Amphotericin B Lipid Complex Research Articles

Comparative Efficacies, Toxicities, and Tissue Concentrations of Amphotericin B Lipid Formulations in a Murine Pulmonary Aspergillosis Model

Invasive aspergillosis, an important cause of morbidity and mortality in immunosuppressed (IS) patients, is often treated with amphotericin B lipid formulations. In the present study, liposomal amphotericin B (L-AMB) and amphotericin B lipid complex (ABLC) were compared in treatment of murine pulmonary aspergillosis. Uninfected, IS mice were treated for 4 days with 1, 4, 8, or 12 mg L-AMB or ABLC/kg of body weight, and their lungs were analyzed by high-performance liquid chromatography for drug concentrations. IS mice intranasally challenged with Aspergillus fumigatus were treated with 12, 15, or 20 mg/kg L-AMB or ABLC and monitored for survival, fungal burden (CFU), and tissue drug concentration. Blood urea nitrogen (BUN) levels and kidney histopathology were determined for uninfected and infected mice given 15 or 20 mg/kg L-AMB or ABLC. The results showed that both drugs had therapeutic levels of drug (>3.0 microg/g) in the lungs of uninfected or infected mice, and 24 h after the last dose, ABLC levels were significantly higher than L-AMB levels (P < 0.02). L-AMB and ABLC at 12 mg/kg both produced 57% survival, but only L-AMB at 15 or 20 mg/kg further increased survival to 80 to 90%, with BUN levels and kidney morphology similar to those of controls. Survival at 15 or 20 mg/kg ABLC was not significantly different than that of controls, and BUN levels were significantly elevated, with tubular alterations in uninfected animals and acute necrosis in kidney tubules of infected animals. In conclusion, although both drugs were effective in prolonging survival at 12 mg/kg, the reduced nephrotoxicity of L-AMB increased its therapeutic index, allowing for its safe and effective use at 15 or 20 mg/kg.

The experience is CLEAR ®

Conventional amphotericin B has been the ‘gold standard’ for antifungal efficacy, but nephrotoxicity problems limit its clinical utility. In the late 1990s, three lipid-based formulations of amphotericin B were introduced, all of which offered comparable efficacy and reduced renal complications. However, to date, robust safety and comparative efficacy data have been sparse. This paper briefly reviews the available clinical data on amphotericin B lipid complex (ABLC). Also, in detail, it reviews the findings of Collaborative Exchange of Antifungal Research (CLEAR ®), the most extensive dataset on systemic antifungal treatment with the lipid-based agent ABLC.

Deoxycholate amphotericin B and amphotericin B lipid complex exert additive antifungal activity in combination with pulmonary alveolar macrophages against Fusarium solani

Fusarium spp. have emerged as important causes of invasive fungal infections in immunocompromised patients. Rabbit pulmonary alveolar macrophages (PAMs) exhibited fungicidal activity against conidia of Fusarium solani and achieved a time-dependent increase in killing. Neither deoxycholate amphotericin B (DAMB) nor amphotericin B lipid complex (ABLC) exerted a suppressive effect on PAMs by decreasing their conidiocidal activity against F. solani. On the contrary, at a concentration of 0.125 microg ml(-1), ABLC and, to a lesser degree, DAMB additively augmented the fungicidal activity of pulmonary alveolar macrophages against conidia of Fusarium solani.

Pharmacokinetic-Pharmacodynamic Comparison of Amphotericin B (AMB) and Two Lipid-Associated AMB Preparations, Liposomal AMB and AMB Lipid Complex, in Murine Candidiasis Models

It is generally accepted that the lipid formulations of amphotericin B (AMB) are not as potent as conventional AMB on a milligram-per-kilogram basis. We used a neutropenic murine disseminated candidiasis model to compare the in vivo potencies of AMB, liposomal AMB (L-AMB), and AMB lipid complex (ABLC) pharmacodynamically. The pharmacokinetics of the antifungals were examined in serum and in three organs commonly seeded in disseminated candidiasis (kidneys, liver, and lung). Both single-dose time-kill studies and multiple-dosing-regimen studies were used with each of the compounds. Determinations of the numbers of CFU in the kidneys were performed following the administration of three escalating single doses of the polyenes at various times over 48 h. The areas under the time-kill curves (AUTKs) for each dose level of the drugs were compared by analysis of variance (ANOVA). In the multiple-dosing-regimen studies with five Candida isolates, AMB, L-AMB, and ABLC were administered daily for 72 h. The organism burdens in the mouse kidneys were similarly used as the treatment end point. Additional multiple regimen-dosing-studies were performed with a single Candida albicans isolate, and the microbiologic outcomes in four internal organs (kidneys, liver, spleen, and lung) were examined at the end of therapy (48 h). The relationship between the dose and the drug exposure expressed by the pharmacokinetics of the dosing regimens in serum and organ tissue were analyzed by using a maximum-effect model. ANOVA was used to compare the drug exposures necessary to achieve the 25% effective dose (ED25), ED50, ED75, and 1 log10 killing. Comparison of AUTKs suggested that AMB was 4.3- to 5.9-fold more potent than either ABLC or L-AMB. The time-kill curves for both lipid formulations were very similar. In the multiple-dosing-regimen studies, AMB was 5.0- to 8.0-fold more potent than each of the lipid formulations against five Candida isolates in the kidneys. Similar differences in potency (5.1- to 7.2-fold) were observed in the other end organs. The difference in pharmacokinetics in serum accounted for much of the difference in potency between AMB and ABLC (ratio of serum ABLC area under the curve of effective doses to serum AMB area under the curve of effective doses, 1.2). The differences in the kinetics in the various end organs between AMB and L-AMB were better at explaining the disparate potencies at these infection sites (ratio of organ L-AMB area under the curve of effective doses to organ AMB area under the curve of effective doses, 1.1).

Analisi Costo-Efficacia di Amfotericina B Liposomiale (L-AmB) versus Amfotericina B Complesso Lipidico (ABLC) nel trattamento empirico della neutropenia febbrile

Current international guidelines for the management of immuno-compromised patients with febrile neutropenia recommend a systemic antimicrobial therapy if fever hasn’t receded after three days of antibiotic treatment. Amphotericin B remains the gold standard because of its broad spectrum fungicidal action and minimal resistance development risk. Nonetheless, therapeutic use of the standard formulation, Amphotericin B deoxycholate, is limited by its toxicity, especially on the kidneys. To counteract this, amphotericin B has been encapsulated in liposomes, a process which reduces its toxicity and allows higher doses to be given. Three lipid formulations have been developed and are now available in most countries: amB colloidal dispersion (ABCD), amB lipid complex (ABLC), and liposomal amB (L-AmB). These lipid formulations differ in pharmacodynamics and pharmacokinetics, and can’t therefore be considered interchangeable. Besides, they are more expensive than Amphotericin B deoxycholate. Aim of the study is to perform a cost/effectiveness analysis (CEA) comparing L-AmB (3mg/kg/die or 5mg/kg/ die) and ABLC (5mg/kg/die) as first-line antimicrobial empirical treatments in immuno-compromised patients with febrile neutropenia resistant to broad spectrum antibiotics. Secondly, we present a cost-minimization analysis (CMA) of the considered alternatives, assuming the same efficacy for all treatments. At the end we value the principal cost items from the point of view of the Italian Health Service, with a particular focus on the economic burden caused by adverse reactions.

Population Pharmacokinetics of Amphotericin B Lipid Complex in Neonates

The pharmacokinetics of amphotericin B lipid complex (ABLC) were investigated in neonates with invasive candidiasis enrolled in a phase II multicenter trial. Sparse blood (153 samples; 1 to 9 per patient, 1 to 254 h after the dose) and random urine and cerebrospinal fluid (CSF) samples of 28 neonates (median weight [WT], 1.06 kg; range, 0.48 to 4.9 kg; median gestational age, 27 weeks; range, 24 to 41 weeks) were analyzed. Patients received intravenous ABLC at 2.5 (n = 15) or 5 (n = 13) mg/kg of body weight once a day over 1 or 2 h, respectively, for a median of 21 days (range, 4 to 47 days). Concentrations of amphotericin B were quantified as total drug by high-performance liquid chromatography. Blood data for time after dose (TAD) of <24 h fitted best to a one-compartment model with an additive-error model for residual variability, WT0.75 (where 0.75 is an exponent) as a covariate of clearance (CL), and WT as a covariate of volume of distribution (V). Prior amphotericin B, postnatal age, and gestational age did not further improve the model. The final model equations were CL (liters/h) = 0.399 x WT(0.75) (interindividual variability, 35%) and V (liters) = 10.5 x WT (interindividual variability, 43%). Noncompartmental analysis of pooled data with a TAD of >24 h revealed a terminal half-life of 395 h. Mean concentrations in the urine after 1, 2, and 3 weeks ranged from 0.082 to 0.430 microg/ml, and those in CSF ranged from undetectable to 0.074 microg/ml. The disposition of ABLC in neonates was similar to that observed in other age groups: weight was the only factor that influenced clearance. Based on these results and previously published safety and efficacy data, we recommend a daily dosage between 2.5 and 5.0 mg/kg for treatment of invasive Candida infections in neonates.

Clinical Response in ABLC-Treated Mould Infections, the CLEAR II™ Registry.

Mould infections are an important complication in immunocompromised patients. Aspergillus spp. is the most common mould pathogen and invasive aspergillosis (IA) is associated with high morbidity and mortality, with limited clinical response rates to available antifungals. Amphotericin B has been proven to be effective on IA, although it's tolerability and toxicity often limit the ability to provide full courses of therapy. It is hypothesized that high doses and/or prolonged duration of therapy might contribute to improved outcomes in IA and other invasive mould infections, but previous data were lacking. With the availability of amphotericin B lipid complex (ABLC), toxicities related to Amphotericin B (the parent compound) are attenuated and therefore, increased dosing is better tolerated. The CLEAR II study, a clinical practice registry study of ABLC utilization, provided data to evaluate the possibility that higher dose and longer duration of therapy might affect outcome of invasive mould infections. Data are from CLEAR II™, a multi-center registry in which patients with fungal infections are prospectively enrolled and data about organism, site clinical presentation and course and therapy are retrospectively collected. Patients with proven or probable mould infections were identified according to MSG criteria and available 1-month-post-treatment-start clinical response data were included. Outcomes included clinical response according to treatment with or without ABLC, as well as outcomes in patients treated with high dose (HD; ≥ 5 mg/kg/d), long duration (LDUR; ≥ 15 days) ABLC vs. low dose (LD), short duration (SDUR) ABLC. Also, outcomes according to ABLC use as initial versus second-line therapy were evaluated.Of the 735 patients who have been enrolled to date, baseline data has been entered for 378. One-month post-treatment-start clinical response data are available for 59 mould (45 proven or probable) infections. Among the 45 proven or probable mould infections (patients' mean age 54.3 yrs., 53.3% female, 73.3% Caucasian), 17 infections included treatment with ABLC while 28 did not; the majority of patients in both groups received more than 1 antifungal. Aspergillus spp. was the most common pathogen (53% in ABLC-treated; 69% in non-ABLC) and the lung was the most common infection site. The most common underlying diseases were hematologic malignancy (35.6%), chronic lung disease (15.6%), liver disease (11.1%), solid organ transplant (11.1%), and autoimmune disease (8.9%). 28.9% were neutropenic and 22.2% had a prior HSCT. Complete or partial response was achieved in 47.7% of ABLC -treated infections (those who received any amount of ABLC) vs. 23.3% of non-ABLC-treated infections. Complete or partial response was achieved in: 44.4% of infections treated with ABLC as an initial therapy (n=9) vs. 37.5% of infections treated with ABLC as a 2nd-line therapy (n=8). Complete or partial response was achieved in 50.0% of patients (n=6) receiving HD/LDUR vs. 33.3% of LD/SDUR ABLC patients (n=3). ABLC-associated response rates appear to be double relative to rates in non-ABLC-treated mould infections. High-dose, long duration ABLC appears to be more effective than low dose, short duration, as does 1st vs. 2nd line. More data will be available in the next few months and allow for a larger sample size from which to base conclusions and recommendations. A complete description of antifungal agents used including length of therapy will also be available.

Efficacy and toxicity of intermediate-dose amphotericin B lipid complex as a primary or salvage treatment of fungal infections in patients with hematological malignancies

We treated 74 adults with a hematological malignancy and documented or suspected invasive fungal infection (IFI) with amphotericin B lipid complex (ABLC) at 3 mg/kg/day. Forty-five patients (61%) received upfront therapy and 29 patients (39%) received salvage therapy for their IFI. Forty-eight of 71 evaluable patients responded [complete responses in 40 (56%) and partial responses in 8 (11%)] and 15 (21%) died as a consequence of the IFI. Response rates in invasive aspergillosis were 33 out of 49 (67%) for probable/definite cases and 6 out of 11 (55%) for invasive candidiasis. In 40 patients with neutropenia-associated IFI, rapid neutropenic recovery ( < 10 days from study entry) was essential for response to therapy (90% vs. 32%, P < 0.01). Treatment was well tolerated, with 15% infusions followed by infusion-related adverse events, nephrotoxicity in 7% of patients and 11% of withdrawals due to toxicity. These data suggest that intermediate-doses of ABLC may be of similar efficacy than higher doses with less toxicity, making it a cost-effective alternative worthy of study in future trials.

Nebulization of four commercially available amphotericin B formulations in persistently granulocytopenic rats with invasive pulmonary aspergillosis: evidence for long-term biological activity

The nebulization of amphotericin B desoxycholate (AMB-DOC), liposomal amphotericin B (L-AMB), amphotericin B lipid complex (ABLC) and amphotericin B colloidal dispersion (ABCD) has been investigated. Particle sizes of generated aerosol droplets were measured. Pulmonary amphotericin B deposition and amphotericin B concentration in blood directly after nebulization and at six weeks after nebulization was measured in healthy rats. The efficacy of nebulized amphotericin B formulations was evaluated in persistently granulocytopenic rats with invasive pulmonary aspergillosis. Treatment was given either after or before fungal inoculation. The endpoint was survival of animals. Aerosol particle sizes, expressed as the values for the mass median diameter were 1.38, 2.43, 0.90 and 2.29 microm for AMB-DOC, L-AMB, ABLC and ABCD, respectively. Amphotericin B concentrations in the lungs directly after nebulization exceeded the minimum inhibitory concentration of Aspergillus fumigatus and amphotericin B was still detected in lungs of rats at six weeks after nebulization. Treatment, started at 16 h after fungal inoculation, resulted in a significantly prolonged survival as compared with sham-treated rats for all four formulations. Prophylactic treatment at one week before fungal inoculation resulted in a significantly prolonged survival for all four formulations. Aerosol treatment given at two weeks before inoculation was effective only for AMB-DOC and L-AMB, whereas treatment given at six weeks resulted in a significantly prolonged survival for L-AMB only. All commercially available amphotericin B preparations could be nebulized efficiently and may be of value in the prophylactic treatment of invasive pulmonary aspergillosis.

Release of TNF-α and IL-1β from porcine brain endothelium corresponds to the pyrogenic potential of three marketed formulations of amphotericin

Formulations of amphotericin include a deoxycholate suspension (d-Amph), an amphotericin-B lipid complex (Ablc), and a liposomal product (L-Amph). Fever is most frequent with d-Amph, intermediate with Ablc, and lowest with L-Amph. To determine if the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1) from brain endothelium corresponds to the incidence of amphotericin fever. Release of TNF-alpha and IL-1beta after L-Amph treatment was similar to negative controls while after d-Amph treatment release was similar to lipopolysaccharide. Ablc treatment produced intermediate pyrogen release.NF-kappaB expression, a transcriptional regulator for TNF-alpha and IL-1beta genes, corresponded to this secretion pattern. TNF-alpha release was elevated 2 hours (p = 0.0021) after treatment while significant elevations in IL-1beta required 6 hours (p = 0.0009). Results from this in vitro study suggest that amphotericin fever may be directly mediated by brain endothelium. These experiments also suggest that amphotericin fever is initially mediated by TNF-alpha.

Effectiveness of amphotericin B lipid complex (ABLC) treatment in allogeneic hematopoietic cell transplant (HCT) recipients with invasive aspergillosis (IA)

A total of 85 allogeneic hematopoietic cell transplant (HCT) recipients with invasive aspergillosis treated with amphotericin B lipid complex (ABLC) were identified from the Collaborative Exchange of Antifungal Research (CLEAR) database. Of these patients, 78% (66/85) presented with pulmonary aspergillosis. Graft-versus-host disease (GVHD) was present in 24 of 85 patients. The response rate to ABLC was 31% (26/85) overall and 21% (5/24) in patients with GVHD. The overall response rate to first-line ABLC treatment was 41% (11/27). Four of nine (44%) patients with GVHD responded to first-line treatment with ABLC, while only one of 13 (8%) responded to ABLC as second-line therapy. Five of 18 (28%) and four of 14 (29%) patients, respectively, responded to sequential or concurrent treatment with ABLC and itraconazole. None of seven patients responded who continued receiving itraconazole after the start of ABLC therapy. At the end of ABLC therapy, serum creatinine had doubled in 12% of patients (10/85), and 2% (2/85) had developed a requirement for dialysis. These data suggest that ABLC, especially when administered as first-line therapy, can result in clinical response even in the most immunocompromised patients, that is, HCT recipients with GVHD, with minimal effects on renal function.

Amphotericin B Lipid Complex in the Management of Invasive Aspergillosis in Immunocompromised Patients

The efficacy and renal safety of amphotericin B lipid complex (ABLC) were assessed in 398 patients with invasive aspergillosis. The most common underlying conditions were hematopoietic stem-cell transplantation (101/398 [25%]), hematologic malignancy (101/398 [25%]), and solid-organ transplantation (109/398 [27%]). The most common reason for administration of ABLC was lack of response to prior antifungal therapy. Overall, 65% of patients had a favorable clinical response: 44% were cured or improved, and 21% were stabilized. Clinical responses were similar for patients who received ABLC as either first-line or second-line therapy. One hundred forty-four patients whose results could be evaluated received ABLC concurrently with or after therapy with itraconazole. No antagonism was observed when therapy with ABLC followed therapy with itraconazole. Patients infected with Aspergillus terreus, an innately polyene-resistant species, experienced a 37% response rate. Changes in serum creatinine levels were not clinically significant in most patients; however, dialysis was initiated in 7 patients, of whom 6 had prior antifungal therapy or preexisting renal disease. Analysis of this large database demonstrated the efficacy and safety of ABLC in the treatment of invasive aspergillosis.

Successful Use of Amphotericin B Lipid Complex in the Treatment of Cryptococcosis

The efficacy and renal safety of amphotericin B lipid complex (ABLC) injection were assessed in 106 patients with cryptococcal infection. Eighty-three patients (78%) had a central nervous system (CNS) infection. Of these patients, 20 initiated azole therapy concomitantly with ABLC therapy, and 7 had received prior azole therapy, which continued during administration of ABLC. Clinical response (cured or improved) was achieved in 67 (66%) of 101 patients whose results could be evaluated. Response rates were 65% (51/78) for patients with a CNS infection and 70% (16/23) for patients without a CNS infection. The response rate for patients with HIV infection was 58% (30/52). Response rates were 56% (19/34) for patients who were refractory to prior antifungal therapy, 65% (11/17) for patients who were intolerant of prior antifungal therapy, 60% (3/5) for patients with underlying renal disease who received prior antifungal therapy, 76% (25/33) for patients with underlying renal disease who did not receive prior antifungal therapy, and 73% (8/11) for patients with no renal disease who did not receive prior antifungal therapy. A mean serum creatinine level decrease of 0.02 mg/dL occurred. ABLC was an effective treatment for cryptococcal infection in immunocompromised patients.

Treatment of Non-Aspergillus Moulds in Immunocompromised Patients, with Amphotericin B Lipid Complex

An assessment was made of the efficacy and renal safety of amphotericin B lipid complex (ABLC) in the treatment of patients with invasive fungal infections caused by moulds other than Aspergillus species, on the basis of a retrospective analysis of data from the Collaborative Exchange of Antifungal Research (CLEAR) database. Data from CLEAR for 64 patients with zygomycosis were published previously. The database was further queried and yielded results for 28 patients with fusariosis and 84 patients infected with other non-Aspergillus moulds. Of 26 patients with fusariosis whose results could be evaluated, 46% (n = 12) were cured or improved, and an additional 12% (n = 3) were stable. Of 79 patients infected with other non-Aspergillus moulds whose results could be evaluated, 61% (n = 48) were cured or improved, and an additional 15% (n = 12) were stable. In an area with little guidance for therapy, the CLEAR data indicate that ABLC can be an effective broad-spectrum treatment choice for several invasive and refractory non-Aspergillus mould infections.

Treatment of Candida Infections with Amphotericin B Lipid Complex

The efficacy and renal safety of amphotericin B lipid complex (ABLC) were assessed in >900 patients with candidiasis. Overall, a favorable clinical response (cured or improved) was observed in 61% of patients infected with Candida species only, in 62% of patients infected with C. albicans, and in 61% of patients infected with a non-albicans Candida species. Clinical responses were similar in patients infected with invasive C. albicans and non-albicans Candida species (63% and 62%, respectively). Similarly, response rates of 60% and 59% were observed in patients infected with noninvasive C. albicans and non-albicans Candida species, respectively. Compared with patients who received lower doses of ABLC, patients who required higher doses of ABLC because of more-virulent infections did not demonstrate significant renal impairment, as assessed by end-of-therapy changes in serum creatinine level from baseline (median, 0.1 mg/dL; range, -3.9 to 2.4 mg/dL), incidence of serum creatinine doubling (16%), and need for new dialysis (7%). These data indicate the safety and efficacy of ABLC in treating candidiasis.

Study of Renal Safety in Amphotericin B Lipid Complex–Treated Patients

To investigate the renal safety of amphotericin B lipid complex (ABLC), records from 3514 ABLC-treated patients with fungal infections were reviewed. The median change in predicted creatinine clearance (CCr) from baseline to the end of therapy was -3 mL/min (range, -119 to 118 mL/min); doubling of serum creatinine (S-Cr) level occurred in 13% of patients, and new dialysis was needed for 3% of patients. Patients with underlying renal disease who had received prior antifungal therapy demonstrated a median CCr of 0.5 mL/min (range, -107 to 52 mL/min). Despite increased risk for renal impairment in allogeneic hematopoietic stem-cell transplant recipients, only 17% of patients demonstrated end-of-therapy doubling of S-Cr levels, and the median change in CCr was -10 mL/min (range, -107 to 108 mL/min). In ABLC-treated patients, concomitant treatment with potentially nephrotoxic agents and a baseline S-Cr level of <2 mg/dL were factors predisposing for the development of nephrotoxicity. These data provide evidence that ABLC may be used safely to treat patients who are at increased risk for renal impairment.

Differential Expression of Cytokines and Chemokines in Human Monocytes Induced by Lipid Formulations of Amphotericin B

The immunomodulatory effects of liposomal amphotericin B (LAMB), amphotericin B lipid complex (ABLC), and amphotericin B colloidal dispersion (ABCD) on mRNA and protein profiles of five cytokines and chemokines expressed by human monocyte-enriched mononuclear leukocytes (MNCs) were comprehensively evaluated by semiquantitative reverse transcription-PCR and enzyme-linked immunosorbent assays; they were compared to those of deoxycholate amphotericin B (DAMB). mRNAs of interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1ra), tumor necrosis factor alpha (TNF-alpha), monocyte chemotactic protein 1 (MCP-1), and macrophage inflammatory protein 1beta (MIP-1beta) were assessed after treatment of MNCs with each drug for 0.5, 2, 6, and 22 h. The cytokine protein profiles were obtained after incubation of MNCs with the drugs for 2 h (TNF-alpha) or 6 h (all the others). In the mRNA studies, DAMB resulted in an early increase of inflammatory cytokines or chemokines IL-1beta, TNF-alpha, MCP-1, and MIP-1beta (2 to 6 h) and in a late increase of anti-inflammatory IL-1ra (22 h). ABCD showed a general similar trend of inflammatory gene up-regulation. LAMB and ABLC decreased or did not affect IL-1beta and TNF-alpha, whereas ABLC additionally decreased MIP-1beta. In protein measurement studies, DAMB and ABCD up-regulated production of IL-1beta (P < 0.05), decreased the IL-1ra/IL-1beta ratio, and up-regulated the production of MCP-1 and MIP-1beta. In comparison, LAMB and ABLC down-regulated or did not affect the production of these cytokines/chemokines compared to untreated MNCs; furthermore, ABLC tended to increase the IL-1ra/IL-1beta ratio. These studies demonstrate that amphotericin B formulations differentially affect gene expression and release of an array of proinflammatory and anti-inflammatory cytokines that potentially may explain the differences in infusion-related reactions and dose-dependent nephrotoxicity as well as modulation of the host immune response to invasive fungal infections.

Twice-weekly ABLC prophylaxis for patients at high risk of invasive fungal infection after allogeneic stem cell transplantation

Invasive fungal infections (IFIs) are increasing after allogeneic stem cell transplantation (aSCT). Known prognostic factors for IFI include mismatched donors, severe GvHD, CMV infection, and the use of steroids. Our group treated all patients during their initial neutropenic episode with oral fluconazole or itraconazole (200–400 mg/day). Starting on day +30, patients who received prednisone≥ 30 mg/day were switched to intravenous amphotericin-B lipid complex (ABLC; Abelcet) at a dosage of 4 mg/kg twice a week.

Combination Therapy with Amphotericin B Lipid Complex and Caspofungin Acetate of Disseminated Zygomycosis in Diabetic Ketoacidotic Mice

We studied the combination of amphotericin B lipid complex (ABLC) and caspofungin in mice with disseminated Rhizopus oryzae. Combination therapy improved survival compared to that of mice given monotherapy and that of untreated controls (P < 0.05) but did not improve organ clearance. In addition, prophylactic combination therapy was not more effective than prophylactic ABLC alone.

Aspergillosis in the CLEAR outcomes trial: working toward a real-world clinical perspective

Aspergillosis is a potentially lethal infection of immunocompromised patients. Until 10 years ago, antifungal therapy was largely limited to amphotericin B deoxycholate. Perceived poor response rates and inherent toxicities with amphotericin B deoxycholate were a major stimulus for the development of newer antifungals, including lipid-formulated amphotericin B, broad spectrum azoles, and echinocandins. Response rates to antifungals are highly dependent on the underlying diagnosis and degree of immune suppression of the patient. Patients at highest risk of death from aspergillosis also have very high mortality rates from other causes as well. Outcomes reported in historical literature reviews fail to distinguish between overall mortality and death attributable to aspergillosis. While this distinction can often be difficult to assess clinically, the net effect is to underestimate the therapeutic success rates of antifungals. The CLEAR (Collaborative Exchange of Antifungal Research) project started as a post approval survey to monitor clinical use of amphotericin B lipid complex (ABLC). The scope of the CLEAR project included collection of clinical data to assess outcomes in patients with invasive fungal infections treated with ABLC. Clinical data from more than 3500 patients were entered into the CLEAR database. Outcomes were assessed for 509 patients with documented aspergillosis and complete data records. Overall response rate was 63% (cured/improved/stable) with site-specific response rates of 61%, 59%, and 32% for lung, sinus, and central nervous system infections, respectively. Solid organ transplant recipients had higher response rates than patients with hematological malignancies. Bone marrow transplant recipients had the lowest response rates. Clinical response rates with ABLC reported in the CLEAR trial are higher than response rates reported for amphotericin B deoxycholate in other trials. Since it is unlikely we will see any new comparative Phase III trials for aspergillosis, CLEAR-type outcome studies will prove useful for the foreseeable future to guide clinical management of aspergillosis.