scholarly journals Antifungal Agents for the Treatment of Systemic Fungal Infections in Children

2010 ◽  
Vol 21 (4) ◽  
pp. e116-e121 ◽  
Author(s):  
UD Allen
Keyword(s):  
Combination Therapy ◽  
Amphotericin B ◽  
Antifungal Therapy ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Invasive Pulmonary Aspergillosis ◽  
Fungal Diseases ◽  
Pulmonary Aspergillosis ◽  
Amphotericin B Deoxycholate ◽  
Systemic Antifungal Therapy

Traditionally, the mainstay of systemic antifungal therapy has been amphotericin B deoxycholate (conventional amphotericin B). Newer agents have been developed to fulfill special niches and to compete with conventional amphotericin B by virtue of having more favourable toxicity profiles. Some agents have displaced conventional amphotericin B for the treatment of specific fungal diseases. For example, voriconazole has emerged as the preferred treatment for invasive pulmonary aspergillosis. This notwithstanding, conventional amphotericin B remains a useful agent for the treatment of paediatric fungal infections. Knowledge of the characteristics of the newer agents is important, given the increasing numbers of patients who are being treated with these drugs. Efforts need to be directed at research aimed at generating paediatric data where these are lacking. The antifungal agents herein described are most often used as monotherapy regimens because there is no uniform consensus on the value of combination therapy, except for specific scenarios.

Use of Antifungal Therapy in Hospitalized Patients I. Results Prior to the Marketing of Fluconazole

1994 ◽  
Vol 28 (2) ◽  
pp. 252-260 ◽  
Author(s):  
Thaddeus H. Grasela ◽  
S. Diane Goodwin ◽  
Mary T. Pasko ◽  
Cynthia A. Walawander ◽  
Marsha A. Raebel
Keyword(s):  
Amphotericin B ◽  
Antifungal Therapy ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Empiric Therapy ◽  
Hospitalized Patients ◽  
Chronic Obstructive ◽  
Solid Organ ◽  
Candida Spp ◽  
Systemic Antifungal Therapy

OBJECTIVE: To evaluate the use of antifungal agents in hospitalized patients prior to marketing of fluconazole and to assess characteristics associated with their use. DESIGN: A cohort of hospitalized patients receiving topical or systemic antifungal therapy was monitored concurrently. SETTING: Sixty-nine hospitals ranging in size from 100 to more than 500 beds, 70.1 percent affiliated with medical schools. PATIENTS: Participating clinical pharmacists each identified 15 consecutive patients receiving systemic antifungal therapy and 5 consecutive patients receiving topical antifungal therapy at their institutions. Data collection began October 1989 and ended March 1990. INTERVENTION: All data collected were observational in nature, and no patient intervention was required. MEASURES: Characteristics of patients receiving antifungal therapy were compared using t-tests and chi-square tests. Utilization and patterns of use of antifungal therapy were reported. RESULTS: The most common risk factors necessitating antifungal therapy, in descending order, were: administration of broadspectrum antibiotics and/or presence of invasive catheters, carcinoma, AIDS, leukemia or lymphoma, diabetes mellitus, solid organ or bone marrow transplantation, and chronic obstructive pulmonary disease. Five hundred seventeen patients received systemic therapy and 464 (89.7 percent) received a single systemic agent. Of these, 242 (52.2 percent) received amphotericin B, 215 (46,3 percent) received ketoconazole, 6 (1.3 percent) received flucytosine, and 1 (0.2 percent) received intravenous miconazole. Fifty-three patients received two systemic agents either concurrently or consecutively, Ketoconazole was most often used for presumed or documented oral, urogenital, or esophageal infections and amphotericin B was the preferred agent for disseminated infections and fungemia (p<0.001). Almost half of the patients receiving amphotericin B or ketoconazole (48.3 percent) received these drugs as empiric therapy. Documented infections were more likely to be treated with amphotericin B (54.8 percent) than with ketoconazole (27.4 percent) (p<0,001). The predominant fungal isolates were Candida albicans, Candida spp., and unspecified yeasts. Amphotericin B toxicity led to discontinuation of drug therapy in only 5.1 percent of cases. Two hundred sixty-nine patients (34.2 percent) received topical antifungal therapy only. Nystatin oral suspension was prescribed to 65.3 percent of the patients, c1otrimazole troches to 23.0 percent, amphotericin B irrigation to 10.9 percent, and nystatin tablets to 0,8 percent. CONCLUSIONS: The utilization patterns of antifungal agents in this survey follow established therapeutic guidelines. Prior to the introduction of fluconazole, amphotericin B was the agent of choice for documented systemic fungal infections. Ketoconazole was more often used for prophylaxis of fungal infections and treatment of oral and esophageal infections.

Use of Antifungal Therapy in Hospitalized Patients II. Results after the Marketing of Fluconazole

1994 ◽  
Vol 28 (2) ◽  
pp. 261-270 ◽  
Author(s):  
Thaddeus H. Grasela ◽  
Mary T. Pasko ◽  
S. Diane Goodwin ◽  
Cynthia A. Walawander ◽  
Nicole Blackwelder ◽  
...  
Keyword(s):  
Phase I ◽  
Amphotericin B ◽  
Phase Ii ◽  
Antifungal Therapy ◽  
Antifungal Agent ◽  
Phase I Study ◽  
Antifungal Agents ◽  
Hospitalized Patients ◽  
Prescribing Patterns ◽  
Systemic Antifungal Therapy

OBJECTIVE: To evaluatethe prescribing patternsof antifungal agents in the hospital setting after the introduction of fluconazole, a new broad-spectrum bis-triazole antifungal agent. Also comparedare the prescribing patterns of antifungal agents prior to (phase I) and following (phase II) fluconazole marketing. DESIGN: A prospective cohort of hospitalized patients prescribed topical or systemic antifungal agents. Data were collected from December 1990 to April 1991. SETTING: Fifty-seven hospitals ranging in size from 100 to more than 500 beds. Sixty-three percentare affiliated with medical schools. PATIENTS: Participating pharmacists consecutively identified 15 patients receiving systemic antifungal therapy and 5 patients receiving topical antifungal therapy. INTERVENTIONS: Observational data on patient antifungal therapy, risk factors for fungal infections, comorbidities, concurrent medications, and culture data were collected. MEASURES: Differences in prescribing patterns before and after the marketing of fluconazole were assessed using t-tests and chi-square tests. RESULTS: Of 818 patients studied, 615 (75.2 percent) received systemic antifungal therapy. Five hundred forty-six patients received a single antifungal agent; 348 (63.7 percent) received fluconazole, 105 (19.2 percent) received ketoconazole, 92 (16.8 percent) received amphotericin B, and 1 (0.2 percent) received flucytosine. Sixty-nine patients received two or more systemic agents either concurrently or consecutively. The use of parenteral amphotericin B, alone or in combination with flucytosine and/or an azole, declined from 56.8 percent in the phase I study to 24.2 percent in the current study. The use of parenteral therapy also declined from 56.8 to 40.2 percent. Ketoconazole was used in more than 90 percent of the oral and esophageal infections in the phase I study, but its use declined to only 33 percent in this study. Fluconazole was used most frequently across all sites of presumed or documented infections, with the exception of fungemia. Of the presumed or proven systemic or blood infections, amphotericin B was used alone or in combination in 48.4 percent of the patients and fluconazole was used exclusively in 39.0 percent of the patients. Fluconazole was used more often than amphotericin B (22 vs. 3 patients, respectively) for prophylaxis of systemic infections. The overall use of antifungal prophylaxis also increased from the phase I (9.5 percent) to phase II (13.7 percent). CONCLUSIONS: The introduction of fluconazole had a major impact on the prescribing patterns of antifungal therapy. Although amphotericin B remained the preferred agent for treatment of suspected or proven systemic, central nervous system, or blood infections, use of fluconazole for these indications approached nearly 40 percent. Further studies are needed to address the role of fluconazole in the prophylaxis and treatment of systemic mycoses.

scholarly journals Pharmacokinetics and Pharmacodynamics of Amphotericin B Deoxycholate, Liposomal Amphotericin B, and Amphotericin B Lipid Complex in an In Vitro Model of Invasive Pulmonary Aspergillosis

2010 ◽  
Vol 54 (8) ◽  
pp. 3432-3441 ◽  
Author(s):  
Jodi M. Lestner ◽  
Susan J. Howard ◽  
Joanne Goodwin ◽  
Lea Gregson ◽  
Jayesh Majithiya ◽  
...  
Keyword(s):  
Confocal Microscopy ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Invasive Pulmonary Aspergillosis ◽  
Host Cells ◽  
Pulmonary Aspergillosis ◽  
Lipid Complex ◽  
Amphotericin B Deoxycholate ◽  
Amphotericin B Lipid Complex

ABSTRACT The pharmacodynamic and pharmacokinetic (PK-PD) properties of amphotericin B (AmB) formulations against invasive pulmonary aspergillosis (IPA) are not well understood. We used an in vitro model of IPA to further elucidate the PK-PD of amphotericin B deoxycholate (DAmB), liposomal amphotericin B (LAmB) and amphotericin B lipid complex (ABLC). The pharmacokinetics of these formulations for endovascular fluid, endothelial cells, and alveolar cells were estimated. Pharmacodynamic relationships were defined by measuring concentrations of galactomannan in endovascular and alveolar compartments. Confocal microscopy was used to visualize fungal biomass. A mathematical model was used to calculate the area under the concentration-time curve (AUC) in each compartment and estimate the extent of drug penetration. The interaction of LAmB with host cells and hyphae was visualized using sulforhodamine B-labeled liposomes. The MICs for the pure compound and the three formulations were comparable (0.125 to 0.25 mg/liter). For all formulations, concentrations of AmB progressively declined in the endovascular fluid as the drug distributed into the cellular bilayer. Depending on the formulation, the AUCs for AmB were 10 to 300 times higher within the cells than within endovascular fluid. The concentrations producing a 50% maximal effect (EC50) in the endovascular compartment were 0.12, 1.03, and 4.41 mg/liter for DAmB, LAmB, and ABLC, respectively, whereas, the EC50 in the alveolar compartment were 0.17, 7.76, and 39.34 mg/liter, respectively. Confocal microscopy suggested that liposomes interacted directly with hyphae and host cells. The PK-PD relationships of the three most widely used formulations of AmB differ markedly within an in vitro lung model of IPA.

scholarly journals Pharmacodynamics of Amphotericin B Deoxycholate, Amphotericin B Lipid Complex, and Liposomal Amphotericin B against Aspergillus fumigatus

2015 ◽  
Vol 59 (5) ◽  
pp. 2735-2745 ◽  
Author(s):  
Zaid Al-Nakeeb ◽  
Vidmantas Petraitis ◽  
Joanne Goodwin ◽  
Ruta Petraitiene ◽  
Thomas J. Walsh ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Invasive Pulmonary Aspergillosis ◽  
Liposomal Amphotericin B ◽  
Complete Suppression ◽  
Pulmonary Aspergillosis ◽  
Lipid Complex ◽  
Amphotericin B Deoxycholate ◽  
Amphotericin B Lipid Complex ◽  
Dose Dependent

ABSTRACTAmphotericin 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.

scholarly journals The Initial 96 Hours of Invasive Pulmonary Aspergillosis: Histopathology, Comparative Kinetics of Galactomannan and (1→3)-β-d-Glucan, and Consequences of Delayed Antifungal Therapy

2010 ◽  
Vol 54 (11) ◽  
pp. 4879-4886 ◽  
Author(s):  
William W. Hope ◽  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Tamarra Aghamolla ◽  
John Bacher ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Amphotericin B ◽  
Antifungal Therapy ◽  
Time Course ◽  
Invasive Pulmonary Aspergillosis ◽  
Rabbit Model ◽  
Pulmonary Aspergillosis ◽  
Lung Weight ◽  
Kinetics Of

ABSTRACT Acute invasive pulmonary aspergillosis is a rapidly progressive and frequently lethal infection. Relatively little is known about early events in the pathogenesis and relationship between the cell wall biomarkers galactomannan and (1→3)-β-d-glucan. The consequences of delayed antifungal therapy are also poorly defined. A persistently neutropenic rabbit model of invasive pulmonary aspergillosis was used to describe the histopathology of early invasive pulmonary aspergillosis and the kinetics of galactomannan and (1→3)-β-d-glucan. The time course of both molecules was mathematically modeled by using a population methodology, and Monte Carlo simulations were performed. The effect of progressive delay in the administration of amphotericin B deoxycholate 1 mg/kg at 24, 48, 72, and 96 h postinoculation on fungal burden, lung weight, pulmonary infarct score, and survival was determined. Histopathology showed phagocytosis of conidia by pulmonary alveolar macrophages at 4 h postinoculation. At 12 to 24 h, there was a progressive focal inflammatory response with conidial germination and hyphal extension. Subsequently, hyphae invaded into the contiguous lung. Galactomannan and (1→3)-β-d-glucan had similar trajectories, and both exhibited considerable interindividual variability, which was reflected in Monte Carlo simulations. Concentrations of both molecules began to rise <24 h postinoculation before pulmonary hemorrhagic infarction was present. Delays of 72 and 96 h in the administration of amphotericin B resulted in fungal burdens and lung weights that were indistinguishable from those of controls, respectively. Galactomannan and (1→3)-β-d-glucan have similar kinetics and are comparable biomarkers of early invasive pulmonary aspergillosis. Antifungal treatment at ≥48 h postinoculation is associated with suboptimal therapeutic outcomes.

scholarly journals Increased Efficacy of Oral Fixed-Dose Combination of Amphotericin B and AHCC® Natural Adjuvant against Aspergillosis

Pharmaceutics ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 456 ◽  
Author(s):  
Alba Pérez-Cantero ◽  
Dolores R. Serrano ◽  
Patricia Navarro-Rodríguez ◽  
Andreas G. Schätzlein ◽  
Ijeoma F. Uchegbu ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Lentinula Edodes ◽  
Fungal Infections ◽  
Chitosan Nanoparticles ◽  
Invasive Pulmonary Aspergillosis ◽  
Fixed Dose ◽  
Control Group ◽  
Pulmonary Aspergillosis ◽  
Cytokine Analysis

Invasive pulmonary aspergillosis represents one of the most serious fungal infections among immunocompromised patients. In this study, we aimed to analyze the in vivo efficacy of prophylactic oral amphotericin B (AMB) encapsulated in modified chitosan-nanoparticles (Nanomerics’ Molecular Envelope Technology (MET)) supplemented with a standardized extract of cultured Lentinula edodes mycelia (AHCC®) in a murine model of pulmonary aspergillosis. We determined fungal burden and survival of mice and additionally, we carried out a cytokine analysis in an attempt to understand the immunomodulation of the extract. Our results evidenced equivalent efficacy between orally administered AMB-MET and the intravenous liposomal AMB marketed formulation. Addition of the AHCC® supplement significantly improved efficacy in terms of burden reduction and survival increase of both oral and intravenous AMB therapies compared to the untreated control group. Moreover, a protective effect of the extract was observed in terms of weight loss. Regarding the cytokine profiles, the Th1 immune response was stimulated in treated animals when compared to the control group. This response was marked by an enhancement in the MCP-1, GM-CSF, VEGF, RANTES and IL-17 levels and a decrease in the IL-6, a biomarker related to the severity of the infection.

scholarly journals Pretreatment with Empty Liposomes Attenuates the Immunopathology of Invasive Pulmonary Aspergillosis in Corticosteroid-Immunosuppressed Mice

2006 ◽  
Vol 51 (3) ◽  
pp. 1078-1081 ◽  
Author(s):  
Russell E. Lewis ◽  
Georgios Chamilos ◽  
Randall A. Prince ◽  
Dimitrios P. Kontoyiannis
Keyword(s):  
Body Weight ◽  
Antifungal Activity ◽  
Amphotericin B ◽  
Murine Model ◽  
Liposomal Amphotericin ◽  
Invasive Pulmonary Aspergillosis ◽  
Pulmonary Aspergillosis ◽  
Amphotericin B Deoxycholate ◽  
Immunomodulatory Properties ◽  
Immunosuppressed Mice

ABSTRACT In a nonneutropenic murine model of invasive pulmonary aspergillosis, pretreatment with empty liposomes (E-lipo) was nearly as effective as 10 mg/kg of body weight liposomal amphotericin B and superior to 1 mg/kg amphotericin B deoxycholate. The beneficial immunomodulatory properties of E-lipo appear to compensate for their lack of direct antifungal activity.

scholarly journals Pharmacodynamic Activity of Amphotericin B Deoxycholate Is Associated with Peak Plasma Concentrations in a Neutropenic Murine Model of Invasive Pulmonary Aspergillosis

2006 ◽  
Vol 50 (2) ◽  
pp. 469-473 ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Vincent H. Tam ◽  
Jingduan Chi ◽  
Randall A. Prince ◽  
Dimitrios P. Kontoyiannis ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Invasive Pulmonary Aspergillosis ◽  
Dose Fractionation ◽  
Pharmacokinetic Analysis ◽  
Pulmonary Aspergillosis ◽  
Fungal Burden ◽  
Drug Concentrations ◽  
Amphotericin B Deoxycholate

ABSTRACT 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 [C max]/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 C max/MIC, with maximal activity occurring as the C max/MIC approached 2.4. In our model, C max/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.

scholarly journals The outcome of two patients with myeloblastic acute leukemia and invasive pulmonary aspergillosis using clinical adjustment of Voriconazol therapy

2015 ◽  
Vol 10 (1) ◽  
pp. 62-66
Author(s):  
Ana-Maria NEAGU ◽  
◽  
Ana Maria VLĂDĂREANU ◽  
Horia BUMBEA ◽  
Diana CÎŞLEANU ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Invasive Aspergillosis ◽  
Antifungal Therapy ◽  
Fungal Infections ◽  
Invasive Pulmonary Aspergillosis ◽  
Young Patients ◽  
Favourable Outcome ◽  
Invasive Fungal Infections ◽  
Severe Neutropenia ◽  
Pulmonary Aspergillosis

Background. Patients with acute leukemia are at high risk to develop invasive fungal infections, and Aspergillus spp is the most common pathogen. Aim. The two cases that are presented highlight the importance of adjusting the algorithm for diagnosis and treatment of invasive fungal infections in acute leukemia patients according to the particularities of each case in order to obtain an optimal response to the antifungal therapy. Methods and results. We present two cases of acute leukemia in young patients, who develop pulmonary invasive aspergillosis during severe neutropenia following chemotherapy. The diagnosis is clinical, mycrobiological, and esspecially imagistic, the CT scan revealing images typical for pulmonary invasive aspergillosis and allowing early antifungal therapy. Conclusions. The two cases illustrate the favourable outcome of patients with acute leukemia and pulmonary invasive aspergillosis when treated early with Voriconazole and the importance of dose adjusting according to clinical evolution.

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