Determination of Cefalothin and Cefazolin in Human Plasma, Urine and Peritoneal Dialysate by UHPLC-MS/MS: application to a pilot pharmacokinetic study in humans.

An ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the analysis of cefazolin and cefalothin in human plasma (total and unbound), urine and peritoneal dialysate has been developed and validated. Total plasma concentrations are measured following protein precipitation and are suitable for the concentration range of 1-500 µg/mL. Unbound concentrations are measured from ultra-filtered plasma acquired using Centrifree(®) devices and are suitable for the concentration range of 0.1-500 µg/mL for cefazolin and 1-500 µg/mL for cefalothin. The urine method is suitable for a concentration range of 0.1-20 mg/mL for cefazolin and 0.2-20 mg/mL for cefalothin. Peritoneal dialysate concentrations are measured using direct injection, and are suitable for the concentration range of 0.2-100 µg/mL for both cefazolin and cefalothin. The cefazolin and cefalothin plasma (total and unbound), urine and peritoneal dialysate results are reported for recovery, inter-assay precision and accuracy, and the lower limit of quantification, linearity, stability and matrix effects, with all results meeting acceptance criteria. The method was used successfully in a pilot pharmacokinetic study with patients with peritoneal dialysis-associated peritonitis, receiving either intraperitoneal cefazolin or cefalothin. Copyright © 2015 John Wiley & Sons, Ltd.

[Studies on administration of cephalothin sodium after open heart surgery (author's transl)].

Critical cardiac contamination may occur during extracorporeal circulation in open heart surgery. Prophylactic administration of cephalothin sodium (CET) was studied for their safe and adequate serum concentration after open heart surgery in infants and adults. Methods of administration of CET were discussed for infants and adults.

Clinical pharmacology of cefamandole as compared with cephalothin.

We compared the pharmacology of cefamandole and cephalothin in six healthy adult male volunteers. After a 1-g, 20-min intravenous (i.v.) infusion, the average peak blood level of cefamandole was 87.6 versus 64.1 mug/ml for cephalothin. An i.v. infusion of 500 mg/h for 2 h (after a loading dose of 750 mg) gave an average steady-state blood level of 28.5 mug/ml for cefamandole and 18.2 mug/ml for cephalothin. Mean peak serum levels after 1 g intramuscularly were similar for the two antibiotics (about 21 mug/ml), but with cefamandole they persisted longer, and the area under the blood level curve was about 25% greater. The average t((1/2)) as determined from both i.v. studies was 34 min for cefamandole versus 30 min for cephalothin. The mean serum clearance for cephalothin, due to its partial conversion to a metabolite, was much greater than for cefamandole (425 versus 272 ml/min per 1.73 m(2)), but the renal clearances were similar for the two antibiotics (268 versus 257 ml/min per 1.73 m(2)). Other values for cefamandole and cephalothin were: 24-h urinary excretion, 80 and 66%; serum protein binding, 74 and 70%; and apparent volume of distribution, 12.8 and 18.5 liters/1.73 m(2), respectively. Thus, the pharmacology of the two antibiotics was similar. Blood levels were somewhat higher with cefamandole i.v., but the results suggest that dosage regimens should be the same for the two antibiotics.

Concentration of antibiotics in renal interstitial fluid: an experimental model.

In a new canine experimental model the time concentration relationship of cephalothin in serum, urine, soft tissue interstitial fluid (STIF) and renal interstitial fluid (RIF) were compared simultaneously. Antibiotic concentration in RIF was less than urinary levels but exceeded the serum concentration. Urinary antibiotic concentration does not necessarily reflect concentration in the renal interstitium. This model helps to understand the basic pharmacokinetics of antibiotics in the renal interstitium where pyelonephritis occurs.

Comparison of absorption and excretion of cefazolin with cephalothin and cephapirin.

Since the discovery of cephalothin in 1962, many semi-synthetic cephalosporins have appeared. To choose the most suitable drug for the clinical treatment of infections, the characteristics of these antibiotics must be sufficiently understood. When cephalosporins which are or will be commercially available are divided into two categories, one consists of cephaloridine, cefazolin and cephalexin which are comparatively stable in the living body; and the other cephalothin, cephaloglycin, cephapirin and cephacetrile which are metabolized into desacetyl compounds with low antibacterial activity. In this study, the author compared the absorption, excretion and some other properties of cefazolin and cephalothin, (widely used clinically), and cephapirin (still under study in Japan).

Serum levels and urinary excretion of parent antibiotics and desacetyl forms after parenteral administration of cephalothin and cephapirin.

When the antibacterial substances of cephalothin and cephapirin in the serum and urine after intramuscular injection were separated and assayed, desacetyl metabolities of both drugs were detected. These tendencies were especially apparent in the tissue concentrations. When both the drugs were given intravenously to healthy volunteers, the amounts of their desacetyl metabolites were not greater in man than in rats.

Effect of diuretics on urinary excretion of cephalothin in humans.

Diuretics and antibiotics are frequently used concomitantly. The possibility of drug interactions led us to study the effects of several diuretics on the renal elimination of cephalothin. Five healthy volunteers received a constant infusion of 500 mg of sodium cephalothin per h for 9 h on 4 consecutive days. Each day, after the third hour of infusion, the subjects were given one of the following in varying order: (i) furosemide (1 mg/kg, intravenous), (ii) mercaptomerin (250 mg, intramuscular), (iii) mannitol (25 g, intravenous), or (iv) no diuretic (control day). Fluid losses were replaced hourly. Serum and complete urine collections were obtained each hour and assayed for creatinine and cephalothin (bioassay). Clearances (milliliter per minute) and urinary excretions (milligram per hour) of cephalothin did not differ either when the diuretic day values were compared with control day, or when pre- and postdiuretic results on the same day were compared. Creatinine clearances were not affected by diuretics except for a transient rise after furosemide.