Interaction between fluconazole and amphotericin B in mice with systemic infection due to fluconazole-susceptible or -resistant strains of Candida albicans. (73/2502)

The interaction between fluconazole (Flu) and amphotericin B (AmB) was evaluated in a murine model of systemic candidiasis for one Flu-susceptible strain (MIC, 0.5 microg/ml), two strains with intermediate Flu resistance (Flu mid-resistant strains) (MIC, 64 and 128 microg/ml), and one highly Flu-resistant strain (MIC, 512 microg/ml) of Candida albicans. Differences in fungal densities in kidneys of infected mice after 24 h of therapy and in survival rates at 62 days of mice treated with an antifungal drug or a combination of antifungal drugs for 4 days were compared. For the Flu-susceptible and Flu mid-resistant strains, the combination of Flu and AmB was antagonistic, as shown by both quantitative culture results and survival. The interaction was additive for the highly Flu-resistant strain. These results suggest that the combination of Flu and AmB should be used with caution in infections due to fungi that are usually susceptible to both antifungal agents and as empirical antifungal drug therapy.  (+info)

Efficacy of the triazole SCH 56592 against Leishmania amazonensis and Leishmania donovani in experimental murine cutaneous and visceral leishmaniases. (74/2502)

Current therapy for leishmaniasis is unsatisfactory. Efficacious and safe oral therapy would be ideal. We examined the efficacy of SCH 56592, an investigational triazole antifungal agent, against cutaneous infection with Leishmania amazonensis and visceral infection with Leishmania donovani in BALB/c mice. Mice were infected in the ear pinna and tail with L. amazonensis promastigotes and were treated with oral SCH 56592 or intraperitoneal amphotericin B for 21 days. At doses of 60 and 30 mg/kg/day, SCH 56592 was highly efficacious in treating cutaneous disease, and at a dose of 60 mg/kg/day, it was superior to amphotericin B at a dose of 1 mg/kg/day. The means of tail lesion sizes were 0.32 +/- 0.12, 0.11 +/- 0.06, 0.17 +/- 0.07, and 0.19 +/- 0.08 mm for controls, SCH 56592 at 60 and 30 mg/kg/day, and amphotericin B recipients, respectively (P = 0.0003, 0.005, and 0.01, respectively). Parasite burden in draining lymph nodes confirmed these efficacy findings. In visceral leishmaniasis due to L. donovani infection, mice treated with SCH 56592 showed a 0.5- to 1-log-unit reduction in parasite burdens in the liver and the spleen compared to untreated mice. Amphotericin B at 1 mg/kg/day was superior to SCH 56592 in the treatment of visceral infection, with a 2-log-unit reduction in parasite burdens in both the liver and spleen. These studies indicate very good activity of SCH 56592 against cutaneous leishmaniasis due to L. amazonensis infection and, to a lesser degree, against visceral leishmaniasis due to L. donovani infection in susceptible BALB/c mice.  (+info)

Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis. (75/2502)

The records of 239 immunosuppressed patients receiving amphotericin B for suspected or proven aspergillosis were reviewed to determine rates of nephrotoxicity, dialysis, and fatality. The mean and median durations of treatment were 20.4 and 15.0 days, respectively. The creatinine level doubled in 53% of patients and exceeded 2.5 mg/dL in 29%; 14.5% underwent dialysis; and 60% died. A multivariate Cox proportional hazards analysis showed that patients whose creatinine level exceeded 2.5 mg/dL (hazard ratio [HR], 42.02; P<.001), allogeneic bone marrow transplantation (BMT) patients (HR, 6.34; P<. 001), and autologous BMT patients (HR, 5.06; P=.024) were at greatest risk for requiring hemodialysis. Use of hemodialysis (HR, 3. 089; P<.001), duration of amphotericin B use (HR, 1.03 per day; P=. 015), and use of nephrotoxic agents (HR, 1.96; P=.017) were associated with greater risk of death, whereas patients undergoing solid organ transplantation were at lowest risk (HR, 0.46; P=.002). These data indicate that elevated creatinine levels during amphotericin B treatment are associated with a substantial risk for hemodialysis and a higher mortality rate, but the risks vary in different patient groups.  (+info)

A pilot study of the management of uncomplicated candidemia with a standardized protocol of amphotericin B. (76/2502)

We evaluated an amphotericin treatment strategy on the basis of duration of candidemia and clinical findings. Patients without neutropenia who had uncomplicated candidemia received 200 mg of amphotericin B over 5-7 days if they had had 1 day of positive cultures (PC group). The clinical cure rate was 93% (95% confidence interval [CI], 77%-99%; n=29 episodes) in the SC group, with no relapses (median follow-up, 272 days). The clinical cure rate was 83% (95% CI, 64%-94%; n=29 episodes) in the PC group, with 1 relapse (4.2%). The results of this pilot study suggest that patients with candidemia may be stratified into risk groups on the basis of the duration of positive blood cultures and other clinical findings. Decisions about the duration of therapy can be made 4-7 days after initiation of treatment. Carefully selected patients with transient uncomplicated candidemia may be safely treated with a short course of amphotericin B. Further prospective validation of this concept should be undertaken particularly to evaluate the impact on low-frequency late complications (e.g., endophthalmitis).  (+info)

Amphotericin B lipid complex (ABLC)-associated hypertension: case report and review. (77/2502)

Amphotericin B (AmB) continues to be the mainstay of therapy for serious fungal infections, despite its relatively toxic side-effect profile. Lipid preparations of the medication have been marketed in the past few years in an attempt to reduce some of these side effects, especially nephrotoxicity. Although 6 cases of severe hypertension associated with the use of AmB deoxycholate have been reported in the literature, no cases of hypertension associated with a lipid-containing preparation of the medication have been reported. We report here the first case of severe hypertension associated with the infusion of AmB lipid complex (ABLC) in a patient with multiple intraperitoneal and urinary fungal pathogens. We also provide a brief review of the previously reported cases of hypertension associated with the deoxycholate formulation of AmB.  (+info)

In-vitro susceptibility of Aspergillus spp. isolates to amphotericin B and itraconazole. (78/2502)

The MICs of amphotericin B and itraconazole for 230 isolates of Aspergillus spp., comprising 156 Aspergillus fumigatus, 20 Aspergillus terreus, 22 Aspergillus flavus, 17 Aspergillus nidulans and 15 Aspergillus niger, were determined by a broth microdilution method with RPMI 1640 medium. No isolate was detected with an MIC of amphotericin B >2 mg/L. Itraconazole MICs >16 mg/L were detected for four Aspergillus fumigatus and one Aspergillus nidulans isolates.  (+info)

Amphotericin B lipid complex at 3 mg/kg/day for treatment of invasive fungal infections in adults with haematological malignancies. (79/2502)

We treated 10 consecutive adults with a haematological malignancy, and an invasive aspergillosis (n = 8) or invasive candidosis (n = 2), with amphotericin B lipid complex (ABLC) at 3 mg/kg/day. Nine patients responded (five complete and four partial responses), and one died with invasive aspergillosis. Treatment was well tolerated, with only 4% of infusions followed by infusion-related adverse events, and the renal function improved in six patients who had an elevated serum creatinine before therapy. These data suggest that lower doses of ABLC may be equally effective but less toxic than higher doses. However, a controlled study is required to confirm these observations.  (+info)

Antifungal activity of amphotericin B-lipid admixtures in experimental systemic candidosis in naive mice. (80/2502)

We have shown previously that admixtures of amphotericin B (AMB) and Intralipid (AMB-IL) obtained by vigorous and prolonged agitation are stable and can be standardized. These preparations exhibited in-vitro activity against various Candida spp., and had significantly lower toxicity. The present study was undertaken to evaluate the activity of AMB-IL admixtures in vivo in comparison with the conventional formulation of AMB (Fungizone), using a murine model of experimental systemic candidosis. ICR female mice (4-6 weeks old) were injected iv with 5 x 10(4) Candida albicans CBS 562. The animals developed a lethal infection (100%) within 10 days. Systemic candidosis was demonstrated by the presence of fungal elements in kidneys and spleen tissue, and by enumeration of cfu of Candida in the tissue homogenates. AMB-IL or AMB was administered iv 48 h post-Candida inoculation for 5 consecutive days. Four experiments with 108 mice treated with AMB 5 x 0.4 mg/kg and followed up for 6 weeks, showed that the mean survival percentages at the end of the experiment were 0, 24.9 and 52.5% for the untreated group, conventional AMB-treated and AMB-IL-treated groups, respectively. The mean survival time (MST) was 7.4, 25 and 30 days for the untreated, conventional AMB-treated and AMB-IL-treated groups, respectively. Use of increased doses of AMB showed that conventional AMB at doses greater than 5 x 1 mg/kg caused immediate animal death. AMB-IL was used at doses of AMB up to 5 x 2 mg/kg. Experiments with 104 mice revealed that the mean survival percentage at the end of the experiment was 0, 34.5, 58.6 and 97% for the untreated, conventional AMB-treated (5 x 1 mg/kg), AMB-IL-1-treated (5 x 1 mg/kg) and AMB-IL-2-treated (5 x 2 mg/kg) groups, respectively. The MST was 7, 27.8, 34.8 and 41.4 days for the untreated, conventional AMB-treated, AMB-IL-1-treated and AMB-IL-2-treated groups, respectively. The results of this study reveal that AMB-IL is significantly more effective in treating systemic murine candidosis than conventional AMB.  (+info)