Activities of D0870, a novel triazole, against Candida lusitaniae and Trichosporon beigelii in experimental murine infections.

Candida lusitaniae and Trichosporon beigelii may cause life-threatening infections in the immunocompromised host and may be resistant to amphotericin B. We assessed the activities of a new triazole, D0870, against one T. beigelii and four C. lusitaniae strains, in comparison with those of fluconazole and amphotericin B. Immunosuppressed CF1 mice, intravenously infected with each fungal strain, received 3 days of therapy with oral D0870 (5 or 25 mg/kg of body weight daily), fluconazole (5 to 50 mg/kg daily), or parenteral amphotericin B (1 or 2 mg/kg daily). Survival was significantly prolonged and kidney fungus titers were reduced in mice treated with D0870 compared with untreated mice (P < or = 0.05). Treatment with D0870 was significantly more effective than that with amphotericin B or fluconazole in animals infected with two of the C. lusitaniae strains and equally effective for the remaining two C. lusitaniae strains and the T. beigelii strain. Fluconazole and amphotericin B failed to improve the survival of mice infected with one and two C. lusitaniae strains, respectively. D0870 was active against all the organisms tested, including those resistant to fluconazole and amphotericin B.     

SCH 51048, a new antifungal triazole active against hematogenous Candida krusei infections in neutropenic mice.

Candida krusei is increasingly recognized as an opportunistic pathogen in immunocompromised patients and is inherently resistant to fluconazole. We tested the in vivo efficacy of SCH 51048, an investigational antifungal triazole, in experimental hematogenous murine infection caused by two C. krusei isolates and compared its activity with those of amphotericin B and fluconazole. CF1 mice were immunosuppressed with cyclophosphamide and cortisone acetate and were challenged intravenously with infecting inocula of each C. krusei isolate. Treatment with SCH 51048 (50 or 100 mg/kg of body weight per day orally) or amphotericin B (2 mg/kg/day intraperitoneally) significantly prolonged the survival of infected mice and significantly reduced fungal titers in the kidneys (P < or = 0.05). Treatment with fluconazole (100 mg/kg/day orally) had no effect. Both dosages of SCH 51048 were as effective as amphotericin B in improving survival, but the higher dosage was significantly (P < or = 0.05) better in reducing the fungal burden in the kidneys of infected animals. A dose-dependent response was observed with SCH 51048 treatment, especially in organ clearance. Our results indicate that SCH 51048 is the first triazole that has in vivo activity against experimental infection with C. krusei and deserves further evaluation.     

Treatment of Candida glabrata infection in immunosuppressed mice by using a combination of liposomal amphotericin B with caspofungin or micafungin

While Candida albicans remains the most common Candida isolate, Candida glabrata accounts for approximately 15 to 20% of all Candida infections in the United States. In this study we used immunosuppressed mice infected with C. glabrata to investigate the efficacy of liposomal amphotericin B alone or in combination with the echinocandin caspofungin or micafungin. For monotherapy, mice were given six daily doses of liposomal amphotericin B (3 to 20 mg/kg of body weight), caspofungin (1 to 5 mg/kg), or micafungin (2.5 to 10 mg/kg). With concomitant therapy, mice received liposomal amphotericin B (7.5 mg/kg) in addition to caspofungin (2.5 mg/kg) or micafungin (2.5 mg/kg) for 6 days. For sequential therapy, liposomal amphotericin B was administered on days 1 to 3 and caspofungin or micafungin was given on days 4 to 6; conversely, caspofungin or micafungin was administered on days 1 to 3 and liposomal amphotericin B was given on days 4 to 6. Efficacy was based on the number of CFU per gram of kidney 21 days postchallenge. Monotherapy with liposomal amphotericin B (7.5 to 20 mg/kg) was significantly more effective than no drug treatment (control group) (P < 0.05) and demonstrated a dose-dependent response, with 20 mg/kg lowering the CFU/g from 6.3 to 4.2 (significantly different from the value for the control group [P < 0.001]). Monotherapy with all echinocandin doses lowered the CFU/g from 6.0 to 6.4 to 2.7 to 3.3 (significantly different from the value for the control group [P < 0.001]) with no dose-dependent response. Complete clearance of infection could be achieved only when liposomal amphotericin B was given either concomitantly with caspofungin or micafungin or if liposomal amphotericin B was given sequentially with caspofungin. In conclusion, the combination of liposomal amphotericin B with an echinocandin markedly improved the therapeutic outcome in murine C. glabrata systemic infection.     

In vivo activity of micafungin in a persistently neutropenic murine model of disseminated infection caused by Candida tropicalis

Micafungin is a new echinocandin with broad-spectrum in vitro and in vivo antifungal activity against both Aspergillus and Candida species. We compared the activity of micafungin with that of amphotericin B and fluconazole in a persistently immunocompromised murine model of disseminated candidiasis against a strain of Candida tropicalis that was resistant to amphotericin B and fluconazole in vitro. Mice were rendered persistently neutropenic with multiple doses of cyclophosphamide and infected intravenously with C. tropicalis. Mice were treated with either intraperitoneal amphotericin B (0.5-5 mg/kg per dose), oral fluconazole (50 mg/kg twice a day), intravenous micafungin (1-10 mg/kg per dose) or solvent control for 7 days. Mice were killed at 11 days post-infection and kidneys, lungs, brain and liver removed for quantitative culture. Overall mortality in the model was low, with rates varying between 10% and 25% in treatment groups. Micafungin at doses between 2 and 10 mg/kg were the only regimes able to reduce cfu below the level of detection of tissues infected with C. tropicalis. Micafungin was well tolerated by the mice and was much more effective than amphotericin B or fluconazole against an amphotericin B- and fluconazole-resistant C. tropicalis.     

Efficacy of continuous flucytosine infusion against Candida lusitaniae in experimental hematogenous murine candidiasis.

Candida lusitaniae may cause life-threatening infections in the immunocompromised host and may be resistant to amphotericin B. Flucytosine (5-FC) is very active against C. lusitaniae isolates in vitro, while the in vivo response of murine infection to 5-FC is not as good. To evaluate the hypothesis that this discrepancy may be primarily due to the short half-life of 5-FC in mice, we compared the same total dosage of 75 mg of 5-FC per kg of body weight per day given by bolus injections or infused continuously via a subcutaneously implanted pump in immunosuppressed CF1 mice infected with C. lusitaniae. The fungal titers in the kidneys of mice treated with the continuous 5-FC infusion were significantly lower (P < or = 0.05) than those in the kidneys of mice that received bolus injections once or thrice daily. The antifungal activity of 5-FC against murine candidiasis is best evaluated when the drug is administered by continuous infusion.     

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.     

In-vitro antifungal activity of liposomal nystatin in comparison with nystatin, amphotericin B cholesteryl sulphate, liposomal amphotericin B, amphotericin B lipid complex, amphotericin B desoxycholate, fluconazole and itraconazole.

The in-vitro susceptibilities of 120 clinical isolates of yeasts to liposomal nystatin were compared with those to amphotericin B lipid complex (ABLC), liposomal amphotericin B (LAB), amphotericin B cholesteryl sulphate (ABCD), amphotericin B desoxycholate, nystatin, fluconazole and itraconazole. Yeast isolates examined included strains of Candida albicans, Candida parapsilosis, Candida glabrata, Candida krusei, Candida guilliermondii, Candida tropicalis, Candida kefyr, Candida viswanathii, Candida famata, Candida rugosa, Rhodotorula rubra, Trichosporon spp., Cryptococcus laurentii and Cryptococcus neoformans. The mean MICs for all strains examined were: liposomal nystatin 0.96 mg/L; nystatin 0.54 mg/L; ABLC 0.65 mg/L; LAB 1.07 mg/L; ABCD 0.75 mg/L; amphotericin B 0.43 mg/L; fluconazole 5.53 mg/L; and itraconazole 0.33 mg/L. No significant differences were seen between the activity of liposomal nystatin and the polyene drugs or itraconazole, but liposomal nystatin was more active than fluconazole. MICs were lower than the reported blood concentrations following therapeutic doses of this drug, indicating the potential for a therapeutic use of liposomal nystatin in humans. These results indicate good activity in vitro against medically important yeasts, which compares favourably with the activities of other currently available antifungal drugs. Liposomal nystatin may have a role in the treatment of disseminated and systemic mycoses.     

Antifungal activity of amphotericin B cochleates against Candida albicans infection in a mouse model

Cochleates are lipid-based supramolecular assemblies composed of natural products, negatively charged phospholipid, and a divalent cation. Cochleates can encapsulate amphotericin B (AmB), an important antifungal drug. AmB cochleates (CAMB) have a unique shape and the ability to target AmB to fungi. The minimal inhibitory concentration and the minimum lethal concentration against Candida albicans are similar to that for desoxycholate AmB (DAMB; Fungizone). In vitro, CAMB induced no hemolysis of human red blood cells at concentrations of as high as 500 microg of AmB/ml, and DAMB was highly hemolytic at 10 microg of AmB/ml. CAMB protect ICR mice infected with C. albicans when the agent is administered intraperitoneally at doses of as low as 0.1 mg/kg/day. In a tissue burden study, CAMB, DAMB, and AmBisome (liposomal AmB; LAMB) were effective in the kidneys, but in the spleen CAMB was more potent than DAMB at 1 mg/kg/day and was equivalent to LAMB at 10 mg/kg/day. In summary, CAMB are highly effective in treating murine candidiasis and compare well with AmBisome and AmB.     

Treatment of murine Candida krusei or Candida glabrata infection with L-743,872.

L-743,872 is a broad-spectrum pneumocandin antifungal drug developed by Merck Research Co., and in the present work it was evaluated in vivo in murine models of Candida krusei and Candida glabrata infection. Mice were infected intravenously with two isolates of C. krusei and treated with fluconazole or L-743,872. Fluconazole was beneficial only in immune-competent mice infected with isolate 94-2696. At > 0.5 mg/kg of body weight/day, L-743,872 was effective against both infecting isolates in immune-competent and immune-suppressed mice. Against C. glabrata, L-743,872 was effective, at doses > or = 0.5 mg/kg, in reducing fungal cell counts in the kidneys but not in the spleen. L-743,872 has significant potential for clinical development.     

In vitro susceptibility of 245 yeast isolates to amphotericin B, 5-fluorocytosine, ketoconazole, fluconazole and itraconazole.

The in vitro activity of amphotericin B, 5-fluorocytosine, ketoconazole, fluconazole and itraconazole was tested against 245 yeast strains isolated from clinical specimens (68 Candida albicans, 74 Candida tropicalis, 43 Candida krusei, 28 Candida glabrata, 19 Candida parapsilosis, 8 Candida lusitaniae and 5 Candida guilliermondii). An agar dilution method was employed to carry out testing. Minimal inhibitory concentrations to restrain 90% of isolate growth (MIC90) ranged from 0.12 to 2 mg/l for amphotericin B and for 5-fluorocytosine, from 0.03 to 8 mg/l for ketoconazole, from 0.05 to 50 mg/l for itraconazole and from 0.1 to > 100 mg/l for fluconazole. Among the azole derivatives, the most active was ketoconazole, followed by itraconazole. Only 1 strain of C. albicans was resistant to amphotericin B (MIC > 4 mg/l). Both C. tropicalis and C. krusei responded poorly to fluconazole and the former to itraconazole as well. The species most susceptible to the antifungal agents tested was C. glabrata and the most resistant were C. tropicalis and C. krusei.     

Comparative efficacies of amphotericin B, triazoles, and combination of both as experimental therapy for murine trichosporonosis.

We assessed the activities of amphotericin B deoxycholate, liposomal amphotericin B, fluconazole, and SCH 39304 against 10 strains of Trichosporon beigelii in mice with hematogenous infections. Cyclophosphamide-immunosuppressed CF1 male mice were challenged intravenously with a lethal inoculum of T. beigelii (5 x 10(6) conidia per mouse) and were assigned to different treatment groups or were left untreated. Amphotericin B deoxycholate (1 mg/kg of body weight and liposomal amphotericin B (1, 5, and 10 mg/kg) were given parenterally once daily. Escalating doses (5, 10, and 20 mg/kg/day) of fluconazole and SCH 39304 were tested. We also compared the activity of amphotericin B deoxycholate plus fluconazole (1 and 10 mg/kg/day, respectively) with that of each agent alone. Fluconazole significantly prolonged the survival of mice infected with each of the 10 strains tested. Amphotericin B deoxycholate achieved various responses, improving the outcomes in mice infected with seven of the strains. Liposomal amphotericin B was not more effective than amphotericin B deoxycholate against the two strains tested. Both fluconazole and SCH 39304 reduced the kidney fungal counts in a dose-dependent pattern, with SCH 39304 being more active than fluconazole against one of the two strains tested. The activity of the combination of amphotericin B deoxycholate plus fluconazole appeared to be superior to that of either agent alone, especially in reducing the kidney fungal burden. Fluconazole is more active than amphotericin B deoxycholate against experimental murine trichosporonosis.     

Tolerance to amphotericin B in clinical isolates of Candida tropicalis

A broth microdilution method was used for testing amphotericin B against 33 clinical isolates of Candida tropicalis. All isolates were in vitro susceptible to the polyene (MIC [minimal inhibitory concentration] < or = 1.0 microg/mL). However, when the isolates were cultured in a medium containing amphotericin B at a concentration of 1.5 microg/mL, a wide interstrain variation of growth rate was observed. Five isolates (15%) proved to be highly tolerant to the drug and grew at a frequency ranging from 1 x 10(-1) to 2 x 10(-2). Twenty-three isolates (70%) grew at a frequency ranging from 1 x 10(-5) to 1 x 10(-8). The remaining five isolates (15%) failed to grow in drug-containing medium. In general, this growth variation was not associated with amphotericin B MICs displayed by the single isolates. In addition, the strains grown in drug-containing medium did not represent amphotericin B-resistant mutants, as shown by the maintenance of MICs similar to those of their respective parent isolates. Killing experiments conducted in selected isolates confirmed a variation of fungicidal activity of amphotericin B. To see whether this phenomenon was associated with a variation of amphotericin B response in vivo, we established an experimental model of systemic murine candidiasis in CD1 mice by intravenous injection of cells belonging to Candida tropicalis 3147 (growth rate at a frequency of 1 x 10(-1) in amphotericin B medium) and Candida tropicalis 4055 (no growth). Low (0.3 mg/kg/day) and high (1 mg/kg/day) doses of amphotericin B were both effective at reducing the fungal burdens in the kidneys of mice infected with either strain (p, 0.01 to 0.02). However, whereas the burden of mice infected with isolate 3147 and treated with the polyene at 0.3 mg/kg/day was reduced by 1.2 +/- 0.25 (mean +/- standard deviation) log10 cfu/g compared to untreated mice, the same dosing regimen yielded a burden reduction of 2.6 +/- 0.07 log10 cfu/g in mice infected with isolate 4055 (p < 0.001). Similarly, amphotericin B at 1 mg/kg/day yielded a burden reduction of 1.8 +/- 0.20 vs. 2.5 +/- 0.30 log10 cfu/g in mice infected with isolates 3147 and 4055, respectively (p < 0.001). Our data revealed a variable pattern of tolerance to amphotericin B among isolates of Candida tropicalis and showed that this phenomenon might influence the rate of organ clearance during therapy.     

Activity of a new liposomal formulation of amphotericin B against two strains of Leishmania infantum in a murine model.

The efficacy of a new liposomal formulation of amphotericin B was compared to that of amphotericin B deoxycholate (Fungizone) in a murine model of visceral leishmaniasis induced by Leishmania infantum. Median effective doses (ED50) were determined with two different strains: strain 1 was obtained from an untreated patient, and strain 2 was obtained from a patient who had received 12.5 g of amphotericin B over 3 years. BALB/c mice were infected intravenously on day 0 with promastigotes and then treated on days 14, 16, and 18 (strain 1) or on days 21, 23, and 25 (strain 2) with the liposomal formulation of amphotericin B (five doses were tested for each strain: 0.05, 0.1, 0.5, 0.8, and 3 mg/kg of body weight) or with conventional amphotericin B (four doses were tested for each strain: 0.05, 0.1, 0.5, and 0.8 mg/kg). Mice in the control group received normal saline solution. The liposomal amphotericin B formulation was about three times more active than the conventional drug against both strains. ED50 of the liposomal formulation were 0.054 (strain 1) and 0.194 (strain 2) mg/kg. ED50 of conventional amphotericin B were 0.171 (strain 1) and 0.406 (strain 2) mg/kg. Determination of drug tissular levels, 3 days after the last drug administration, showed a drug accumulation in hepatic and splenic tissues much higher after administration of liposomal amphotericin B than after conventional amphotericin B. A lack of toxicity was noted in all groups treated with the liposomal formulation.     

In-vitro activity of five antifungal agents against uncommon clinical isolates of Candida spp

A broth microdilution method and an agar dilution method were used for testing fluconazole, itraconazole, ketoconazole, flucytosine and amphotericin B against 98 clinical isolates belonging to seven species of Candida. The approximate rank order of fluconazole MICs was Candida lusitaniae approximately Candida kefyr < Candida famata approximately Candida guilliermondii < Candida pelliculosa approximately C. lipolytica approximately Candida inconspicua. Candida lypolitica and C. pelliculosa were the species least susceptible to itraconazole and ketoconazole. Flucytosine MICs revealed the highest prevalence of resistant strains among C. lipolytica and C. lusitaniae. All isolates were susceptible to amphotericin B.     

Activity of aminocandin (IP960) compared with amphotericin B and fluconazole in a neutropenic murine model of disseminated infection caused by a fluconazole-resistant strain of Candida tropicalis

OBJECTIVES: To compare the activity of aminocandin (IP960), a new echinocandin with broad-spectrum in vitro activity against Aspergillus and Candida spp., with that of amphotericin B and fluconazole in a temporarily immunocompromised murine model of disseminated candidiasis. METHODS: Mice were rendered neutropenic with cyclophosphamide and infected intravenously 3 days later with a fluconazole-resistant Candida tropicalis strain. Mice were treated with intraperitoneal amphotericin B (5 mg/kg/dose), oral fluconazole (50 mg/kg/dose), intravenous aminocandin (0.1--5 mg/kg/dose) or solvent control for 9 days. Mice were observed for survival and survivors were sacrificed 11 days post-infection. Kidneys, liver, brain and lungs were removed for semi-quantitative culture. RESULTS: Control mice had 90--100% mortality. After infection with C. tropicalis, aminocandin 2.5 and 5 mg/kg/day and amphotericin B yielded 80% survival; aminocandin 1 mg/kg/day yielded 70% survival; aminocandin 0.25 and 0.1 mg/kg/day yielded 30% and 20% survival, respectively; and fluconazole 50 mg/kg/day and control regimens yielded 10% and 0--10% survival, respectively. Aminocandin 2.5 and 5.0 mg/kg/day and amphotericin B were superior in reducing mortality compared with aminocandin 0.25 and 0.1 mg/kg/day, fluconazole and controls (P<0.047). The only regimen to reduce organ burdens below detectable levels was amphotericin B, which cleared 40% of mice. All organ burdens in the aminocandin 1.0, 2.5 and 5.0 mg/kg/day and amphotericin B regimens were significantly lower than other groups (P<0.02). CONCLUSIONS: The data demonstrate that aminocandin at doses of >or=1.0 mg/kg/day is as effective as amphotericin B at improving survival and reducing organ burdens in this murine model of disseminated C. tropicalis.     

Economic evaluation of targeted treatments of invasive aspergillosis in adult haematopoietic stem cell transplant recipients in the Netherlands: a modelling approach

OBJECTIVES: The aim of this study was to assess the cost-effectiveness of a targeted treatment model of antifungal treatment strategies for adult haematopoietic stem cell transplant (HSCT) recipients in the Netherlands from a hospital perspective, using a decision analytic modelling approach. METHODS: The economic evaluation of desoxycholate amphotericin B, liposomal amphotericin B, voriconazole and caspofungin was undertaken. These drugs could be used alone, in various combinations or sequentially. In our model, first-line therapy consisted of either voriconazole or liposomal amphotericin B. If necessary, treatment was switched to a second-line treatment, including combination antifungal therapy. The theoretical population in this model consisted of adult HSCT recipients with proven or probable invasive aspergillosis (IA). Long-term survival was extrapolated from survival after 12 weeks of treatment and life expectancy. RESULTS: First-line antifungal treatment strategies with voriconazole were both more effective and less costly over first-line strategies employing liposomal amphotericin B at a dosage of 4 mg/kg/day. The strategy of voriconazole followed by caspofungin (voriconazole/caspofungin) was dominant over the strategies of voriconazole followed by liposomal amphotericin B (voriconazole/liposomal amphotericin B) or desoxycholate amphotericin B (voriconazole/desoxycholate amphotericin B). However, the voriconazole followed by the combination of liposomal amphotericin B and caspofungin strategy (voriconazole/liposomal amphotericin B+caspofungin) was more effective though more expensive than the voriconazole/caspofungin strategy resulting in an incremental cost-effectiveness ratio (ICER) of about euro107,000 for a life-year saved. At a dosage of 1 mg/kg/day of liposomal amphotericin B, the voriconazole/caspofungin strategy was more effective but more costly than the voriconazole/desoxycholate amphotericin B strategy with an ICER of euro10,000 for each extra life-year saved. Between the voriconazole/liposomal amphotericin B+caspofungin and the voriconazole/caspofungin strategies, the ICER was euro40,000. CONCLUSIONS: Probabilistic analyses on net monetary benefit showed that the voriconazole/caspofungin strategy had the highest probability of being the most cost-effective strategy.     

Susceptibility of clinical isolates of Candida lusitaniae to five systemic antifungal agents

OBJECTIVES: The aim of the present study was to expand the MIC database for Candida lusitaniae in order to further determine its antifungal susceptibility pattern. METHODS: The activities of amphotericin B, fluconazole, itraconazole, voriconazole and flucytosine were determined in vitro against 80 clinical isolates of C. lusitaniae. A set of 59 clinical isolates of Candida albicans and of 51 isolates of Candida glabrata was included to compare the susceptibilities to amphotericin B. The MICs were determined by Etest with RPMI 1640 agar, and with both this medium and antibiotic medium 3 (AM3) agar for testing of amphotericin B. RESULTS: All isolates were highly susceptible to fluconazole. The susceptibility to itraconazole was good; only 4% of isolates had dose-dependent susceptibility (MICs 0.25-0.5 mg/L). Voriconazole was very active in vitro (100% of isolates were inhibited at < or =0.094 mg/L). Flucytosine MICs ranged widely (0.004->32 mg/L). The set included 19% of flucytosine-resistant isolates. For amphotericin B, 100% of isolates were inhibited at < or =0.75 mg/L (MIC(50) 0.047 mg/L; MIC(90) 0.19 mg/L) and at < or =4 mg/L (MIC(50) 0.25 mg/L; MIC(90) 0.75 mg/L) on RPMI and on AM3, respectively. A single isolate was categorized as resistant to amphotericin B (MIC 0.75 and 4 mg/L on RPMI and on AM3, respectively). Amphotericin B thus appeared very active in vitro against C. lusitaniae. Whatever the test medium, the level of susceptibility of C. lusitaniae to amphotericin B did not differ much from those of C. albicans and C. glabrata. CONCLUSION: C. lusitaniae appears to be susceptible to amphotericin B, azole antifungal agents, and, to a lesser extent, flucytosine.     

Isolation and characterization of fluconazole- and amphotericin B-resistant Candida albicans from blood of two patients with leukemia.

Infections with fluconazole-resistant Candida albicans isolate have rarely been described in clinical settings other than oropharyngeal candidiasis in patients with late-stage AIDS. We report on two patients with leukemia who developed fungemia caused by fluconazole-resistant C. albicans after receiving fluconazole prophylaxis (400 mg/day) and empiric amphotericin B therapy (0.5 mg/kg of body weight per day). The fluconazole MICs for the isolates were > or = 64 micrograms/ml, and the isolates were resistant to other azoles and had membrane sterol changes consistent with a mutation in the delta 5,6-sterol desaturase gene. The lack of ergosterol in the cytoplasmic membrane of the fluconazole-resistant strains also imparted resistance to amphotericin B. Both patients were successfully treated with high-dose amphotericin B (1 to 1.25 mg/kg/day) and flucytosine (150 mg/kg/day).     

Comparative efficacies of cilofungin (Ly121019) and amphotericin B against disseminated Candida albicans infection in normal and granulocytopenic mice.

The efficacies of cilofungin (Ly121019), a semisynthetic lipopeptide antifungal agent, and amphotericin B in the treatment of disseminated candidiasis in normal and neutropenic mice were compared. In mice infected with 2 x 10(6) CFU of Candida albicans, treatment with cilofungin in twice-daily doses of 25 or 35 mg/kg of body weight by intraperitoneal injection for 10 days gave survival rates of 83 and 90%. In contrast, there was 97% mortality in infected controls receiving 2 x 10(6) CFU intravenously and 93% survival in mice treated with 1 mg of amphotericin B per kg once a day. Mice rendered granulocytopenic by the administration of cyclophosphamide showed survival rates of 83 and 80% when treated with 25 or 35 mg of cilofungin per kg for 10 days compared with 43% survival rate in mice treated with 1 mg of amphotericin B per kg (P = 0.0030 and P = 0.0080, respectively). Similar results were obtained when the two antifungal agents were administered for a period of 30 days. Administration of 25 or 35 mg of cilofungin per kg twice a day to granulocytopenic mice receiving 10(6) CFU of C. albicans gave survival rates of 93% and 93% compared with 53% survival with amphotericin B. With 15 mg of cilofungin per kg twice a day for 10 days, a survival rate of 43 to 50% was observed in both normal and granulocytopenic mice compared with 56 and 60%, respectively, when this dosage was continued for 30 days. Cilofungin eradicated C. albicans from the kidneys, spleens, and livers of surviving animals. No toxic effects were observed with any of the dosage regimens used. The clearance of C. albicans from the kidneys, spleens, livers, and brains in normal mice was studied following infection with 5 x 10(5) and 1 x 10(5) intravenously. The mice in the treatment groups received 25 mg of cilofungin per kg twice a day for 10 days. In 8 to 12 days, this treatment was able to clear the organisms from the kidneys, spleens, and livers of mice infected with 5 x 10(5) C. albicans. Mice infected with 10(5) C. albicans and treated with cilofungin (25 mg/kg) twice a day for 10 days had no organisms in the kidney, spleen, and liver at days 8, 2, and 8, respectively. There was 1-log-unit reduction in C. albicans counts in brain tissue from mice of one of the treated groups between 2 h and 2 days postinfection, after which the numbers of organisms remained the same until day 12. These data demonstrate the efficacy of cilofungin in the treatment of disseminated C. albicans infections in normal and granulocytopenic mice. The treatment regimen used in this study was able to clear C. albicans from the kidneys, spleen, and liver but not from brain tissue.     

Comparison of fluconazole and amphotericin B for treatment of experimental Candida endocarditis caused by non-C. albicans strains.

Amphotericin B and fluconazole were compared for the treatment of experimental Candida endocarditis caused by Candida tropicalis and C. parapsilosis. Rabbits received no therapy, amphotericin B (1 mg/kg of body weight per day intravenously), or fluconazole (100 mg/kg/day intraperitoneally) for either 11 or 21 days. Against both species, amphotericin B and fluconazole were equally effective overall; however, amphotericin B was more rapidly fungicidal than fluconazole in vivo against C. tropicalis.