The pathophysiology associated with major burns is complex and subject to a state of flux. The combination of beta-lactamase inhibitors with powerful penicillins is an interesting and an attractive potential solution to the emergence of bacterial resistance. The kinetics in serum and urine and the clinical safety of a fixed combination of 4 g of piperacillin (PPR) and 0.5 g of tazobactam (TZB) were studied in 10 patients (22 to 50 years old and weighing 45 to 105 kg) with major burns who were infected with Pseudomonas aeruginosa and various entero-bacteria. All of them received additional antimicrobial drugs. Treatment involved one dose every 6 h. The mean body surface area affected by third-degree burns was 30.0% +/- 4.0%. The study took place in accordance with current ethical guidelines. Two series of blood samples were drawn after the first (day 1) and ninth (day 3 at steady state) doses; urine was collected during the same periods. Levels of PPR and TZB in serum and urine were measured by high-pressure liquid chromatography. A noncompartmental method was used for kinetic and graphic analysis of concentration-time pairs. The safety of the treatment was excellent. There was no systemic accumulation of the beta-lactam combination. Residual concentrations measured on days 1 and 3 [mean (standard error of the mean)] were above the MIC for the organism responsible for infection; i.e., C(min)day1 = 26.3 (8.5) and C(min)day3 = 21.0 (9.1) for PPR and C(min)day1 = 1.9 (0.6) and C(min)day3 = 1.4 (0.3) for TZB. There was no statistically significant difference between pharmacokinetic parameters determined for day 1 and day 3. Evidence was found in burn patients, in contrast to healthy subjects, of a marked increase in apparent volumes of distribution, in such a way that the apparent elimination half-lives of the combination were notably prolonged, i.e., 1.8 (0.3) versus 1.5 (0.3) h for PPR in patients and healthy subjects, respectively, and 1.7 (0.3) versus 1.4 (0.3) h for TZB. These findings indicate the possibility of nonrenal translesional diffusion of PPR-TZB in burn patients. The polarity of the association would further support this hypothesis. It has been shown here that the recommended dosage regimen for administration of PPR-TZB must be high in major-burn patients, i.e., 4 g/0.5 g every 6 h. The data obtained provide valuable information, which is suitable for immediate application in everyday clinical practice.

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 ...

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Midazolam (M) is used as an induction agent for anesthesia. The main metabolite is alpha-hydroxymidazolam (OM), which is pharmacologically active. Use of M for sedation is a recent application, rapidly gaining favor. Monitoring of the level of sedation is fundamental in that an excessive and prolonged effect is associated with the risk of complications. Thus, it was felt both necessary and useful to measure circulating M levels. We compared a high-performance liquid chromatography (HPLC) assay with fluorescence polarization immunoassay (FPIA) for the measurement of M in the serum of 138 sedated patients in the intensive care unit (i.e., 179 samples). Response of the OM was also assessed. The degree of crossover of the metabolite was between 76.8 and 32.7%. The equation of the regression line for sigma HPLC (i.e., the sum M + OM) versus FPIA was TDx = 1.1585 sigma HPLC + 143.42 (R = 0.966). The 95% confidence interval for the slope was 1.1551, 1.1619. The regression slope differed significantly from 1 (p < 0.001) and shows that FPIA measurements overestimated concentrations obtained by HPLC on the order of 19%. The discrepancy between the two techniques was all the more notable when concentrations were > 1,000 ng/ml. The relative selectivity of Abbott industrial reagent in terms of benzodiazepines leads to the identification of what might be called a midazolam-like (M-like) activity covering both M and OM. The development of a global FPIA method for measurement of this M-like activity in sedated patients provides a satisfactory solution to the question raised.

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