deoxycholic-acid and Aspergillosis

Voriconazole, amphotericin B (AmB) formulations, and isavuconazole are all included in guideline recommendations for treatment of patients with invasive aspergillosis (IA) but the relative efficacy of isavuconazole versus AmB formulations has not been directly compared. We aimed to estimate the relative efficacy of isavuconazole compared with AmB deoxycholate (AmB-D), liposomal AmB (L-AmB), and voriconazole for the treatment of patients with proven/probable IA.. Nine literature databases were screened for randomized controlled trials comparing treatments with any of voriconazole, AmB-D, L-AmB and isavuconazole for treatment of proven/probable IA. Articles meeting the criteria were included in a meta-analysis to determine the efficacy of AmB-D, L-AmB and voriconazole relative to isavuconazole based on all-cause mortality (ACM) and overall response using a fixed-effects model.. Four articles were identified that compared L-AmB with AmB-D (Study 1), standard-dose L-AmB (3-5 mg/kg/day) with high-dose L-AmB (10 mg/kg/day; Study 2), voriconazole with AmB-D (Study 3), and isavuconazole with voriconazole (Study 4). In the network meta-analysis, isavuconazole was statistically superior to AmB-D on both ACM (odds ratio [95% credible intervals] shown as natural log, 1.00 [0.26, 1.74]) and overall response (-1.39 [-2.21, -0.63]). Differences between isavuconazole, and standard-dose L-AmB, high-dose L-AmB and voriconazole were not statistically significant for either ACM (0.18 [-1.17, 1.53], 0.50 [-1.11, 2.13] and 0.32 [-0.19, 0.84], respectively) or overall response (-0.99 [-2.21, 0.29], -0.89 [-2.41, 0.65] and 0.06 [-0.43, 0.57], respectively).. This data suggests that the efficacy of isavuconazole for treatment of IA is superior to AmB-D and comparable with both L-AmB and voriconazole.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Deoxycholic Acid; Drug Combinations; Humans; Network Meta-Analysis; Nitriles; Pyridines; Randomized Controlled Trials as Topic; Treatment Outcome; Triazoles; Voriconazole

Renal, liver, heart and lung transplantation are now considered to be the standard therapeutic interventions in patients with end-stage organ failure. Infectious complications following transplantation are relatively common due to the transplant recipients overall immunosuppressed status. The incidence of invasive mycoses following solid organ transplant ranges from 5 to 42% depending on the organ transplanted. These mycoses are associated with high overall mortality rates. Candida and Aspergillus spp. produce most of these infections. This article will review the risk factors, clinical presentation and treatment of invasive fungal infections in solid organ transplant patients, and evaluate the role of prophylactic therapy in this group of patients.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Clinical Trials as Topic; Cryptococcosis; Deoxycholic Acid; Drug Combinations; Echinocandins; Fluconazole; Humans; Incidence; Lipopeptides; Organ Transplantation; Peptides, Cyclic; Postoperative Complications; Premedication

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.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Chemistry, Pharmaceutical; Colloids; Deoxycholic Acid; Drug Combinations; Humans; Liposomes; Phosphatidylcholines; Phosphatidylglycerols; Treatment Outcome

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Deoxycholic Acid; Drug Combinations; Echinocandins; Hematologic Neoplasms; Humans; Itraconazole; Lipopeptides; Liposomes; Mycoses; Organ Transplantation; Peptides, Cyclic; Pyrimidines; Risk Factors; Stem Cell Transplantation; Triazoles; Voriconazole; Zygomycosis

Zygomycosis is an opportunistic fungal infection that is increasingly reported in hematological patients. We describe 2 cases of successfully treated rhino-cerebral zygomycosis and give an overview of 120 patients from the literature with underlying hematological or oncological disorders. These data document the improved survival in sinus (15/17 patients surviving) and cutaneous (6/9 patients surviving) disease. Hematological patients with pulmonary (9/30 patients surviving) or disseminated (4/38 patients surviving) zygomycosis still have a poor prognosis. The clinical course of sinus-orbital involvement (4/11 patients surviving) follows sinus-cerebral (2/3 patients surviving) or cerebral (3/6 patients surviving) disease. Besides deoxycholate amphotericin B (AmB) (24/62 patients surviving), patients seem to benefit from liposomal amphotericin B (L-AmB) (10/16 patients surviving) or sequential AmB/L-AmB treatment (6/8 patients surviving). Alternative treatment options lead only in a few patients to success.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Aspergillus fumigatus; Combined Modality Therapy; Deoxycholic Acid; Ethmoid Sinusitis; Female; Hematologic Diseases; Humans; Immunocompromised Host; Itraconazole; Ketoconazole; Liposomes; Lymphoma, Large B-Cell, Diffuse; Male; Maxillary Sinusitis; Middle Aged; Mucor; Mucormycosis; Multiple Myeloma; Nose Diseases; Opportunistic Infections; Prognosis; Treatment Outcome; Zygomycosis

Candidiasis and aspergillosis are the most common fungal infections in hematopoietic stem cell transplant recipients and other hematology/oncology patients. Strategies for reducing the morbidity and mortality associated with these infections include antifungal prophylaxis, empiric therapy in patients with persistent fever and neutropenia, and preemptive therapy. Antifungal therapies include amphotericin B deoxycholate, lipid formulations of amphotericin B, the triazoles (fluconazole, itraconazole, and voriconazole), and the echinocandins (caspofungin and the investigational agents micafungin and anidulafungin). Fluconazole is a reasonable choice for the treatment of invasive candidiasis if the patient has not previously received a triazole and the institution has a low incidence of triazole resistance. If resistance is a concern, an echinocandin, such as caspofungin, is an appropriate option. Voriconazole may be the initial choice in most patients with invasive aspergillosis. If patients are intolerant of or refractory to conventional therapy, effective alternatives include a lipid formulation of amphotericin B or an echinocandin.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Resistance, Fungal; Echinocandins; Fungal Proteins; Hematopoietic Stem Cell Transplantation; Humans; Liposomes; Mycoses; Neoplasms; Neutropenia; Peptides, Cyclic; Randomized Controlled Trials as Topic; Survival Analysis; Triazoles

Considering the significant morbidity and mortality associated with invasive fungal infections in immunocompromised patients, it is particularly important to make the diagnosis as early as possible and to make best use of the available antifungal drugs for prophylaxis and treatment. The newer antifungal drugs include the lipid products of amphotericin B, such as amphotericin B lipid complex (ABLC) and liposomal amphotericin B; voriconazole (a triazole); and caspofungin (an echinocandin). ABLC and liposomal amphotericin B are as effective as amphotericin B deoxycholate but are less nephrotoxic; ABLC is probably the drug of choice for zygomycosis. Voriconazole is approved for use in the treatment of invasive aspergillosis and may have a role in preventing breakthrough fungal infections in patients with persistent fever and neutropenia. Caspofungin is effective against both invasive aspergillosis and invasive candidiasis.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Liposomes; Mycoses; Peptides, Cyclic; Phosphatidylcholines; Phosphatidylglycerols; Pyrimidines; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Triazoles; Voriconazole; Zygomycosis

Despite significant advances in the management of immunosuppressed patients, invasive fungal infections remain an important life-threatening complication. In the last decade several new antifungal agents, including compounds in pre-existing classes (new generation of triazoles, polyenes in lipid formulations) and novel classes of antifungals with a unique mechanism of action (echinocandins), have been introduced in clinical practice. Ongoing and future studies will determine their exact role in the management of different mycoses. The acceleration of antifungal drug discovery offers promise for the management of these difficult to treat opportunistic infections.

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Aspergillosis; Candidiasis; Deoxycholic Acid; Drug Combinations; Echinocandins; Fungal Proteins; Humans; Immunocompromised Host; Mycoses; Peptides; Peptides, Cyclic; Phosphatidylcholines; Phosphatidylglycerols; Triazoles

Systemic fungal infections cause almost 25% of the infection-related deaths in leukaemic patients. Particularly those with prolonged neutropenia are at risk but mycoses also feature in critically ill intensive care patients and in individuals who are treated for solid tumours and AIDS, or who received an organ transplant. The spread of AIDS and the more aggressive cytotoxic chemotherapy in combination with an improved management of haemorrhages and bacterial infections in leukaemic and other cancer patients facilitated the occurrence of these invasive fungal infections. These life-threatening complications remain both difficult to diagnose and to treat and therefore carry a poor prognosis. For many years, the only realistic option to treat systemic infections was amphotericin B, whose administration was known to be associated with numerous adverse effects. Now less toxic formulations of amphotericin have become available for clinical use, as well as several new triazoles that appear to provide an effective and less toxic alternative for the treatment of certain fungal infections.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Cryptococcosis; Deoxycholic Acid; Drug Combinations; Fluconazole; Flucytosine; Fungemia; Histoplasmosis; Humans; Immunocompromised Host; Mycoses; Zygomycosis

A review of series of > or = 4 cases of invasive aspergillosis (total, 1,223 cases) was undertaken to establish the crude mortality and rate of response to therapy with amphotericin B in the major at-risk host groups. In association with pulmonary, sinus, and cerebral aspergillosis in immunocompromised patients, the crude mortality rates were 86%, 66%, and 99%, respectively. No untreated patient survived. Among 84 patients treated for 1-13 days, only one survived. Among those with invasive pulmonary aspergillosis treated for > or = 14 days, the response rates to amphotericin B deoxycholate were 83% (in cases of heart and renal transplantation), 54% (leukemia), 33% (bone marrow transplantation) and 20% (liver transplantation). Patients with AIDS mostly received both amphotericin B and itraconazole, and 37% of those treated for > or = 14 days responded to therapy. Substantial variation in outcome from series to series was related to underlying disease status, site of disease, and management. Invasive aspergillosis remains a devastating opportunistic infection despite current treatment.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Deoxycholic Acid; Drug Combinations; Humans; Itraconazole; Opportunistic Infections

In a previous randomized trial of voriconazole versus amphotericin B deoxycholate for primary therapy of invasive aspergillosis, voriconazole demonstrated superior efficacy and better survival. In that trial, treatment with voriconazole or amphotericin B deoxycholate could be followed with other licensed antifungal therapies (OLAT). Here, we report the impact of OLAT on the outcome of patients with invasive aspergillosis.. Data on dose, duration, and the reason for switching to the first OLAT were analyzed, and outcome at week 12 was assessed.. Fewer patients in the voriconazole group (52 [36%] of 144) switched to OLAT, compared with patients in the amphotericin B deoxycholate group (107 [80%] of 133). Lipid formulations of amphotericin B were the most common OLAT (38% of patients). Switches were made because of intolerance or insufficient response in 70% for patients in the amphotericin B deoxycholate group, compared with 24% of patients in the voriconazole group. Favorable responses to OLAT in the amphotericin B deoxycholate group occurred in only 19% of patients with initial insufficient response and 38% of patients with intolerance. Salvage therapy with a lipid formulation of amphotericin B after initial treatment with amphotericin B deoxycholate was successful for only 30% of patients (14 of 47). Treatment success among patients randomized to receive amphotericin B, including those whose treatment was switched to OLAT, was 32%, compared with 55% among patients who received voriconazole alone (P<.001).. This study highlights the limited efficacy of salvage antifungal therapy, including therapy with lipid formulations of amphotericin B, and demonstrates the importance of effective initial therapy in invasive aspergillosis.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Deoxycholic Acid; Drug Combinations; Humans; Itraconazole; Pyrimidines; Salvage Therapy; Treatment Outcome; Triazoles; Voriconazole

Patients with persistent or recurrent neutropenic fevers at risk of invasive fungal disease (IFD) are treated empirically with antifungal therapy (AFT). Early treatment using a diagnostic-driven (DD) strategy may reduce clinical and economic burdens. We compared costs and outcomes of both strategies from a UK perspective.. An empirical strategy with conventional amphotericin B deoxycholate (C-AmB), liposomal amphotericin B (L-AmB), or caspofungin was compared with a DD strategy (initiated based on positive ELISA results for galactomannan antigen) and/or positive results for Aspergillus species on polymerase chain reaction assay) using C-AmB, voriconazole, or L-AmB in a decision-analytic model. Rates of IFD incidence, overall mortality, and IFD-related mortality in adults expected to be neutropenic for ≥10 days were obtained. The empirical strategy was assumed to identify 30% of IFD and targeted AFT to improve survival by a hazard ratio of 0.589. AFT-specific adverse events were obtained from a summary of product characteristics. Resource use was obtained, and costs were estimated by using standard UK costing sources. All costs are presented in 2012 British pounds sterling.. Total costs were 32% lower for the DD strategy (£1561.29) versus the empirical strategy (£2301.93) due to a reduced incidence of adverse events and decreased use of AFT. Administration of AFT was reduced by 41% (DD strategy, 74 of 1000; empirical strategy, 125 of 1000), with similar survival rates.. This study suggests that a DD strategy is likely to be cost-saving versus empirical treatment for immunocompromised patients with persistent or recurrent neutropenic fevers.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Caspofungin; Cost Savings; Decision Trees; Deoxycholic Acid; Drug Combinations; Echinocandins; Febrile Neutropenia; Galactose; Health Care Costs; Health Resources; Humans; Immunocompromised Host; Lipopeptides; Mannans; Survival Rate; Voriconazole

Whether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or amphotericin B for the treatment of invasive molds infections has not been studied. Our in vitro combination studies showed that isavuconazole and micafungin are synergistically active against Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, and Cunninghamella bertholletiae. These results suggest that isavuconazole, in combination with micafungin, may have a role in the treatment of invasive aspergillosis and warrants further investigation.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Cunninghamella; Deoxycholic Acid; Drug Combinations; Drug Interactions; Echinocandins; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mucormycosis; Nitriles; Pyridines; Triazoles

Immune cells express the vitamin D receptor and vitamin D metabolizing enzymes. Favorable vitamin D effects have been indicated in tuberculosis. Vitamin D deficiency increases T helper (Th) 2 responses to Aspergillus, and it suppresses Th2 responses in cystic fibrosis-allergic bronchopulmonary aspergillosis. Can vitamin D modulate the proinflammatory effects of amphotericin B (AmB) therapy in aspergillosis? Groups of mice were infected intravenously (IV) with 3-8 × 10(6) Aspergillus fumigatus conidia. In six experiments, doses of 0.08, 2, or 4 μg/kg calcitriol (active form of vitamin D) were given intraperitoneally +/- AmB-deoxycholate (AmBd) at 0.4, 0.8, 1.2, 1.8, 3.3, or 4.5 mg/kg or 0.8 or 1.2 mg/kg IV. Calcitriol doses were selected to range from doses used in humans to those just below doses shown to decalcify murine bones. In most experiments, doses of calcitriol and AmBd (or control diluents) were given five times, on alternate days, to minimize drug-drug interactions. Calcitriol treatment began on the day of challenge, and survival assessed for 10 days. In no experiments did calcitriol alone significantly worsen or enhance survival or affect residual infection in survivors. Calcitriol also did not affect the efficacy of AmBd. In a representative experiment, AmBd at 0.8 or 1.2 mg/kg IV alone +/- calcitriol at 2 μg/kg enhanced survival (P ≤ 0.01). However, the AmBd regimens with calcitriol were not different than those without, and calcitriol alone was identical to controls. In disseminated invasive aspergillosis, calcitriol did not affect outcome nor influence antifungal efficacy.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Calcitriol; Colony Count, Microbial; Deoxycholic Acid; Disease Models, Animal; Drug Combinations; Female; Mice; Survival Analysis

A number of agents are now available for empirical antifungal treatment (EAFT) of patients with persistent fever and neutropenia. We carried out a study of efficacy of antifungal drugs to prevent breakthrough invasive aspergillosis by reviewing the medical records of all consecutive patients who received EAFT from November 2005 to February 2006. Patients' characteristics and the type, dose and duration of antifungal therapy were recorded. Breakthrough invasive fungal infections were documented according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) definition. Fifty-six episodes of persistent fever with neutropenia requiring EAFT were recorded among 49 patients. All patients received high-dose chemotherapy for acute myeloid leukaemia (51%), acute lymphoid leukaemia (12%), lymphoma (14%) or other haematologic conditions (22%). Fourteen (29%) and five (10%) patients were allogeneic and autologous haematopoietic stem cell transplant recipients, respectively. Caspofungin was prescribed initially in 40 episodes (71%), amphotericin B (AmB) desoxycholate and liposomal AmB being prescribed in six (10%) and ten (18%) episodes, respectively. Six patients were switched from liposomal AmB to caspofungin because of adverse events. The median duration of antifungal therapy was 9 days. During follow-up, six patients (12%) were diagnosed with invasive aspergillosis after a median of 8 days (range 3-16 days) of EAFT. Invasive aspergillosis breakthrough occurred in 6/46 (13%) caspofungin recipients and in 0/16 (0%) AmB recipients (OR 3.1, p 0.32). The observed high rate of invasive aspergillosis among caspofungin recipients requires further evaluation.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Caspofungin; Deoxycholic Acid; Drug Combinations; Drug Resistance, Fungal; Echinocandins; Female; Fever of Unknown Origin; Hematologic Neoplasms; Humans; Immunocompromised Host; Lipopeptides; Male; Middle Aged; Neutropenia; Young Adult

Invasive fungus infections caused by aspergillus spp. occur most frequently in immunocompromised patients. A high infection-associated death rate of up to and over 50% is attributed even today to these fungi. The disease in humans is caused mainly by Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger. Other species, for example, Aspergillus terreus or Aspergillus nidulans are quantitatively less prevalent. Evidence based treatment of invasive aspergillosis has become safer and more effective within the last ten years through the introduction of the new azoles and the echinocandines. Voriconazole has become the medication of choice for initial therapy. The efficacy of voriconazole is well documented, to include the treatment of disseminated infections of the central nervous system. Amphotericin B-desoxycholate is associated with definite side-effects in intravenous therapy. On the grounds of its substantial toxicity, the North American Infectious Disease Society's (IDSA) Guidelines of 2008 recommend amphotericin B-desoxycholate for regions with restricted resources only, which could be the case in underdeveloped countries. Liposomal amphotericin B in the daily standard dose of 3 mg/kg offers a rate of response similar to the one with voriconazole in the first-line treatment of invasive aspergillosis. However, a direct comparison with voriconazole on the basis of randomized studies is not available. As a secondary therapeutic treatment, in case of failure or intolerance of the primary treatment, caspofungin, micafungin and posaconazole have recently been under study. Both the echinocandines and posaconazole have proven effective in daily clinical practise. In refractory cases of invasive aspergillosis a combination therapy has been employed clinically. The results of prospective comparative controlled studies on combination therapy versus monotherapy will not be available until after 2010.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Azoles; Deoxycholic Acid; Drug Combinations; Echinocandins; Humans; Immunocompromised Host; Practice Guidelines as Topic

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Brain Abscess; Caspofungin; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Echinocandins; Fatal Outcome; Humans; Leukoencephalopathy, Progressive Multifocal; Lipopeptides; Male; Middle Aged; Pulmonary Aspergillosis; Pyrimidines; Triazoles; Voriconazole

We conducted a dose fractionation study of neutropenic, corticosteroid-immunosuppressed mice to characterize the pharmacodynamic/pharmacokinetic (PK/PD) parameter most closely associated with amphotericin B (AMB) efficacy in the treatment of invasive pulmonary aspergillosis. Pharmacokinetic parameter estimates were determined by a nonparametric population pharmacokinetic analysis of plasma drug concentrations following single intraperitoneal doses (0.25, 1.0, and 3.0 mg/kg of body weight) of amphotericin B deoxycholate. Three dosage groups (0.5, 0.75, and 1.0 mg/kg) fractionated into three dosing intervals (every 8 h [q8h], q24h, or q72h) were tested to discriminate between the PK/PD parameters (the ratio of maximum concentration of drug in serum [Cmax]/MIC, the ratio of area under the concentration-time curve/MIC, and percentage of time above MIC) most closely associated with AMB efficacy over a range of clinically achievable exposures in humans. The efficacy of each regimen was determined by quantitative PCR and survival. Reductions in pulmonary fungal burden and improvements in survival were maximized at the highest peak plasma concentrations in each of the dosage groups. Reductions in pulmonary fungal burden and increased survival were most closely associated with Cmax/MIC, with maximal activity occurring as the Cmax/MIC approached 2.4. In our model, Cmax/MIC is the PK/PD parameter most closely associated with efficacy in the treatment of invasive pulmonary aspergillosis. These data predict that less frequently administered, higher dosages of AMB would optimize efficacy.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Deoxycholic Acid; DNA, Fungal; Drug Combinations; Female; Lung; Lung Diseases, Fungal; Mice; Microbial Sensitivity Tests; Models, Biological; Neutropenia

Invasive aspergillosis is a severe disease, with an increased incidence in last decades. It occurs mainly in immunocompromised patients and rarely affects immunocompetent hosts. We describe a previously healthy 8 -year-old boy who acquired an invasive aspergillosis of abdominal origin associated with an opened laparotomy; within three weeks the patient progressed to a multiple organic failure syndrome and died despite amphotericin B deoxycolate plus voriconazole treatment and aggressive surgical debridement. Necropsy revealed multiple parenchyma involvement with characteristic findings of angioinvasive aspergillosis. Invasive aspergillosis must be considered an emergent infection in critical pediatric patients, including previously immunocompetent hosts; it is associated with high mortality despite adequate and opportune therapy.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Child; Deoxycholic Acid; Drug Combinations; Fatal Outcome; Humans; Immunocompromised Host; Male; Pyrimidines; Triazoles; Voriconazole

Pulmonary infiltrates in neutropenic hosts with invasive pulmonary aspergillosis are caused by vascular invasion, hemorrhagic infarction, and tissue necrosis. Monitoring the dynamics of pulmonary infiltrates of invasive aspergillosis is an important tool for assessing response to antifungal therapy. We, therefore, introduced a multidimensional volumetric imaging (MDVI) method for analysis of the response of the volume of pulmonary infiltrates over time to antifungal therapy in experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits. We developed a semiautomatic method to measure the volume of lung lesions, which was implemented as an extension of the MEDx visualization and analysis software using ultrafast computerized tomography (UFCT). Volumetric infiltrate measures were compared with UFCT reading, histopathological resolution of lesions, microbiological clearance of Aspergillus fumigatus, and galactomannan index (GMI). We also studied the MDVI method for consistency and reproducibility in comparison to UFCT. Treatment groups consisted of deoxycholate amphotericin B (DAMB) at 0.5 or 1 mg/kg of body weight/day and untreated controls (UC). Therapeutic monitoring of pulmonary infiltrates using MDVI demonstrated a significant decrease in the infiltrate volume in DAMB-treated rabbits in comparison to UC (P

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Deoxycholic Acid; Drug Combinations; Female; Lung; Lung Diseases, Fungal; Rabbits; Tomography, X-Ray Computed

The objective of this study was to conduct an economic evaluation of voriconazole compared with conventional amphotericin B deoxycholate (CAB) using data from a recently reported randomized comparative trial in patients with various underlying immunosuppressive conditions. This trial demonstrated the superiority of voriconazole in terms of clinical response, survival and safety when used as primary therapy for invasive aspergillosis.. A decision analytic model was designed using an expert panel and populated primarily with efficacy and resource utilization data collected prospectively during the clinical trial. The analysis was carried out from the perspective of the health care system and all costs are reported in 2002 US dollars.. Average total treatment costs per patient were 10% lower in the voriconazole arm ($30 664) than in the CAB arm ($34 144), resulting from reduced consumption of hospital resources and fewer changes in antifungal therapy. In the base case analysis, voriconazole provided an average saving of $3481 per treated patient, resulted in a lower cost per survivor ($43 310 versus $58 971) and a lower cost per successfully treated patient ($58 100 versus $108 124) compared with CAB. Sensitivity analyses demonstrated that the cost savings observed were maintained over a wide range of alternative values for both unit costs and resource utilization, including length of hospital stay, time spent in intensive care units, bed day costs and the cost of lipid formulations of amphotericin B.. Incremental cost-effectiveness analysis indicated the dominance of voriconazole because of both lower costs and greater efficacy.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Cost Savings; Cost-Benefit Analysis; Deoxycholic Acid; Drug Combinations; Health Care Costs; Humans; Immunocompromised Host; Pyrimidines; Triazoles; Voriconazole

Using data from a published clinical trial, our objectives were to compare the cost advantage of voriconazole over amphotericin B deoxycholate (AmBd) for primary treatment of invasive aspergillosis and to determine the financial impact the findings would have in a real-world clinical setting.. Pharmacoeconomic analysis.. University hospital.. Two hundred seventy-seven patients in the modified intent-to-treat population.. An analysis was performed of drug acquisition costs for all patients in the modified intent-to-treat population, which consisted of 144 patients in the voriconazole group and 133 in the AmBd group. The analysis included costs of initial drug therapy; conversion from intravenous to oral treatment for patients receiving voriconazole; and the types, dosages, and duration of other licensed [Food and Drug Administration-approved] antifungal therapy (OLAT) for up to three OLAT regimens/patient. Current drug costs for our university hospital were used for all calculations. Total voriconazole costs were $784,405 ($581,008 for initial therapy with voriconazole, $203,397 for OLAT) compared with $852,238 for AmBd ($31,677 for initial AmBd therapy, $820,561 for OLAT). Over the 12-week study period, the cost/patient was $961 less for patients whose initial treatment was voriconazole than for those whose initial treatment was AmBd. Other licensed antifungal therapy accounted for 26% and 96% of total drug costs for voriconazole and AmBd, respectively. Other licensed antifungal therapy was given to 36% of voriconazole-treated patients and 80% of AmBd-treated patients.. These data demonstrate the importance of evaluating total drug costs when comparing treatment regimens and not just initial therapy. Initial therapy with voriconazole had a cost advantage over AmBd in total antifungal drug cost/patient.

Topics: Administration, Oral; Amphotericin B; Antifungal Agents; Aspergillosis; Deoxycholic Acid; Drug Combinations; Economics, Pharmaceutical; Humans; Injections, Intravenous; Multicenter Studies as Topic; Pyrimidines; Randomized Controlled Trials as Topic; Triazoles; Voriconazole

Cochleates containing amphotericin B (CAMB) were administered orally at doses ranging from 0 to 40 mg/kg of body weight/day for 14 days in a murine model of systemic aspergillosis. The administration of oral doses of CAMB (20 and 40 mg/kg/day) resulted in a survival rate of 70% and a reduction in colony counts of more than 2 logs in lungs, livers, and kidneys. Orally administered CAMB shows promise for the treatment of aspergillosis.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Combinations; Female; Kidney; Liver; Lung; Mice; Mice, Inbred BALB C; Pharmaceutical Vehicles; Survival Analysis; Tissue Distribution

The management of invasive aspergillosis in patients with hematological malignancies remains controversial. A major problem is how to manage patients who had invasive aspergillosis during remission induction and consolidation therapy and then undergo SCT. Indeed in these patients the mortality rate related to invasive aspergillosis recurrence remains unacceptably high. We report two cases of patients who underwent remission induction for AML, developed invasive aspergillosis during antifungal prophylaxis with itraconazole, failed amphotericin B deoxycholate and liposomal amphotericin B treatment, were successfully treated with voriconazole and eventually underwent SCT with voriconazole prophylaxis without reactivation of invasive aspergillosis.

Topics: Adult; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Bone Marrow Transplantation; Combined Modality Therapy; Cytarabine; Daunorubicin; Deoxycholic Acid; Drug Combinations; Drug Resistance, Fungal; Etoposide; Fatal Outcome; Humans; Immunocompromised Host; Itraconazole; Leukemia, Megakaryoblastic, Acute; Leukemia, Myelomonocytic, Acute; Liposomes; Lung Diseases, Fungal; Male; Middle Aged; Peripheral Blood Stem Cell Transplantation; Pyrimidines; Recurrence; Remission Induction; Salvage Therapy; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Triazoles; Voriconazole

The effects of treatment with aerosolized amphotericin B desoxycholate and aerosolized liposomal amphotericin B were evaluated in severely immunosuppressed rats with invasive pulmonary aspergillosis. Aerosol treatment with amphotericin B desoxycholate consisted of a single dose (60 min) with amphotericin B concentrations in the nebulizer reservoir of 1, 2 and 4 mg/mL, respectively. For liposomal amphotericin B, aerosol treatment consisted of single, double or quadruple doses with a nebulizer reservoir concentration of 4 mg/mL of amphotericin B. Treatment, started at 30 h after inoculation, with aerosolized amphotericin B desoxycholate (nebulizer reservoir concentration 2 mg/mL) significantly prolonged survival of rats as compared with placebo-treated rats, whereas treatment with aerosolized amphotericin B desoxycholate with nebulizer reservoir concentration of 1 or 4 mg/mL did not have a significant effect on survival. Treatment with aerosolized liposomal amphotericin B significantly prolonged survival with all treatment regimens when compared with placebo-treated animals. Aerosol treatment did not prevent dissemination of the infection. The effects of amphotericin B desoxycholate and liposomal amphotericin B on pulmonary surfactant function were also evaluated in vitro. Amphotericin B desoxycholate inhibited surfactant function in a dose-dependent fashion. Liposomal amphotericin B had no detrimental effect on surface activity of surfactant. These results indicate that aerosol administration of amphotericin B, especially the liposomal formulation, could be an additional approach to optimizing treatment of invasive pulmonary aspergillosis.

Topics: Aerosols; Amphotericin B; Animals; Aspergillosis; Deoxycholic Acid; Drug Carriers; Drug Combinations; Female; Immunocompromised Host; Liposomes; Lung Diseases, Fungal; Rats; Surface Tension

This study compared the biodistribution of two amphotericin B formulations in normal and Aspergillus infected mice. Amphotericin B cholesterol hemisuccinate vesicles (ABCV) which reduces the toxicity of amphotericin B and thereby enhances its therapeutic efficacy in a murine model of aspergillosis was compared with conventional amphotericin B deoxycholate suspension (AmB(DOC)).. ABCV (12 mg/kg wt) and AmB(DOC) (2 mg/kg wt) were intravenously administered to normal and A. fumigatus infected mice. The concentration of amphotericin B in plasma and other organs was determined at different time points.. It was observed that ABCV had a significantly different pharmacokinetic profile compared to conventional amphotericin B. In comparison to AmB(DOC) significantly lower levels of amphotericin B were observed in kidneys and plasma, the major target organs of toxicity. Animals receiving ABCV demonstrated high levels of amphotericin B in liver (38% retention till 48 h) and spleen (2.6% retention till 48 h) in comparison to AmB(DOC) (7.3% and 0.21% retention in liver and spleen respectively till 48 h). Biodistribution studies of ABCV in infected mice demonstrated that there was a moderate enhancement in levels of amphotericin B in liver, spleen, lungs and kidneys as compared to normal mice and the plasma levels were reduced. However, such observations were not made after AmB(DOC) administration to infected mice except for kidneys in which there was a marked increase in uptake as compared to normal mice.. Our results suggest that prolonged retention of high concentrations of ABCV in reticuloendothelial system organs is the reason for its reduced toxicity. Enhanced localization of the drug at the infected site may lead to improvement in therapeutic efficacy.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Buffers; Cholesterol Esters; Deoxycholic Acid; Detergents; Drug Carriers; Drug Stability; Male; Mice; Mice, Inbred BALB C; Suspensions; Tissue Distribution

Using an isolate of Aspergillus fumigatus that is less susceptible in vivo to amphotericin B than most other isolates, we compared different doses of liposomal nystatin (L-nystatin), liposomal amphotericin B (L-amphotericin), and amphotericin B lipid complex (ABLC) with amphotericin B deoxycholate. Four experiments with intravenously infected neutropenic mice were conducted. A dose of L-nystatin at 10 mg/kg of body weight was toxic (the mice had fits or respiratory arrest). The optimal dosage of L-nystatin was 5 mg/kg daily on days 1, 2, 4, and 7 (90% survival). This was superior to L-amphotericin (5 mg/kg [P = 0.24] and 1 mg/kg [P < 0.0001]), ABLC (5 mg/kg [P = 0.014] and 1 mg/kg [P < 0.0001]), and amphotericin B deoxycholate (5 mg/kg [P = 0.008]). In terms of liver and kidney cultures, L-nystatin (5 mg/kg) was superior to all other regimens (P = 0.0032 and <0.0001, respectively). Higher doses of L-amphotericin (25 and 50 mg/kg) in one earlier experiment were more effective (100% survival) than 1 mg of L-amphotericin per kg and amphotericin deoxycholate (5 mg/kg) in terms of mortality and both liver and kidney culture results and to L-amphotericin (5 mg/kg) in terms of liver and kidney culture results only. ABLC (25 mg/kg) given daily for 7 days was superior to ABLC (50 mg/kg [P = 0.03]) but not to ABLC at 5 mg/kg or amphotericin B deoxycholate in terms of mortality, although it was in terms of liver and kidney culture results. No dose-response for amphotericin B (5 and 1 mg/kg) was demonstrable. In conclusion, in this stringent model, high doses of L-amphotericin and ABLC could overcome reduced susceptibility to amphotericin B deoxycholate, but all were inferior to 5- to 10-fold lower doses of L-nystatin.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Colony Count, Microbial; Cyclophosphamide; Deoxycholic Acid; Drug Carriers; Drug Combinations; Drug Resistance, Microbial; Immunosuppressive Agents; Liposomes; Mice; Neutropenia; Nystatin

Targeted intrapulmonary delivery of drugs may reduce systemic toxicity, improve treatment efficacy, but inhaled drugs may also interfere with pulmonary surfactant function. We hypothesized that the lipophilic drug amphotericin B used to treat or prevent pulmonary infections with aspergillus species, might destroy surface activity of lung surfactant, as assessed in a pulsating bubble surfactometer. Pure amphotericin B had no effect on a natural surfactant preparation or on the lipid extracted surfactant SurvantaTM. However, amphotericin BTM (containing deoxycholic acid) or deoxycholic acid alone inhibited surfactant surface activity dose dependently and perturbed lipid organization. AmbisomeTM containing amphotericin B associated with liposomes, only marginally affected surfactant function. Intrapulmonary delivery of large amounts of amphotericin BTM has to consider the potential of interferences with lung surfactant function.

Topics: Administration, Inhalation; Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Biological Products; Cattle; Deoxycholic Acid; Humans; In Vitro Techniques; Liposomes; Lung Diseases, Fungal; Pulmonary Surfactants; Surface Tension

To evaluate and compare in vivo the protective efficacy of unilamellar liposomal amphotericin B (L-AmB) with that of deoxycholate amphotericin B (D-AmB) in experimental endocarditis.. In the rabbit model of experimental Aspergillus fumigatus endocarditis, two doses of each antifungal agent (1.5 mg/kg each) were administered intravenously at 4 hours and at 30 minutes before challenge with an inoculum of A. fumigatus. Three days later, the animals were sacrificed, and the aortic vegetations were analyzed.. All 19 animals that did not receive chemoprophylaxis acquired endocarditis. In contrast, endocarditis developed in 2 of 10 animals pretreated with D-AmB (P < 0.01) and 3 of 8 animals pretreated with L-AmB (P < 0.01). Both D-AmB and L-AmB prevented the development of endocarditis due to A. fumigatus and decreased the concentration of fungi in the aortic vegetations by more than 1 log10.. In the rabbit experimental model of Aspergillus endocarditis, D-AmB and L-AmB were equally effective in reducing the incidence of the infection and the tissue burden of fungi.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Cholagogues and Choleretics; Deoxycholic Acid; Disease Models, Animal; Endocarditis; In Vitro Techniques; Liposomes; Male; Rabbits

The efficacy of AmBisome, a liposomal formulation of amphotericin B, was compared with that of Fungizone (amphotericin B desoxycholate), in a rat model of unilateral, pulmonary aspergillosis. Repeated administration of cyclophosphamide resulted in persistent, severe granulocytopenia. The left lung was inoculated with a conidial suspension of Aspergillus fumigatus, thus establishing an unilateral infection. Antifungal treatment was started 40 h after fungal inoculation, at which time mycelial disease was confirmed by histological examination. Both Fungizone 1 mg/kg and AmBisome 10 mg/kg resulted in increased survival in terms of delayed as well as reduced mortality. Quantitative cultures of lung tissue showed that only AmBisome 10 mg/kg resulted in reduction of the number of fungal cfus in the inoculated left lung. Compared with Fungizone, both AmBisome 1 mg/kg/day and AmBisome 10 mg/kg/day significantly prevented dissemination from the infected left lung to the right lung. In addition, both AmBisome regimens reduced hepatosplenic dissemination, and the 10 m/kg dosage fully prevented this complication. In conclusion, when compared with Fungizone, in this model AmBisome is more effective in reducing dissemination of unilateral, pulmonary aspergillosis, even when given in relatively low dosage. Such low dosages may have a place in prophylactic settings.

Topics: Agranulocytosis; Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Deoxycholic Acid; Disease Models, Animal; Drug Combinations; Liposomes; Lung Diseases, Fungal; Rats

Invasive aspergillosis is a severe complication in the immunocompromised patient. Despite antifungal treatment the mortality rate is higher than 90% if the immunity deficiency is not corrected. The use and dosage of conventional amphotericin B (deoxycholate-suspended formulation) is limited by its toxicity, especially nephrotoxicity. To reduce these untoward effects, amphotericin B has been formulated in liposomes. Better tolerance and lower nephrotoxicity in the liposomal formulations allow higher doses to be given safely, even in the presence of renal failure. Liposomal encapsulated amphotericin B (LAmB) is a safe and effective alternative to conventional formulations for antifungal therapy. We present a case of a 60-year-old man affected by chronic lymphocytic leukaemia. In the course of his disease and after chemotherapy treatment, he presented an invasive aspergillosis of the lung and paransal sinuses. The rhino-sinusal lesion had progressed despite surgical debridement and treatment with amphotericin B in a dosage of 50 mg per day. Moreover, renal impairment caused by conventional amphotericin was detected. Then, LAmB was started at a dose of 150 mg per day. Treatment with LAmB has resulted in clinical recovery and radiologic ressolution.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillosis, Allergic Bronchopulmonary; Deoxycholic Acid; Drug Carriers; Drug Combinations; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Liposomes; Male; Middle Aged; Remission Induction; Sinusitis; Treatment Failure

An immunosuppressed rabbit model of invasive aspergillosis was used to evaluate a novel micellar preparation of cholesterol sulfate complexed to amphotericin B. The acute LD50 of amphotericin B-deoxycholate was 5.1 mg/kg versus 20 mg/kg for the amphotericin/cholesterol-sulfate complexes. Amphotericin B-deoxycholate given iv at a dose of 1.5 mg/kg was more effective in sterilizing liver and kidney than the amphotericin/cholesterol-sulfate complexes given iv at 1.5-4.5 mg/kg, but infection persisted in the lungs of all rabbits treated with those doses. Infection persisted even when the rabbits were given a lethal dose of amphotericin B-deoxycholate (4.5 mg/kg), but a dose of 15 mg/kg of the amphotericin/cholesterol-sulfate complexes sterilized tissues and was associated with no acute lethality. Equivalent doses of the amphotericin/cholesterol-sulfate complexes were less effective than amphotericin B-deoxycholate, but a fourfold decrease in acute lethality improved the therapeutic index of amphotericin B. The amphotericin/cholesterol-sulfate complexes appear to be an improved means of amphotericin B delivery and may improve therapy for invasive aspergillosis.

Topics: Amphotericin B; Animals; Aspergillosis; Brain; Cholesterol Esters; Deoxycholic Acid; Drug Combinations; Immunosuppression Therapy; Kidney; Liver; Lung; Micelles; Rabbits