Mezlocillin Pharmacokinetics After Single Intravenous Doses to Patients with Varying Degrees of Renal Function

Frimodt‐Møller, Niels; Maigaard, Svend; Toothaker, Roger D.; Bundtzen, Robert W.; Brodey, Mitchell V.; Craig, William A.; Welling, Peter G.; Madsen, Paul O.

doi:10.1128/aac.17.4.599

Cited by 19 publications

(7 citation statements)

References 15 publications

(19 reference statements)

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“…This resembles the values of most other penicillins [2] and is similar to values of 0.23 liters/kg in 5 sub jects with normal renal function reported previously by Leroy et al [7]. FrimodtM0ller et al [4] found a V,| SS of 0.18-0.24 liters/kg for mezlocillin which com pares well with our 0.16 liters/kg for this agent.…”

Section: Discussionsupporting

confidence: 77%

“…Only patients with severe renal impair ment clearly exhibited dose dependence of mezlocillin [4]. The renal route of excre tion is clearly important for both agents.…”

Section: Discussionmentioning

confidence: 99%

“…However, the recovery of mezlocillin in the present investigation was low in relation to other studies, although variable results have been reported for this agent. Thus, in pa tients with normal renal function, Bergan [1] reported a 60-70% excretion of antibacterially active mezlocillin, for doses of 1.0-5.0g, F rimodt-M filler et al [4] found 55% after 4.0 g and Kosmidis et al [6] found 52-55% after 2.0-5.0 g. However, our value of a 43% recovery for mezlocillin is comparable to the 45% recovery found by Frimodt-Mfiller et al [4] after the same dose as ours, 2.0 g.…”

Section: Discussionmentioning

confidence: 99%

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Dose-Dependent Pharmacokinetics of Azlocillin Compared to Mezlocillin

1982

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The pharmacokinetics of azlocillin at intravenous doses of 1.0, 2.0 and 5.0 g and of 2.0 g mezlocillin were studied in a cross-over study on 10 healthy volunteers. The serum concentrations and total area under the serum curves for azlocillin increased more than expected from the multiples of the dose size. Likewise, the percentage of urinary excretion of an antibacterially active agent increased steadily with higher doses. The same applied to the serum half-life (t½), whereas the total body clearance was reduced. All these characteristics are indicative of dose-dependent, i.e. capacity-limited pharmacokinetics. The t½ was 0.89, 0.98, and 1.53 h for each dose. For 2.0 g mezlocillin, the serum values, urinary recovery, and t½ were lower than the values after the same dose of azlocillin. The t½ was 0.64 h. The total body clearance was 12.0, 9.2, and 6.4 liters/h for the three doses of azlocillin and 14.4 liters/h for 2.0 g mezlocillin. Dose dependence appears to be more pronounced with azlocillin than found previously with mezlocillin. Unchanged azlocillin and its biotransformation products are excreted more slowly than mezlocillin and its metabolites.

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Section: Discussionsupporting

confidence: 77%

“…Only patients with severe renal impair ment clearly exhibited dose dependence of mezlocillin [4]. The renal route of excre tion is clearly important for both agents.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Dose-Dependent Pharmacokinetics of Azlocillin Compared to Mezlocillin

1982

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“…The mean area under the curve calculated for the 5-g dose (365 mg h/liter) is comparable to values previously reported (4). The area under the curve after the 4-g dose (285 mg-h/liter) is similar to that reported by Lode et al (14) but is lower than the other reported value of 402 mg h/liter (9). However, in the latter study the mean age of the subjects was 67 years, and the smaller body mass and diminished urinary excretory capacity are likely responsible for the difference.…”

Section: Discussionsupporting

confidence: 62%

Comparative pharmacokinetics of two multiple-dose mezlocillin regimens in normal volunteers

Colaizzi¹,

Coniglio²,

Poynor³

et al. 1986

Antimicrob Agents Chemother

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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...

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“…The single-dose pharmacokinetics of mezlocillin has been well described (1,5,11) and shown to be nonlinear by Bergan (1). Because of this nonlinearity, Mangione et al conducted a trial of single doses of 1 and 5 g administered to volunteers with renal dysfunction (10).…”

mentioning

confidence: 99%

Effect of saturable clearance during high-dose mezlocillin therapy

Drusano¹,

Forrest²,

Fiore³

et al. 1984

Antimicrob Agents Chemother

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As mezlocillin has been shown to display nonlinear pharmacokinetics in single-dose evaluations, we evaluated a crossover trial in patients with renal dysfunction the impact on serum clearance of fixed-dose versus fixed-interval administration of identical daily doses of the drug. In four patients with creatinine clearances of 0.00 to 1.78 liters/h per 1.73 m2, equal serum clearances were observed when the calculated daily total dose of mezlocillin was given either as a fixed dose of 5,000 mg at various intervals or every 4 h at various doses. We found that repetitive large daily doses that are equivalent to 30 g/day in patients with normal renal function can be administered to patients with impaired renal function as a reduced dose every 4 h instead of prolonging the dosing interval, as suggested by Mangione et al. (Antimicrob. Agents Chemother. 21:428-435, 1982). The observed serum clearances were equal for the two schedules, probably owing to the degree of continuing saturation of the nonlinear clearance mechanisms of mezlocillin.

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Mezlocillin Pharmacokinetics After Single Intravenous Doses to Patients with Varying Degrees of Renal Function

Cited by 19 publications

References 15 publications

Dose-Dependent Pharmacokinetics of Azlocillin Compared to Mezlocillin

Dose-Dependent Pharmacokinetics of Azlocillin Compared to Mezlocillin

Comparative pharmacokinetics of two multiple-dose mezlocillin regimens in normal volunteers

Effect of saturable clearance during high-dose mezlocillin therapy

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