Pharmacokinetics of flucloxacillin and cloxacillin in healthy subjects and patients on chronic intermittent haemodialysis.

Nauta, E. H.; Mattie, H.

doi:10.1111/j.1365-2125.1975.tb01566.x

Cited by 54 publications

(27 citation statements)

References 19 publications

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“…Moreover, the addition of fluids not containing the antibiotic further dilutes its concentration. For cloxacillin, the changes described above are particularly significant since it has a small distribution, volume (1,12,14), which corresponds mainly to the extracellular fluid compartment.…”

Section: Resultsmentioning

confidence: 99%

“…The importance of this difference was modified, in part, by correcting clearance for body weight (milliliters per minute per kilogram of body weight). Since renal clearance accounts for about 60 to 70% of cloxacillin total body clearance (10,12,13), one would not expect significant age-related differences in cloxacillin clearance between children over 1 year old and young adult subjects after correction for body weight. Similarly, renal tubular secretion, protein binding, and volume of distribution of penicillin are not age dependent after the neonatal period (11).…”

Section: Resultsmentioning

confidence: 99%

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Pharmacokinetic analysis of cloxacillin loss in children undergoing major surgery with massive bleeding

Levy

Egersegi

Strong

et al. 1990

Antimicrob Agents Chemother

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Pharmacokinetic analysis of cloxacillin loss in children undergoing major surgery with massive bleeding

Levy

Egersegi

Strong

et al. 1990

Antimicrob Agents Chemother

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“…administration were collected for only two penicillins (cloxacillin and dicloxacillin), the results suggest that there were no exceptional differences in the amounts metabolized. Thus, the isoxazolylpenicillins appear not to be liable to a so-called first-pass effect, a phenomenon that was suggested as a possible explanation for the observed discrepancies between resorption estimated from urine and serum data (9). Indeed, other phenomena, such as dose-dependent kinetics, may be the explanation for that observation (E. H. Nauta, Ph.D. thesis, Univ.…”

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confidence: 96%

Active Metabolites of Isoxazolylpenicillins in Humans

Thijssen

Mattie²

1976

Antimicrob Agents Chemother

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Metabolites of the isoxazolylpenicillins that still possessed antibacterial activity were shown to be present in urine and serum. In healthy subjects, the amounts excreted in urine were low; 10 to 23% of the excreted penicillin activities represented the metabolites. The highest amount of metabolite in urine was found for oxacillin, and the lowest was found for flucloxacillin. No extreme differences in the amounts of metabolite excreted were observed when the compounds were administered orally or intravenously. In one healthy subject metabolite levels were estimated for cloxacillin in serum. Very low levels were found, i.e., about 9% of the activity. In subjects with highly impaired renal function, the nmetabolite may represent up to 50% of the total level of penicillin in serum. The antibacterial activities of the different metabolites were of the same order of magnitude as those of the respective parent compounds. Also, the activity against benzylpenicillin-resistant staphylococci was retained. It is not likely that the formation of the active metabolites should influence therapeutic results.During their passage through animals and humans, penicillins, like other drugs and xenobiotics, are subject to biomodification. Cleavage of the f8-lactam ring, resulting in the formation of the corresponding inactive penicilloic acids, seems to be the main route by which the penicillins are metabolized (4, 6, 7, 13). In addition, as the result of other metabolic pathways, metabolites of penicillins are formed that are still active es antimicrobials. For instance, the para-hydroxy derivative of phenoxymethylpenicillin is known (15), and of dicloxacillin the 5-hydroxymethyl derivative is the active metabolite (16). Also, active metabolites are formed out of oxacillin and cloxacillin (12). Nishida et al. described the formation of an active transformation product of ampicillin (10). The role of drug-metabolizing systems in its formation, however, is questionable, since this metabolite is also formed during incubation of ampicillin with urine and/or serum (10).In view of the scanty qualitative and semiquantitative data on this topic, it seemed worthwhile to investigate the formation of active metabolites of penicillins in more detail because the formation of these metabolites might influence the correct estimation of relevant pharmacokinetic parameters as suggested by Nauta and Mattie (9) or, in case of differences in activity between parent compound and metabolite, because they might influence therapeutic results.Data concerning the metabolic disposition of the isoxazolylpenicillins are described in the present paper. Aspects of the nature of the metabolites will be discussed elsewhere.MATERIALS AND METHODS Subjects and dosages. The isoxazolylpenicillins used are commercial preparations; oxacillin (Pentastapho) and dicloxacillin (Diclocil) were kindly provided by Bristol (The Netherlands), and cloxacillin (Orbenin) and flucloxacillin (Floxapen) were provided by Beecham Research Laboratories (The Netherlands). The compounds w...

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“…The elimination half-life (t 1/2 ) ranges between 0.75 and 1.1 h in individuals with normal renal function (package insert) and is prolonged up to 2.8 h in patients with renal impairment [7]. Dependent on the characteristics of the renal replacement technique and the membrane used, half-lives of flucloxacillin during intermittent hemodialysis and continuous renal replacement therapy (CRRT) are between 2.5 and 9.9 h, respectively [5,8].…”

Section: Introductionmentioning

confidence: 99%

“…Flucloxacillin is primarily excreted by the kidney (47-72%) in patients with normal glomerular function [4,5] and its protein binding rate is extremely high with about 95% comparable to ceftriaxone or teicoplanin [6]. The elimination half-life (t 1/2 ) ranges between 0.75 and 1.1 h in individuals with normal renal function (package insert) and is prolonged up to 2.8 h in patients with renal impairment [7].…”

Section: Introductionmentioning

confidence: 99%

How to Calculate Clearance of Highly Protein-Bound Drugs during Continuous Venovenous Hemofiltration Demonstrated with Flucloxacillin

Meyer

Gendy

Karth³

et al. 2003

Kidney Blood Press Res

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Background: Flucloxacillin is an important antimicrobial drug in the treatment of infections with Staphylococcus aureus and therefore is often used in staphylococcal infections. Furthermore, flucloxacillin has a high protein binding rate as for example ceftriaxone or teicoplanin – drugs which have formerly been characterized as not being dialyzable. Methods: The pharmacokinetic parameters of 4.0 g flucloxacillin every 8 h were examined in 10 intensive care patients during continuous venovenous hemofiltration (CVVH) using a polyamide capillary hemofilter. In addition, the difficulty of calculating the hemofiltration clearance of a highly protein-bound drug is described. Results: Flucloxacillin serum levels were significantly lowered (56.9 ± 24.0%) even though only 15% of the drug was detected in the ultrafiltrate. Elimination half-life, total body clearance and sieving coefficient were 4.9 ± 0.7 h, 117.2 ± 79.1 ml/min and 0.21 ± 0.09, respectively. These discrepancies can be explained by the high protein binding of flucloxacillin, the adsorbing property of polyamide and the equation in order to calculate hemofiltration clearance. The unbound fraction of a 4.0 g flucloxacillin dosage facilitates time above the minimum inhibitory concentration (T > MIC) of 60% only for strains up to a minimum inhibitory concentration (MIC) of 0.5 mg/l. Conclusion: Based on the data of this study, we conclude that intensive care patients with staphylococcal infections on CVVH should be treated with 4.0 g flucloxacillin every 8 h which was safe and well tolerated. Moreover, further studies with highly protein-bound drugs are recommended to check the classical ‘hemodialysis’ equation as the standard equation in calculating the CVVH clearance of highly protein-bound drugs.

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Pharmacokinetics of flucloxacillin and cloxacillin in healthy subjects and patients on chronic intermittent haemodialysis.

Cited by 54 publications

References 19 publications

Pharmacokinetic analysis of cloxacillin loss in children undergoing major surgery with massive bleeding

Pharmacokinetic analysis of cloxacillin loss in children undergoing major surgery with massive bleeding

Active Metabolites of Isoxazolylpenicillins in Humans

How to Calculate Clearance of Highly Protein-Bound Drugs during Continuous Venovenous Hemofiltration Demonstrated with Flucloxacillin

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