The intrapulmonary pharmacokinetics of orally administered clarithromycin (500 mg every 12 h for five doses) or erythromycin (250 mg every 6 h for nine doses) were studied in 32 healthy adult volunteers. Four of the subjects, two in the clarithromycin group and two in the erythromycin group, were smokers. Bronchoscopy, bronchoalveolar lavage, and venipuncture were performed at 4, 8, 12, 24, and 48 h after administration of the last dose of clarithromycin and at 4, 8, and 12 h after administration of the last dose of erythromycin. Clarithromycin was measured by high-performance liquid chromatography, and erythromycin was measured by a microbiological assay. No systemic sedation was used. There were no major adverse events. The concentrations of antibiotics in epithelial lining fluid (ELF) were calculated by the urea dilution method. The volumes (mean ؎ standard deviation) of ELF were 1.9 ؎ 2.0 ml and 1.5 ؎ 0.7 ml in the clarithromycin and erythromycin groups, respectively (P > 0.05). There was no effect of smoking on the amount of bronchoalveolar lavage fluid recovered, the volume of ELF, or the number of erythrocytes present in the lavage fluid (P > 0.05 for all comparisons). The total number of alveolar cells, however, was almost threefold greater in the smokers versus that in the nonsmokers (P < 0.05). Clarithromycin was concentrated in ELF (range, 72.1 ؎ 73.0 g/ml at 8 h to 11.9 ؎ 3.6 g/ml at 24 h) and alveolar cells (range, 505.8 ؎ 293.1 g/ml at 4 h to 17.0 ؎ 34.0 g/ml at 48 h). 14-(R)-Hydroxyclarithromycin was also present in these compartments, but at lower concentrations than the parent compound. The concentrations of erythromycin in ELF and alveolar cells were low at 4, 8, and 12 h following the last dose of drug (range, 0 to 0.8 ؎ 0.1 g/ml in ELF and 0 to 0.8 ؎ 1.3 g/ml in alveolar cells). The clinical significance of any antibiotic concentrations in these compartments is unclear. The data suggest, and we conclude, that clarithromycin may be a useful drug in the treatment of pulmonary infections, particularly those caused by intracellular organisms.Clarithromycin is a semisynthetic macrolide antibiotic that contains a 14-member lactone ring (32). It is active against Streptococcus pneumoniae, Haemophilus influenzae group A streptococci, Staphylococcus aureus, Staphylococcus epidermidis, Moraxella catarrhalis, Chlamydia pneumoniae, Mycobacterium pneumoniae, Toxoplasma gondii, Listeria monocytogenes, legionellae, atypical mycobacteria, and Mycobacterium leprae (2,7,19,22,23,25,28,31,38,42). Like other macrolides, clarithromycin is concentrated in phagocytic cells (5,6,9,30), and it is active against intracellularly growing bacteria (1, 15, 36).The kinetics of clarithromycin are nonlinear (11,13,16). The apparent half-life varies with the dose and ranges from 2 to 6 h for clarithromycin and from 2 to 9 h for its 14-(R)-hydroxyclarithromycin metabolite after the administration of doses of 100 to 1,200 mg given orally. The elimination half-life of erythromycin is approximately 1 to 6 h after oral administrat...
The pharmacokinetics of a single 2.0-g intravenous dose of cefpiramide in patients with normal or impaired renal function were studied. Serial concentrations in serum and urine were measured by using highperformance liquid chromatography, and the effect of the concentration in serum on protein binding was assessed. Thirty patients (ten with creatinine clearances of >80 mi/min, ten with creatinine clearances between 10 and 80 ml/min, and ten on dialysis) were studied. The concentration-time curve of cefpiramide was best described by an open two-compartment model. The elimination half-lives in patients with normal or impaired renal function or those on dialysis were 5.41 ± 1.44, 8.3 ± 2.82, and 8.38 ± 4.06 h, respectively, and the serum clearances in the same groups were 2.0 ± 0.84, 1.29 ± 0.45, and 2.04 ± 1.10 liters/h, respectively. There were no significant differences in any of the parameters among the three groups of patients. In patients with normal or impaired renal function, protein binding varied between 93.0 ± 1.3% at 304.4 ,ug/ml and 99.3 ± 0.8% at 41.1 ,ug/ml and was linearly and inversely related to the cefpiraniide concentration in serum. In patients on dialysis, protein binding was significantly lower (P < 0.05) and varied between 88.5 ± 7.1% at 173.4 ,ug/ml to 94.9 ± 4.8% at 46.8 ,ug/ml. In patients with normal or abnormal renal function, renal cefpiramide clearance decreased linearly with declining renal function, whereas plasma clearance was maintained. Therefore, nonrenal elimination becomes more important as renal impairment progresses.
The pharmacokinetics of amdinocillin (mecillinam) after multiple intravenous doses to healthy subjects are described. Assay of plasma and urine samples was carried out with a sensitive and specific high-pressure liquid chromatographic technique. A dose of 10 mg/kg of body weight was administered every 4 h for six doses. No accumulation was noted. Mean peak plasma concentrations were approximately 50 ,ug/ml, and the plasma half-life was approximately 53 min. Total plasma clearance was 4.6 ml/min per kg after the first dose, which declined slightly to 4.1 mlmin per kg after the last dose. Renal clearance remained fairly constant at approximately 2.9 ml/min per kg, or twice the creatinine clearance. The fraction excreted unchanged totaled 63% during the 4-h interval after the first dose and was nearly 70% overall. The steady-state volume of distribution was calculated to be 0.26 liter/kg. Urinary concentrations of amdinocillin were far in excess of the usual inhibitory concentrations for susceptible pathogens and were as high as 3,000 ,ug/ml. Doses of amdinocillin every 4 h provide plasma and urine concentrations which should be effective for the treatment of infections.Amdinocillin (formerly mecillinam) is a new amidino-penicillin derivative (5) which is active in vitro against a wide variety of gram-negative bacteria (6, 7). The compound exerts a synergis- Recently, we determined the pharmacokinetic disposition of amdinocillin in healthy volunteers after a single intravenous dose (4). The purpose of the current study was to characterize the disposition of amdinocillin after multiple doses in healthy individuals and to quantitate any possible drug accumulation. MATERIALS AND METHODSEleven healthy volunteers (nine male, two female) took part in the study. They ranged from 21 to 48 years old, and their weights ranged from 44 to 92 kg (mean, 70.5 kg). Creatinine clearance of the subjects was determined from two separate 24-h collections and ranged from 71 to 128 ml/min (mean, 103 ml/min). Subjects were informed of the nature and risks of the investigation, and consent was obtained before participation. Each subject received a physical examination and panel of laboratory tests before and after the study. The subjects did not ingest any medication for 1 week before the study and abstained from alcohol and caffeine-containing beverages for 24 h before and after the study.An intravenous dose of 10 mg of amdinocillin per kg of body weight was administered in 40 ml of 5% dextrose over a 15 min period every 4 h for six doses. A constant-rate Harvard infusion pump was used to administer each dose.Amdinocillin was obtained from Hoffmann-La Roche Inc. Lot no. 314-079 (43-790516) was assayed at 101.3% purity. Blood samples (6 ml) for amdinocillin assay were obtained before the first dose, immediately after the 15-min infusion, and then at 20, 30, 45, 60, 75, 90, 120, 150, 180, 210, and 240 min after the start of the infusion. For doses two through five, blood was taken immediately after the infusion and just before the next d...
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