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The disposition of methicillin in normal subjects and in subjects with cystic fibrosis (CF) was studied after administration of single intravenous doses of 15 mg/kg. The area under the serum concentration vs. time curve for CF patients was, on the average, only 75% of that found for normal subjects. The low concentrations in serum were caused by more rapid urinary excretion of the antibiotic, with rates of renal clearance averaging 425 ml/min per 1.73 m2 in the patients with CF and 362 ml/min per 1.73 m2 in the normal subjects. No differences were found in volumes of distribution and metabolic clearance rates of methicillin or in rates of creatinine clearance between the two groups of subjects. These data support previous findings with dicloxacillin which show that patients with CF exhibit unusually rapid, active tubular secretion of certain penicillins that may necessitate use of larger doses of these drugs in treatment of infections.

Single oral doses of 6.25 mg/kg of dicloxacillin suspension were given to ten cystic fibrosis (CF) patients and eight normal subjects. Peak serum concentrations and areas under the concentration versus time curves for dicloxacillin were variable and, on average, were 2 1/2 times lower in the CF patients. The time of occurrence of the peak serum concentration was similar in both groups and the total urinary recovery of dicloxacillin was normal or increased in the CF patients, suggesting that the intestinal absorption of the drug was unaffected by the disease. The low serum concentrations in the CF patients were caused by unusually high renal clearances of dicloxacillin which average 282 +/- 135 compared to 95 +/- 28 ml/min/1.73 sq m in the normal subjects. Creatinine clearances were also elevated in the CF patients by 55% on average, while urea clearances were normal. The serum protein binding of dicloxacillin was similar in both groups of subjects. Because the rapid excretion results in low and variable serum concentrations of the antibiotic, treatment of CF patients with dicloxacillin may warrant use of increased or more frequent doses and monitoring of serum antibiotic levels.

The pharmacokinetics of gentamicin were examined on two occasions using intravenous and intraperitoneal routes in five children undergoing intermittent peritoneal dialysis for chronic renal failure. Serum, urine and dialysis fluid (DF) were assayed microbiologically for gentamicin and the data were subjected to computer analysis using equations evolved for a two-compartment model which considered the bi-directional flux of the drug. Following i.v. injection of 1 mg/kg of gentamicin, the apparent volume of distribution averaged 23% (range, 13 to 36%) of body wt (similar to normal), the mean half-life was 21 hr (range 9 to 37 hr; normal, 2 hr) and the peritoneal clearance averaged 4.0 ml/min/m2 (range, 1.2 to 7.0 ml/min/m2). During peritoneal administration of gentamicin (15 mg/liter of DF, 0.7 liters/m2 administered in each cycle over 9 to 12 cycles), serum concentrations increased towards extrapolated steady-state levels which averaged 42% (range, 25 to 68%) of DF concentrations. The mean renal clearance of gentamicin was only 1.6 ml/min/m2 while total body clearance ranged from 2.3 to 8.0 ml/min/m2 mostly occurring by a variable degree of dialysance. Peritoneal clearances and half-lives of gentamicin were similar in each patient following either treatment mode. The appreciable variability in gentamicin pharmacokinetics among adolescent patients with renal insufficiency necessitates dosage adjustments based on measurements of serum concentrations.