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Introduction. The development of invasive candidiasis leads to high mortality after liver transplantation. Choosing an effective prophylaxis is an important task.The study purpose was to compare the results of invasive candidiasis prevention with anidulafungin vs. the lipid formulation of amphotericin B in high-risk patients in the early postoperative period after liver transplantation. Material and methods. The study included 80 patients with risk factors for the development of invasive mycosis who underwent liver transplantation. Patients were divided into 2 groups. In the first group (n = 40), anidulafungin was prescribed for prophylaxis; in the 2nd group (n = 40), the lipid complex of amphotericin B was used.Results. The most common of Candida spp. isolated in the patients of our study, as expected, was Candida albicans accounting for 31.2%, significantly less than a half. Neither fungal infection breakthrough nor invasive mycosis development were reported in any patient. In group 2, renal replacement therapy was significantly more frequently used. In two cases, the amphotericin B lipid complex was canceled and the conversion to echinocandin was undertaken due to the occurrence of adverse events (chills and fever) associated, in our opinion, with the drug used. Conclusions. 1. Patients after liver transplantation with 2 or more risk factors have absolute indications to invasive mycosis prevention. 2. Anidulafungin and the lipid formulation of amphotericin B are effective for prophylaxis and prevention of fungal infection breakthrough. 3. Anidulafungin has an advantage in safety over the lipid formulation of amphotericin B.

In recent years, substantial advances have been achieved in the treatment of mucormycosis. It is now clear that early initiation of therapy results in substantially better outcomes, underscoring the need to maintain a high index of suspicion and aggressively biopsy potential lesions. Increasing data support the need for surgical excision of infected and/or necrosed tissue whenever feasible. Based on their superior safety and efficacy, lipid formulations of amphotericin B have become the standard treatment for mucormycosis. Posaconazole may be useful as salvage therapy, but cannot be recommended as primary therapy for mucormycosis based on available data. Pre-clinical and limited retrospective clinical data suggest that combination therapy with lipid formulations of amphotericin and an echinocandin improves survival during mucormycosis. A definitive trial is needed to confirm these results. The use of the iron chelator, deferasirox, as adjunctive therapy also improved outcomes in animal models of mucormycosis. However, its efficacy was not confirmed in a recent, phase 2 clinical trial. Additional study is required of the potential for abrogation of iron acquisition as adjunctive treatment of mucormycosis. Combination polyene-posaconazole therapy was of no benefit in pre-clinical studies. Adjunctive therapy with recombinant cytokines, hyperbaric oxygen, and/or granulocyte transfusions can be considered in selected patients. Large-scale, prospective, randomized clinical trials are needed to define optimal management strategies for mucormycosis.

In prospective multicenter study were included 20 pediatriconcohematologic patients with mucormycosis. Age: 3 – 17 yy (median – 11), females – 60%. The diagnosiswas made according to EORTC/MSG 2008 criteria (post mortem – 25%). The main underlying disease was acutel eukemia (70%), risk factors – prolong severe neutropenia (median – 31 d) and lymphocytopenia (median – 33 d) after cytostatic chemotherapy or hematopoietic stem cells transplantation. Etiology agents were Lichtheimia corуmbifera, Rhizopus spp. and Rhizomucor spp. Main sites of infection were lungs (65%) and paranasal synuses (30%), dissemination – 45%. Antifungal therapy (amphotericin B lipid coplex, posaconazole, caspofungin, amphotericin B) was used in 75% patients, surgery – 30%. Overall mortality in 12 weeks was 70%.

Introduction. Based on clinical studies data voriconazole is recommended as the drug of choice for treatment of invasive aspergillosis (IA) – a widespread infectious complications occurring in immunocompromised patients and is characterized by severe clinical course and high mortality.The aim of this study was to assess the cost-effectiveness of voriconazole compared to other preparations recommended in the Russian practice for the treatment of IA in adult patients.Materials and methods. The authors constructed a «decision tree» type of model, which compared the three treatment alternatives for the IA in adult patients, depending on the drug in first-line therapy: 1) voriconazole, 2), caspofungin, or 3) amphotericin B lipid complex (LC). Efficacy was assessed as the probability of patient survival within 14 weeks of starting treatment. We took into account the drugs cost and an increase in the hospitalization duration due to the development of serious adverse events. The model parameters were determined on the basis of the published results of clinical studies, the costs were calculated on the basis of medicines prices in the public procurement and the average bed-day cost in system of obligatory health insurance. Probabilistic sensitivity analysis was performed.Results. It has been shown that the use of voriconazole for treatment of IA is the dominant strategy compared to the use of caspofungin and amphotericin B LC, providing cost reduction while achieving maximum effect. Probabilistic sensitivity analysis (1000 simulations) showed stability of the revealed pattern.Conclusion. The use of voriconazole in the treatment of IA allows to save the greatest number of lives at minimal cost compared to other preparations recommended in the Russian practice.

Objectives: It is not yet established the advantages between amphotericin B lipid complex (ABLC) and liposomal (L-AmB) in patients with invasive fungal infections refractory to usual doses of conventional AmB (d-AmB), previous renal impairment, or unacceptable d-AmB renal toxicity. This systematic review aims to compare ABLC and L-AmB effectiveness and safety outcomes in these subgroups of patients.Methods: The search was performed on Medline, Cochrane Library, EMBASE, and LILACS databases.Inclusion Criteria: treatment comparing L-AmB with ABLC; patients who had (i) refractory infection after being treated with d-AmB, (ii) previous renal impairment, or (iii) unacceptable d-AmB toxicity. Two investigators independently screened the search results, assessed trial quality, and extracted data. A total of 1,054 articles were identified in the literature. Among those, eleven were selected for full-text reading and five met the inclusion criteria.Results: The five articles included reported on four separate observational studies. Overall, no significant difference was found in clinical relevant outcomes as new-onset dialysis, length of hospital stay, or mortality when comparing both lipid formulations. The studies reported a trend toward lower nephrotoxicity in patients treated with L-AmB. However, the results were imprecise and heterogeneous and the studies presented important methodological biases.Conclusions: The studies included in this systematic review pointed toward less nephrotoxicity events in the L-AmB group. However, due to low quality of evidence and no statistically significant differences in other clinical relevant outcomes, there is no definitive evidence of overall superiority in effectiveness or safety outcomes regarding one lipid formulation or another in this population subgroup. [ABSTRACT FROM AUTHOR]

An overview of the literature data concerning the comparison of toxicity, efficacy and cost of amphotericin B lipid complex and liposomal amphotericin B, as well as their comparison with amphotericin B deoxycholate are provided.

Introduction: Immunocompromised patients carry a high risk for invasive fungal disease (IFD), which is associated with high mortality. Materials and Methods: This is a retrospective chart review of a 4 years’ experience of ABLC utilization for the management of suspected IFD at the Hematology/Oncology and Bone Marrow Transplantation unit at Makassed General Hospital, Beirut, Lebanon between January 2011 and December 2014. We focused on treatment strategy, response rate and adverse drug events associated with ABLC therapy. We also reviewed ABLC indications in international guidelines beyond its Food and Drug Administration approval. Results: A total of 89 patients received ABLC therapy for suspected fungal infection. Forty eight percent (48%) were treated for a possible fungal infection, 19% for a problable fungal infection, 12% based on hospital guidelines, and 20% based on treating physician’s recommendations. The overall response rate was 71%. Nephrotoxicity occurred in 24% of patients and serum creatinine improved in 10% of these patients. Moderate hypokalemia was observed in 61% of the patients and severe hypokalemia in 10% but was corrected in both cases. Hepatotoxicity was observed in 12% of the patients throughout ABLC therapy. Drug delivery reactions were observed in 36% of the patients. There was a decrease in the incidence of these reactions upon using combination of premedication drugs. Conclusion: In this study, ABLC proved to be an effective and safe option in the management of suspected IFD in immunocompromised patients failing previous therapies.

The total curative dose of amphotericin B for any given fungal infection or specific patient is not precisely known. Prior to the availability of lipid formulations of amphotericin B (LFAB), dosing of amphotericin B was dictated by its associated toxicity. The unique pharmacokinetic features of each LFAB have led to differences in their recommended doses. Most published data have evaluated doses of 3-5 mg/kg/day, although niches exist for both higher and lower doses. Low-dose LFAB allows for intravenous broad-spectrum antifungal coverage without drug-drug interactions and with reduced toxicity. High-dose LFAB demonstrates increased fungal clearance in animal models, although this has not translated to improved clinical outcomes for most invasive fungal infections. Although available data do not demonstrate significant benefit associated with high-dose therapy, for liposomal amphotericin B, the data also demonstrate no significant harm. As such, the use of high-dose liposomal amphotericin B for salvage therapy may be a consideration. [ABSTRACT FROM AUTHOR]

Abstract: The objective of this study was to examine the effect of continuous venovenous haemodiafiltration (CVVHDF) on the pharmacokinetics of amphotericin B (AmB) in critically ill patients following administration of amphotericin B lipid complex (ABLC). Plasma and ultrafiltrate (UF) samples were collected from patients administered ABLC and either receiving or not receiving CVVHDF. Pharmacokinetic (PK) analysis was performed on eight profiles from patients receiving CVVHDF and six profiles from patients not receiving CVVHDF. For patients receiving CVVHDF, the following median PK data were calculated: area under the concentration–time curve (AUC)=13.9h·μg/mL, volume of distribution at steady state (V ss)=1476L and drug clearance (CL)=27.4L/h; for patients not receiving CVVHDF, the corresponding median PK data were 11.5hμg/mL, 2048L and 43.7L/h, respectively. The median half-lives calculated during the dosage interval (t 1/2int) were 30.9h and 32.5h on and off CVVHDF, respectively, and the total range of t 1/2int values was 15.6–180.4h. Observed median peak concentrations on Day 1 were 0.563μg/mL and 0.468μg/mL in patients on and off CVVHDF, respectively. From AmB present in the UF, clearance via CVVHDF contributed<1% of total plasma clearance. The AmB concentration–time profiles for patients administered ABLC on and off CVVHDF were compared and no statistically significant differences in AUC, CL, t 1/2int and V ss were observed. In conclusion, CVVHDF had no clinically significant effect on the pharmacokinetics of AmB following administration of ABLC. [Copyright &y& Elsevier]

Abstract: Nephrotoxicity evaluations between liposomal amphotericin B (L-AMB) and amphotericin B lipid complex (ABLC) have provided mixed results. This retrospective study used an electronic medical record database of hospitalized patients with invasive fungal infections treated with either L-AMB or ABLC. Patients had renal insufficiency, clinical condition suggesting intolerance to amphotericin B deoxycholate (CAB), or recent CAB exposure. Baseline SCr, exposure to other nephrotoxic agents, and total amphotericin B exposure were similar between the groups. In 105 patients administered L-AMB, 10.6% had nephrotoxicity versus 22.6% of 222 patients administered ABLC (P = 0.020). A logistic regression model found ABLC patients had 3.48 higher odds (95% CI 1.05–11.52) than L-AMB of developing nephrotoxicity. Infusion reactions were more prevalent with ABLC (23.9% versus 9.5%, P = 0.002) as was hypomagnesemia (44.3% versus 28.1%, P = 0.033). This study demonstrated that L-AMB is associated with less nephrotoxicity, infusion reactions and hypomagnesemia than ABLC in patients at increased risk of nephrotoxicity. [Copyright &y& Elsevier]

Antifungal prophylaxis with liposomal amphotericin B in high-risk liver transplant recipients is recommended, but experience with amphotericin B lipid complex (ABLC, Abelcet®) in this setting is limited. Data from 615 liver transplants performed during 1999-2005 were analyzed retrospectively. High-risk patients ( n = 146) received a mean cumulative ABLC dose of 955 ± 609 mg (mean duration of 23.3 ± 11.9 days). Low-risk patients ( n = 469) received no prophylaxis. During a mean follow-up of 43.8 ± 29.2 months, fungal infections occurred in 32.2% of ABLC patients versus 43.5% of non-prophylaxis patients ( P = 0.015). The overall rate of invasive fungal infection was 12.3% in the ABLC group versus 15.6% in the non-prophylaxis patients ( P = 0.34). Any Candida infection (ABLC 29.5%, non-prophylaxis 41.2%, P = 0.011), probable or proven invasive Candida infection requiring systemic antifungal treatment (ABLC 18.5%, non-prophylaxis 32.4%, P = 0.001) and invasive abdominal candidiasis during the first 3 months (ABLC 4.1%, non-prophylaxis 9.2%, P = 0.049) were significantly less frequent in the ABLC group. There was no significant difference between groups in the incidence of Aspergillus infections. The ABLC group showed no evidence of nephrotoxicity. In conclusion, the marked and significant differences in infection rates and requirement for systemic treatment in this large population suggest that targeted use of low-dose ABLC therapy to high-risk patients is a valid prophylactic strategy following liver transplantation. [ABSTRACT FROM AUTHOR]

Amphotericin B deoxycholate is the main option for intravenous (i.v.) treatment of severe paracoccidioidomycosis (PCM). This is the first report of amphotericin B lipid complex (ABLC) in the treatment of PCM. Among 28 patients, cure was achieved in all patients (100%) using ABLC. Mean and median daily doses of ABLC were 3.39 mg/kg/day and 3.35 mg/kg/day, respectively. ABLC may be a choice in the treatment of severe forms of PCM or when i.v. options are required. [ABSTRACT FROM AUTHOR]

Zygomycosis is a difficult to treat and frequently fatal infection affecting immunocompromised and, rarely, immunocompetent patients. The early diagnosis and immediate initiation of treatment with an antifungal agent in combination with surgical intervention has proved critical for the favourable outcome of the disease. Few antifungal agents are available for treatment. Amphotericin B (AmB) deoxycholate has been the drug of choice for many years and is usually given at high daily doses which can result in renal toxicity. Currently, lipid formulations of AmB (liposomal AmB (L-AmB), AmB lipid complex (ABLC), AmB colloidal dispersion (ABCD)), mainly L-AmB, rather than conventional AmB have become the standard therapy. The rationale behind the use of lipid formulations is that they decrease the nephrotoxicity associated with longterm AmB use. Although there is a developing consensus that high doses of lipid formulations of AmB should be the antifungal therapy of choice for all patients with zygomycosis, until now there have been no data available with which to define the appropriate dose. The duration of therapy remains an unresolved issue, regarding both lipid formulations of AmB as well as sequential or combination treatments consisting of lipid formulations of AmB with posaconazole, a drug which has now emerged as a new therapeutic option. [ABSTRACT FROM AUTHOR]

The aim of this retrospective, case–control study was to determine the effect of the amphotericin B lipid complex (ABLC) on serum creatinine (SCr), blood urea nitrogen (BUN), sodium (Na), and potassium (K) in very low birth weight (VLBW) infants. Medical records of all VLBW infants who were admitted to our Neonatal Intensive Care Unit between May 1998 and May 2006 and had received ABLC for at least 2 weeks were reviewed for patient demographics, use of medications (ABLC, diuretics, xanthines, indomethacin, vancomycin, gentamicin, pressors, and inotropes), fluid intake, urinary output, and serum electrolytes. Thirty-five patients who received ABLC were identified and matched by gestational age (GA) to 35 patients who served as controls. Infants who received ABLC had an average GA of 25.7 ± 2.1 weeks and a birth weight of 764 ± 196 g. Between day 1 and 14 of ABLC treatment, the BUN decreased from 17.5 ± 11.5 to 10.5 ± 6.8 mg/dl ( p = 0.01), the SCr varied between 0.78 ± 0.32 and 0.69 ± 0.32 mg/dl, Na varied between 136.6 ± 5.8 and 137.8 ± 3.6 mEq/l, and K varied between 4.8 ± 0.9 and 4.9 ± 0.6 mEq/l, respectively. Based on these results, we conclude that treatment with ABLC for 2 weeks did not increase BUN or SCr, nor decrease Na or K in VLBW infants. [ABSTRACT FROM AUTHOR]

The goal of this study was to determine the effect of apolipoprotiens on Amphotericin B lipid complex (ABLC). We report that incubation of ABLC with recombinant human apolipoprotein A-I (apoA-I) induces solubilization of ABLC by transforming the micron sized phospholipid/AMB assemblies into discrete nanoscale disk-shaped complexes termed nanodisks (ND). ApoA-I induced changes in ABLC solubility and morphology were monitored by spectroscopy and electron microscopy. AMB efficacy was evaluated in yeast and pathogenic fungi growth inhibition assays and the effect of AMB formulation on cell toxicity was assessed in cultured Hep3B cells. AMB associated with ND were more efficiently nebulized than AMB associated with ABLC. Thus, transformation of ABLC into ND preserves the potent biological activity of AMB as well as the reduced toxicity of the ABLC formulation. ABLC derived AMB-ND offer advantages over conventional ABLC in terms of stability, storage, nebulization efficiency and provides an intrinsic “handle” for tissue specific targeting via genetic engineering of its protein component. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:4425–4432, 2008 [ABSTRACT FROM AUTHOR]

Abstract: Background: Abnormal liver function test (LFT) results are common in patients with hematologic abnormalities, making the assessment of drug-related hepatotoxicity difficult. Studies based on elevated LFT levels have found that use of liposomal amphotericin B (L-AMB) was associated with increased hepatotoxicity compared with amphotericin B (AMB)/deoxycholate or amphotericin B lipid complex (ABLC). Because LFT abnormalities are multifactorial in severely immunocompromised patients, uncertainty remains regarding the clinical significance of these laboratory findings. Objective: The aim of this study was to present the hepatic histopathologic findings on autopsy in patients who had hematologic malignancies and fungal infections and had received L-AMB or ABLC. Methods: This study was conducted at The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Records from 1995 to 2004 of patients who had received L-AMB or ABLC for ≥7 days, within 30 days before death, were reviewed by 1 investigator. Hepatic autopsy slides were independently reviewed by another investigator (pathologist) in a blinded fashion. Histopathologic evidence of amphotericin-related hepatotoxicity was predetermined based on histopathologic abnormalities reported in animal studies (eg, macrophage vacuolation, multifocal hepatocellular necrosis). Based on data from animal studies and in view of the lack of studies in humans, multifocal necrosis, fatty infiltration, macrophage vacuolation, and/or “foamy macrophage” accumulation were all considered histopathologic abnormalities associated with the use of lipid formulations of AMB. Results: Data from 64 patients were included (32 patients per group). The demographic characteristics were comparable between the ABLC and L-AMB groups (median ages, 47.5 and 53.0 years, respectively; male, 44% and 53%; white, 75% and 78%; median weight, 67 and 78 kg; active underlying malignancy, 84% and 78%). There were no significant between-group differences in cumulative dose (6 and 7 g), median daily dose (both, 5 mg/kg), or median duration of treatment (19.5 and 19.0 days). Abnormal results (>5 x from baseline) on LFT were found in 12 (38%) and 10 (31%) patients who received ABLC and L-AMB, respectively, but these findings were thought to be associated with concomitant use of triazoles (4/12 [33%] and 1/10 [10%] patients, respectively), hepatotoxic antibiotics (8/12 [67%] and 5/10 [50%]), and/or other hepatotoxic medications (2/12 [17%] and 1/10 [10%]). Nonspecific abnormalities were observed on histopathology in 94% of patients. There was no evidence of histopathologic abnormalities reported in animal toxicity studies of lipid AMB, such as macrophage vacuolation or multifocal hepatocellular necrosis. Conclusions: Although abnormal results on LFT and/or histopathologic changes in liver were found in 92% of these debilitated patients with hematologic malignancy, direct histopathologic evidence of toxicity associated with lipid formulations of AMB was not established in our study. [Copyright &y& Elsevier]

Zygomycosis is an infrequent and difficult-to-treat fungal infection that is found in patients with underlying immunocompromised states. The advent of the lipid amphotericin B products has allowed for treatment with higher doses of therapy and less systemic toxicity. We reviewed the outcomes of 6 renal transplant recipients diagnosed with biopsy-proven invasive zygomycosis who received amphotericin B lipid complex (ABLC) in doses greater than 5 mg/kg between 2000 and 2004. All 6 patients had baseline diabetes mellitus, were receiving immunosuppressive agents, and subsequently underwent concomitant surgery. Three of the 6 patients that survived had undergone significant surgical debridement, reduction of their immunosuppression to minimal prednisone, and received prolonged course of ABLC at 10 mg/kg/day. All survivors lost graft function during the course of their therapy. The 3 patients who died all had delays in diagnosis of their disease and subsequent surgical and appropriate medical therapy. Therefore, in renal transplant recipients the early diagnosis of invasive zygomycosis is imperative along with early therapy with surgical debridement, reduced immunosuppression, and the use of high doses of ABLC. [ABSTRACT FROM AUTHOR]

Abstract: The following case illustrates an ileal perforation and reactive hemophagocytic syndrome (RHS) resulting from disseminated histoplasmosis in a patient with Human Immunodeficiency Virus (HIV) from Puerto Rico. Although the diagnosis was established by histopathologic findings and a positive bone marrow culture, Histoplasma capsulatum-specific real-time Polymerase Chain Reaction (PCR) allowed to confirm the diagnosis from formalin-fixed, paraffin-embedded tissue. Interestingly, the Histoplasma antigens in both serum and urine samples were falsely negative. Amphotericin B lipid complex (Abelcet), followed by oral itraconazole, led to a successful response and resolution of symptoms. A short review of the clinical signs and symptoms, diagnostic tests, and therapeutic options for disseminated histoplasmosis is done, with emphasis on the role of Histoplasma-specific real-time PCR as a molecular diagnostic tool and the efficacy of treatment with one of the lipid formulations of amphotericin B. [Copyright &y& Elsevier]

Invasive fungal infections (IFI) are frequent causes of mortality after allogeneic stem-cell transplantation (SCT). A very important risk factor for IFI is the use of steroids. We used a risk-based chemoprevention in an open-labelled pilot study. All patients received oral fluconazole or itraconazole (200–400 mg day−1) during their neutropenic episode. Starting on day +30, patients receiving prednisone ≥30 mg day−1 were switched to twice weekly Amphotericin-B-lipid-complex (ABLC) in a dose of 4 mg kg−1. Patients receiving lower steroid doses continued on the fluconazole/itraconazole prophylaxis. Between 1999 and 2002, 100 patients were enrolled and followed for IFI for 1 year. Seven patients were started on therapeutic daily ABLC treatment before day +30 because of documented or suspected IFI; four had definite or probable aspergillosis, and two had candidaemia. Thirty patients did not need prophylactic ABLC; only one developed candidaemia. Sixty-three patients received ABLC prophylaxis for a median of 52 days (range: 1–289). Seven of these patients developed IFI; one definite and two probable cases of aspergillosis, one case of probable Trichosporon beigelii infection, and three cases of candidaemia. The twice weekly ABLC was well tolerated. This risk-based chemoprevention appears to be effective and might diminish the role of steroids as risk factor for IFI after allogeneic SCT. The relatively high incidence of early IFI suggests that additional prophylaxis for IFI may be indicated for poor-risk patients prior to day +30. [ABSTRACT FROM AUTHOR]

A 53-year-old woman with an intraabdominal infection secondary to Candida albicans experienced hyperbilirubinemia after receiving amphotericin B in two different formulations--amphotericin B deoxycholate and amphotericin B lipid complex. Only a few case reports of amphotericin B-induced hyperbilirubinemia have been documented in the literature, each with different patterns of corresponding abnormalities in liver function tests. The unpredictable nature of this adverse effect warrants monitoring of bilirubin levels and liver function at baseline and potentially during therapy with amphotericin B, regardless of formulation, dosage, or duration of therapy. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: The use of antifungal combination therapy is a new clinical approach for combating fungal infections. Although few conclusive clinical studies have been performed to date, data exist that strongly suggest that combination therapy would benefit specific patient subgroups (e.g. stem-cell transplant recipients). This paper examines the evidence available from in vitro, experimental, and clinical studies, and seeks to discover viable clinical strategies for this promising new therapeutic approach. [Copyright &y& Elsevier]

Abstract: Many patients who receive antifungal agents are immunocompromised or critically ill. This leaves many of these patients prone to renal failure, especially following transplantation. A wealth of clinical data have shown that older antifungal agents, particularly conventional amphotericin B deoxycholate (AmBd), are still highly efficacious, except that AmBd confers extensive nephrotoxicity. This paper examines the pharmacological alternatives that could provide a more suitable balance between clinical efficacy and renal safety. [Copyright &y& Elsevier]

Abstract: Amphotericin B deoxycholate has been the ‘gold standard’ treatment for invasive fungal infections for over 40 years. Driven to improve on the renal toxicity of amphotericin B deoxycholate, extensive pharmaceutical research has led to the development of several new antifungals including lipid formulations of amphotericin B, broad-spectrum azoles and echinocandins. Compared with amphotericin B deoxycholate, the lipid formulations of amphotericin B (amphotericin B lipid complex, amphotericin B colloidal dispersion and liposomal amphotericin B) share distinct advantages in improved drug safety, in particular reduced incidence and severity of amphotericin B deoxycholate-related nephrotoxicity. However, the lipid formulations of amphotericin B are significantly more expensive than amphotericin B deoxycholate and, as for many of these new antifungals, there are as yet insufficient published studies to guide clinicians. This paper examines aspects of safety, efficacy, and health economic data for the lipid formulations of amphotericin B in particular, in order to provide a rationale to justify substituting amphotericin B deoxycholate with the lipid formulations of amphotericin B. [Copyright &y& Elsevier]

Allogeneic hematopoietic stem cell transplant (HSCT) recipients are at increased risk for invasive fungal infections (IFIs) over prolonged periods of time. Aerosolized amphotericin B lipid complex (ABLC) has shown promise in lung transplant recipients as a convenient means of delivering protective drug to the upper airways avoiding systemic toxicities. The safety and tolerability of aerosolized ABLC in 40 subjects undergoing allogeneic HSCT was prospectively investigated in an open-labeled, non-comparative study. Subjects received aerosolized ABLC treatment once daily for 4 days, then once weekly for 13 weeks; fluconazole was administered daily as standard of care through post-transplant day 100. Pulmonary mechanics were measured before and after each dose of inhaled ABLC; adverse events (AEs) and the development of IFI were also monitored. Cough, nausea, taste disturbance, or vomiting followed 2.2% of 458 total inhaled ABLC administrations; 5.2% of inhaled ABLC administrations were associated with ≥20% decrease in pulmonary function measurements (forced expiratory volume in 1 second or forced vital capacity) and none required treatment with bronchodilators or withdrawal from study. Four mild AEs were considered possibly or probably related to study treatment; no deaths or withdrawals from treatment were attributed to study drug. Of 3 proven IFIs occurring during the study period, only 1, a catheter-related case of disseminated fusariosis, occurred while the subject was receiving study medication. Aerosolized ABLC was well tolerated in allogeneic HSCT recipients. With only 1 of 40 subjects developing IFI while receiving treatment, the combination of fluconazole and inhaled ABLC warrants further study as antifungal prophylaxis following allogeneic HSCT. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Background:: 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. Objective:: 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). Methods:: 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). Results:: 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). Conclusion:: 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. [Copyright &y& Elsevier]

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 Cmax was 0.56 μg/ml, the mean AUC0−24 h was 7.46 mg h/l, Vss 9.13 l/kg, and t1/2 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. [Copyright &y& Elsevier]

The in vitro and in vivo antifungal activities of liposomal amphotericin B (L-AMPH) and amphotericin B lipid complex (ABLC), which is composed of amphotericin B and the phospholipids dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol, were compared with those of conventional amphotericin B (Fungizone®, AMPH). The acute intravenous toxicity was markedly lower in BALB/c mice; 50% lethal doses (LD) were 2.75 mg/kg in AMPH, 32.9 mg/kg in L-AMPH and >75 mg/kg in ABLC. In vitro antifungal activities against Candida albicans, C. parapsilosis, C. tropicalis, C. glabrata, and C. krusei were evaluated by the agar plate dilution method. The activities were unchanged against C. albicans, but MICs increased more than four fold in 18 of the 20 strains other than C. albicans in L-AMPH and in 9 of the 20 in ABLC. L-AMPH and ABLC were as efficacious as AMPH in the treatment of mice infected with C. albicans, and at a dose of 0.5 and 1.0 mg/kg of body weight, ABLC was more efficacious on survival. A ten-times larger dose (10 mg/kg) of L-AMPH and ABLC was administered to mice with 100% survival, suggesting improved tolerability as compared to amphotericin B. [ABSTRACT FROM AUTHOR]

Fungal keratitis is an important ophthalmic problem in the developing world. Filamentous fungi are the most frequently reported pathogens in fungal keratitis. This report aimed to present a case with Lecythophora mutabilis keratitis that treatment failure was seen with topical and systemic amphotericin B lipid complex. Then she was treated successfully topical voriconazole. [ABSTRACT FROM AUTHOR]

Mycoleptodiscus indicus, a dematiaceous mold, occurs on the leaves of a number of different host plants and has been only recently described as a cause of human infection. Immunosuppressed individuals are at risk for developing infections with opportunistic fungal pathogens, which are a major cause of morbidity and mortality in this population. In addition, the treatment of infections caused by these fungi is frequently challenging. We report a case of M. indicus subcutaneous infection in a 51-year-old man with human immunodeficiency virus and hepatitis C co-infection, who had a liver transplant. He developed skin nodules with a sporotrichoid lymphangitic distribution. Histopathology demonstrated unusual fungal elements with angioinvasion. Mycology cultures isolated a dematiaceous mold with the characteristic curved hyaline conidia of M. indicus. Initial treatment involved a combination of amphotericin B lipid complex and voriconazole, followed by monotherapy with voriconazole. The subcutaneous lesions resolved completely after 4 months of antifungal therapy. [ABSTRACT FROM AUTHOR]

The toxicity of amphotericin B deoxycholate has led to increased preference for lipid formulations with more favorable safety profiles. However, the primary use of lipid formulations is cost prohibitive, and many hospital formularies list both lipid and nonlipid formulations. A dispensing and administration error that caused amphotericin B deoxycholate to be given instead of liposomal amphotericin B related in a fatality. Measures to prevent confusion and aid in understanding the differences between lipid and nonlipid formulations of amphotericin B should be implemented. [ABSTRACT FROM AUTHOR]

This study describes the safety and efficacy of amphotericin B lipid complex (ABLC) in 11 neonates with systemic Candida infections. Nine of the 11 improved clinically, and eight of nine evaluable patients had a mycological cure with ABLC. Creatinine levels improved or did not significantly change in eight of the 11 patients. [ABSTRACT FROM AUTHOR]