Amphotericin B Lipid Complex Research Articles

Use of amphotericin B lipid complex in elderly patients

The safety and effectiveness of amphotericin B lipid complex (ABLC) treatment in elderly patients was investigated using a large multicenter database. Data analysis was conducted on retrospectively collected patient data from 572 patients >65 years of age and 2930 patients < or =65 years of age treated for fungal infections at 160 North American hospitals. Patients were typically treated with ABLC for Candidiasis, multiple fungal pathogen infections and Aspergillosis, or were treated empirically. The median cumulative dose of ABLC in patients >65 years of age and those 65 years of age was similar (3000 and 3258 mg, respectively, P=0.127). Despite higher median pretreatment serum creatinine (S-Cr) among patients >65 years of age (1.7 mg/dl vs. 1.4 mg/dl, respectively), both groups showed only a 0.1mg/dl median S-Cr change from baseline by the end of therapy (P=0.525). Clinical response was 56 and 51%, respectively, in patients >65 years of age and patients 65 years of age or younger (P=0.049). This study suggests that ABLC can be safely and effectively used in the treatment of invasive fungal disease in elderly patients.

Pharmacoeconomic analysis of amphotericin B lipid complex versus liposomal amphotericin B in the treatment of fungal infections.

Potential differences in toxicity, potency and acquisition price among the liposomal amphotericin B formulations makes it unclear which agent is less costly when total resource consumption and treatment-associated costs are considered. A retrospective cost-minimisation analysis in 51 patients was performed to compare the cost of amphotericin B lipid complex (ABLC) and liposomal amphotericin B (L-AMB) from the hospital perspective. Costs ($US, 2001 values) were divided into level I (acquisition price only), level II (costs of all associated treatment, i.e. adverse events, failures, etc.) and level III (total fungal-related hospitalisation) costs. No significant differences in patient demographics or length of therapy were apparent among those receiving ABLC or L-AMB. The clinical success rate in this population was similar between ABLC and L-AMB (53% vs 60%, p = 0.68), thus justifying the use of a cost-minimisation analysis. Among patients with baseline elevations in serum creatinine, 47% receiving ABLC and 10% receiving L-AMB experienced further increases in serum creatinine (p = 0.025). No differences in total treatment costs (level I, II, or III) were evident between patients receiving ABLC or L-AMB. When adjusted for duration of therapy, however, costs were significantly lower for ABLC than for L-AMB (level I: ABLC $US340 versus L-AMB $US435, p = 0.002; level II: ABLC $US361 versus L-AMB $US454, p = 0.027). The costs attributable to the prevention or treatment of adverse events were not different between the two treatments, and the economic outcome in this analysis was highly sensitive to the acquisition price and dosage of the lipid antifungal formulation. Two-way sensitivity analysis revealed that as long as the milligram price of L-AMB was greater than 135% of the milligram price of ABLC, ABLC remained the less costly formulation. In this patient population, total hospitalisation costs were not different between lipid antifungal formulations. However, after controlling for duration of therapy, ABLC was less costly than L-AMB, when considering acquisition costs of the lipid antifungal agent and costs associated with concomitant antifungal therapy and the treatment of adverse events or lipid failures, indicating that the acquisition price of these agents should be predictive of their cost differences.

Corneal Concentrations following Systemic Administration of Amphotericin B and Its Lipid Preparations in a Rabbit Model

Background: Amphotericin B (AmB) and various lipid formulations of AmB are available for the treatment of fungal infections of the eye. Currently, the recommended route of administration for the treatment of fungal keratitis is by topical application. Nevertheless, because of the risk of a difficult to treat exogenous fungal endophthalmitis, a combined topical and systemic treatment is frequently given when treating deep fungal keratitis. To date, little is known about the pure corneal availability of these drugs following systemic treatment. In this study, the corneal concentration following 7 daily doses of parenteral AmB lipid complex (ABLC) or liposomal AmB (L-AmB) was compared to that of AmB deoxycholate (D-AmB) in a rabbit model. Methods: Following induction of uveitis in one rabbit eye by intravitreal injection of endotoxin, daily doses of D-AmB (1 mg/kg), ABLC (5 mg/kg) or L-AmB (5 mg/kg) were given intravenously on 7 consecutive days. Five or more rabbits per treatment were used. AmB concentrations were determined by high-performance liquid chromatography (HPLC) in corneas collected at autopsy 24 h after the 7th and final dose. Data were analyzed using the Mann-Whitney U test. Results: After 7 days of treatment, mean corneal concentrations of AmB in the inflamed eyes were significantly higher (2.38 ± 1.47 µg/g; p < 0.01) following treatment with L-AmB compared with ABLC (<0.1 µg/g) and D-AmB (0.46 ± 0.2 µg/g). No AmB could be detected in the corneas of the non-inflamed eyes. Conclusion: In our rabbit model, AmB penetration into the cornea was significantly higher after systemic administration of L-AmB compared with conventional D-AmB or ABLC.

Pharmacokinetics of amphotericin B lipid complex in critically ill patients on continuous veno-venous haemofiltration

Pharmacokinetics of amphotericin B lipid complex (ABLC) was determined in two critically ill patients requiring continuous veno-venous haemofiltration (CVVH) because of acute renal failure. ABLC was administered at a mean daily dose of 4.94 mg/kg for suspected invasive mycosis. Mean C max was 0.56 μg/ml, the mean AUC 0−24 h was 7.46 mg h/l, V ss 9.13 l/kg, and t 1/2 was 13.21 h. The haemofilter clearance accounted about 20% of the total ABLC clearance. In one patient sampling was repeated after CVVH had been discontinued. The concentration–time profiles were very similar on and off haemofiltration. Data on our two patients suggest, that pharmacokinetics of ABLC is not significantly affected by CVVH and that ABLC can be administered at the standard doses during CVVH.

Successful Outcome of DisseminatedFusariumInfection with Skin Localization Treated with Voriconazole and Amphotericin B-Lipid Complex in a Patient with Acute Leukemia

A disseminated Fusarium oxysporum infection with skin localization was diagnosed in a woman with a relapse of B-acute leukemia during induction chemotherapy. The infection was refractory to amphotericin B-lipid complex alone but responded successfully when voriconazole was added.

1214 A large scale chemotherapy quality improvement project; initiating standardized treatment, administration and information in the hospitals in the region of the comprehensive cancer centre rotterdam

Patients with fungal infections who are treated with amphotericin B lipid complex (ABLC) often receive dosages less than that recommended in the product information (5 mg/kg·d). This occurs despite the described safety and increased efficacy in select patients treated with higher ABLC dosages.The purpose of this study was to compare the renal effects of high-dosage/long-duration (HDos/LDur) ABLC therapy (>5 mg/kg·d for >12 days) with those of low-dosage/short-duration (LDos/SDur) ABLC therapy (≤5 mg/kg·d for ≤12 days).Male and female ABLC-treated patients of all ages were prospectively enrolled, and data were retrospectivelycollected for those who had received ≥4 ABLC doses according to a large, multicenter patient database, the Collaborative Exchange of Antifungal Research (CLEAR) registry. The safety profile of each dosage was evaluated using serum creatinine concentration (S-Cr) and calculated creatinine clearance (CCcr).A total of 1726 patients were studied. The HDos/LDur group included 309 patients and theLDos/SDur group included 1417 patients. The median ages of the HDos/LDur and LDos/SDur groups were 42 and 48 years, respectively (ranges, <1 to 83 and <1 to 95 years; P < 0.001); females comprised 51% and 42% of the 2 populations (P = 0.004); and 6% and 12% had solid tumors (P = 0.002). The HDos/LDur group was more likely than the LDos/SDur group to have been treated for multiple systemic fungal pathogen infections (16% and 9%, respectively) and for mold infections (28% and 12%, respectively) (both, P < 0.001). The median change in S-Cr from baseline was 0.1 mg/dL in both groups (range, −4.9 to 5 mg/dL in the HDos/LDur group and −3.96 to 4.7 mg/dL in the LDos/SDur group). No increased risk for renal dysfunction, as reflected in the median change from baseline in CCcr, was observed in either cohort (−3 mL/min [range, −118.65 to 69.03 mL/min] in the HDos/LDur group; −2.17 mL/min [range, −107.48 to 104.45 mL/min] in the LDos/SDur group).These data suggest that higher ABLC dosages appear to be as well tolerated as lower dosages, warrantingfurther study of ABLC dosages >5 mg/kg·d for >12 days in the treatment of systemic fungal infections.

1216 Education in groups — the path for improved clinical practise? — a comparative study on benefits from preparatory education in radiation therapy measured before and after modified educational procedure

Patients with fungal infections who are treated with amphotericin B lipid complex (ABLC) often receive dosages less than that recommended in the product information (5 mg/kg·d). This occurs despite the described safety and increased efficacy in select patients treated with higher ABLC dosages.The purpose of this study was to compare the renal effects of high-dosage/long-duration (HDos/LDur) ABLC therapy (>5 mg/kg·d for >12 days) with those of low-dosage/short-duration (LDos/SDur) ABLC therapy (≤5 mg/kg·d for ≤12 days).Male and female ABLC-treated patients of all ages were prospectively enrolled, and data were retrospectivelycollected for those who had received ≥4 ABLC doses according to a large, multicenter patient database, the Collaborative Exchange of Antifungal Research (CLEAR) registry. The safety profile of each dosage was evaluated using serum creatinine concentration (S-Cr) and calculated creatinine clearance (CCcr).A total of 1726 patients were studied. The HDos/LDur group included 309 patients and theLDos/SDur group included 1417 patients. The median ages of the HDos/LDur and LDos/SDur groups were 42 and 48 years, respectively (ranges, <1 to 83 and <1 to 95 years; P < 0.001); females comprised 51% and 42% of the 2 populations (P = 0.004); and 6% and 12% had solid tumors (P = 0.002). The HDos/LDur group was more likely than the LDos/SDur group to have been treated for multiple systemic fungal pathogen infections (16% and 9%, respectively) and for mold infections (28% and 12%, respectively) (both, P < 0.001). The median change in S-Cr from baseline was 0.1 mg/dL in both groups (range, −4.9 to 5 mg/dL in the HDos/LDur group and −3.96 to 4.7 mg/dL in the LDos/SDur group). No increased risk for renal dysfunction, as reflected in the median change from baseline in CCcr, was observed in either cohort (−3 mL/min [range, −118.65 to 69.03 mL/min] in the HDos/LDur group; −2.17 mL/min [range, −107.48 to 104.45 mL/min] in the LDos/SDur group).These data suggest that higher ABLC dosages appear to be as well tolerated as lower dosages, warrantingfurther study of ABLC dosages >5 mg/kg·d for >12 days in the treatment of systemic fungal infections.

A systematic review of the antifungal effectiveness and tolerability of amphotericin B formulations

Objective: A systematic review was performed to compare the effectiveness and tolerability of lipid-based amphotericin B (AmB) formulations and conventional AmB in the treatment of systemic fungal infections. Methods: The literature and unpublished studies were searched using MEDLINE, EMBASE, Biological Abstracts, AIDSLINE, CANCERLIT, CRD database, Cochrane Controlled Trials Register, and other databases. Search terms included: amphotericin, liposom ∗, lipid ∗, colloid ∗, antifungal agents , and mycoses. Studies were selected according to predetermined criteria. The outcome measures reviewed were efficacy, mortality, renal toxicity, and infusion-related reactions. Meta-analyses and number-needed-to-treat (NNT) analyses were performed. Results: Seven studies (8 publications) met the entry criteria. Meta-analysis showed that lipid-based formulations significantly reduced all-cause mortality risk by an estimated 28% compared with conventional AmB (odds ratio [OR], 0.72; 95% CI, 0.54 to 0.97). There was no significant difference in efficacy between the lipid-based formulations and conventional AmB (OR, 1.21; 95% CI, 0.98 to 1.49). AmB lipid complex (ABLC) and liposomal AmB (L-AmB) significantly reduced the risk of doubling serum creatinine by an estimated 58% (OR, 0.42; 95% CI, 0.33 to 0.54). There was no significant reduction in risk of infusion-related reactions with lipid-based formulations, although this was difficult to interpret given the lack of consistent control of confounding factors. Comparing the lipid-based formulations with conventional AmB, the overall NNT to prevent 1 death was 31. The NNT to prevent a doubling of serum creatinine for both ABLC and L-AmB compared with conventional AmB was 6. Conclusions: This study demonstrates advantages with lipid-based formulations over conventional AmB in terms of reduced risk of mortality and renal toxicity. Future trials in patients with proven fungal infection should control for factors such as premedication, infusion rates, fluid preloading, sodium/potassium supplementation, and concomitant medication.

Release of prostaglandin E-2 in bovine brain endothelial cells after exposure to three unique forms of the antifungal drug amphotericin-B: role of COX-2 in amphotericin-B induced fever

Common formulations of amphotericin-B include a deoxycholate colloidal suspension (d-Amph), an amphotericin-B lipid complex (Ablc), and a liposomal product (l-Amph). The clinical incidence of infusion related fever is highest with d-Amph, intermediate with Ablc, and lowest with l-Amph. In the present study, we measured the activation of cyclooxygenase-2 (COX-2) and subsequent release of prostaglandin E-2 (PgE-2) from brain microvessel endothelium treated with these three formulations of amphotericin-B. Primary cultured bovine brain microvessel endothelial cells (BBMEC) were exposed to d-Amph, Ablc and l-Amph at concentrations that can be achieved in the plasma of patients receiving the drug. Media samples from the cells were collected and analyzed for PgE-2. Release of PgE-2 from BBMEC monolayers treated with l-Amph was similar to cells receiving culture media alone. In contrast, Ablc and d-Amph caused significantly greater release of PgE-2 from BBMEC monolayers compared to controls receiving culture media alone. PgE-2 release after d-Amph treatment was similar in magnitude to that observed with bacterial lipopolysaccharide (LPS). Western blot analysis indicated significant induction of COX-2 expression in BBMEC following LPS, Ablc or d-Amph treatment. Furthermore, PgE-2 release following exposure of BBMEC monolayers to either LPS or the various amphotericin-B formulations was reduced by the addition of the selective COX-2 inhibitor, NS-398. These studies indicate that amphotericin-B induces COX-2 expression in brain microvessel endothelium resulting in release of fever producing PgE-2. The magnitude of PgE-2 release from BBMEC following exposure to various amphotericin-B formulations mirrors the clinical observations regarding amphotericin-B induced fever and serves as initial support for the clinical use of COX-2 inhibitors to reduce amphotericin-B fever.

Comparison of in vitro Antifungal Activities of Amphotericin B Lipid Complex with Itraconazole against 708 Clinical Yeast Isolates and Opportunistic Moulds Determined by National Committee for Clinical Laboratory Standards Methods M27-A and M38-P

We compared the in vitro antifungal activity of amphotericin B lipid complex (ABLC) with that of itraconazole (ITZ) against 535 yeast strains and 173 opportunistic filamentous fungi by using a microdilution method (National Committee for Clinical Laboratory Standards M27-A and M38-P). The overall geometric mean MIC was 0.13 µg/ml and 0.177 µg/ml for ITZ and ABLC, respectively, and the MIC₅₀ was 0.125 µg/ml for both agents against yeast isolates. ITZ had a similar or slightly superior efficacy compared to ABLC when tested against Candida albicans, Candida parapsilosis, Cryptococcus neoformans, Candida krusei, Candida glabrata and Candida tropicalis. Effectiveness against C. glabrata was lower for ITZ (MIC₉₀ 2 µg/ml, and for ABLC, 0.5 µg/ml). For Aspergillus fumigatus, activity of ITZ was superior in comparison with ABLC (MIC₉₀ 1 and 16 µg/ml, respectively); MIC₉₀ for Aspergillus niger was 4 and 2 µg/ml for ABLC and ITZ, respectively. Scedosporium spp. showed a low susceptibility to both ABLC and ITZ. In conclusion, ABLC and ITZ are useful alternatives for the treatment of severe fungal infections. The selection of an antifungal agent should be made considering the toxicological and pharmacological properties and cost/benefit relationship and be supported by the susceptibility of the isolate.

Ocular distribution of intravenously administered lipid formulations of amphotericin B in a rabbit model.

Little is known about the ocular penetration of amphotericin B (AMB) and its lipid formulations, the current drug of choice in fungal endophthalmitis. The ocular distribution of AMB lipid complex (ABLC), liposomal AMB (L-AMB), and AMB deoxycholate (D-AMB) was studied in a rabbit model. D-AMB (1 mg/kg of body weight/day), ABLC (5 mg/kg/day), or L-AMB (5 mg/kg/day) was given intravenously to rabbits as a single dose or as repeated daily doses on 7 consecutive days after induction of unilateral uveitis by intravitreal injection of endotoxin. AMB concentrations in aqueous humor, vitreous humor, and plasma were determined by high-pressure liquid chromatography 16 h after administration of a single dose or 24 h after the last of seven doses. After single-dose administration, L-AMB achieved at least eightfold-higher AMB concentrations in the aqueous of inflamed eyes than ABLC or D-AMB (1.21 +/- 0.58 micro g/ml versus 0.14 +/- 0.04 and 0.11 +/- 0.09 micro g/ml, respectively). At that time point no drug was detectable in the vitreous. After 7 days of treatment, the concentration of AMB in the vitreous was higher after treatment with L-AMB (0.47 +/- 0.21 micro g/ml) than after treatment with ABLC (0.27 +/- 0.18 micro g/ml) and D-AMB (0.16 +/- 0.04 micro g/ml). Similarly, AMB concentration in the aqueous was higher after repeated doses of L-AMB (0.73 +/- 0.43 micro g/ml) than after repeated doses of ABLC (0.03 +/- 0.02 micro g/ml) or D-AMB (0.13 +/- 0.06 micro g/ml). No AMB was detected in noninflamed eyes. Following systemic administration, AMB distribution to the eye is inflammation dependent and occurs sequentially, first to the aqueous and then to the vitreous. Compared to D-AMB and ABLC, L-AMB reaches higher drug concentrations in both ocular compartments.

Infrequent occurrence of amphotericin B lipid complex-associated nephrotoxicity in various clinical settings at a university hospital: A retrospective study

Background: Lipid-based formulations of amphotericin B (AMB) have been shown to significantly lessen the occurrence of nephrotoxicity associated with the conventional form of AMB. A MEDLINE search of literature published from 1983 to 2002, using the search terms amphotericin B and nephrotoxicity, identified only 1 large, randomized, prospective trial that has tried to compare the nephrotoxicity rates among lipid-based AMB formulations. Using the nephrotoxicity surrogate marker of doubling of serum creatinine (SCr) level, the investigators reported a high rate of AMB lipid complex (ABLC)-associated nephrotoxicity (42.3%). However, enrollment in that study was limited to only febrile neutropenic patients. Objective: This retrospective study estimated the rate of ABLC-associated nephrotoxicity in various clinical settings at a university hospital and compared that rate with previously reported rates of nephrotoxicity. Methods: Data from adult neutropenic and nonneutropenic patients receiving ABLC were collected and the degree of nephrotoxicity was determined using 2 definitions: (1) doubling of baseline SCr level using the peak value within the first 7 days, and (2) end-of-therapy doubling of baseline SCr level using the end-of-therapy value. Results: Data from 33 patients (20 men, 13 women; mean age, 48.6 years) were collected. Using these definitions of ABLC-associated nephrotoxicity, only 2 cases (6.1%) were observed. This rate was significantly below the 42.3% rate reported in the only large published study (95% CI, 1.7–19.6; P < 0.001). The median change in SCr level was 0.1 mg/dL (range, −1.1 to 4.3 mg/dL). Rates of change were higher in patients who died during hospitalization, but the difference was not significant. Use of concomitant nephrotoxic agents did not account for significant changes in SCr level. Conclusions: Data from this study suggest that ABLC infrequently causes clinically significant nephrotoxicity. Therefore, when formulary decisions are made in the selection of a drug for use in various clinical settings, earlier data derived from a single study in febrile neutropenic patients that suggested a significantly higher rate of nephrotoxicity should be interpreted cautiously. Larger trials with more diverse patient populations are needed to better characterize institutional rates of ABLC-associated nephrotoxicity and to aid formulary decision makers.

Liposomal Amphotericin B for Visceral Leishmaniasis in a Kidney Allograft Patient

Objective To report a case of visceral leishmaniasis treated with liposomal amphotericin B (LAB) after probable failure with amphotericin B lipid complex (ABLC). Case Summary A 62-year-old white renal transplant recipient was admitted for pyrexia, hepato-splenomegaly, and pancytopenia. Leishmania amastigotes were detected from bone marrow aspirate and in circulating blood monocytes and neutrophils. The patient, who weighed 56 kg, received ABLC at a starting dose of 200 mg/d (3.6 mg/kg of body weight per day) for 13 days, achieving a total dose of 2,600 mg (46 mg/kg) without clinical improvement. The patient was switched to 100 mg/d (1.8 mg/kg) of LAB for 10 days, after which a dose of 250 mg (4.5 mg/kg) was repeated on days 17,24,31, and 38. Twenty-four hours after the first dose of LAB, the patient showed an excellent clinical response. On the following days, there was a progressive increase in hemoglobin concentration and leukocyte and platelet counts. Three months later, the patient was asymptomatic. Discussion Although treatment with ABLC appears to be effective for the treatment of Indian patients with visceral leishmaniasis, experience with immunocompromised patients is limited. This is the first case of a renal transplant recipient in which ABLC was used to treat visceral leishmaniasis without remarkable efficacy, but with infusion-related adverse effects perhaps due to the use of higher doses. Conclusions A randomized comparative trial is needed to compare LAB with ABLC in the treatment of visceral leishmaniasis in patients who have received kidney allografts.

Amphotericin B formulations exert additive antifungal activity in combination with pulmonary alveolar macrophages and polymorphonuclear leukocytes against Aspergillus fumigatus.

Deoxycholate amphotericin B (DAMB) and amphotericin B lipid complex (ABLC) additively augmented the fungicidal activity of pulmonary alveolar macrophages against the conidia of Aspergillus fumigatus. DAMB, ABLC, and liposomal amphotericin B similarly displayed additive effects with polymorphonuclear leukocytes in damaging the hyphal elements of A. fumigatus.

Lipid formulation as a drug carrier for drug delivery.

In recent years, a Drug Delivery System (DDS), a preparative approach attracts the attention in the development of new drugs. DDS focuses on the regulation of the in vivo dynamics, such as absorption, distribution, metabolism, and elimination, thereby improving the effectiveness and the safety of the drugs by an applicable use of drug preparation technologies. A conventional intravenous dosage form of Amphotericin B (AmB), Fungizone, is the most effective clinically available for treating fungal infections. However, the clinical efficacy of AmB is limited by its adverse effects. Several lipid formulations, such as Liposomal AmB (L-AmB), AmB lipid complex (ABLC), and AmB colloidal dispersion (ABCD), with reduced side effects have been developed. These formulations are reported to have excellent safety and efficacy. However, comparable efficacy can be achieved only when they are administered at high doses than AmB. One of the problems of using these formulations is that they are easily taken up by the reticuloendothelial system (RES). An artificial lipoprotein-like particles, a novel drug carrier Lipid Nano-Sphere (LNS), which is 25 - 50 nm in size and is composed of phospholipids and simple lipid. LNS show a higher plasma concentration of drugs and lower uptake by RES-tissue different forms other lipid base drug carriers. In vitro and in vivo, LNS incorporating AmB, NS-718, shows reduced toxicity, while maintaining activity against fungi. LNS have a unique characteristic as an effective carrier of AmB for treatment of fungal infection.

Drug delivery system of anti-fungal and parasitic agents.

The antifungal agents for systemic mycoses are only a few in number. Among them amphotericin-B is still the most widely used drug, but substantial side effects including nephrotoxicity limits its clinical usefulness. Efforts to lower the toxicity are synthesis of AMPH-B analogues such as AMPH-B esters and encapsulation in lipid vesicles in the forms of liposomal AMPH-B (AmBisome), amphotericin-B lipid complex (Abelcet), amphotericin-B colloidal dispersion (Amphocil) and intralipid AMPH-B. The newer formulations are effective against wide range of fungi, may be given in higher doses and nephrotoxicity is lowered. Although all of them showed comparable efficacies, a standard formulation is yet to be determined. In Japan, studies on efficacies of lipid nanosphere-encapsulated AMPH-B are in progress. Special drug career systems and dosage forms, such as nanoparticles and liposomes hold the promise of overcoming the pharmacokinetic limitations. Nanoparticles are stable, solid colloidal particles consisting of macromolecular material and vary in size. Nanoparticles represent an interesting carrier system for the specific enrichment in macrophage containing organs like liver and spleen. Injectable nanoparticle carriers have important potential applications as in site-specific drug delivery. Modifications of liposomes in order to avoid uptake by RES, thus increase targetability has been attempted. A novel targetable liposome 34A-PEG-L modified with polyethylene glycol conjugated with MoAb, 34A specific to murine pulmonary epithelia has been evaluated in murine pulmonary aspergillosis. 34A-PEG-L-AmB showed higher tissue concentration and comparable efficacy than other AMPH-B formulations.

Fungal phospholipase activity and susceptibility to lipid preparations of amphotericin B.

It has been postulated that phospholipases of fungal origin can affect in vitro susceptibility testing of amphotericin B lipid complex (ABLC). We used specific phospholipase-deficient mutants of Candida albicans and Cryptococcus neoformans in susceptibility testing and demonstrated that extracellular fungal phospholipase activity does not influence the in vitro susceptibilities of these two fungi to ABLC.

Amphotericin B lipid complex or amphotericin B multiple-dose administration to rabbits with elevated plasma cholesterol levels: pharmacokinetics in plasma and blood, plasma lipoprotein levels, distribution in tissues, and renal toxicities.

The purpose of the present study was to determine if a relationship exists between the plasma cholesterol concentration, the severity of amphotericin B (AmpB)-induced renal toxicity, and the pharmacokinetics of AmpB in plasma in hypercholesterolemic rabbits administered multiple doses of amphotericin B (AmB) deoxycholate (Doc-AmB) and AmB lipid complex (ABLC). After 7 days of administration of a cholesterol-enriched diet (0.50% [wt/vol]) or a regular rabbit diet, each rabbit was administered a single intravenous bolus of Doc-AmB (n = 8) or ABLC (n = 10) (1.0 mg/kg of body weight) daily for 7 consecutive days (a total of eight doses). Blood samples were obtained daily before and 24 h after the administration of each dose and serially thereafter following the administration of the last dose for the assessment of pharmacokinetics in plasma, kidney toxicity, plasma lipoprotein levels, and drug distribution in tissue. The pharmacokinetics of AmB in blood following the administration of ABLC were also determined in rabbits fed cholesterol-enriched and regular diets (n = 3 each group). Before drug treatment, cholesterol-fed rabbits demonstrated marked increases in total, low-density lipoprotein (LDL), and triglyceride-rich lipoprotein (TRL) cholesterol levels in plasma compared with the levels in rabbits on a regular diet. No significant differences in total plasma triglyceride levels were observed. Significant increases in plasma creatinine levels were observed in rabbits fed a cholesterol-enriched diet (P < 0.05) and rabbits fed a regular diet (P < 0.05) when administered AmB. However, the magnitude of this increase was twofold greater in rabbits fed a regular diet than in rabbits fed a cholesterol-enriched diet. An increase in plasma creatinine levels was observed only in rabbits on a cholesterol-enriched diet administered ABLC. The pharmacokinetics of AmB were significantly altered in rabbits on a cholesterol-enriched diet administered Doc-AmB or ABLC compared to those in rabbits on a regular diet administered each of these compounds. The pharmacokinetics of AmB in blood were significantly different following ABLC administration but not following Doc-AmB administration in both rabbits fed cholesterol-enriched diets and rabbits fed regular diets compared to their corresponding pharmacokinetics in plasma. An increased percentage of AmB was recovered in the TRL fraction when Doc-AmB was administered to rabbits fed a cholesterol-enriched diet than when it was administered to rabbits fed a regular diet. Furthermore, an increased percentage of AmB was recovered in the LDL and TRL fractions when ABLC was administered to rabbits fed a cholesterol-enriched diet rabbits fed a regular diet. These findings suggest that an increase in plasma cholesterol levels modifies the pharmacokinetics of AmB and renal toxicity following the administration of multiple intravenous doses of Doc-AmB and ABLC.

Efficacy of amphotericin B lipid complex in the treatment of invasive fungal infections in immunosuppressed paediatric patients.

The safety and efficacy of amphotericin B lipid complex (ABLC) were evaluated in a retrospective study of 46 paediatric patients with invasive infections. The study included a large proportion of patients who were refractory to or intolerant of conventional antifungal therapy. The mean age of the children was 9.7 +/- 4.8 years. Primary underlying conditions included mainly haematopoietic stem cell transplantation, leukaemia and lung transplantation. The mean daily dose given was 4.11 mg/kg for a mean duration of 38.7 days. At the end of therapy, 38 of 46 (83%) patients responded successfully to treatment with ABLC, including 18 of 23 (78%) with aspergillosis and 17 of 19 (89%) with candidiasis. ABLC was well tolerated, with a low incidence of adverse events. The mean creatinine value was 74.5 microl/mol/l at baseline and 78.2 micromol/l at the end of therapy. These results support the use of ABLC in the treatment of invasive fungal infections in children, including patients who have previously failed, or are intolerant of, traditional antifungal regimens.

Nouvelles formes lipidiques de l’amphotéricine B. Revue de la littérature

Introduction. – Amphotericin B (amB) remains the gold standard for treatment of invasive fungal infections. Lipid formulations of amB have been developed in an attempt to improve both efficacy and tolerability (especially renal toxicity): amB lipid complex (ABLC), liposomal amB (AmBisome®), amB colloidal dispersion (ABCD) and amB in lipid emulsion (Intralipid®). This review analyzes the data available in the literature. Current knowledge and key points. – ABLC, AmBisome and ABCD are effective in various fungal infections, including invasive aspergillosis, systemic candidiasis, cryptococcal meningitis, mucormycosis and fusariosis. These formulations are also effective in persistent febrile neutropenia and in leishmaniosis. The three formulations show little renal toxicity and are safer than conventional amB in this respect. Preliminary data are available on amB in Intralipid: infusion-related adverse effects are reduced, but few data are available on efficacy in documented mycoses. Future prospects and projects. – Large-scale comparative clinical trials may clarify issues of relative efficacy in various forms of fungal infections.