Determination of unbound cefmetazole in rat blood by on-line microdialysis and microbore liquid chromatography: a pharmacokinetic study.

A specific and sensitive microbore liquid chromatographic method for the determination of unbound cefmetazole in rat blood was developed. A microdialysis probe was inserted into the jugular vein/right atrium of a Sprague-Dawley rat. Cefmetazole (10 mg/kg, i.v.) was then administered via the femoral vein. Dialysates were automatically injected into a liquid chromatographic system via an on-line injector. Isocratic elution of cefmetazole was achieved by LC-UV within 10 min. Intra- and inter-assay accuracy and precision of the assay were < or = 10%. The detection limit of cefmetazole was 20 ng/ml. Pharmacokinetic analysis of results indicated that unbound cefmetazole levels in rats best fit a biexponential decay model.

Distribution of free and liposomal cefoxitin in plasma and peritoneal fluid in a porcine intra-abdominal sepsis model.

The plasma and peritoneal fluid pharmacokinetic parameters obtained after the intravenous administration of free and liposomal cefoxitin were studied in a porcine model of intraabdominal sepsis. No prior assumptions were made to predict the number of compartments pertaining to drug clearance from the administration of either cefoxitin formulation. The experimental data obtained were applied to fit mathematical models of multiexponential drug clearance and the pharmacokinetic data were found to best fit a two-compartment open model. Liposomal encapsulation significantly altered the plasma drug distribution pattern resulting in changes in the magnitude of a number of pharmacokinetic parameters examined. The mean post-distributive half-life of liposomal cefoxitin was substantially longer than that of free cefoxitin by at least 3 times. The peritoneal cavity appeared to provide a reservoir for the initial distributive phase of rapid drug clearance from the plasma compartment followed by a less-rapid post-distributive phase. The cumulative drug level, as determined by the area under the concentration curve (AUC) as a function of time, in the plasma of animals treated with liposomal cefoxitin was about 3-4 fold as high as that of animals treated with free cefoxitin. The differences in pharmacokinetic parameters appeared to account for the improved therapeutic efficacy of liposomal cefoxitin in this animal model.

Quantitative determination of semisynthetic cephamycins in human serum and urine by ion-exchange, reversed-phase and ion-pair chromatography.

High-performance liquid chromatographic methods have been developed for the determination of semisynthetic cephamycins: cefoxitin, cefmetazole and cefminox in human serum and urine samples. Serum samples spiked with each cephamycin were combined with an equal volume of methanol to remove proteins and, after centrifugation, and aliquot of the supernatant was analysed by ion-exchange, reversed-phase and ion-pair chromatography with hexadecyltrimethylammonium bromide as the ion-pairing agent. Urine samples were diluted, filtered and analysed by same chromatographic procedure. The cephamycins were detected by their ultraviolet absorbance (265-272 nm). It was possible to determine concentrations of cephamycins to 0.2 micrograms/ml in serum 2 micrograms/ml in urine samples with a good level of reproducibility and accuracy.

Determination of cefoxitin in serum and tissue.

A simple, rapid and sensitive method for the clean-up and analysis of cefoxitin in serum and tissue is described. Serum (0.5 ml) and tissue (100 mg) samples after homogenization underwent high speed centrifugation. Chromatography was performed on a muBondapak C18 cartridge using a mobile phase of 0.005 M potassium dihydrogen phosphate-acetonitrile-glacial acetic acid (77.5:22:0.5, v/v/v) with a flow-rate of 2.0 ml/min. Ultraviolet detection occurred at 235 nm. The procedure produced a linear curve for the concentration range 100-5000 ng/ml. The assay produced accurate, repeatable and rapid results for both tissue and serum samples without the need for chemical extraction.

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.

[Clinical study on transfer into lung tissue of cefminox].

Nineteen patients who underwent pulmonary resection due to lung diseases were administered with 2 g of cefminox (CMNX) by intravenous drip infusion just before surgery. CMNX levels in the serum and lung tissue were determined and pharmacokinetic parameters were derived. The obtained results are summarized as follows: 1. Pharmacokinetic parameter (K1/K2) derived from serum and lung tissue concentrations using deconvolution method was 0.46. 2. CMNX was useful for prophylaxis of postoperative infections with lung resection.

Cefminox: correlation between in-vitro susceptibility and pharmacokinetics and serum bactericidal activity in healthy volunteers.

Plasma concentration of cefminox and serum bactericidal activity against four ATCC strains (Escherichia coli 25992, Klebsiella pneumoniae 13833, Serratia marcescens 8100 and Bacteroides fragilis 25285), were determined over a 24 h period after administration of cefminox 1 and 2 g to six healthy volunteers in a randomized, cross-over, single blind study. The increase observed in the area under the bactericidal curve (AUBC) with the 2 g dose was at least 3.5 times that seen with the 1 g dose for all four test strains and was larger than predicted by the corresponding increase (1.84 times) in the area under the serum concentration versus time curve (AUC); a correlation (r = 0.88, P = 0.0001) between the cefminox concentration and the serum bactericidal titres was, however, observed with all four strains tested. The MBC6h showed a better association with the serum bactericidal titre (P < 0.01) than did the MIC or MBC.

Nanoscale packed capillary liquid chromatography-electrospray ionization mass spectrometry: analysis of penicillins and cephems.

A series of seventeen penicillins and cephems (cephalosporins and cephamycins) was examined by electrospray ionization. Separations by nanoscale packed-capillary liquid chromatography, with sub-microliter flow-rates, were performed using methanol-water and acetonitrile-water both containing trifluoroacetic acid gradients. In the on-column analyses, the protonated species usually predominate, and the fragment ions are often present which can be used for confirmation of compound identity. With combined nanoscale packed-capillary liquid chromatography-electrospray ionization mass spectrometry, separations and full-scan mass spectra can be obtained on *q12-15 ng of analyte, allowing the analysis of therapeutic levels of these antibiotics from only a few microliters of serum.

[Study on the concentration of cefminox sodium in serum and prostatic tissue].

The concentration of cefminox sodium (CMNX) in serum and prostatic tissue was determined in 25 patients with benign prostatic hypertrophy. One gram of CMNX was intravenously administered prior to transurethral prostatectomy. Blood and prostatic tissue were obtained 1 hour after the administration of CMNX. The concentration of CMNX was 69.17 +/- 17.47 micrograms/ml (mean +/- SD) in serum and 5.33 +/- 2.33 micrograms/g (mean +/- SD) in the prostatic tissue. The ratio of the prostatic tissue concentration/serum concentration was 8.18 +/- 4.45% (mean +/- SD). There was no correlation between serum and prostatic tissue level of CMNX.

Effects of cefbuperazone on the chemiluminescence of human neutrophils.

To investigate the in vivo effect of antimicrobial agent on neutrophil chemiluminescence and serum opsonic activity, cefbuperazone sodium (CBPZ) was administered to healthy male volunteers via an intravenous drip. A peripheral blood sample (10 ml) was collected 7 times: prior to injection, then 1, 3, 6, 9, 12 and 24 h after injection. Neutrophil chemiluminescence and serum opsonic activity was measured by the simultaneous multiple measurement system based on luminol-dependent chemiluminescence and indicated by peak height and peak time. Neutrophils were activated at hour 1 from the point of view of peak height and statistical significance was observed. The fluctuation of serum opsonic activity was small and statistical significance was not observed. CBPZ has an in vivo effect on neutrophils which was not supposed from in vitro study.

[Study of the prostatic tissue cefbuperazone (CBPZ) level].

The concentration of Cefbuperazone (CBPZ) was determined in the prostatic tissue and serum of 23 patients with benign prostatic hypertrophy. One or 2 of CBPZ was injected intravenously prior to transurethral prostatectomy. The mean CBPZ level in prostatic tissue and tissue/serum ratio at 1 hour was 17.4 +/- 7.2 micrograms/g (28.9 +/- 9.1%) in 10 patients administered 1 g of CBPZ, and 34.7 +/- 1C.2 micrograms/g (35.7 +/- 13.2%) in 13 patients administered 2 g of CBPZ. Serum and prostatic tissue CBPZ levels responded satisfactorily to the dose of CBPZ. Weights of resected prostatic tissue were not correlated to the tissue CBPZ level. Judging from the inhibitory concentration of CBPZ (minimum inhibitory concentration 80), the prostatic tissue CBPZ level was sufficient against pathogenic bacteria, particularly E. coli, K. pneumoiae and P. mirabilis for a relatively long time. For this reason CBPZ is a very useful drug for treatment of bacterial prostatitis and postoperative infection of prostate.

[Changes in concentration of cefotetan in blood and lung tissue after intravenous administration].

Cefotetan (CTT), a newly-developed cephamycin antibiotic, has been used widely for the treatment of various infectious diseases because of its excellent antibacterial potency and dynamic transport in vivo. Although the drug transfer to almost every organ, tissue, and body fluid has been studied, only a few reports are available regarding the transfer to lung tissue. In the present study, 1 g of CTT was intravenously injected in a single dose to each of 22 patients subjected to pulmonary resection. Subsequently, its concentrations in blood and lung tissue were measured in sequence. The degree of transfer of the drug to the lung tissue was calculated to evaluate the pharmacodynamics of CTT in vivo. The following results were obtained in this analysis. 1. The T1/2(beta) of the concentration in blood was 4.18 hours, and AUC0-infinity was 478.7 micrograms.hr/ml. 2. Cmax in the lung tissue was 31.5 micrograms/g, and Tmax was 0.83 hour, and tissue concentrations decreased in parallel to blood concentrations. CTT was transferred to the lung tissue to achieve high concentrations following an intravenous administration. Since high concentrations are maintained for a long period of time, this antibiotic is expected to exert an excellent effect in the prevention and the treatment of respiratory infections.

The effects of cefotetan disodium on haemostasis.

A 7-day course of intravenous cefotetan disodium was given to nine patients. No significant changes were observed in haematological or biochemical parameters and serum vitamin K1 levels, prothrombin times, factor VII levels, thrombin times and activated partial thromboplastin times remained within the normal ranges throughout the treatment period in all patients. There was no evidence of clinical bleeding in any patient although in two the bleeding time was prolonged up to 13.0 min after 7 days' therapy. Notably, adenosine-5-diphosphate (ADP)-induced platelet aggregation responses were significantly increased (P less than 0.05) at the end of the treatment period. These data indicate that cefotetan disodium at a dose of up to 4 g daily can be used without risk of a bleeding diathesis. In situations associated with vitamin K1 deficiency, potential prolongation of the prothrombin time should be avoided by prophylactic vitamin K1 administration.

[Serum and sputum levels of cefotetan used in respiratory tract infections].

In 5 patients with respiratory tract infections, concentrations of cefotetan (CTT) in serum and sputum after 1 hour intravenous administration of 2 g of CTT to each patient were investigated, and following results were obtained. Serum levels of CTT The mean peak level of CTT was 232.0 +/- 16.2 micrograms/ml immediately after the 1 hour drip infusion, then declined gradually and was 48.0 +/- 8.8 micrograms/ml after 6 hours. Sputum levels of CTT Mean sputum levels of CTT were 2.15 +/- 0.19 micrograms/ml from 2 to 4 hours after the administration and 2.19 +/- 0.18 micrograms/ml from 4 to 6 hours. Clinical evaluation of CTT Clinical effects were excellent in 1 case, good in 3 cases and poor in 1 case. No side effects were observed.

Pharmacokinetics of cefotetan in patients with end-stage renal failure on maintenance dialysis.

The pharmacokinetics of a single intravenous dose of cefotetan were studied in 17 volunteer patients with end-stage renal failure, requiring intermittent haemodialysis in 12 cases or undergoing continuous ambulatory peritoneal dialysis in 5 cases. Between haemodialysis the mean plasma elimination half life was 20.4 h (S.E.M. +/- 2.1). This decreased to 7.5 h (S.E.M. +/- 0.6) during haemodialysis. In patients treated by continuous ambulatory peritoneal dialysis the mean plasma elimination half life was 15.5 h (S.E.M. +/- 1.9). Small amounts of cefotetan (5-9% of the administered dose) were recovered in the peritoneal dialysates removed over the 24 h following the dose.

[Cefotetan: clinical trial in elderly persons using a single daily dose of 2 grams as the sole therapy]. / Céfotétan: essai clinique chez la personne âgée avec une monodose quotidienne de deux grammes en monothérapie.

Effectiveness of cefotetan, a new generation semisynthetic cephamycin, was studied in a clinical trial in elderly patients. Cefotetan was used as single drug therapy. A single daily injection of 2 g was given to each of 33 elderly subjects (mean age 70.2 years, range 69-92 years). The infections were severe: pneumonia in 13 cases, septicemia in 12, upper urinary tract infections in 3 and miscellaneous infections in the remaining cases. The regimen used proved clinically effective (93% successes) and achieved residual serum levels greater than the MICs of all the Gram negative bacteria and most of the Gram positive cocci isolated. In addition to being efficient, the single daily injection regimen causes minimal damage to peripheral veins, provides optimal comfort to the patient, and saves both material and time.

A comparative trial between cefotetan and cephazolin for wound sepsis prophylaxis during elective upper gastrointestinal surgery with an investigation of cefotetan penetration into the obstructed biliary tree.

Cefotetan is a cephamycin antibiotic theoretically suited to prophylaxis of wound infection during upper elective gastrointestinal surgery. In a prophylaxis trial 100 patients undergoing this type of surgery were randomly allocated to receive 1g cefotetan or cephazolin iv at induction of anaesthesia. Cefotetan-treated patients had significantly fewer postoperative infections overall (P less than 0.05) and there were no wound infections recorded in this group. In a separate pharmacokinetic study the penetration of cefotetan into common bile duct bile and gallbladder wall was measured in a further six patients, all of whom had been jaundiced preoperatively. At the time of maximum risk concentrations of cefotetan in bile and biliary tissue as well as blood and wound fat were in excess of the minimum inhibitory concentration for the majority of relevant pathogens. Cefotetan appears to be equally or more effective than cephazolin and is a suitable alternative prophylactic agent in elective upper gastrointestinal surgery.

Effects of phenothiazines and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide on rat colonic absorption of cefmetazole.

Rat colonic absorption of cefmetazole was increased significantly by calmodulin inhibitors such as phenothiazines and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) when they were coadministered at a concentration between 1 and 100 microM. The bioavailability of cefmetazole, determined by area under the blood concentration curve method, increased 20 to 30% by the coadministration of calmodulin inhibitors. It is speculated that the enhancing action of agents on rat colonic absorption of cefmetazole takes place by a paracellular route and coadministration of sodium ion increases their actions.

[Transfer of cefotetan into exudates from excoriated skin wounds].

Transfer of cefotetan (CTT) into exudates from excoriated skin wounds was studied in 9 adult patients. Each subject was given an intravenous bolus injection of 50 mg/kg of body weight. Concentrations of CTT in serum and in exudate fluid were determined by bioassay using Escherichia coli NIHJ as the test organism. The mean (+/- S.D.) CTT concentration in serum reached 274.3 +/- 78.3 micrograms/ml at 30 minutes after the injection and decreased to 30.0 +/- 12.0 micrograms/ml at 8 hours after the injection. The peak value of CTT in exudate fluid was 143.1 +/- 22.3 micrograms/ml at 1 hour. Eight hours after the injection, the mean concentration in the exudate was 25.7 +/- 21.1 micrograms/ml. The data obtained were analysed pharmacokinetically: CTT concentrations in serum were analysed by two-compartment model, and those in exudate fluid from excoriated skin wounds were analysed by the model in which skin was considered as a small part of the peripheral compartment. Thus T1/2(beta) of CTT levels in serum was calculated as 2.38 hours, AUC0----infinity was 1,000.2 micrograms X hr/ml and Vd was 164.5 ml/kg. Tmax and Cmax of CTT levels in exudates were calculated as 1.05 hours and 131.2 micrograms/ml, respectively.