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

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.

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Faculty Opinions recommendation of Pathogenesis of Aspergillus fumigatus and the kinetics of galactomannan in an in vitro model of early invasive pulmonary aspergillosis: implications for antifungal therapy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1058991.510956 ◽

2007 ◽

Author(s):

S Arun Balajee

Keyword(s):

Aspergillus Fumigatus ◽

Antifungal Therapy ◽

In Vitro Model ◽

Invasive Pulmonary Aspergillosis ◽

Pulmonary Aspergillosis ◽

Vitro Model ◽

Kinetics Of

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Antifungal Activity of the Pradimicin Derivative BMS 181184 in the Treatment of Experimental Pulmonary Aspergillosis in Persistently Neutropenic Rabbits

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.9.2399 ◽

1998 ◽

Vol 42 (9) ◽

pp. 2399-2404 ◽

Cited By ~ 13

Author(s):

Corina E. Gonzalez ◽

Andreas H. Groll ◽

Neelam Giri ◽

Daiva Shetty ◽

Ibrahim Al-Mohsen ◽

...

Keyword(s):

Amphotericin B ◽

Drug Disposition ◽

Tissue Injury ◽

Invasive Pulmonary Aspergillosis ◽

Dosage Level ◽

Lavage Fluid ◽

Pharmacokinetic Studies ◽

Pulmonary Aspergillosis ◽

Lung Weight ◽

Dosing Regimens

ABSTRACT The activity of the pradimicin derivative BMS 181184 was evaluated in a model of invasive pulmonary aspergillosis in persistently neutropenic rabbits and compared with that of amphotericin B deoxycholate. BMS 181184 at total daily doses of 50 and 150 mg/kg of body weight was at least as effective as amphotericin B at 1 mg/kg once a day in conferring survival and had comparable activity in reducing organism-mediated tissue injury and excess lung weight. Although treatment at all dosing regimens of BMS 181184 resulted in significant reductions in fungal tissue burden compared to untreated controls, equivalence to amphotericin B occurred only at the higher dosage level. Similar observations were made in bronchoalveolar lavage fluid cultures obtained postmortem. Monitoring of the animals through ultrafast computerized tomography scan revealed a marked resolution of pulmonary lesions during treatment with BMS 181184. The compound was well tolerated at all dosing regimens, and no toxicity was noted. Pharmacokinetic studies revealed nonlinear drug disposition with increased clearance at higher dosages and some evidence for extravascular drug accumulation. BMS 181184 had excellent activity in the treatment of experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits, thus underscoring the potential of pradimicin derivatives in therapy of invasive aspergillosis in the neutropenic host.

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Comparative Analysis of Amphotericin B Lipid Complex and Liposomal Amphotericin B Kinetics of Lung Accumulation and Fungal Clearance in a Murine Model of Acute Invasive Pulmonary Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01449-06 ◽

2007 ◽

Vol 51 (4) ◽

pp. 1253-1258 ◽

Cited By ~ 51

Author(s):

Russell E. Lewis ◽

Guangling Liao ◽

Jinggou Hou ◽

Georgios Chamilos ◽

Randall A. Prince ◽

...

Keyword(s):

Amphotericin B ◽

Liposomal Amphotericin ◽

Invasive Pulmonary Aspergillosis ◽

Drug Distribution ◽

Pulmonary Aspergillosis ◽

Tissue Concentrations ◽

Lipid Complex ◽

Fungal Burden ◽

Amphotericin B Lipid Complex ◽

Kinetics Of

ABSTRACT The reformulation of amphotericin B (AMB) into a lipid complex (AMB lipid complex [ABLC]) or liposomal carrier (liposomal AMB [L-AMB]) changes the rate and extent of drug distribution to the lung. The importance of pharmacokinetic differences among the various lipid AMB formulations in the treatment of invasive pulmonary aspergillosis (IPA) remains unknown. We compared the kinetics of AMB lung accumulation and fungal clearance of ABLC- and L-AMB-treated mice with acute IPA. BALB/c mice were immunosuppressed with cyclophosphamide and cortisone before intranasal inoculation with 1.5 × 106 Aspergillus fumigatus 293 conidia. ABLC or L-AMB was administered in daily intravenous doses (1, 5, or 10 mg/kg of body weight), starting 12 h after infection and continuing until day 5. At predetermined times (0, 24, 72, and 120 h), mice were euthanized, and lungs were harvested for determinations of lung fungal burdens (quantitative PCR) and total AMB lung tissue concentrations. Both ABLC and L-AMB were effective at reducing lung fungal burdens at doses of ≥5 mg/kg/day. Clearance of A. fumigatus during the first 24 h was associated with AMB tissue concentrations of >4 μg/g. At 5 mg/kg/day, ABLC produced a more rapid fungal clearance than did L-AMB, but at the end of therapy, fungal burden reductions were similar for both formulations and were not improved with higher dosages. These data suggest that ABLC delivers active AMB to the lung more rapidly than does L-AMB, resulting in faster Aspergillus clearance in an experimental model of IPA. However, pharmacodynamic differences between the two formulations were less apparent when mice were dosed at 10 mg/kg/day.

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Effect of amphotericin B treatment on kinetics of cytokines and parameters of fungal load in neutropenic rats with invasive pulmonary aspergillosis

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkg367 ◽

2003 ◽

Vol 52 (3) ◽

pp. 428-434 ◽

Cited By ~ 33

Author(s):

M. J. Becker

Keyword(s):

Amphotericin B ◽

Invasive Pulmonary Aspergillosis ◽

Pulmonary Aspergillosis ◽

Fungal Load ◽

Kinetics Of

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Pathogenesis ofAspergillus fumigatusand the Kinetics of Galactomannan in an In Vitro Model of Early Invasive Pulmonary Aspergillosis: Implications for Antifungal Therapy

The Journal of Infectious Diseases ◽

10.1086/510535 ◽

2007 ◽

Vol 195 (3) ◽

pp. 455-466 ◽

Cited By ~ 91

Author(s):

William W. Hope ◽

Michael J. Kruhlak ◽

Caron A. Lyman ◽

Ruta Petraitiene ◽

Vidmantas Petraitis ◽

...

Keyword(s):

Antifungal Therapy ◽

In Vitro Model ◽

Invasive Pulmonary Aspergillosis ◽

Pulmonary Aspergillosis ◽

Vitro Model ◽

Kinetics Of

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Antifungal Agents for the Treatment of Systemic Fungal Infections in Children

Canadian Journal of Infectious Diseases and Medical Microbiology ◽

10.1155/2010/784549 ◽

2010 ◽

Vol 21 (4) ◽

pp. e116-e121 ◽

Cited By ~ 1

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.

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Faculty Opinions recommendation of Pharmacokinetics and pharmacodynamics of posaconazole for invasive pulmonary aspergillosis: clinical implications for antifungal therapy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.9790956.10490054 ◽

2011 ◽

Author(s):

Neil Ampel

Keyword(s):

Antifungal Therapy ◽

Invasive Pulmonary Aspergillosis ◽

Clinical Implications ◽

Pharmacokinetics And Pharmacodynamics ◽

Pulmonary Aspergillosis

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Changing the Drug Delivery System: Does it Add to Non-Compliance Ramifications Control? A Simulation Study on the Pharmacokinetics and Pharmacodynamics of Atypical Antipsychotic Drug

Pharmaceutics ◽

10.3390/pharmaceutics12040297 ◽

2020 ◽

Vol 12 (4) ◽

pp. 297

Author(s):

Mohammed H. Elkomy

Keyword(s):

Monte Carlo ◽

Plasma Concentration ◽

Monte Carlo Simulations ◽

Time Course ◽

Rating Scale ◽

Test Dose ◽

Immediate Release ◽

State Recovery ◽

Psychiatric Rating ◽

Psychiatric Rating Scale

This study investigates the pharmacokinetic (PK) and pharmacodynamic (PD) consequences of shifting from Quetiapine fumarate immediate-release (IR) to extended-release (XR) formulation in non-adherent schizophrenia patients. Monte-Carlo simulations using population PK and PD models were implemented to predict the time course of plasma concentration and Brief Psychiatric Rating Scale (BPRS) scores following the oral administration of 200 mg Seroquel® every 12 h and 400 mg Seroquel XR® every 24 h in patients experiencing dose delay, omission or doubling. Parameters were computed and their distributions were compared using the Kolmogorov–Smirnov test. Dose irregularities with both formulations had different effects on plasma concentration and %reduction in BPRS scores from baseline. However, the odds ratio of getting a %reduction in BPRS below 14%, or plasma concentration exceeding 500 µg/L, were comparable for adherent and non-adherent patients. Plasma therapeutic concentration after treatment cessation was maintained for <24 h in 48% and 29.6% of patients, and a steady state recovery time of <48 h was achieved in 51% and 13.4% of patients on the IR and XR formulations, respectively. Monte-Carlo simulations predict that the risks associated with the IR dose irregularities are not worsened when the XR formulation is used instead. Non-adherence events involving a single dose of either formulation do not require rescue doses.

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