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.

Cephalothin prophylaxis in cardiac valve surgery. A prospective, double-blind comparison of two-day and six-day regimens.

A prospective, double-blind study comparing a 6 day with a 2 day regimen of cephalothin prophylaxis was conducted among 200 patients undergoing prosthetic valve replacement. No cases of endocarditis occurred during the 2 month follow-up. Sternal wound infection developed in 2.8 per cent of the 6 day group and 2.1 per cent of the 2 day group. Pneumonia developed in 8.5 per cent of the 6 day and 5.3 per cent of the 2 day group; most of the bacteria isolated were susceptible to cephalothin. Urinary tract infection developed more frequently in the 2 day group (17.0 versus 8.5 per cent), particularly during the first 6 postoperative days. Three of 11 patients with no detectable cephalothin in their sera at the close of operation developed staphylococcal wound infections, compared with 2 of 175 patients whose sera contained cephalothin at the close of surgery (p = 0.002, Fisher's exact test). A short course of prophylactic antibiotics is prudent, but there is no justification for prolonging their administration.

Double-blind comparison of cefazolin and cephalothin in open-heart surgery.

Ninety-nine patients undergoing cardiac surgery were randomly assigned to treatment with cefazolin and cephalothin to compare the effectiveness of these cephalosporins in the prevention of postoperative infections. The incidence of infections was low with both antibiotics (cefazolin 2.1 percent, cephalothin 4.6 percent). Intraoperative serum cefazolin levels were more evenly distributed, whereas a wide dispersion of cephalothin levels was observed. There was no measurable antibiotic detected in cardiac tissue samples in the majority of the cases. Adverse reactions (skin rashes) occurred only in three patients, all receiving cephalothin. It is concluded that cefazolin is as safe and effective as cephalothin in the prevention of postoperative infection in patients undergoing open-heart surgery.

Cephalothin Prophylaxis and valve replacement.

In a study of antibiotic prophylaxis in adults undergoing heart valve replacement, we found that a 2 gm dose of cephalothin given intraoperatively produced adequate antimicrobial activity in the bloodstream throughout the period of cardiopulmonary bypass. A dosage of 1 gm every four hours postoperatively did not lead to significant accumulation of the antibiotic. With prophylaxis restricted to the intraoperative and early postoperative period, adverse drug reactions and superinfections were not a problem. Further, no cases of prosthetic valvulitis were encountered.

A comparison of the safety, efficacy, and distribution of ceforanide and cephalothin in coronary artery bypass graft surgery.

Antibiotic prophylaxis in open-heart operations is a widely accepted practice. Introduction of new antibiotics with differences in tissue distribution, spectrum of activity and therapeutic index prompts their evaluation as possible effective prophylactic agents. We compared the distribution, clinical efficacy, and safety of ceforanide with cephalothin as a prophylactic agent in coronary artery bypass graft (CABG) procedures. The results indicated that the intravenous administration of ceforanide at the dose of 1 gm every 12 hours for 2.5 days was equivalent to cephalothin 1 gm every 6 hours for 2.5 days. Serum, muscle, and bone concentrations of ceforanide were significantly greater than those of cephalothin. These concentrations consistently exceeded the minimal inhibitory concentration for Staphylococcus aureus, the major pathogen implicated in wound infections. No toxicty was observed with either antibiotic. Ceforanide merits consideration as a prophylactic antibiotic in CABG operations.

The simultaneous quantitative determination of cephalothin and cefazolin in serum by high pressure liquid chromatography.

Conventional microbiological assay procedures for cephalosporins in serum do not allow the determination of serum concentrations if more than one cephalosporin is present in a single sample. An HPLC procedure has been developed which permits the simultaneous quantitative determination of cefazolin sodium and cephalothin sodium in serum. Reverse phase chromatography using methanol in 0.2 M ammonium acetate as the mobile phase was employed to separate and quantitate the two cephalosporins in a trichloroacetic acid supernatant solution prepared from serum.

Serum and dialyzate concentrations of intraperitoneal cephalothin in patients undergoing continuous ambulatory peritoneal dialysis.

The pharmacokinetics of cephalothin sodium were studied in seven patients with chronic renal failure undergoing continuous ambulatory peritoneal dialysis. 100 mg of cephalothin per liter dialyzate were administered intraperitoneally during nine dialysis cycles with 2 liters of dialysis fluid per cycle. Serum levels of the antibiotic, measured microbiologically during the first, fifth and ninth dwell time, revealed peak values of 3.5 +/- 1.7 mg/l, 5.6 +/- 2.2 mg/l and 5.3 +/- 2.5 mg/l, respectively. The mean concentration in the dialysis outflow was 23.6 +/- 15.6 mg/l (range: 2.0-78.7 mg/l). Intraperitoneally administered cephalothin is well tolerated. Serum levels exceeded the minimal inhibitory concentrations of most gram positive bacteria causing peritonitis in these patients.

A new parenteral cephalosporin. SK&F 59962: in vitro and in vivo antibacterial activity and serum levels in experimental animals.

SK&F 59962, a new parenteral cephalosporin was found to have a high order of in vitro and in vivo antibacterial activity against a broad-spectrum of clinical isolates. When tested in vitro against gram-negative organisms, SK&F 59962 was consistently more active than cefazolin and far superior to cephalothin. This new antibiotic had activity equal to that of cephalothin against gram-positive bacteria. Enterobacter species were found to be susceptible to SK&F 59962. In mouse infection studies using bacterial pathogens, SK&F 59962 had protective activity of the order of that of cefazolin and superior to that of cephalothin. Following parenteral administration the serum profile of SK&F 59962 in the mouse, dog and squirrel monkey was similar to that of cephalothin. SK&F 59962 and cephalothin had lower peak serum concentrations and shorter biologic half-lives than those of cefazolin.

Analysis of binary mixtures of cephalothin and cefoxitin by using first-derivative spectrophotometry.

A method for the analysis of two-component mixtures of cephalothin and cefoxitin using zero-crossing first-derivative spectrophotometry is described. This technique permits the quantification of these drugs with closely overlapping spectral bands without any separation step. Linear calibration graphs of first-derivative values at 235.00 and 236.75 nm for cephalothin and cefoxitin, respectively, with negligible intercepts were obtained versus concentration in the range 4.0-32.0 micrograms ml-1 for both antibiotics. This paper presents a systematic examination of the experimental data by applying an exhaustive statistical analysis to demonstrate the validity of the method. The results of the determination of these antibiotics in mixtures of injectable dosage forms are also presented, together with their determinations in physiological serum and glucosed physiological serum.

Whole-blood platelet aggregation, buccal mucosa bleeding time, and serum cephalothin concentration in dogs receiving a presurgical antibiotic protocol.

Whole-blood platelet aggregation (using the impedance method) and adenosine triphosphate (ATP) release, buccal mucosal bleeding time (BT), and serum cephalothin concentration were measured in 21 adult female Beagles before (PRE) and 1 hour (1 HR) after IV administration of cephalothin (22 mg/kg). A second injection of cephalothin (22 mg/kg) was given 3 hours after the first, and blood samples were obtained 1 hour (4 HR, 4 hours after the first injection) and 3 hours (6 HR, 6 hours after the first injection) after the second injection. Samples of jugular blood were obtained from each dog, using citrate as an anticoagulant. A platelet count was obtained for each sample. Platelet aggregation and ATP released from the aggregating platelets were measured within 1 hour of sample collection, using a whole-blood aggregometer. Adenosine diphosphate (ADP) and collagen were used as aggregating agents. Aggregation was measured over 6 minutes for each aggregating agent; ATP release in response to collagen, but not to ADP, was measured over the same period. For 1 HR samples, there was a significant (P < 0.01) reduction from PRE values in the ability of platelets to aggregate in response to ADP. Bleeding time was determined, using a published procedure, with each dog as its own control. Bleeding time during the same period was found to be significantly increased over PRE values for 1 HR (P < 0.01) and 6 HR (P < 0.02) samples. There was no significant difference between BT for 1 HR and 4 HR samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding of cefalotin to human serum albumin.

Binding of cefalotin to human serum albumin was studied in vitro by equilibrium dialysis and the quantitative measurement of cefalotin was made by fluorimetric assay. The binding rate of cefalotin to human serum albumin found to be 61,1%. The determination of drug binding parameters showed a large number of binding sites (n = 9.36) and a moderate affinity (K = 3898 M-1).

Comparative biliary concentrations of cephazolin and cephalothin in patients with biliary tract disease.

The concentration of cephazolin in the serum, gall bladder bile, common duct bile, and gall bladder wall were consideredably higher than cephalothin especially with IV administration and indicate that cephazolin should be a useful antibiotic in the surgical treatment of acute cholecystitis.

[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.

[Experimental studies on the passage of antibiotics into cerebrospinal fluid in staphylococcal meningitis in rabbits. II. Cephaloridine, cephalothin and cefazolin (author's transl)].

Passage of cephaloridine, cephalothin and cefazolin into cerebrospinal fluid (CSF) was evaluated in Staphylococcus aureus meningitis in rabbits and the following results were obtained. 1. Concentration in CSF (microgram/ml) [CSF/serum ratio (%)] was determined 1/2, 1 and 2 hours after a single intravenous injection of 100 mg/kg of each antibiotic, respectively; cephaloridine-7.5 [8.9], 9.7 [13.8], 9.1 [22.6]; cephalothin-0.42 [3.6], 0.23 [6.4], not detectable [0]; cefazolin-7.5 [11.8], 5.2 [19.3], 2.0 [17.5]. 2. When results with cefazolin after an intravenous injection 100 mg/kg and 200 mg/kg were compared, a definite dose response was noted in blood concentration but not in CSF concentration. 3. A standard error of CSF concentrations of each antibiotic was larger than that of penicillins, and "Unpredictability" of their passage into CSF was considered to be one of the characteristics common to these three drugs in respect of their passage into CSF. 4. There was no significant difference noted in antibiotic passage into CSF between cephaloridine of low protein binding rate and cefazolin of very high binding rate. Cephalothin, of which binding rate was intermediate, showed a remarkably lower passage into CSF. These results indicate that a correlation does not always exist between protein binding rate of the antibiotics and their passage into CSF. 5. Based on the above results, a review of the literature was made on clinical applicability of these three antibiotics in the treatment of bacterial meningitis. Low transport rate of cephalothin into CSF and nephrotoxicity of cephaloridine make them to be unsuitable for bacterial meningitis. Cefazolin is considered to be suitable in the treatment of ampicillin-resistant Escherichia coli meningitis and Gram-positive coccal meningitis in which penicillins are not applicable.

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.

[Penetration of cephaloridine and cephalothin into the cerebrospinal fluid-clinical study (author's transl)].

There were 35 cases, treated with Cephaloridine or Cephalothin after neurosurgical operation. Neurological surgeon always troubled with passage of blood-brain barrier when drug was given. Antibiotics was not exceptionally, therefore we, neurological surgeon, must select the effective drug to bacterium, that which penetrated enough to the intracranial organ through the blood-brain barrier. In this paper, we measured the concentration of Cephaloridine and Cephalothin into cerebrospinal fluid in the cases with non inflammatory meninges. We collected the cerebrospinal fluid from continued ventricle tap and serum, then measured the concentration of the drug with bioassay. Cephaloridie treated cases. 22 cases. 1) 1 g intramuscular injection. 4 cases. Serum level got to highest value, 64 mug/ml (mean value) 1 hour after injection. CSF level got to maximum concentration 46.8 mug/ml. (mean value) serum mean level 21.5 mug/ml. CSF mean level 0.73 mug/ml. 2) 1 g 3 minutes-intravenous injection 5 cases. Serum level got to highest value 67.5 mug/ml. CSF maximum level was 5.25 mug/ml. Serum mean level 19.74 mug/ml. CSF mean level 0.61 mug/ml. 3) 1 g 1 hour-intravenous drip. 9 cases. Serum maximum level 121.0 mug/ml. CSF maximum level 2.30 mug/ml. Serum mean level 20.08 mug/ml. CSF mean level 0.67 mug/ml. 4) 1 g 8 hours-intravenous drip. 3 cases. Serum maximum level 61.0 mug/ml. CSF maximum level 1.36 mug/ml. Serum mean level 14.78 mug/ml. CSF mean level 0.47 mug/ml. Cephalothin treated cases, 12 cases. 1) 1 g 8 hours-intravenous drip, 4 cases. In fact we could detect the drug only in one case, in CSF, and we could not in other three cases. In KF - 4 case, serum maximum concentration was 26.0 mug/ml, CSF maximum concentration was 0.07 mug/ml. Serum mean level 16.97 mug/ml. CSF mean level 0.01 mug/ml 2) 2 g 1 hour-intravenous drip, 9 cases. Serum maximum level 690.0 mug/ml. CSF maximum level 2.03 mug/ml. Serum mean level 29.59 mug/ml. CSF mean level 0.06 mug/ml. In cephaloridine cases, the tendency was observed, that which, as concentration of the drug in CSF increased, cell count and protein decreased, and, as concentration of the drug decreased, cell count and protein increased. CSF/serum concentration ratio of Cephaloridine increased, when time passed, in intramuscular, 3 minutes intravenous, and 1 hour-intravenous drip group. Then only in 8-hours-intravenous prip group. Then only in 8-hours-intravenous drip group, concentration ratio decreased. In Cephaloridine group, mean value of CSF/serum ratio showed. 1 g i.m. 0.084 1 g 3 minutes-i.v. 0.098 1 g 1 hour-i.v. 0.194 1 g 8 hours-i.v. 0.044.