Sputum Itraconazole Concentrations in Cystic Fibrosis Patients

Abstract

Itraconazole diffusion in sputum was studied in 11 cystic fibrosis patients with allergic bronchopulmonary aspergillosis. There was a high interindividual variability in sputum itraconazole concentration and sputum/ serum drug concentration ratio. Three children had sputum drug concentrations before oral administration that were lower than the itraconazole MIC at which 90% of Aspergillus fumigatus strains were inhibited, although their serum drug concentrations were within the therapeutic range.Allergic bronchopulmonary aspergillosis (ABPA) is a disease characterized by lung hypersensitivity due to endobronchial colonization with Aspergillus fumigatus. It is a potential respiratory complication of cystic fibrosis (CF) (1, 7). Recent reports describe successful itraconazole treatment of ABPA in CF patients (4,8,10). This azole derivative is effective against A. fumigatus, including strains isolated from sputum of CF patients (5). It might thus minimize the chronic antigenic stimulation provided by the fungal airway colonization. However, its use remains controversial due to the lack of prospective clinical studies regarding its pharmacokinetics and its sputum diffusion, two characteristics that are often considerably modified in CF. We therefore undertook an evaluation of serum and sputum itraconazole concentrations in CF patients to ascertain whether itraconazole penetration into bronchial secretions was effective.Eleven CF patients with ABPA, 5 to 15 years of age, were enrolled in the study during the usual monitoring of itraconazole treatment. All the patients fulfilled the diagnostic criteria for ABPA as proposed by Ricketti et al. (12). All the patients received itraconazole at 10 mg/kg of body weight once a day in capsules, with or immediately following breakfast and in association with inhaled corticosteroids. None of the patients received drugs which could interfere with the hepatic metabolism of itraconazole or affect the drug bioavailability, such as antacids or H 2 blockers. Assays were performed at the presumed steady state of itraconazole at least 15 days after the beginning of treatment, according to the method described by Woestenborghs et al. (14). Blood and sputum samples were taken simultaneously, before (T0) and 4 h after (T4) oral administration. Salivary samples with less than 20 polymorphonuclear cells per ml were discarded. Sputum was then mixed with liquid nitrogen. A total of 106 specimens (54 in serum, 52 in sputum) were analyzed. More than one sample was obtained from three patients, at a three-month interval. Serum and sputum samples were assayed by high-performance liquid chromatography for itraconazole and its main metabolite, hydroxyitraconazole (OH-itraconazole) (14). All samples were studied twice. Controls were regularly performed.Serum drug concentrations were compared with the manufacturer's recommendations for invasive aspergillosis treatment, i.e., at T0, 250 ng/ml for itraconazole and 1,000 ng/ml for total itraconazole-OH-itraconazole, which represents the active antifungal ...

Tissue Penetration of Antifungal Agents

“…7). Consistent with their physicochemical properties (Table 1), the concentration ratios for fluconazole in saliva and sputum compared with serum are ϳ1, while for itraconazole they are generally much lower (73) and very variable (159). Itraconazole can also be detected in esophageal tissue, at 3 times the concentration in plasma (160), and in bronchial exudates (73).…”

“…Fluconazole (67,157,158) and itraconazole (73,159) have both been detected in the saliva and sputum of patients (Fig. 7).…”

Disseminated Aspergillus fumigatus Infection with Consecutive Mitral Valve Endocarditis in a Lung Transplant Recipient

“…This may affect the absorption of lipophilic drugs such as itraconazole. Sermet-Gaudelus et al 13 found only 33% of patients with cystic fibrosis failed to achieve trough steady-state serum itraconazole concentration Ͼ250 ng/ml after at least 15 days of oral itraconazole capsules at a daily dose of 10 mg/kg. Conway et al 14 showed that steady-state itraconazole concentrations of more than 250 ng/ml could be rich in 50% of cystic fibrosis patients older than 16 years.…”

Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis

“…Therefore, therapeutic drug monitoring has been recommended [73]. These problems are exaggerated in patients with CF as compared with asthma and, therefore, higher doses of itraconazole capsule or use of the cyclodextrin liquid formulation have been recommended for CF patients [74][75][76]. It may be difficult to achieve optimal efficacy with itraconazole in CF patients.…”