Amphotericin B Lipid Complex Research Articles

Acute Infusion-Related Side Effects of AmphotericinB Lipid Complex (ABLC) in Oncohematological Patients: Real-World Data from Brazilian Reference Centers.

AmphotericinB lipid complex (ABLC) is an effective antifungal agent for treating invasive fungal infections (IFIs) even though its formulation is associated with potential adverse events, including those related to its infusion. This study aimed to analyze the incidence of acute infusion-related side effects (IRSE) associated with ABLC and their relationship with the profile of patients with oncohematological disease admitted in Brazilian reference tertiary hospitals. This is an observational retrospective study that included clinical records of patients hospitalized, in a period of 6years, diagnosed with probable or proved IFI and treated with at least two doses of ABLC. A total of 229 patients were included, with a male prevalence and an average age of 44years for adults and 10years for children. Seventy-nine (34.5%) developed some IRSE, 5.1% of which progressed in severe form to discontinuation of treatment. The most prevalent events in adults were fever (66.7%), tremor/chills (53.3%), and tachycardia (24.4%). In children, the most common were fever (64.7%), tremors/chills (50%), and skin rash/itching (17.6%). Statistical significance was found for premedication use from the first dose of ABLC in relation to the onset of infusion reactions (P = 0.006). Multivariate analysis revealed that ABLC, when compared to liposomal AMB (L-AMB), and neutropenia were associated with a higher risk of developing IRSE (odds ratio [OR] 3.04, P = 0.008; and OR 11.02, P = 0.025, respectively). The use of premedication was a protective factor against the occurrence of IRSE. Therefore, services providing amphotericinB (AMB) must reinforce protocols or implement new measures that optimize tolerability and safety during the treatment of patients with oncohematological disease, with special attention to patients with neutropenia, prioritizing the liposomal formulation of AMB whenever possible.

Multidisciplinary expert consensus on the clinical rational application of different formulations of amphotericin B (2024 edition)

Amphotericin B (AmB) is a broad-spectrum and potent polyene antifungal drug for the treatment of invasive fungal diseases (IFDs). Currently, amphotericin B deoxycholate (AmB-D) and three AmB lipid formulations, namely liposomal amphotericin B (L-AmB), amphotericin B colloidal dispersion (ABCD), and amphotericin B lipid complex (ABLC) are available for clinical use. In view of clinical concerns and misperceptions in the selection of different formulations of AmB, the present consensus summarized their pharmaceutical characteristics, antifungal mechanism, pharmacokinetics/phamacodynamics, drug interactions, indications, dosage, local administration, and adverse reactions based on the latest clinical research evidence, guidelines, and clinical experience. This consensus also recommends formulation selection and dosage adjustment for the treatment of target IFDs and in special populations, thereby providing expert consensus for clinical decision-making and standardized application of AmB.

Effectiveness, Tolerability, and Safety of Different Amphotericin B Formulations in Invasive Fungal Infections: A Multicenter, Retrospective, Observational Study

Data on the real-life use of amphotericin B lipid complex (ABLC) compared with other available formulations are limited. This study aimed to evaluate the effectiveness, tolerability, and safety of different amphotericin B (AMB) intravenously administered in the context of hospital practice for the treatment of invasive fungal infections (IFI) and to provide new insights into the profile of ABLC. This is a multicenter, retrospective, observational study conducted at 10 tertiary Brazilian hospitals. Patients first exposed to any formulation of AMB for treating endemic and opportunistic IFI who had received at least 2 intravenous doses were screened. Retrospective data (from January 2014 to December 2019) were extracted from the patients' medical records. Clinical parameters were examined pre- and post-treatment to determine effectiveness; acute infusion-related side effects (IRSE) and drug interruption to determine tolerability; and adverse events, toxicity, and treatment interruption were stated to analyze safety. Overall, 1879 medical records of patients were identified. The median (interquartile rate) duration of treatment was 14 (7-21) days. The overall success rate (95% confidence interval [CI]) was 65% (95% CI 60-65). ABLC proved to be effective among AMB formulations with 59% (95% CI 55.6-62.5) within complete response. This was significantly higher in patients who received the drug for a longer period, ≥4 weeks compared to <1 week treatment (P < 0.001). IRSE was observed in 446 (23.7%) patients. Eight cases (1.4%) of severe IRSE in pediatrics and 14 (1.1%) in adults resulted in treatment discontinuation. Regarding safety, 637 (33.9%) patients presented some alteration in creatinine levels during AMB exposure, and 89 (4.74%) had to interrupt or discontinue the drug within the first 14 days of therapy because of renal dysfunction. Overall mortality was 34%. ABLC is an effective formulation for the treatment of invasive fungal infections, with few adverse events leading to drug discontinuation or lethal outcomes. Furthermore, this real-life study confirmed the comparative safety of AMB lipid formulations versus AMB deoxycholate.

Comparison of amphotericin B lipid complex, deoxycholate amphotericin B, fluconazole, and anidulafungin activity against Candida albicans biofilm isolated from breakthrough candidemia

IntroductionBiofilm formation causes virulence and resistance in Candida albicans. However, little is known about breakthrough candidemia isolates. We evaluated the antifungal activity of fluconazole, anidulafungin, deoxycholate amphotericin B (dAMB), and amphotericin B lipid complex (ABLC) against biofilms of C. albicans isolated from patients with breakthrough candidemia. MethodsThe present study used strains of C. albicans isolated from breakthrough and non-breakthrough candidemia patients (control group). The susceptibility of planktonic cells to amphotericin B, anidulafungin, and fluconazole was determined by broth microdilution. Antifungal activity in sessile cells was evaluated using the minimum biofilm eradication concentration (MBEC), metabolic activity was estimated by reducing MTT, and biomass was estimated using crystal violet retention. ResultsThe planktonic strains were susceptible to amphotericin B, anidulafungin, and fluconazole, with minimum inhibitory concentrations of 1, ≤0.03, and 2mg/L, respectively. However, fluconazole and anidulafungin did not exert an antifungal effect on biofilms. Additionally, dAMB and ABCL reduced the metabolic activity and biomass. However, eradication was only achieved using 16mg/L dAMB. C. albicans isolates of breakthrough candidemia exhibited strong biofilm production, and the in vitro activity of available therapeutic options was poor. ConclusionIn the present study, only dAMB and ABCL exhibited antibiofilm effects against sessile breakthrough candidemia isolates.

C-reactive protein interacts with amphotericin B liposomes and its potential clinical consequences.

Amphotericin B (AmB) is the gold standard for treating invasive fungal infections. New liposomal-containing AmB formulations have been developed to improve efficacy and tolerability. Serum/plasma C-reactive protein (CRP) values are widely used for monitoring infections and inflammation. CRP shows a high affinity to phosphocholine and it aggregates structures bearing this ligand, e.g. phosphocholine-containing liposomes. Therefore, we studied the interaction between CRP and phosphocholine-containing liposomal AmB preparations invivo and invitro. CRP was prepared by affinity chromatography. Liposomal AmB (L-AmB, AmBisome®) was spiked (final concentrations of L-AmB: 150mg/L) to CRP-containing serum (final CRP concentration: 300mg/L). Following the addition of L-AmB, complex formation was monitored turbidimetrically. The size of CRP-L-AmB complexes was assessed using gel filtration. CRP was monitored in patients receiving either L-Amb or AmB lipid complex (ABLC). Following addition of L-AmB to CRP-containing plasma, turbidimetry showed an increase in absorbance. These results were confirmed by gel permeation chromatography. Similarly, invivo effects were observed following intravenous administration of AmBisome®: a decline in CRP values was observed. In patients receiving L-Amb, decline of CRP concentration was faster than in patients receiving ABLC. In vitro experiments are suggestive of a complexation between CRP and liposomes in plasma. Interpretation of CRP values following administration of AmBisome® might be impaired due to this complexation. In vivo formation of complexes between liposomes and CRP might contribute, or even lead, to intravascular microembolisation. Similar effects have been described following the administration of Intralipid® and other phosphocholine-containing liposomes.

Cost-effectiveness analysis and budgetary impact of anidulafungin treatment for patients with candidemia and other forms of invasive candidiasis in Brazil.

Candidemia and other forms of invasive candidiasis (C/IC) are serious conditions, especially for immunosuppressed individuals with prolonged hospitalization in intensive care units (ICU). This study analyzed the incremental cost-effectiveness and budgetary impact (BI) of treatment for IC with anidulafungin compared to amphotericin B lipid complex (ABLC) and amphotericin B deoxycholate (ABD) or conventional amphotericin B (CAB), in the Brazilian Unified Health System (SUS). A decision model was conducted with a time horizon of two weeks from the perspective of SUS. The primary effectiveness endpoints were survival and treatment response rate. All patients were followed up until successful therapy or death. BI analysis was performed based on the measured demand method. A five-year time horizon was adopted based on the number of hospitalizations (per 1,000 hospitalizations). For effectiveness measured in the successful response rate (SRR), anidulafungin dominated the ABLC and ABD formulations. In the results of the analysis with the effectiveness measured according to survival, anidulafungin had a better cost-effectiveness ratio (R$988.26/survival) compared to ABD (R$16,359.50/survival). The BI estimate related to the incorporation of anidulafungin suggests savings of approximately 148 million reais in 5 years when comparing it to ABD. The economic evaluation of anidulafungin and its comparators found it to be cost-effective. The consensus of international scientific societies recommends it as a first-line drug for IC, and its incorporation by SUS would be important.

P485 Hiv-positive, solid organ transplant (SOT), and non-Hiv-positive/non-transplant (NHNT) associated with cryptococcosis in Brazil: First national multicenter cohort study

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PM ObjectivesTo describe the characteristics, mortality, and therapeutic response among hospitalized patients with cryptococcosis in Brazil.MethodsThis is a multicenter retrospective cohort study of seven Brazilian public tertiary hospitals (Figure 1). Medical records of patients admitted from January 2014 to December 2019 were evaluated. Confirmed cases of the first episode of cryptococcosis were included. Hosts were classified as HIV-positive, solid organ transplant (SOT), and non-HIV-positive/non-transplant (NHNT). Mortality was defined as the time of patient admission to in-hospital death from any cause. Statistical analysis was performed using the software R and JAMOVI.ResultsA total of 384 patients were included; the median (25th-75th) age was 39 (31-48) years and 283 (73.7%) were men. Hosts were 304 (79.2%) HIV-positive, 16 (4.2%) SOT, and 64 (16.7%) NHNT. More frequent diagnosis tools were culture, direct microscopic examination of infected body fluids using India ink, histological examination of tissue samples, and detection of cryptococcal polysaccharide antigen in body fluids (CrAg) using latex. Central nervous system (CNS) cryptococcosis had a significantly higher counting level across disease categories, with 313 cases or 81.5%. NHNT were more likely to have CNS cryptococcosis than people HIV-positive (84.4% vs. 81.9%, respectively). SOT patients had more pulmonary form infections (31.2%) as compared with HIV-positive (3.3%) and NHNT (1.6%). Other extrapulmonary sites category had HIV-positive and NHNT basically the same percentage of disease involvement (14%) compared with SOT (6.2%) (P < .001, Figure 2). Among cases with identification of specie, 56% were Cryptococcus neoformans and 4.4% were C. gattii. A total of 271 (70.6%) patients were discharged home with total or partial improvement and 113 (29.4%) patients died during hospitalization. In-hospital mortality among HIV-positive, SOT, and NHNT patients was 30.3% (92/304), 12.5% (2/16), and 29.7% (19/64), respectively. Induction therapy with AMB had the conventional deoxycholate mainly in combination with fluconazole (234, 84.2%). Only 80 (22.3%) patients received an AMB lipid formulation (liposomal AMB, n = 35 and AMB lipid complex, n = 45). The median (25th-75th) length of AMB therapy was 20 (14–32) days. Death patients had more age when compared with discharged-to-home cases (43 vs. 38 years, P < .002). Patients with CNS cryptococcosis had lower mortality (83/313, 26.5%) when compared with the other categories [pulmonary, 5/16 (31.2%) and other extrapulmonary sites, 25/55 (45.4%)] (P = .017). Survival benefits were seen for patients who received monotherapy or combination therapy. However, D-AMB alone showed a higher mortality rate, although not statistically significant (P = .537).ConclusionHIV infection is the most important condition among patients with cryptococcosis in Brazil and CNS involvement is the commonest manifestation in all hosts, mainly HIV-positive and NHNT. The proportion of pulmonary cryptococcosis is relevant in SOT patients. Mortality was high in all categories of hosts. Understanding the epidemiology and characteristic of patients admitted to our hospitals will help to understand the burden and causes of mortality and identify strategies to improve this scenario. Optimized diagnosis (i.e., lateral flow assay) and treatment (i.e., AMB lipid formulation plus flucytosine) are urgently necessary for our setting.

Comparison of amphotericin B lipid complex, deoxycholate amphotericin B, fluconazole, and anidulafungin activity against Candida albicans biofilm isolated from breakthrough candidemia

IntroductionBiofilm formation causes virulence and resistance in Candida albicans. However, little is known about breakthrough candidemia isolates. We evaluated the antifungal activity of fluconazole, anidulafungin, deoxycholate amphotericin B (dAMB), and amphotericin B lipid complex (ABLC) against biofilms of C. albicans isolated from patients with breakthrough candidemia. MethodsThe present study used strains of C. albicans isolated from breakthrough and non-breakthrough candidemia patients (control group). The susceptibility of planktonic cells to amphotericin B, anidulafungin, and fluconazole was determined by broth microdilution. Antifungal activity in sessile cells was evaluated using the minimum biofilm eradication concentration (MBEC), metabolic activity was estimated by reducing MTT, and biomass was estimated using crystal violet retention. ResultsThe planktonic strains were susceptible to amphotericin B, anidulafungin, and fluconazole, with minimum inhibitory concentrations of 1, ≤0.03, and 2mg/L, respectively. However, fluconazole and anidulafungin did not exert an antifungal effect on biofilms. Additionally, dAMB and ABCL reduced the metabolic activity and biomass. However, eradication was only achieved using 16mg/L dAMB. C. albicans isolates of breakthrough candidemia exhibited strong biofilm production, and the in vitro activity of available therapeutic options was poor. ConclusionIn the present study, only dAMB and ABCL exhibited antibiofilm effects against sessile breakthrough candidemia isolates.

Cost-effectiveness of amphotericin B formulations in the treatment of systemic fungal infections.

Amphotericin formulations, indicated for invasive fungal infections (IFIs), vary in effectiveness, safety and costs. In Brazil, only the conventional formulation is provided by the Public Health System. The aim of this study was to perform a cost-effectiveness analysis comparing conventional amphotericin B (CAB), liposomal amphotericin B (LAB) and amphotericin B lipid complex (ABLC). Therefore, a decision tree was developed. The model began with high-risking patients on suspicion or confirmation of IFI. The analysis was conducted under the perspective of the Brazilian Public Health System. Model health states were defined according to medication use and clinical evolution. Clinical efficacy (cure) and transition probabilities were derived from the literature. Resource use was estimated from Brazilian data. Time horizon followed the maximum treatment time determined in the patient information leaflets (3 or 6weeks). One-way and probabilistic-sensitivity analyses were conducted. The conventional formulation was the most cost-effective. No dominance was observed; however, high incremental cost-effectiveness ratios were obtained for LAB (USD 313130) and ABLC (USD 1711280). Sensitivity analyses demonstrated the robustness of the results. CAB is the most cost-effective treatment, followed by LAB and ABLC. Although CAB presents critical safety aspects, the high acquisition costs of the other formulations prevent their large-scale use in Brazil.

Evaluation of Amphotericin B Lipid Formulations for Treatment of Severe Coccidioidomycosis.

Patients with severe coccidioidomycosis infections are often treated with either amphotericin B lipid complex (ABLC) or liposomal amphotericin B (L-AmB). Outcome data with these agents in severe coccidioidomycosis cases are currently lacking. The purpose of this study is to evaluate the efficacy and toxicity of ABLC and L-AmB in treating severe coccidioidomycosis. A retrospective pre-post study design was employed. Chart reviews were completed from 1 January 2005 to 31 December 2014 for all patients who received lipid-based amphotericin B. Inclusion criteria included having a follow-up complement fixation (CF) titer or a treatment emergent adverse event (TEAE) prior to follow-up. Patients with meningeal involvement and pregnant patients were excluded. Treatment outcomes were assessed based on documented completion of therapy as well on symptoms, complement fixation titer, and changes to laboratory monitoring parameters. A total of 108 patients were identified, 69 of whom met the inclusion criteria. There were no statistical differences in demographics or disease burden in those that received ABLC and those that received L-AmB, except that those who received L-AmB were more likely to have previously diagnosed chronic kidney disease (nL-AmB = 4, 12.5% vs nABLC = 0, 0.0%; P = 0.042) and to have a lower creatinine clearance at the start of therapy (L-AmB = 79.6 mg/dl versus ABLC = 100.4 mg/dl; P = 0.008). Successful treatment was achieved in 27 (73.0%) of ABLC patients and 22 (68.8%) of L-AmB patients (P = 0.700). Amphotericin B was discontinued due to documented completion of therapy for 17 (45.9%) ABLC patients and 18 (56.3%) L-AmB patients (P = 0.553). Acute kidney injury (AKI) was the documented reason of treatment cessation for 10 (27.0%) ABLC and 1 (3.1%) L-AmB patient (P = 0.007). ABLC and L-AmB both appear to be equally efficacious in the treatment of severe coccidioidomycosis. L-AmB may have less renal toxicity than ABLC and may be the preferred agent in baseline renal impairment.

Burden of acute kidney injury in HIV patients under deoxycholate amphotericin B therapy for cryptococcal meningitis and cost-minimization analysis of amphotericin B lipid complex.

Deoxycholate amphotericin B (d-AMB) has a higher rate of acute kidney injury (AKI) in comparison of lipid formulations. However, lipid amphotericin B has high costs in developing countries. The aim of this study is to assemble a model of cost-minimization of amphotericin B lipid complex (ABLC) in patients with cryptococcal meningitis.This is a retrospective study done in a cohort of patients with cryptococcal meningitis to study the economic impact of its use in developing countries. Cost analysis were based on direct cost of different antifungal therapies, chronic dialysis after discharge, and survival of patients based on a retrospective cohort of 102 patients infected with human immunodeficiency virus with confirmed diagnosis of cryptococcal meningitis. From 102 patients treated with d-AMB, 60.78% developed any grade of AKI and 10.78% developed AKI demanding hemodialysis. The percentage of patients with meningeal cryptococcosis treated with d-AMB that requeired chronic HD was 2.39%. The same model was performed for patient that would be treated with ABLC, which resulted in 0.20% of patients demanding chronic HD due to its lower nephrotoxicity. When the model is applied in 100 patients, the total costs with d-AMB would be US$ 184,543 and with ABLC would be US$ 1,640,109 in 5 years. Treatment with ABLC would be cost saving in comparison to d-AMB treatment, if early switch of treatment occurred in patients presenting AKI. The change should be as soon as possible to avoid further complication, like dialysis, which is associated with a lower life expectancy.

COMPARATIVE EFFECTIVENESS AND SAFETY BETWEEN AMPHOTERICIN B LIPID-FORMULATIONS: A SYSTEMATIC REVIEW.

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. The search was performed on Medline, Cochrane Library, EMBASE, and LILACS databases. 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. 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. 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.

Renal Impairment Related to Different Antifungal Medications in Cases of Invasive Candida Infections in Tawam Hospital Pediatric Population between 2008-2015

Background: As a tertiary hospital, Tawam Hospital has been dealing with more and more complex pediatric cases. Such cases are often at higher risk of developing Invasive Candida Infections (ICI). Amphotericin B preparations continued to provide the widest coverage for all Candida strains and have been the drug of choice for definitive and empirical therapy in our institute. However, renal complications have always been a concern with this group of antifungals. Numerous studies have reported contradicting results in terms of which Amphotericin B preparation has less renal side effects. Therefore, we are here to report our own experience.Methods:We performed a retrospective cohort study of all children (15 years and younger) with ICI who were treated at Tawam Hospital from 2008 to 2015. Results:Out of the 40 patients included in this study, 7 patients were treated with Amphotericin B Liposomal (ABL). Two of them had elevated Urea/Creatinine after initiating the therapy. 11 patients were treated with Amphotericin B Lipid Complex (ABLC). Two of them had elevated Urea/Creatinine after initiating the therapy. Fluconazole was used in 14 patients. 2 of them had high Urea/Creatinine before therapy which did not show any further deterioration while on therapy. Two patients were treated with a combination of Fluconazoleand LAB. They both had high Urea/Creatinine before and after therapy. However, one of them was known to have renal failure. While 4 cases were treated with the combination of Fluconazole and ABLCamong whom one patient had high Urea/Creatinine before therapy that went down while on therapy. Conclusions:Although Amphotericin B is known to be associated with renal side effects, the newer preparations seem to offer a much safer alternative. Among the two available preparations, ABLCseemed to be safer in our experience. Fluconazole continued to have minimal renal side effects. However, just like most of the published studies on this topic, our study was limited by the small number of patients included and the retrospective nature of the study.Keywords: Invasive candida infections, Renal impairment, Amphotericin B Lipid Complex, Amphotericin B Liposomal Fluconazole.Abbreviations:ICI: Invasive Candida Infections, Amphotericin B Lipid Complex (ABLC), Amphotericin B Liposomal (ABL), CSF: cerebrospinal fluid, CLEAR: Collaborative Exchange of Antifungal Research,

Amphotericin B lipid complex in the treatment of severe paracoccidioidomycosis: a case series

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.

Retrospective Analysis on the Use of Amphotericin B Lipid Complex in Neutropenic Cancer Patients with Suspected Fungal Infections in Lebanon, a Single Center Experience and Review of International Guidelines.

Immunocompromised patients carry a high risk for invasive fungal disease (IFD), which is associated with high mortality. This is a retrospective chart review of a 4-year experience of amphotericin B lipid complex (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. A total of 89 patients received ABLC therapy for suspected fungal infection. Forty-eight percent 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. Infusion-related reactions were observed in 36% of the patients. There was a decrease in the incidence of these reactions upon using combination of premedication drugs. In this study, ABLC proved to be an effective and safe option in the management of suspected IFD in immunocompromised patients failing previous therapies.

Pharmacodynamics of amphotericin B deoxycholate, amphotericin B lipid complex, and liposomal amphotericin B against Aspergillus fumigatus.

Amphotericin B is a first-line agent for the treatment of invasive aspergillosis. However, relatively little is known about the pharmacodynamics of amphotericin B for invasive pulmonary aspergillosis. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC), and liposomal amphotericin B (LAMB) by using a neutropenic-rabbit model of invasive pulmonary aspergillosis. The study endpoints were lung weight, infarct score, and levels of circulating galactomannan and (1 → 3)-β-D-glucan. Mathematical models were used to describe PK-PD relationships. The experimental findings were bridged to humans by Monte Carlo simulation. Each amphotericin B formulation induced a dose-dependent decline in study endpoints. Near-maximal antifungal activity was evident with DAMB at 1 mg/kg/day and ABLC and LAMB at 5 mg/kg/day. The bridging study suggested that the "average" patient receiving LAMB at 3 mg/kg/day was predicted to have complete suppression of galactomannan and (1 → 3)-β-D-glucan levels, but 20 to 30% of the patients still had a galactomannan index of >1 and (1 → 3)-β-D-glucan levels of >60 pg/ml. All formulations of amphotericin B induce a dose-dependent reduction in markers of lung injury and circulating fungus-related biomarkers. A clinical dosage of liposomal amphotericin B of 3 mg/kg/day is predicted to cause complete suppression of galactomannan and (1 → 3)-β-D-glucan levels in the majority of patients.

Prophylaxis of Invasive Pulmonary Aspergillosis with Nebulized Lipid Complex Amphotericin B Is Feasible, Well Tolerated and Safe in Children with Acute Leukemia. Results of a Phase II Open Trial

▪ BACKGROUNDAcute leukemia is the most frequent cancer in childhood. The use of dose-intensive chemotherapy regimens has significantly increased the overall survival of acute leukemia during the last years. As a result of more dose-intensive myelosuppressive and immunosuppressive therapies there is a higher risk of systemic fungal infections. Invasive pulmonary aspergillosis (IPA) represents a significant source of morbidity and mortality (>50%), and therefore measures that effectively prevent IPA are needed. Prophylaxis of IPA with anti-mold azoles is effective, but has adverse systemic effects and important drug interactions with some chemotherapeutic agents (i.e. vincristine). Currently there is no optimal prophylaxis for IPA in pediatric patients so new strategies are needed. Because IPA originates from the inhalation of conidia, a prophylactic approach is the topical administration of antifungals inside the lungs. Aerosolized lipid formulations of amphotericin B could prevent IPA and avoid systemic adverse events and drug interactions. There are no published studies reporting feasibility and safety of inhaled lipidic amphotericins in the pediatric population. PATIENTS AND METHODSThe safety, feasibility and tolerance of nebulized lipid complex amphotericin B (ABCL) was evaluated in a phase II open label single arm trial on the use in pediatric patients (3 to 18 year-old) with acute leukemia during intensive chemotherapy. Nebulized therapy was administered by a PARI eFlow®rapid nebulizer system twice weekly, at 50 mg the first week and then 25 mg during intensive chemotherapy until recovery of neutropenia (3 consecutive absolute neutrophil count (ANC) ≥1x109/L or one ANC ≥1.5x109/L). Treatment was resumed during neutropenic episodes following subsequent chemotherapy cycles. Serum galactomannan assay was performed twice weekly during neutropenia. High-resolution chest computed tomography was done when there was a clinical suspicion of IPA. Fluconazole was allowed but antifungal drugs with anti-mold activity were not permitted. The trial is registered at www.clinicaltrials.gov as NCT01615809. RESULTSThirty-two patients were included, 19 were male (59.4%), median age was of 5.5 years (range 3-16). Twenty-nine patients were diagnosed with acute lymphoblastic leukemia (ALL), 3 with acute myeloid leukemia. Among the patients with ALL, 24 had a de novo ALL and 5 a relapsed ALL. A total of 389 administrations of nebulized ABCL were performed, with a median per patient of 13 (range 1-19). All patients tolerated the drug and no patient had to discontinue it due to intolerance or an adverse event. No patient presented a severe adverse event in relation to ABCL. Five patients suffered from mild adverse events (cough, eye discomfort). Nine patients were withdrawn from the study, 2 were referred to another institution to undergo bone marrow transplantation and 7 due to systemic administration of an antifungal agent with anti-mold activity. Three of these patients developed a possible or probable IPA. There were no other cases of IPA. CONCLUSIONSProphylactic nebulizations with ABCL were well tolerated, safe and feasible in children aged 3-18 years diagnosed with acute leukemia. There is a need to perform further studies with a higher number of patients to evaluate the efficacy of this approach. DisclosuresRives:Teva Pharma: Other. Off Label Use: Nebulized Amphotericin-B lipid complex is not approved for prophylaxis of invasive fungal infection in pediatric patients with acute leukemia.

Amphotericin B lipid soluble formulations versus amphotericin B in cancer patients with neutropenia.

Patients with cancer who are treated with chemotherapy or receive a bone marrow transplant have an increased risk of acquiring fungal infections. Such infections can be life-threatening. Antifungal drugs are therefore often given prophylactically to such patients, or when they have a fever. To compare the benefits and harms of lipid soluble formulations of amphotericin B with conventional amphotericin B in cancer patients with neutropenia. We searched PubMed from 1966 to 7 July 2014 and the reference lists of identified articles. Randomised clinical trials comparing lipid soluble formulations of amphotericin B with conventional amphotericin B. The two review authors independently assessed trial eligibility and risk of bias and abstracted data. We found 13 trials (1960 patients). Lipid-based amphotericin B was not more effective than conventional amphotericin B on mortality (relative risk (RR) 0.5; 95% confidence interval (CI) 0.64 to 1.14) but decreased invasive fungal infection (RR 0.65; 95% CI 0.44 to 0.97), nephrotoxicity defined as a 100% increase in serum creatinine (RR 0.45; 95% CI 0.37 to 0.54), and number of dropouts (RR 0.78; 95% CI 0.62 to 0.97).For the drug used in most patients, AmBisome (4 trials, 1214 patients), there was no significant difference in mortality (RR 0.77; 95% CI 0.54 to 1.10) whereas it tended to be more effective than conventional amphotericin B on invasive fungal infection (RR 0.63; 95% CI 0.39 to 1.01, P value 0.053).AmBisome, amphotericin B in Intralipid (6 trials, 379 patients), amphotericin B colloidal dispersion (ABCD) (2 trials, 262 patients), and amphotericin B lipid complex (ABLC) (1 trial, 105 patients) all decreased the occurrence of nephrotoxicity, but conventional amphotericin B was rarely administered under optimal circumstances. It is not clear whether there are any advantages of lipid-based formulations if conventional amphotericin B is administered under optimal circumstances, and their high cost prohibits routine use in most settings. There is a need for large trials comparing lipid-based formulations of amphotericin B with conventional amphotericin B given in the same dose, with routine premedication for prevention of infusion-related toxicity, and with supplementation with fluid, potassium, and magnesium for prevention of nephrotoxicity.

Budget Impact Analysis of Liposomal Amphotericin B and Amphotericin B Lipid Complex in the Treatment of Invasive Fungal Infections in the United States

Liposomal amphotericin B (L-AMB) and amphotericin B lipid complex (ABLC) are both indicated for treating invasive fungal infections (IFIs) caused by Aspergillus, Candida and Cryptococcus spp. among patients who are refractory to or intolerant of conventional amphotericin B (CAB). Prior studies have suggested similar efficacies but differences in adverse event (AE) profiles between L-AMB and ABLC. Our objective was to conduct a cost-minimisation and budget impact analysis for the treatment of IFIs with L-AMB and ABLC in a US hospital setting. A Microsoft® Excel-based budget impact model was developed to estimate the costs associated with using L-AMB and ABLC for the treatment of adult patients with Aspergillus, Candida and Cryptococcus spp. infections, who are refractory to or intolerant of CAB, during a hospital stay. The model was built from a hospital perspective, and included drug costs of L-AMB and ABLC, and costs for treating drug-related AEs (i.e. nephrotoxicity with/without dialysis, infusion-related reactions, anaphylaxis, hypomagnesaemia and hypokalaemia). Average sales price was used as the drug cost estimate in the base-case analyses. The treatment duration and rates of AEs for L-AMB and ABLC were mainly obtained from a retrospective study of these two drugs in the target population using the Cerner Health Facts data. Treatment costs of AEs were obtained from the publicly available sources. The budget impact ($US, year 2011 values) was evaluated for a hypothetical hospital with 100 administrations where L-AMB and ABLC are used for the treatment of the target population by changing the market share of L-AMB and ABLC from 32/68% to an anticipated market share of 60/40% in the base-case analysis. Sensitivity analyses were conducted by varying drug costs, rates of AEs, costs of AEs and anticipated market shares of L-AMB and ABLC. The estimated per-patient cost per hospital episode associated with L-AMB and ABLC use were $US14,563 and $US16,748, respectively. Cost of AEs accounted for 68.7% of the costs for L-AMB and 85.4% for ABLC. In a hypothetical hospital with 100 annual admissions of patients using these two drugs for IFIs, changing the market shares from 32/68% for L-AMB and ABLC, respectively, to 60/40% yielded a 3.8% cost reduction, which corresponded to an absolute cost savings of $US61,191. Sensitivity analyses indicated that the results were robust to changes in input parameter values in most cases. This study suggests that hospitals can realize cost savings by substituting L-AMB for ABLC in the treatment of IFIs. The cost savings are driven by the lower rates of AEs associated with L-AMB use compared with ABLC.

Nebulizer Choice Affects the Airway Targeting of Amphotericin B Lipid Complex Aerosols

Background: Although amphotericin B is highly effective against fungal infections, it has serious adverse effects. Encapsulation of amphotericin B in liposomes reduces its potential for systemic side effects. Administration of liposomal amphotericin via aerosols to the lungs (a main portal of fungal infections) further reduces its toxicity while increasing its therapeutic index and prophylactic efficacy. However, the effectiveness of aerosol therapy depends on the dose deposited and the distribution of the drug within the lungs. The size of the aerosol particle is an important factor that affects the distribution of the drug within the lungs and the effectiveness of therapy. Objective: This study aims to determine the physicochemical suitability of amphotericin B lipid complex (ABLC) for aerosolization and to compare the performance of 3 commercially available air jet nebulizers in generating ABLC aerosols in terms of aerosol output (mg/min) and drug amount aerosolized within various particle-size ranges, the latter of which affects airway deposition. Methods: We aerosolized 2 concentrations (5 mg/mL and 10 mg/mL) of ABLC and evaluated their physicochemical properties, including osmolality, pH, and viscosity. The aerosolization performances of Pulmo-Aide/Micromist, Envoy/Sidestream, and Proneb/Pari LC Star systems were then evaluated in terms of output rate (mg/min), percent aerosolized, and milligram per minute of drug aerosolized within particle-size ranges of 1 to 3.5 µm, 3.5 to 6 µm, and 1 to 6 µm. Results: The output rate increased with higher drug concentration regardless of device. Pulmo-Aide/Micromist and Envoy/Sidestream showed high output rates. Proneb/Pari LC Star and Envoy/Sidestream delivered the highest percentages of aerosolized particles within the 1 to 3.5 µm particle-size range, favoring deposition within the alveolar/distal end area of the airways. Pulmo-Aide/Micromist delivered a higher percentage of aerosol within the 3.5 to 6 µm than the 1 to 3.5 µm particle-size range, favoring deposition in the central airways. Conclusion: The present study shows that different nebulizers produced different size ranges of aerosolized particles of ABLC preferentially targeting different parts of the airways. Thus, effective aerosol therapies may require the evaluation of different nebulizers for optimal targeting.