The human pharmacokinetics of cefotaxime and its metabolites and the role of renal tubular secretion on their elimination

The dispositions of cefotaxime and its metabolite desacetylcefotaxime were investigated in patients with different forms of chronic parenchymal liver disease (CPLD). A total of 31 subjects (27 patients and 4 controls) received a single 2-g dose of cefotaxime by infusion, and serial blood samples were drawn. The area under the concentration-time curve ranged from 176 to 241 micrograms.h/ml, the apparent half-life ranged from 1.49 to 2.42 h, and clearance ranged from 2.06 to 3.10 ml/min/kg in patients with four different forms of CPLD. The area under the concentration-time curve and the apparent half-life of desacetylcefotaxime ranged from 72 to 128 micrograms.h/ml and 7.1 to 13.4 h, respectively. Pharmacokinetic parameters were significantly different in patients with CPLD compared with those in control subjects and were related to clinical indices of hepatic impairment. Modest accumulation of cefotaxime in patients with severe hepatic impairment is unlikely to produce toxicity because of its high therapeutic index, and dosing modifications may not be required.

Section: Discussionsupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics of cefotaxime and desacetylcefotaxime in patients with liver disease

Sattler

Nichols

et al. 1991

“…4, the microbiological assay gave similar concentration profiles in plasma for cefotaxime and desacetylcefotaxime, as has previously been reported by using high-pressure liquid chromatography (15). The precision and accuracy are within the range reported for microbiological assays, and it is very unlikely that antibiotics given prior to cefotaxime therapy would have reached the concentrations required to interact with the test strains.…”

Section: Discussionsupporting

confidence: 82%

Penetration of cefotaxime and desacetylcefotaxime into brain abscesses in humans

Sjölin

Eriksson

Arneborn

et al. 1991

Since clinical trials comparing the efficacies of different antibiotic regimens for treatment of brain abscesses are difficult to perform, the choice of antibiotics must rely on the antibacterial spectrum and the ability of the drug to penetrate into the abscess fluid. The aim of this investigation was to study the ability of cefotaxime and its active metabolite desacetylcefotaxime to penetrate into brain abscesses. Eight patients were given 3 g of cefotaxime intravenously every 8 h. Abscess fluid samples, obtained at surgery at various times after dosing, and blood samples were analyzed for their concentrations of cefotaxime and desacetylcefotaxime by using a newly developed microbiological assay. The brain abscess concentrations of cefotaxime and desacetylcefotaxime were 1.9 1.7 and 4.0 2.2 mg/liter, respectively. Simultaneous concentrations in plasma were 2.0 1.0 and 3.9 1.8 mg/liter, respectively. With increasing time following cefotaxime dosing there was a significant increase in the abscess:plasma concentration ratio of desacetylcefotaxime. Since both cefotaxime and desacetylcefotaxime penetrate well into the brain abscess, reaching concentrations above the MIC for probable bacteria except gram-negative anaerobes, it is concluded that cefotaxime in combination with metronidazole may be used as an alternative in the treatment of brain abscesses.Brain abscesses are often caused by gram-positive bacteria such as streptococci, staphylococci, and anaerobic cocci. Less often the causative agent may be a gram-negative rod such as Escherichia coli or a Klebsiella or Bacteroides species. Frequently a mixed flora is found (1,8,14,22).Antibiotic treatment has often to be initiated before surgery and before the etiology of the brain abscess is known. It is therefore of importance that empiric antibiotic treatment be effective against possible etiological agents. Since brain abscess is an uncommon disease, it is unlikely that clinical trials comparing the efficacies of different antibiotics for treatment of brain abscesses will comprise sufficient numbers of patients to obtain a reasonable statistical evaluation of differences between regimens. The choice of antibiotics must therefore rely on the antibacterial spectrum and the ability of the drug tZ jenetrate into the abscess fluid (7,11,29).For many years, penicillin G in combination with chloramphenicol has been regarded as the empiric standard therapy (5, 7, 11). Recently, the efficacies of different antibiotic regimens in the treatment of brain abscesses were reviewed, and it was stated that chlorampenicol was not an efficacious therapy and that cefotaxime plus metronidazole might be an alternative for the treatment of brain abscess (5).Cefotaxime, ond ifiember of the broad-spectrum cephalosporins, has a suitable antibacterial spectrum covering most bacteria causing brain abscesses. Cefotaxime undergoes desacetylation in the liver by nonmicrosomal pathways to desacetylcefotaxime (6,28). Although this metabolite is less active than cefotaxime, its antibacterial spec...

“…Two studies of cefotaxime pharmacokinetics in dogs have appeared (10,17 [11,18]). Third, desacetylcefotaxime generally has much lower antibacterial activity than fleroxacin (except against a few species, notably, streptococci).…”

mentioning

confidence: 99%

Pharmacokinetics of Ro 23-9424, a dual-action cephalosporin, in animals

Christenson

Chan

Cleeland

et al. 1990

Ro 23-9424 is a dual-action cephalosporin with an aminothiazolylmethoxyimino-type side chain at the 7 position and fleroxacin esterified at the 3' position. The new compound has broad and potent antibacterial activity in vitro and in vivo, reflecting contributions from both the , (-lactam Ro 23-9424 is a cephalosporin with an aminothiazolylmethoxyimino-type side chain at the 7 position and fleroxacin esterified at the 3' position (1). Ro 23-9424 has broad and potent antibacterial activity in vitro (2, 9, 12) and in vivo (3). The antibacterial spectrum reflects contributions of both the cephalosporin moiety (notably, streptococci) and the quinolone moiety (notably, ,-lactamase-overproducing strains). Ro 23-9424 binds to penicillin-binding proteins and inhibits replicative DNA biosynthesis (8). These observations have led to the use of the term "dual-action cephalosporins" for Ro 23-9424 and analogous compounds (1,8).It was originally proposed by O'Callaghan et al. (15) that the second "warhead" of such a cephalosporin, in this case, the fleroxacin moiety of Ro 23-9424, is released when the ,-lactam ring is opened by a bacterial enzyme, such as a P-lactamase. In the case of Ro 23-9424, active quinolone may also be released by enzymatic or nonenzymatic hydrolysis of the ester linkage. It is well known that 3'-acetoxy cephalosporins, such as cephalothin, cephapirin, and cefotaxime, are deesterified in vivo to form 3-hydroxymethylcephalosporins (4, 5, 19). These metabolites have antibacterial activity, but they are less potent than the acetylated cephalosporins. Hydrolysis of the ester bond of Ro 23-9424 presumably results in the formation of fleroxacin and the 3-hydroxymethylcephalosporin desacetylcefotaxime, both of which have antibacterial activity. The extent to which Ro 23-9424 exerts the proposed mechanism of action in vivo (wherein the quinolone is released by a bacterial process), or acts as a combination of active metabolites, is therefore determined by its pharmacokinetic properties. This study *