day) was also improved when trovafloxacin (40 mg/kg) given twice daily was included (0 versus 27%, respectively; P < 0.05). While the mechanisms of action of the combination of trovafloxacin and amphotericin B or fluconazole are unclear, further work focused on fungal topoisomerase inhibition and the mechanism of the antifungal effect of quinolone antibacterial drugs is warranted.     

Comparison of in vivo activity of fluconazole with that of amphotericin B against Candida tropicalis, Candida glabrata, and Candida krusei.

Fluconazole (UK-49,858) is a new oral bis-triazole antifungal agent with demonstrated activity against Candida albicans. Because of the increasing importance of infections due to other species of Candida, we studied the efficacy of fluconazole in a rat model of established systemic candidiasis, using clinical isolates of C. tropicalis, C. glabrata, and C. Krusei. In normal rats, oral fluconazole at both 20 and 80 mg/kg per day for 7 days reduced both kidney and liver titers of C. tropicalis and C. glabrata compared with those in control animals and was only slightly inferior to amphotericin B. Both fluconazole and amphotericin B were ineffective in reducing kidney titers of C. krusei, but amphotericin B was more effective than fluconazole in reducing liver titers. Fluconazole showed no increased efficacy at the higher dose of 80 mg/kg per day compared with 20 mg/kg per day in any experiment. These results suggest that oral fluconazole may be useful in the treatment of established disseminated candidiasis caused by species other than C. albicans. Further in vivo studies are needed, however, to define minimum effective doses and length of therapy and to test additional Candida isolates.     

Synergy between cilofungin and amphotericin B in a murine model of candidiasis.

The efficacies of cilofungin and amphotericin B separately and together in mice with disseminated candidiasis were studied. Male CD-1 mice (age, 5 weeks) were infected intravenously with 3 X 10(5) CFU of Candida albicans. At 4 days postinfection, intraperitoneal therapy was initiated and was continued for 14 days. Therapy groups included those given cilofungin at 6.25 or 62.5 mg/kg/day (given twice daily), amphotericin B at 0.625 mg/kg/day (given once daily), cilofungin at 6.25 mg/kg/day plus amphotericin B, and cilofungin at 62.5 mg/kg/day plus amphotericin B. Mice were observed through 30 days postinfection. All infected untreated mice died of infection between days 6 and 18. Eighty-five percent of mice receiving cilofungin at 6.25 mg/kg/day died between days 13 and 30. All other mice survived. Quantitative determination of the number of CFU of C. albicans in the spleens and kidneys of all survivors revealed that mice that had received both drugs had lower residual burdens of C. albicans. All mice treated with cilofungin at 62.5 mg/kg/day plus amphotericin B had sterile spleens, whereas 42 to 58% of mice given cilofungin or amphotericin B monotherapy had sterile spleens. All kidneys were infected in mice which had received cilofungin at 62.5 mg/kg/day or amphotericin B. Neither organ was infected in 17% of each group receiving combination therapy with cilofungin and amphotericin B. The number of CFU in the kidneys of mice treated with cilofungin at 62.5 mg/kg/day plus amphotericin B was lower than those cultured from mice treated with cilofungin at 62.5 mg/kg/day (P less than 0.001, Mann-Whitney) or amhotericin B (P less than 0.05). Modest synergy was noted in inhibition of the C. albicans isolate in vitro. Pharmacokinetic studies showed elevated levels of cilofungin but not amphotericin B in sera of mice treated with combined therapy compared with those in mice given monotherapy. No overt toxicity was evident with any regimen. The mechanism of increased efficacy may be altered cilofungin distribution, excretion, or metabolism; antifungal synergy; or both. These results indicate that concurrent cilofungin-amphotericin B therapy has synergistic or additive efficacy in vivo.     

Therapeutic evaluation of free and liposome-encapsulated amphotericin B in the treatment of systemic candidiasis in mice.

Various doses of amphotericin B encapsulated into unilamellar vesicles of 0.1 micron diameter (lip-AMB) (1.0 to 20.0 mg/kg of body weight) were compared with free amphotericin B (AMB) (0.5 to 2.0 mg/kg of body weight) in a murine model of disseminated candidiasis. CD2F1 mice injected intravenously with 3 x 10(5) Candida albicans cells were treated with either single- or multiple-dose regimens. Untreated infected mice had a median survival of 7 days, with all mice dead by 12 days. Single doses of AMB resulted in a median survival range from 18 to 23.5 days, with less than or equal to 38% survival by day 42. Single doses of lip-AMB resulted in 88 to 100% survival by day 42. The multiple-dose AMB regimen provided median survival of only 30 to 33 days, with less than or equal to 38% survival by day 42. The multiple-dose lip-AMB regimen resulted in greater than 90% survival by day 42. With single-dose regimens, lip-AMB levels in plasma were severalfold higher than AMB levels in plasma. By 10 h, at equivalent doses, lip-AMB levels in plasma were much higher, whereas AMB levels in plasma were not detectable. Compared with normal values, the blood urea nitrogen, serum glutamic pyruvic transaminase, serum glutamic oxaloacetate transaminase, and serum lactate dehydrogenase levels were not significantly altered by high doses of lip-AMB treatment. Viable C. albicans was recoverable from the kidneys of some of the lip-AMB-treated mice at day 42. Thus, encapsulation into unilamellar liposomes enhances the antifungal efficacy of amphotericin B while reducing the toxicity normally associated with administration of free amphotericin B.     

Comparison of the efficacies of amphotericin B, fluconazole, and itraconazole against a systemic Candida albicans infection in normal and neutropenic mice.

We compared the efficacies of the new triazole antifungal drugs fluconazole and itraconazole with that of amphotericin B in vitro and in an animal model of systemic candidiasis in normal and neutropenic mice. Antifungal treatment with fluconazole (2.5 to 20 mg/kg orally twice daily), itraconazole (10 to 40 mg/kg orally twice daily), or amphotericin B (0.1 to 4 mg/kg intraperitoneally once daily) was started 1 day after intravenous injection of 10(4) Candida albicans into normal mice or 10(3) C. albicans into neutropenic mice; the drugs were administered for 2 days. In normal mice the efficacy of treatment, which was assessed on the basis of the number of C. albicans cultured from the kidney, was greater for amphotericin B than for the triazoles. Fluconazole was more potent than itraconazole on the basis of equivalent doses, although itraconazole was more potent on the basis of the amount of free drug that was available. In neutropenic mice amphotericin B was less effective than it was in normal mice, whereas the triazoles were equally effective in normal and neutropenic mice. This was not expected, since in vitro data showed that amphotericin B was highly fungicidal, whereas both fluconazole and itraconazole had only a minimal effect on the growth of C. albicans in vitro.     

In vitro and in vivo antifungal activities of T-2307, a novel arylamidine

The in vitro and in vivo antifungal activities of T-2307, a novel arylamidine, were evaluated and compared with those of fluconazole, voriconazole, micafungin, and amphotericin B. T-2307 exhibited broad-spectrum activity against clinically significant pathogens, including Candida species (MIC range, 0.00025 to 0.0078 microg/ml), Cryptococcus neoformans (MIC range, 0.0039 to 0.0625 microg/ml), and Aspergillus species (MIC range, 0.0156 to 4 microg/ml). Furthermore, T-2307 exhibited potent activity against fluconazole-resistant and fluconazole-susceptible-dose-dependent Candida albicans strains as well as against azole-susceptible strains. T-2307 exhibited fungicidal activity against some Candida and Aspergillus species and against Cryptococcus neoformans. In mouse models of disseminated candidiasis, cryptococcosis, and aspergillosis, the 50% effective doses of T-2307 were 0.00755, 0.117, and 0.391 mg.kg(-1).dose(-1), respectively. This agent was considerably more active than micafungin and amphotericin B against candidiasis and than amphotericin B against cryptococcosis, and its activity was comparable to the activities of micafungin and amphotericin B against aspergillosis. The results of preclinical in vitro and in vivo evaluations performed thus far indicate that T-2307 could represent a potent injectable agent for the treatment of candidiasis, cryptococcosis, and aspergillosis.     

Effects of amphotericin B and fluconazole on the extracellular and intracellular growth of Candida albicans.

The effects of amphotericin B and fluconazole on the extracellular and intracellular growth of Candida albicans were studied. With respect to the extracellular growth of C. albicans, antifungal activity was measured in terms of MICs and minimal fungicidal concentrations as well as by determination of the concentration that effectively killed (greater than 99.9%) C. albicans in the absence or presence (amphotericin B only) of serum. Amphotericin B was highly active in terms of killing, even at an increased inoculum size. In the presence of serum, amphotericin B activity was substantially reduced. For fluconazole, activity was restricted to inhibition of fungal growth, even after the inoculum size was reduced. With respect to the intracellular growth of C. albicans, antifungal activity was measured by using monolayers of murine peritoneal macrophages infected with C. albicans and was measured in terms of inhibition of germ tube formation as well as effective killing (greater than 99%) of C. albicans. Amphotericin B was highly active against C. albicans. At an increased ratio of infection, amphotericin B activity was slightly reduced. Fluconazole had no antifungal activity. Neither a reduction in the ratio of infection nor exposure of C. albicans to fluconazole prior to macrophage ingestion resulted in activity against intracellular C. albicans by fluconazole. Previous exposure of C. albicans to amphotericin B resulted in increased intracellular activity of amphotericin B. The intracellular antifungal activity of the combination of fluconazole with amphotericin B was less than that of amphotericin B alone. Amphotericin B showed fungicidal activity against C. albicans growing both extracellularly and intracellularly, whereas fluconazole inhibited growth only of extracellular C. albicans. A slight antagonistic effect between fluconazole and amphotericin B was found with respect to intracellular as well as extracellular C. albicans.     

Efficacy of aminocandin in the treatment of immunocompetent mice with haematogenously disseminated fluconazole-resistant candidiasis

OBJECTIVES: The objective of this study was to compare the activity of aminocandin, a new echinocandin with broad-spectrum activity against Candida spp., with that of amphotericin B, caspofungin and fluconazole, in an immunocompetent murine model of haematogenously disseminated candidiasis caused by a fluconazole-resistant Candida albicans. METHODS: Mice were infected with a fluconazole-resistant strain of C. albicans and treated with aminocandin 5 and 10 mg/kg intravenously (iv) once and twice weekly, amphotericin B 0.5 mg/kg iv every other day for 5 days, fluconazole 20 mg/kg orally (po) once a day for 5 days and caspofungin 0.5 mg/kg intraperitoneally (ip) once daily for 5 days. RESULTS: Treatment with aminocandin, given iv twice a week, resulted in 100% survival. Further, the tissue fungal burden of the aminocandin group was equivalent to that of amphotericin B (administered every other day) and caspofungin (administered daily). CONCLUSIONS: Aminocandin may be an effective addition to the arsenal of antifungal compounds for the treatment of candidiasis caused by fluconazole-resistant C. albicans.     

Susceptibility of Candida dubliniensis to salivary histatin 3

Candida dubliniensis is a recently described Candida species associated with oral candidiasis in human immunodeficiency virus (HIV)-infected patients and patients with AIDS. The majority of C. dubliniensis clinical isolates tested to date are susceptible to the commonly used antifungal drugs, including fluconazole, ketoconazole, itraconazole, and amphotericin B. However, the appearance of fluconazole-resistant C. dubliniensis strains in this patient group is increasing. Histatins are a family of basic histidine-rich proteins present in human saliva which have therapeutic potential in the treatment of oral candidiasis. The mechanism of action of histatin is distinct from that of commonly used azole and polyene drugs. Characterization of the antifungal activity of histatin has mainly been carried out using C. albicans but it is also effective in killing C. glabrata and C. krusei. Here we report that C. dubliniensis is also susceptible to killing by histatin 3. The concentration of histatin 3 giving 50% killing (the IC(50) value) ranged from 0.043 to 0.196 mg/ml among different strains of C. dubliniensis. The least-susceptible C. dubliniensis strain, P9224, was found to internalize histatin at a lower rate than the C. albicans reference strain CA132A. The dissociation constant (K(d)) for the least-susceptible strain (C. dubliniensis 9224) was ninefold higher than that for the C. albicans reference strain. These results suggest that histatin 3 may have potential as an effective antifungal agent, particularly in the treatment of oral candidiasis in HIV-infected patients and patients with AIDS in which resistance to the commonly used antifungal drug fluconazole has emerged.     

Combined antifungal therapy in a murine infection by Candida glabrata

OBJECTIVES: To develop proper treatments for patients who do not respond to current antifungal treatments, we tested new combinations of antifungal drugs for treating disseminated infections by Candida glabrata in a murine model. METHODS: Mice were rendered neutropenic by intraperitoneal cyclophosphamide and intravenous 5-fluorouracil administration. The animals were infected intravenously with 2 x 10(8) cfu of C. glabrata. The efficacies of micafungin combined with amphotericin B, fluconazole or flucytosine, and of amphotericin B combined with fluconazole were evaluated by survival and tissue burden reduction. RESULTS AND CONCLUSIONS: Micafungin plus amphotericin B was the most effective combination at reducing tissue burden. Micafungin at 10 mg/kg combined with amphotericin B at 0.75, 1.5 or 3 mg/kg prolonged survival with respect to the monotherapies, but only the second combination showed a synergistic effect in reducing fungal load in spleen and kidney. Amphotericin B at 1.5 mg/kg combined with micafungin at 5, 10 or 20 mg/kg reduced tissue burden with respect to the monotherapies, but the effects of the three combinations were very similar. These results suggest that amphotericin B in combination with micafungin is promising for the treatment of disseminated C. glabrata infections.     

Safety and Efficacy of Multilamellar Liposomal Nystatin against Disseminated Candidiasis in Persistently Neutropenic Rabbits

The activity of liposomal nystatin (L-Nys) against subacute disseminated candidiasis was investigated in persistently neutropenic rabbits. Antifungal therapy was administered for 10 days starting 24 h after intravenous inoculation of 10(3) blastoconidia of Candida albicans. Responses to treatment were assessed by the quantitative clearance of the organism from blood and tissues. Treatments consisted of L-Nys at dosages of 2 and 4 mg/kg of body weight/day (L-Nys2 and L-Nys4, respectively) amphotericin B deoxycholate at 1 mg/kg/day (D-AmB), and fluconazole at 10 mg/kg/day (Flu). All treatments were given intravenously once daily. Compared to the results for untreated but infected control animals, treatment with L-Nys2, L-Nys4, D-AmB, and Flu resulted in a significant clearance of the residual burden of C. albicans from the kidney, liver, spleen, lung, and brain (P < 0.0001 by analysis of variance). When the proportion of animals infected at at least one of the five tissue sites studied was evaluated, a dose-dependent response to treatment with L-Nys was found (P < 0.05). Compared to D-AmB-treated rabbits, mean serum creatinine and blood urea nitrogen levels at the end of therapy were significantly lower in animals treated with L-Nys2 (P < 0.001) and L-Nys4 (P < 0.001 and P < 0.01, respectively). L-Nys was less nephrotoxic than conventional amphotericin B and had dose-dependent activity comparable to that of amphotericin B for the early treatment of subacute disseminated candidiasis in persistently neutropenic rabbits.