Mezlocillin was previously reported to exhibit dose-dependent pharmacokinetics. These reports suggest that it may be possible to administer a relatively large dose at a longer interval than is usual and still achieve therapeutic concentrations in serum. In a randomized, crossover study, we compared concentrations of mezlocillin in serum after a single dose and at steady state in 12 healthy volunteers who received 4 g every 6 h and 5 g every 8 h. A slight, but statistically significant, dose-dependent effect was observed upon the area under the concentration-time curve and total body clearance. No accumulation was observed with either schedule. Although concentrations in serum were higher after the 5-g dose, the more frequent administration of the 4-g dose schedule produced serum concentrations above the MIC for susceptible bacteria for a greater portion of the day. In the absence of clear guidelines from human studies which relate serum concentrations to clinical response, the available data indicate that the more frequent dosage schedule is appropriate for severe infections.Mezlocillin is a broad-spectrum acylampicillin penicillin which has increased activity against many members of the family Enterobacteriaceae when compared with the carboxypenicillins carbenicillin and ticarcillin (7,18). The recommended dosage of mezlocillin for serious infections is 16 to 24 g per day, and because it has a relatively short half4life of approximately 1 h the usual dose interval is 4 to 6 h (18). Since the frequency of administration is an important determinant of the hospital charges for antibiotics (6), it would be desirable to administer the same daily dosage of mezlocillin at a longer interval if therapeutic efficacy were not compromised (21). A longer dose interval may be possible due to dose-dependent pharmacokinetics described for mezlocillin, resulting in a prolonged duration of effective serum concentrations as the individual doses are increased (2,4,11,16). The purpose of this study was to compare serum concentrations of mezlocillin in normal volunteers after a dosage of 5 g every 8 h versus 4 g every 6 h. MATERIALS AND METHODS Subjects. Twelve healthy male volunteers were enrolled after written informed consent was obtained. The subjects ranged in age from 21 to 30 years (mean, 23 years) and in weight from 66.7 to 83.6 kg (mean, 75 kg). Results of baseline laboratory tests (routine chemistries and complete blood counts) and physical examinations were within normal limits. Exclusion criteria included a history of renal or hepatic dysfunction or a previous hypersensitivity reaction from any beta-lactam antibiotic. Penicillin skin testing with the major determinant (penicilloyl polylysine, Pre-Pen) was performed on all subjects before the study. The subjects did not take any other medications during the study period or for 3 days before beginning the study.Design. The subjects were admitted to the Clinical Re- on the morning of the first study day of each phase of the trial and remained overnight. Subjects were random...