Multicenter clinical trials comparing cefotetan with moxalactam or cefoxitin as therapy for obstetric and gynecologic infections.

The clinical efficacy and safety of cefotetan was assessed in two multicenter clinical trials involving 335 evaluable patients hospitalized with obstetric and gynecologic infections. In Study I, cefotetan was compared with moxalactam and in Study II, cefotetan was compared with cefoxitin. The clinical response rate in Study I was 67 of 70 patients for cefotetan (96 percent) and 33 of 34 patients (97 percent) for moxalactam. In Study II, the clinical response rate was 138 of 147 patients in the cefotetan group (94 percent) and 76 of 84 patients in the cefoxitin group (91 percent). For the patients with bacteriologic response data, 196 of 205 cefotetan patients (96 percent), 23 of 24 moxalactam patients (96 percent), and 70 of 75 cefoxitin patients (93 percent) had a satisfactory bacteriologic response. Cefotetan was well tolerated and produced no major adverse reactions. The mean amount of cefotetan given was lower than that of moxalactam or cefoxitin.

Comparative effectiveness and safety of cefotetan and cefoxitin as prophylactic agents in patients undergoing abdominal or vaginal hysterectomy.

In a multicenter, randomized clinical trial, 282 women who underwent abdominal or vaginal hysterectomy were given a single preoperative 2 g dose of cefotetan (171 evaluable patients) or three perioperative 2 g doses of cefoxitin (84 evaluable patients) as antibiotic prophylaxis. A successful clinical response occurred in 92 percent of those receiving cefotetan and 90 percent of those receiving cefoxitin who underwent abdominal hysterectomy, and in 94 percent of those receiving cefotetan and 93 percent of those receiving cefoxitin who underwent vaginal hysterectomy. The incidence of vaginal cuff cellulitis was 3.4 percent and 5 percent for cefotetan and cefoxitin patients, respectively, who underwent abdominal hysterectomy, and 4.8 percent and 4.5 percent, respectively, for those who underwent vaginal hysterectomy. The incidence of major wound infection was 3.4 percent and 2.5 percent for cefotetan and cefoxitin, respectively, in the abdominal hysterectomy group. Postoperative changes in oral body temperature, duration of hospitalization, and postoperative grading of surgical wounds were similar. Both drugs were well tolerated. These results suggest that a single dose of cefotetan is equally effective and as safe as multiple-dose cefoxitin for prophylaxis in patients undergoing hysterectomy.

Release of lipoteichoic acid from Staphylococcus aureus by treatment with cefmetazole and other beta-lactam antibiotics.

The effect of cefmetazole on the growth together with the release of cellular lipoteichoic acid from cefazolin-resistant strains of Staphylococcus aureus was compared with that of cefazolin, cefotiam, cefoxitin and cefuroxime. Bacteriolytic actions were measured by turbidity and bactericidal actions were followed by viable cell count. Release of cellular lipoteichoic acid was measured by the radioactivity in the supernatant of the cultures. Cefmetazole exerted more potent effects on the bacterial growth and induced more marked release of cellular lipoteichoic acid from resistant strains as compared with other beta-lactams.

[Toxicological studies on a new cephamycin, MT-141. VII. Its locally-irritating activity in rabbits].

The local irritation of MT-141 was compared with that of cefmetazole (CMZ) in rabbits to obtain following results. Microscopic observations revealed that the irritative activity of 10% solution of MT-141 in blood vessels was not so much different from that of saline and 10% solution of CMZ when they were injected twice a day into vein retroauricularis of rabbits for 7 days. The histopathological changes induced by 10% solution of MT-141 were similar to those by 10% solution of CMZ but somewhat different from those by saline, because both compounds caused slight necrosis in the tissue around vessels. Histopathological observations suggested that the occurrence of necrosis was due to the leakage of them during injections. The local irritation of MT-141 by an injection of 1 ml of its solution into muscle vastus lateralis was compared with that of CMZ in rabbits. The potencies of irritative activity of the test solutions were summarized in the following order; saline less than 5% MT-141 less than 10% MT-141 not equal to 10% CMZ much less than 0.75% acetic acid less than 6.0% acetic acid. The above-mentioned results suggest that MT-141 has low irritating activity when injected through intravenous or intramuscular route for clinical practice as 5% or 10% solution.

[Muscle irritation study on T-1982].

The local irritation effect of T-1982 after the intramuscular injection into the musculus vastus lateralis was examined in rabbits. T-1982 was dissolved by the way of clinical use and was injected singly into the musculus vastus lateralis. Then the degree of muscular injury at the time of 2 days and 7 days after the injection was judged from muscle weight ratio, gross local observation and histological observation. The degree of muscular injury caused by T-1982 was compared with that of saline, 0.75% acetic acid and 6% acetic acid. On the degree of muscular injury of T-1982 was almost equal to that of 0.75% acetic acid, but milder than 6% acetic acid. From these, it was concluded that the local irritation effect of T-1982 was grade 3.

[Toxicological studies on a new cephamycin, MT-141. V. Its subacute toxicity in beagle dogs].

The 30-day subacute toxicity of MT-141 was studied in adult Beagle dogs with intravenous (i.v.) administrations of 100 to 1,200 mg/kg/day. The obtained results were as follows. MT-141 at the doses lower than 800 mg/kg/day i.v. had no toxicity in male and female Beagle dogs. An increase in water intake was closely related to that in urine excretion after i.v. treatments with 1,200 mg/kg/day of MT-141 in the males and females. MT-141 at the doses higher than 1,000 mg/kg/day i.v. of MT-141 caused slight local irritation at the site of injection in the males and females. In the females, the dose-dependent changes induced by treatments with the doses above 1,000 mg/kg/day i.v. of MT-141 were a significant decrease in the level of serum K and a significant increase in the activity of serum LAP. In the males, this compound produced significant dose-dependent changes in toxicological parameters such as a decrease in the activity of GOT at the doses higher than 1,000 mg/kg/day i.v., a descent in the levels of U-K, U-Cl and OP at the dose of 1,200 mg/kg/day i.v., an elevation in the level of serum alpha 1- and alpha 2-G, and an increase in the volume of excreted urine at the dose of 1,200 mg/kg/day i.v. It is concluded from the above-mentioned results that the maximal "no effective" dose of MT-141 is 800 mg/kg/day i.v. and the toxic dose of MT-141 is above 1,000 mg/kg/day i.v. in male and female Beagle dogs.

[Toxicological studies on a new cephamycin, MT-141 IX. Its teratogenicity test in rats and rabbits].

A teratogenicity study of MT-141 was performed in SD rats and Japanese white rabbits. The pregnant rats were administered intramuscularly (i.m.) with MT-141 at the dose levels of 200, 400, 800 and 1,600 mg/kg/day from the day 7 up to the day 17 of gestation. The pregnant rabbits were administered intravenously (i.v.) with the drug at the dose levels of 10, 20 and 40 mg/kg/day from the day 6 up to the day 18 of gestation. The results are summarized as follows. Rats: Though the administrations with MT-141 at all dose levels did not change body weight gain and water intake of treated dams, a slight suppression in the food consumption was produced by MT-141 at the dose of 1,600 mg/kg/day. The examinations on cesarean section revealed no effect of MT-141 on teratological parameters such as external malformation and frequency of visceral and skeletal anomalies in the fetuses. MT-141 at all dose levels exerted no toxic effect on developmental, functional and behavioral parameters in F1 rats and on mating, fertility and pregnancy of F1 rats. Furthermore, there was no effect of MT-141 on the findings in cesarean section of F1 rats. The fetuses from F1 rats had no malformation of external appearance, viscera and skeleton. Rabbits: MT-141 had no significant effect on body weight gain and food consumption of dams at the all dose levels, but caused a slight suppression in the water intake at the doses more than 20 mg/kg/day. One rabbit aborted in each group given 20 or 40 mg/kg/day. One rabbit died in the group given 20 mg/kg/day. Examinations on cesarean section showed that MT-141 at the dose of 40 mg/kg/day produced a decrease in body weights of females and an increase in dead or resorbed fetuses followed by a decrease in live fetuses. MT-141 is no effect malformation of external appearance, viscera and skeleton in the fetuses of all treated groups. The above-mentioned results suggest that MT-141 has no teratogenic effect on pregnant rats and rabbits. It is concluded from these results that the maximal "no effective" dose of MT-141 on fetal toxicity is above 1,600 mg/kg/day i.m. for pregnant rats and 10 mg/kg/day i.v. for pregnant rabbits.

[Chronic toxicity study of latamoxef in beagle dog (author's transl)].

Chronic toxicity study of latamoxef (LMOX, 6059-S) by intravenous administration at dose levels of 100, 200 and 400 mg/kg daily for 6 months was carried out in adult Beagle dogs. All dogs of the 6059-S treated groups survived throughout the experimental period without showing any toxic signs other than occasional vomiting. Slight decrease of RBC, Ht, Hb and platelet, and increase of reticulocytes were noted in the 400 mg/kg group. Blood chemistry revealed decreased activity in GPT in the 6059-S treated groups, and increased contents of total protein and lipids in the 400 mg/kg group. These clinical changes were slight and transient in most instances. Liver and kidneys weights increased slightly without accompanying any pathological alterations. Inflammatory changes, probably due to mechanical irritation, were found in the subcutis and around the vein at the injection sites in all groups including the mannitol control group. From these results it is concluded that the maximum nontoxic dose in dogs is in the range of 200 to 400 mg/kg when the 6059-S was intravenously administered daily for 6 months.

[Toxicological studies on a new cephamycin, MT-141, IV. Its acute toxicity in beagle dogs].

The acute toxicity of MT-141 was studied in adult Beagle dogs with intravenous (i.v.) or intramuscular (i.m.) administration to obtain following results. MT-141 at the doses ranging from 2,500 to 7,500 mg/kg i.v. caused no effect on life, bodyweight, food intake, eyeground and ECG in male and female Beagle dogs. MT-141 produced an increase in water intake, urine volume, WBC and LAP and a decrease in Lymph., U-Na, U-K and OP, but any histopathological change was not caused in the organs and tissues. It is suggested that these changes in blood, serum and urine are due to mechanical and transient effects induced by infusing a large volume of hypertonic solution of MT-141 into cephalic vein. When 1,000 or 2,000 mg/kg of MT-141 was injected into the muscles of hind legs, the hind legs had difficulty in walking. It is very probable that this change was due to mechanical effects induced by injecting a hypertonic solution of MT-141 at a rate of 70--130 ml/dog. An injection of 1,000 or 2,000 mg/kg i.m. of MT-141 changed activity of GPT, GOT and CPK in the serum within the limit of physiological variations but did not caused any effect on the other toxicological parameters such as bodyweight, food intake, water intake, urine volume, eyeground examination, ECG and histopathological examination. It is concluded from the above-mentioned results that MT-141 at the dose of 2,500--7,500 mg/kg i.v. or 1,000--2,000 mg/kg i.m. has no significant toxicity in Beagle dogs.

[Toxicological studies on a new cephamycin, MT-141. VI. Its chronic toxicity in beagle dogs].

MT-141 was dosed to male and female Beagle dogs through intravenous (i.v.) route at 100, 200, 400 and 800 mg/kg/day for 182 days. The toxic effects of MT-141 were as follows. The male and female Beagle dogs exhibited no particular behavior and symptom except vomiting and soft stool after treatments with 800 mg/kg/day i.v. of MT-141. MT-141 even at the high doses of 400 to 800 mg/kg/day i.v. did not significantly change toxicological parameters such as consumption of food and water, volume of excreted urine, electrocardiogram, eyeground and analysis of blood, serum and urine. Only one of 4 male Beagle dogs died of severe intestinal invagination, which is not related to the drug effect, at 120th day after the start of treatments with the highest dose of 800 mg/kg/day i.v. of MT-141. The fatality of Beagle dogs for 800 mg/kg/day of MT-141 was 25% (1/4) in males and 0% (0/4) in females. MT-141 caused the hemorrhage accompanied with fibrosis and round cells at the site of injections but the change induced by MT-141 was not so much different from that by saline. MT-141 at the highest dose induced histopathological changes in only 2 females, such as atrophy and degeneration of cardiac muscle, necrosis and fibrosis of hepatic cells and hyperplasia of spleen and bone marrow cells. Electron-microscopic examinations revealed no ultrastructural change related to the toxicity of MT-141 in the livers and kidneys. It is considered from the above-mentioned results that the maximal "no effective" dose is 400 mg/kg/day i.v. in male and female Beagle dogs.

[Toxicological studies on a new cephamycin, MT-141. I. Its acute toxicities in mice and rats].

Acute toxicities of MT-141 were studied in mice and rats to obtain the following results. LD50 value of MT-141 by i.v. administration was 6,100 mg/kg for male mice and 5,200 mg/kg for female mice. The LD50 value by i.m. administration was 8,200 mg/kg for the males and 8,600 mg/kg for the females, respectively. The mice administered with a lethal dose of MT-141 showed abnormal syndromes such as decreased spontaneous movement, decreased rate of respiration, ataxic gait, sedative state and loss of righting reflex, followed by a decrease of body weight. Gross inspection revealed no remarkable change in the organs and tissues of mice after a treatment with a lethal dose of MT-141. LD50 value of this compound was 6,600 mg/kg for male rats and 5,700 mg/kg for female rats by i.v. administration, 8,600 mg/kg for the males and 8,550 mg/kg for the females by i.p. administration, 9,600 mg/kg for the males and 9,700 mg/kg for the females by i.m. administration and more than 15,000 mg/kg for both sexes by s.c. or p.o. administration, respectively. The rats given a lethal dose of MT-141 showed abnormal syndromes such as stepping gait, face-down position, decreased rate of respiration, ataxic gait, decreased spontaneous movement and loss of righting reflex, followed by a decrease of body weight. The rats exhibited stretching behavior when given MT-141 through i.p. route and manifested vocalization when given it through s.c. and i.m. routes. The results of gross inspection and histopathological observation suggested that high doses of MT-141 induced slight renal toxicity in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

[Toxicological studies of a new cephamycin, MT-141. III. Its chronic toxicity in rats].

The chronic toxicity of MT-141 was studied in male and female Wistar rats with 182-time intramuscular injections of 50, 100, 200, 400, 800 and 1,600 mg/kg/day and the following results were obtained. MT-141 at all dosage levels caused no lethal effect on rats. However, it induced local inflammatory changes at the site of injection, such as hemorrhage, infiltration of round cells and fibrosis particularly at high doses. MT-141 at a high dose of 1,600 mg/kg/day decreased the gain of body weights in male rats but not in female rats. MT-141 increased the water intake in male and female rats from 8th day till last day after treatments with the doses more than 800 mg/kg/day. This compound also softened the feces and distended the cecum. MT-141 at the highest dosage level of 1,600 mg/kg/day increased the weight of kidney in male and female rats. Electron-microscopic findings revealed dissociation of basal infolding and dilatation of endoplasmic reticulum in renal epithelial cells of rats treated with the doses more than 800 mg/kg/day. These results suggest that MT-141 may induce renal toxicity in rats at these doses. The administration of MT-141 changed some toxicological parameters in gross and histopathological examinations and analyses of blood, serum and urine. However, the changes were accidental, independent on the dose and within physiological variations. It is concluded from above-mentioned results that the maximal "no effective" dose of MT-141 is 400 mg/kg/day in male and female rats.

[The mutagenicity evaluation of MT-141, a new cephamycin].

Mutagenicity of MT-141, a new cephamycin, was evaluated by in vitro and in vivo assays. MT-141 did not induce mutations of the test strains, Escherichia coli WP2 (uvr A) and Salmonella typhimurium TA1535, TA1537, TA1538, TA100 and TA98, with and without metabolic activation in vitro. In bone marrow micronucleus assay with male mice, MT-141 showed no induction of micronucleated polychromatic erythrocyte at 6 hours and 30 hours after administration. In addition MT-141 was found not to cause any dominant lethal effects on male mice for 8 weeks after administration.

[Comparative nephrotoxicity of latamoxef and other cephalosporins in rabbits. Combined administration with furosemide or tobramycin. (author's transl)].

I. The nephrotoxic potential of latamoxef (LMOX, 6059-S) was evaluated in male rabbits after combined administration of 500 or 2,000 mg/kg of the compound (ear vein) with subcutaneous injection of furosemide (FUR) at 50 mg/kg. Histological examination of kidney tissues of all animals were performed after 72 hours. Three rabbits were used at each dose level, and comparative studies were performed using several cephalosporins, such as CET and CEZ. Neither LMOX nor CET produced nephrotoxic effects at 500 mg/kg when given in combination with FUR. Although slight elevation of BUN and creatinine in plasma and hyaline casts in lumen of the distal tubules were observed in animals receiving 2,000 mg/kg of LMOX or CET when dosed with FUR, no histological changes were found in renal tissues. Significantly more nephrotoxicity was observed with the treatment of CEZ alone, and this toxicity was augmented in combination with FUR. II. Concomitant administration of LMOX with intramuscular injection of tobramycin (TOB) was estimated in male rabbits. Rabbits received daily intramuscular injection of TOB at 50 mg/kg for 10 days in combination with single dosing of LMOX (500 or 2,000 mg/kg) on the 8th day after the start of TOB treatment. Three rabbits were used at each dose level, and comparative studies were conducted using CET or CEZ. All rabbits were killed 48 hours after the last injection of TOB and examined histopathologically. Combined administrations of LMOX or CET did not aggravate the nephrotoxicity induced by TOB. However, CEZ enhanced renal injuries produced by TOB injection.

[A study of safety of cefmetazole (CS-1170) in pregnant women during the perinatal stage (author's transl)].

Cefmetazole has a high safety rating when used in perinatal stage chemotherapy and thus it is a very useful antibiotic. However, cefmetazole is not an antibiotic to be administered primarily as a preventive. It should be used mainly in treating other agents resistant Gram-negative bacilli infections. In doing so, cefmetazole will become highly useful. 2. The safe dose of cefmetazole (CMZ) to the mother in the perinatal period is 1 approximately equal to 2 g/day. The administration of 4 g/day in a severe case is not contraindicated. 2. The fetus showed no signs of distress or side effects from cefmetazole (CMZ) crossing the mother's placental barrier. The transition of cefmetazole (CMZ) into the mother's milk is insignificant quantitatively but remains unknown qualitatively.

[Toxicological studies on a new cephamycin, MT-141. VIII. Its fertility test in rats].

A fertility study of MT-141 was performed in SD rats with the intramuscular (i.m.) injections at the dose levels of 400, 800 and 1,600 mg/kg/day. The male rats were injected with MT-141 for 63 days before mating and during the mating period, while the female rats were injected with MT-141 from the 14th day before mating up to the day 7 of gestation. All pregnant rats were sacrificed on day 20 of gestation followed by external, visceral and skeletal observations of their fetuses. The results are summarized as follows. The suppression of body weight gain was observed in males given above 800 mg/kg/day i.m. and in females of all treated groups during early period of gestation. However, no significant differences were found between treated groups and the control with regard to copulation rate and conception rate. Though no defects were observed for visceral and skeletal specimens in the fetuses of treated groups, MT-141 produced a delayed ossification of forelimbs in the fetuses at the doses above 800 mg/kg/day and of sternebrae at the dose of 1,600 mg/kg/day. It is concluded from the above-mentioned results that the maximal "no 'effective" dose of MT-141 on the fertility is above 1,600 mg/kg/day i.m. in parental rats and less than 800 mg/kg/day i.m. for the fetuses.

[Toxicological studies of a new cephamycin, MT-141. II. Its subacute toxicity in rats].

In this subacute study, male and female rats were administered with 100, 200, 400, 800 and 1,600 mg/kg/day of MT-141 through an intramuscular (i.m.) route or with 50, 100, 200, 400 and 800 mg/kg/day through an intravenous (i.v.) route for 30 days. MT-141 did not cause lethal effect on male and female rats even at the high dosage of 1,600 mg/kg/day i.m. (approx. one-6th of LD50) and 800 mg/kg/day i.v. (approx. one-8th of LD50). Histopathological findings revealed that MT-141 induced slight local irritation at the sites of i.m. and i.v. injection. Only at a high dose of 1,600 mg/kg/day i.m., MT-141 reduced significantly the gain of body weight in male rats, which was closely related to the decrease of food intake. A slight decrease in serum Cr. and Glc. was observed in male rats at the doses more than 200 mg/kg/day i.m. and a slight decrease of liver weight at the doses more than 800 mg/kg/day i.m., while a slight increase of serum CPK, GOT, A1-P and LDH was perceived at the doses more than 800 mg/kg/day i.m. The distention of cecum was induced by the doses more than 400 mg/kg/day i.m. but histopathological findings revealed no abnormality in the cecum. These results suggest that MT-141 at the dosage level of 1,600 mg/kg/day i.m. causes nonspecific slight toxicity based on the disturbance of nourishment in male rats. In female rats given 100 to 1,600 mg/kg/day i.m., MT-141 at the high doses induced a slight increase of serum GOT, LDH and CPK and distention of the cecum. It is assumed from these results that MT-141 at the dosage level of 1,600 mg/kg/day causes nonspecific slight toxicity in female rats. In male rats given 50 to 800 mg/kg/day through an i.v. route, the level of serum Glc. and Cr. and the liver weight slightly decreased at the doses more than 200 mg/kg/day i.v. The cecum distended at the doses more than 100 mg/kg/day i.v. The dose of 800 mg/kg/day i.v. increased the activity of LDH and CPK in the serum. In female rats, MT-141 raised slightly the level of serum GOT, A1-P, LDH and CPK even at the doses more than 400 mg/kg/day i.v., reduced the liver weight at the dose of 800 mg/kg/day i.v. and distended the cecum at the all doses. These results suggest that MT-141 at the dosage level of 800 mg/kg/day i.v. induces nonspecific slight toxicity in male and female rats.(ABSTRACT TRUNCATED AT 400 WORDS)