Moxalactam kinetics in hemodialysis.

In eight patients with end-stage renal disease undergoing chronic hemodialysis moxalactam kinetics were examined. Volume of distribution (Vd), dialysance (Cd), and serum half-life (t1/2) were determined during dialysis with a 1.3 or 1.6 m2 dialyzer. The t1/2 was also determined during the interdialytic period. Vd was 0.25 +/- 0.04 l/kg and Cd was 32.6 +/- 11.7 ml/min and 67 +/- 25.5 ml/min with the 1.3 and 1.6 m2 dialyzers. The t1/2 was 4.8 +/- 0.9 hr using the 1.3 m2 dialyzer and 2.8 +/- 0.6 hr using the 1.6 m2 dialyzer. Moxalactam t1/2 during the interdialytic period was 23.4 +/- 9.6 hr.

Moxalactam concentration in human aqueous humor after intravenous administration.

Two grams of moxalactam disodium was administered intravenously to 20 patients before cataract extraction. Mean aqueous humor concentrations of moxalactam were 0.92, 0.87, 1.98, 2.13, and 1.24 micrograms/ml 30 minutes and 1, 2, 4, and 6 hours, respectively, after treatment. Adequate levels against Staphylococcus aureus and Staphylococcus epidermidis were not achieved. With the exception of Pseudomonas species, therapeutic levels three to ten times greater than the median minimum inhibitory concentration of moxalactam against Enterobacteriaceae were achieved for up to six hours after administration.

Penetration of intravenous moxalactam into human aqueous humor.

Intraocular penetration of moxalactam disodium, a new broad-spectrum oxa-beta-lactam antibiotic, was studied in 18 patients undergoing cataract surgery. The antibiotic was administered in a 2-g single dose by intravenous drip during a 20-minute period. After 40 to 230 minutes, moxalactam aqueous humor concentrations ranged from 1.1 to 5.0 micrograms/mL (mean, 2.3 micrograms/mL). The ratio of aqueous humor concentrations to concomitant serum concentrations ranged from 1.6% to 9.8%. The achievable aqueous moxalactam concentrations were well above the minimum inhibitory concentrations of most Gram-negative enteric bacilli but not of Pseudomonas and staphylococci.

Activity of third-generation cephalosporins in human blood.

Activity of cefotaxime, ceftriaxone, cefotetan, and latamoxef against Escherichia coli was evaluated in whole human blood. At subinhibitory levels no effect was seen. At concentrations at or exceeding the MIC, cefotaxime was rapidly bactericidal, and latamoxef was the second most active compound. With ceftriaxone and cefotetan, the organism grew better in blood containing the antibiotic than in blood alone.

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.

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.

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.

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.

Cephamycin derivatives: comparison of the in vitro and in vivo antibacterial activities of SQ 14,359, CS-1170, and cefoxitin.

SQ 14,359 is a new cephamycin-type (7alpha-OCH3) antibiotic belonging to a series containing a 7alpha-ureidoacetyl substituent. The compound is the most potent extended spectrum derivative of this type yet reported, surpassing CS-1170 and cefoxitin by a wide margin. This activity in vitro which extends throughout the Enterobacteriaceae is particularly prominent against Gram-negative organisms that are producers of "cephalosporinase-type" beta-lactamases such as Enterobacter, Serratia, Citrobacter and indole-positive Proteus species. Superior activity also is demonstrated in vitro against streptococci, beta-lactamase-producing staphylococci, Haemophilus influenzae, Neisseria gonorrhoeae, and many Gram-negative pathogens resistant to aminoglycoside antibiotics. Experimental chemotherapeutic studies have confirmed these observations in wound and selected systemic infections in mice as well as acute pyelonephritis and meningitis in rats. The pharmacokinetics for each drug including antibiotic bound to serum was similar in both mice and rats. The pharmacokinetic profile in blood and cerebrospinal fluid favored SQ 14,359.

In vivo activity of cefbuperazone (T-1982) against various experimental infections in mice.

The protective activity of cefbuperazone (T-1982) was compared with those of latamoxef, cefotaxime, and cefmetazole against intraperitoneal and urinary tract infections in mice. In both tests, cefbuperazone manifested a higher activity than the other cephems against infections with Escherichia coli and Klebsiella pneumoniae. Cefbuperazone also showed a comparatively high degree of prophylactic effect; this activity was observed even when given 4 hours before bacterial challenge. The good in vivo activity of cefbuperazone could not be explained by the differences between the antibiotics on the basis of the serum levels and vitro activity. Mice, treated with cefbuperazone, showed a statistically significant prolongation of survival time against intraperitoneal challenge with Candida albicans, but not when treated with the other cephems. This finding suggests that the host defense mechanisms stimulated by cefbuperazone may contribute to the good in vivo activity of this antibiotic.

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.

Peri-incisional and preoperative administration of cefmetazole for the prophylaxis of wound infection after appendicectomy.

The tissue and blood levels of Cefmetazole are compared after preoperative administration of a single dose of 30 mg/K body weight of the antibiotic administered intravenously (15 patients) and peri-incisionally (30 patients) to patients scheduled for emergency appendicectomy. Local and general tolerance to the antibiotic was good by both routes. No local or general complications arose in any of the patients. As expected, the tissue concentrations achieved with peri-incisional infiltration were significantly higher than those obtained by the intravenous route. With the blood levels, exactly the opposite happens at the start of the operation whereas at the end, there were no significant differences between the two routes employed. The prophylactic administration by peri-incisional infiltration is an easy and safe method which provides high tissue concentrations simultaneously with adequate blood levels and should be considered as useful in the preoperative administration of antibiotics for prophylaxis.

[Treatment of septicemia with latamoxef. Multicentric study of 60 cases]. / Traitement des septicémies par le latamoxef. Etude multicentrique de soixante cas.

Sixty patients including forty two males and eighteen females, age range: 18-87 years, received antibacterial single drug treatment with latamoxef for septicemia. Forty nine patients had underlying conditions including multiple trauma, neoplasm, cardiovascular, metabolic and respiratory tract diseases. Causative pathogens were isolated in all cases. The predominant isolates were E. coli (thirty), Klebsiella pneumoniae (tent) and Enterobacter (seven). A single organism was isolated in fifty seven cases; in the other three cases two organisms were isolated from blood cultures. Mean daily dosage was 46.6 +/- 6.1 mg . kg-1 (range: 14-113 mg . kg-1). In the majority of cases (fifty two) dosage was 3 g . d-1 or less; in thirty cases it was no higher than 2 g . d-1. Duration of therapy ranged from six to thirty eight days. Serum titer was measured in many cases and latamoxef blood levels were assayed in nine patients. A satisfactory clinical response was achieved in fifty eight cases and fifty eight bacteriological cures were also obtained. There was no statistically significant difference in therapeutic response between the 2 g and 3 g daily dosage groups. Tolerance was very good; untoward effects were few and required drug discontinuation in one case only.

[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.

[Tissue distribution of cefminox in beagle dogs].

A new cephamycin antibiotic, cefminox (MT-141, CMNX), was intravenously infused into Beagle dogs at a dose of 40 mg/kg in order to study it's distribution to various tissues. The following results were obtained. The maximum serum concentration of CMNX observed at the end of the infusion period was 102.3 micrograms/ml, and then the concentration decreased. The biological half-life of CMNX in serum was 37.0 minutes. This half-life was similar to the results of previous studies with Beagle dogs and rabbits. The maximum concentrations in tissues and body fluids were highest in B-bile followed by kidney, urinary bladder, serum, liver, vagina, uterus, pericardiac fluid, trachea, ovary, lung, gallbladder, parotid gland, heart, tonsil, thymus, spleen, pancreas, aqueous humor and cerebrospinal fluid, in that order and not detected in brain. The maximum concentrations in gallbladder, B-bile, pericardiac fluid and cerebrospinal fluid were found at 1-2 hours after administration. In other tissues and body fluids, they were obtained at the end of the infusion period. The area under the tissue concentration curve (AUC) was highest in the urinary bladder followed by the kidney, vagina, liver, uterus, gallbladder, trachea, ovary and lung, in that order. These results suggest that CMNX is useful for various infectious diseases in these tissues. The pharmacokinetic parameter (K1i/K2i) derived from serum and tissue concentrations using the deconvolution method well correlated to maximum tissue concentrations.

[Penetration of cefbuperazone, a new cephamycin antibiotic, into human peritoneal exudate].

Pharmacokinetic studies were carried out on cefbuperazone ( CBPZ ) in 9 patients undergoing postoperative drainage. The concentration of CBPZ in serum and peritoneal exudate after one shot intravenous administration of 1 g was measured by bioassay and calculated respectively by two- and one-compartment open model. The results obtained were as follows: The pharmacokinetic parameters calculated from the serum levels were compared to those reported previously; T1/2 = 101 min., Vd = 4.06 L and Cl = 76 ml/min. The simulation curve of the peritoneal exudate level fit fairly with the mean values of 6 patients. It appeared that CBPZ penetrated somewhat slowly into peritoneal exudate with the peak value of 27.05 micrograms/ml at about 1 hour after the administration. The exudate levels thereafter declined more slowly than the serum ones (T1/2 = 134 min.). IT was 6.2 micrograms/ml even at 6 hours after the administration.

[Concentration of antibiotics in the prostate: cefmetazole].

Sixteen patients who underwent transurethral resection of prostate preoperatively received intravenous injection of cefmetazole in a doses of 2 gram. Pharmacokinetic study revealed that concentration of cefmetazole in prostatic tissue well correlated to serum concentration with nearly the same half-life times.

[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.

[A study on transference of cefminox into intrapelvic tissues].

Intravenous administrations of cefminox (CMNX, MT-141) 1 g as both single shot injection and drip infusion were absorbed rapidly. CMNX showed good transference into intrapelvic organs such as uterus, oviduct and ovary, with the tissue/serum ratios of 37.6% for myometrium, 35.1% for endometrium, 41.4% for cervix uteri, 49.5% for portio vaginalis, 54.3% for ovary and 59.7% for oviduct. From these results, usefulness of CMNX in the field of obstetrics and gynecology was confirmed.

[Basic study on cefminox in the field of obstetrics and gynecology].

In patients with carcinoma of the uterine cervix, cefminox (CMNX, MT-141) was given intravenously after panhysterectomy and the pelvic dead space exudate and serum levels of the drug were determined at various periods. The pelvic dead space exudate level reached its peak of 67.21 +/- 39.81 micrograms/ml at 2 hours, which decreased gradually to 26.04 +/- 6.66 micrograms/ml at 6 hours. In the serum, the drug level attained the peak of 152.98 +/- 85.37 of 7.26 +/- 1.66 micrograms/ml was still detected. The pelvic dead space exudate level was much higher than its MIC or 3h-MBC at all periods studied. From these results it was considered that CMNX achieves levels high enough to be expected of clinical efficacy in the pelvic dead space exudate and serum.