Influence of coadministration on the pharmacokinetics of mezlocillin and cefotaxime in healthy volunteers and in patients with renal failure

Abstract

The pharmacokinetic disposition of cefotaxime, desacetyl cefotaxime, and mezlocillin after the administration of each drug singly and in combination was examined in eight healthy volunteers and in five anuric patients with end-stage renal disease (ESRD). In the presence of ESRD, the total body clearance of cefotaxime decreased from 256.7 +/- 41.5 to 65.4 +/- 42.0 ml/min, and its elimination half-life (t1/2) increased from 1.1 to 3.6 hours as compared with healthy volunteers. Concomitant administration of mezlocillin in healthy volunteers decreased the total body clearance of cefotaxime by 42% and increased its steady-state volume of distribution. This reduction in clearance was reflected by a decrease in both renal and nonrenal clearances. In the presence of ESRD, coadministration of mezlocillin increased the t1/2 of cefotaxime to 5.8 hours. Desacetyl cefotaxime accumulated in ESRD with a prolongation of its elimination t1/2 to 18.7 hours from 1.7 hours in healthy volunteers. Desacetyl cefotaxime peak plasma concentrations occurred later with the combination regimen in the presence of ESRD. The clearance of mezlocillin was reduced and t1/2 prolonged in ESRD from 194.6 +/- 31.9 to 76.4 +/- 38.8 ml/min and 1.4 to 2.3 hours, respectively. Concomitant administration of cefotaxime did not alter the pharmacokinetics of mezlocillin. These data suggest that in the presence of normal renal function, lower doses of cefotaxime may be adequate to maintain similar cefotaxime plasma concentrations when mezlocillin is coadministered compared to when cefotaxime is given alone. Additional pharmacodynamic and clinical studies with this combination are warranted to further elucidate the clinical impact of this pharmacokinetic interaction.

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

“…Concomitant administration of mezlocillin with cefotaxime in eight healthy volunteers and five patients with end-stage renal disease (ESRD) suggested that the lower cefotaxime doses may prove to be adequate in patients with normal renal function with co-administered mezlocillin [341]. Although the mechanism of this nonrenal PK interaction is still unclear, the authors suspected the character of the interaction to be of metabolic origin [341].…”

“…Although the mechanism of this nonrenal PK interaction is still unclear, the authors suspected the character of the interaction to be of metabolic origin [341]. …”

Multiple Pharmacokinetic Parameter Prediction for a Series of Cephalosporins

“…The PK parameters of a series of 20 cephalosporins were collected from the literature,11–32 and compounds were divided into working (training and testing) and validation subsets (Table 1). Data for all compounds were taken from studies using intravenous administration of the drug, with the exception of cefaclor.…”

Inhibition of flucloxacillin tubular renal secretion by piperacillin

“…This has been frequently shown with β‐lactams and probenecid, a well‐known inhibitor of tubular secretion [9, 12, 13]. Renal interactions have also been reported when two β‐lactams were given together [14–17]. Therefore, the possibility of PK drug–drug interactions should be considered when two or more β‐lactams are given in combination.…”