ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 2001, p. 1937–1938 0066-4804/01/$04.00⫹0 DOI: 10.1128/AAC.45.6.1937–1938.2001 Copyright © 2001, American Society for Microbiology. All Rights Reserved.
Vol. 45, No. 6
Sputum Itraconazole Concentrations in Cystic Fibrosis Patients I. SERMET-GAUDELUS,1* A. LESNE-HULIN,2 G. LENOIR,1 E. SINGLAS,2 P. BERCHE,3 AND C. HENNEQUIN3 Service de Pe´diatrie Ge´ne´rale,1 Pharmacie,2 and Service de Microbiologie,3 Ho ˆpital Necker-Enfants Malades, 75015 Paris, France Received 30 October 2000/Returned for modification 27 November 2000/Accepted 22 March 2001
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. (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 compound, and at T4, 2,500 ng/ml for total itraconazole–OH-itraconazole (3). The mean (⫾ standard deviation [SD]) serum itraconazole concentration at T0 was 405 ⫾ 295 ng/ml. Ten of the 15 samples were above the recommended concentration of 250 ng/ml (Table 1). The mean (⫾ SD) concentration at T0 of total itraconazole–OH-itraconazole was 1,170 ⫾ 788 ng/ml. Nine samples were above the recommended concentration of 1,000 ng/ml. At T4, the mean (⫾ SD) concentration of total itraconazole–OH-itraconazole was 2,355 ⫾ 1,510 ng/ml. A value higher than the 2,500-ng/ml concentration recommended was observed in five samples. Sputum itraconazole concentrations at T0 were compared to the itraconazole MIC that inhibited 90% of strains (MIC90) determined in A. fumigatus isolates from CF sputum, i.e., 0.06 mg/liter. The concentration was lower than the MIC90 in five samples. For the 10 remaining samples, the mean concentration was 180 ⫾ 124 ng/ml. The mean (⫾ SD) sputum/serum drug concentration ratio at T0 was 0.44 ⫾ 0.56 for itraconazole and 0.48 ⫾ 0.61 for total itraconazole–OH-itraconazole. There was no correlation between serum and sputum itraconazole concentrations. The serum drug concentration was lower than 250 ng/ml in five samples. Corresponding sputum drug concentrations were higher than 60 ng/ml in three samples. Conversely, 3 out of 10 serum samples with drug concentrations higher than 250 ng/ml had corresponding sputum drug concentrations lower than 60 ng/ml. Among the three patients who had repeated samples, patient 2 had serum and sputum itraconazole concentrations within the same range 3 months later. Patients 1 and 3 had variable serum and sputum drug concentrations although the dosage did not change and the patients were compliant. This study documents a high interindividual variability in serum itraconazole concentrations. Similar findings have been reported in healthy volunteers and in patients suffering from neutropenia or renal dysfunction, as well as in a few CF patients (4, 6; T. Nawata, Progr. Abstr. 39th Gen. Meet. Jpn. Soc.
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 H2 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
* Corresponding author. Mailing address: Service de Pe´diatrie Ge´ne´rale, Ho ˆpital Necker-Enfants Malades, 149 rue de Se`vres, 75015 Paris, France. Phone: (33)1 44 49 38 73. Fax: (33)1 47 83 32 26. E-mail:
[email protected]. 1937
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NOTES
ANTIMICROB. AGENTS CHEMOTHER. TABLE 1. Itraconazole and OH-itraconazole concentrations Itra ⫹ OH-itraconazoleb concn (ng/ml)
Itraconazole concn (ng/ml) Patient
1 2 3 4 5 6 7 8 9 10 11 a b
Serum
Sputum
T0
T4
T0
T4
363 137 581 115 81 663 931 300 905 297 524 ⬍10 680 174 328
883
117 169 135 127 159 391 423 41 143 81 61 ⬍10 18 14 ⬍10
461
140 133 929 2160 2271 1231 1005 308 742 594 2779
128 496 514 156 243 55 53 ⬍10 36 37
Serum T0 ratioa
0.32 1.23 0.23 1.1 1.96 0.59 0.45 0.13 0.16 0.27 0.11 0.02 0.08 ⬍0.03
Sputum
T0
T4
T0
T4
T0 ratioa
1,340 344 1,386 364 205 2,044 2,161 643 2,476 1,070 1,833 33 1,937 619 1,106
2,283
244 359 270 244 376 898 921 87 307 178 232 60 49 33 15
904
0.18 1.04 0.19 0.67 1.83 0.44 0.42 0.13 0.12 0.16 0.12 1.82 0.02 0.05 0.01
456 302 2,518 4,486 4,502 2,386 2,502 866 2,040 1,383 4,545
266 1,057 1,102 328 390 610 151 ⬍10 74 77
Sputum/serum drug concentration ratio at T0. Total itraconazole plus OH-itraconazole concentration.
Med. Mycol., 1995). Out of the 15 samples, 5 were below the recommended level despite administration of higher doses than usually prescribed (10 mg/kg/day versus 5 mg/kg/day). This is probably not due to poor drug absorption, since CF patients have gastric hyperacidity, a condition known to increase itraconazole absorption. The explanation could be a shorter half-life of itraconazole due to an increased volume of distribution and total body clearance, as is frequently reported in CF patients for various drugs (11). There was also a marked interpatient variation in sputum itraconazole concentrations and sputum/serum ratio (0 to 423 ng/ml and 0 to 1.96) that was even greater than that in healthy volunteers (15 to 442 ng/ml and 0.07 to 0.38) (6) or in non-CF patients with ABPA (120 to 364 ng/ml and 0.05 to 0.28) (Nawata, 39th Gen. Meet. Jpn. Soc. Med. Mycol.). Concentrations in sputum are not correlated to levels in serum, as reported by Denning et al. (4). Sputum itraconazole concentrations lower than the MIC90 of A. fumigatus were found in three patients, although the corresponding serum concentrations were higher than 250 ng/ml, i.e., within the therapeutic range. Thus, adequate serum drug concentrations do not guarantee effective concentrations in bronchial secretions and therefore monitoring of serum drug concentration does not seem to be a suitable method to assess antifungal activity. This also suggests that sputum itraconazole concentrations might not always be adequate for antifungal activity. Moreover, itraconazole bioavailability may be decreased in sputum of CF patients due to mucin glycoprotein binding as already described for tobramycin (9). Thus, the clinical improvement reported in CF patients could also be due to the non-antifungal properties of the drug. Itraconazole has indeed an antiallergic and anti-inflammatory action because of its 5-lipoxygenase-inhibiting effect (2, 13). It also increases chloride transepithelial exchange, a pathway whose defect is supposed to be one of the main features of the CF lung disease (J. Jeschke, S. Heiduk, and U. Kersting, Prog. Abstr. XXII Eur. Cystic Fibrosis Conf., 1998). To our knowledge, this is the first study focusing on itraconazole diffusion in sputum of CF patients. This study demon-
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