Antifungal Activity and Pharmacokinetics of Posaconazole (SCH 56592) in Treatment and Prevention of Experimental Invasive Pulmonary Aspergillosis: Correlation with Galactomannan Antigenemia

Abstract

The antifungal efficacy, safety, and pharmacokinetics of posaconazole (SCH 56592) (POC) were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Antifungal therapy consisted of POC at 2, 6, and 20 mg/kg of body weight per os; itraconazole (ITC) at 2, 6, and 20 mg/kg per os; or amphotericin B (AMB) at 1 mg/kg intravenously. Rabbits treated with POC showed a significant improvement in survival and significant reductions in pulmonary infarct scores, total lung weights, numbers of pulmonary CFU per gram, numbers of computerized-tomography-monitored pulmonary lesions, and levels of galactomannan antigenemia. AMB and POC had comparable therapeutic efficacies by all parameters. By comparison, animals treated with ITC had no significant changes in outcome variables in comparison to those of untreated controls (UC). Rabbits receiving prophylactic POC at all dosages showed a significant reduction in infarct scores, total lung weights, and organism clearance from lung tissue in comparison to results for UC (P < 0.01). There was dosage-dependent microbiological clearance of A. fumigatus from lung tissue in response to POC. Serum creatinine levels were greater (P < 0.01) in AMB-treated animals than in UC and POC-or ITC-treated rabbits. There was no elevation of serum hepatic transaminase levels in POC-or ITC-treated rabbits. The pharmacokinetics of POC and ITC in plasma demonstrated dose dependency after multiple dosing. The 2-, 6-, and 20-mg/kg dosages of POC maintained plasma drug levels above the MICs for the entire 24-h dosing interval. In summary, POC at >6 mg/kg/day per os generated sustained concentrations in plasma of >1 g/ml that were as effective in the treatment and prevention of invasive pulmonary aspergillosis as AMB at 1 mg/kg/day and more effective than cyclodextrin ITC at >6 mg/kg/day per os in persistently neutropenic rabbits.

Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin

“…10 However, studies have shown that orally administered posaconazole can achieve plasma concentrations that exceed the minimum inhibitory concentration for Aspergillus. 29,30 In addition, Krishna et al 31 have shown that oral posaconazole in allogeneic stem cell transplant patients with graft-versus-host disease achieves efficacious plasma concentrations and is not affected by variables such as body weight or grade of graftversus-host disease. In the patient population evaluated in this study, almost half of whom underwent stem cell transplant, with the majority of those having graft-versus-host disease, posaconazole was not expected to demonstrate superiority in terms of response and survival to parenteral antifungal therapy.…”

A model of cerebral aspergillosis in non-immunosuppressed nursing rats

“…Most rodent models of invasive aspergillosis require immunosuppression to produce consistent disease [12,17,20,25,26]. Immunocompetent mice can be infected by the i.v.…”

Diagnosis of Aspergillus niger Peritonitis in a Peritoneal Dialysis Patient by Peritoneal Galactomannan and β–d-Glucan Detection

“…Most instances are external breaks associated with mechanical or chemical stress (1)(2)(3). Internal breaks are relatively uncommon, but they can be caused by product defects, accidental needle-stick injury, the catheter becoming brittle with aging, and the intrinsic properties of polyurethane (4)(5)(6)(7)(8). In particular, it has been widely accepted that polyurethane catheters are highly biocompatible, but vulnerable to various types of physical and chemical stress that lead to polyurethane degradation (7,8).…”

“…In 2003, the US Food and Drug Administration approved the use of a double-sandwich GM enzyme immunoassay (Platelia Aspergillus EIA: Bio-Rad Laboratories) for the diagnosis of invasive aspergillosis in adult patients (7). The double-sandwich ELISA for detection of GM is reported to have high sensitivity and high specify for invasive aspergillosis when a cut-off value of 0.8 ng/mL is used (8).…”

“…Internal breaks are relatively uncommon, but they can be caused by product defects, accidental needle-stick injury, the catheter becoming brittle with aging, and the intrinsic properties of polyurethane (4)(5)(6)(7)(8). In particular, it has been widely accepted that polyurethane catheters are highly biocompatible, but vulnerable to various types of physical and chemical stress that lead to polyurethane degradation (7,8). Moreover, Weaver et al (9) reported that mupirocin containing polyethylene glycol causes structural changes in PD catheters and that the resulting abnormalities increase in severity with longer duration of mupirocin use.…”