A subacute toxicity study on T-2588 was carried out in juvenile rats (6 days-old 48 males and 48 females) by oral administrations at dose levels of 250, 500 and 1,000mg/kg/day for 1 month.
The results obtained were summarized below.
1. During the study, there were no clinical signs considered to be related to the treatment. There were no T-2588-related abnormalities in urinalysis, hematological examinations, biochemical examinations and ophthalmological examinations.
2. Slight increases in relative liver and kidney weights were observed in the 1,000mg/kg-treated group and slight increases in relative kidney weight were detected in the 500mg/kg-treated female group. Histologically, however, T-2588-related abnormality was not observed.
3. The maximum safety dose of T-2588 was estimated to be 250mg/kg/day.
4. In addition to the above examinations, male reproductive performance was examined in the group administered with a dose level of 1,000mg/kg/day. No adverse effects were observed in male fertility and F₁ generation.

View full abstract

A study on disulfiram-like reaction of T-2588 was carried out using Sprague-Dawley male rats. A 500mg/kg/day dose of T-2588 was given orally to 14 male rats once daily for 7 days. Disulfiram (200mg/kg/ day×3 days, p. o.), cephalexin (CEX)(500mg/kg/day×7 days, p. o.) and cefmetazole (CMZ)(500mg/kg/day×7 days, i. v.) were used as the positive control and 2 comparative controls, respectively.
The results obtained were summarized below.
1. Each parameter (aldehyde dehydrogenase activity and the blood aldehyde level) in the disulfiram-like reaction was not affected by the T-2588 administration.
2. A marked inhibition of aldehyde dehydrogenase activity (low-Km ALDH, Enzyme I) and a significant increase of the blood aldehyde level were observed in the rats receiving disulfiram.
3. No drug-related disulfiram-like reaction was induced in the male rats receiving CEX, while alterations similar to the disulfiram action were recognized in rats receiving CMZ.

View full abstract

The present study was carried out to examine the effect of single or consecutive administration of T-2588 on liver of male rat injured by the administration of D-galactosamine·HCl.
The T-2588 was orally given to hepatic-injured rats at doses of 125mg/kg and 1,000mg/kg singly or for consecutive 5 days. A 10ml/kg dose of the vehicle was orally given to control rats.
The results obtained were summarized below.
Single administration of T-2588.
1. Twenty-four hours after a single administration of T-2588, the liver taken from control rats apparently indicated galactosamine-induced hepatitis.
No drug-related alterations were observed in hepatic functional test, liver weight and histological examinations at either dose of T-2588.
Galactosamine-induced hepatitis was not affected by a single administration of T-2588.
Consecutive administration of T-2588.
2. Twenty-four hours after a 5-consecutive-day administration of T-2588, galactosamine-induced hepatitis in control rats was restored to the normal state.
The cure of galactosamine-induced hepatitis was not affected by a 5-consecutive-day administration of T-2588.
3. The hepatic aldehyde dehydrogenase activity in hepatic-injured rats was not affected by a 5-consecutive-day administration of T-2588.

View full abstract

Ototoxic effects of T-2588 on the spiral and the vestibular organs of the inner ear were investigated in 50 rats of Sprague-Dawley strain. Fifty female rats were divided into 5 groups consisting of 2 T-2588-test groups at dose levels of 500 and 1,000mg/kg/day, respectively, and 2 kanamycin (KM) groups at dose levels of 200 and 400mg/kg/day, respectively, and the control group. The administration of T-2588 was done orally through gastric tube daily for 5 weeks. The ototoxic effect was evaluated by the differential frequency pinna reflex test with frequency ranging from 200Hz to 20,000Hz before, during and after the administration of a test substance, then investigated histopathologically on serial celloidin sections of the bilateral temporal bones.
The results were summarized below.
1. In any rat receiving either level of T-2588, pinna reflex impairment was not detected at any frequencies. And there was no noticeable change either in the cochlea or in the vestibulum.
2. In 10 rats which received KM at a dose level of 200mg/kg/day, there was no impairment in pinna reflex, but, histopathologically, the loss of outer hair cells was observed, though inner hair cells were present. In the vestibular organ, a scattered loss of hair cells was observed in 8 rats.
3. One of 9 rats which received KM at a dose level of 400mg/kg/day showed the loss of pinna reflex in the frequency range tested. This rat showed histopathologically extensive loss of both outer and inner hair cells. In other rats showing no impaired pinna reflex, the loss of outer hair cells was rather extensive, but inner hair cell loss was unilaterally confined in the basal end of the first turn. In the vestibular organs of all rats, a scattered loss of hair cells was observed.

View full abstract

Fosfomycin (FOM) otic solution was administered to 587 patients with suppurative otitis media infections including 190 patients in the dose-establishment test, 126 patients in the open clinical trial and 271 patients in the double blind test. Various bacteria were detected in the 549 cases in which bacteriological investigation was possible. Main bacteria detected from the above cases were S. aureus (261 strains, 47.5%), P. aeruginosa (93 strains, 16.9%), coagulase negative Staphylococci (CNS)(89 strains, 16. 2%), Providencia spp.(35 strains, 6.4%) and Proteus spp.(28 strains, 5.1%). Twenty-seven strains of anaerobic bacteria (4.9%) were also detected.
The MIC of FOM, and the reference drugs, chloramphenicol (CP), fradiomycin (FRM), cefmenoxime (CMX) and cephalexin (CEX), were determined up to a concentration of 800μg/ml with inoculum sizes of 10⁶ and 10⁸CFU/ml.
1. About 30% of S. aureus was multi-drug resistant, including methicillin and cephems, but FOM showed excellent antibacterial activity against it. The FOM had superior antibacterial activity against P. aeruginosa to CP, FRM and CMX, and was also active against other bacteria.
2. The antibacterial activity of FOM was inferior to other drugs against CNS, Enterobacter spp., P. putida and P. cepacia. The detection rate of these bacteria, however, was low and since their role as causative organisms is not well defined, the inferior activity of FOM has no effect on the bacteriological evaluation of FOM.
3. Since the concentration in the tympanic cavity about 1 hour after the administration of 3% FOM solution was estimated to be 2,000 to 3,000μg/ml, it could be presumed that bacteria inhibited by 800μg/ml of FOM at an inoculum size of 10⁸CFU/ml would be eradicable.
4. The low ototoxicity of FOM is likely due to its characteristic as an inhibitor of bacterial cell wall synthesis.
From these results, 3% FOM otic solution may be considered as a remarkably useful topical preparation for the treatment of suppurative otitis media.

View full abstract

Cefsulodin (CFS), a new antipseudomonal cephalosporin, shows a potent antibacterial activity against Pseudomonas aeruginosa and some Gram-positive bacteria, whereas it shows low activity against many Gram-negative rods. Against clinical isolates of P. aeruginosa, CFS was about 10 times more active than sulbenicillin and carbenicillin, and had a similar activity to gentamicin and dibekacin. The CFS was administered by an intravenous bolus injection at a dose of 1g to each of 14 patients operated for acute peritonitis with drainage or radical mastectomy with drainage to treat breast cancer. These cases included 3 of localized peritonitis due to perforative appendicitis, 3 of diffuse peritonitis due to perforative duodenal ulcer, 2 of panperitonitis due to intestinal obstruction and perforative sigmoid colon cancer, 4 of subacute cholangitis, localized peritonitis T-tube choledochal drainage due to choledocholithiasis, and 2 of breast cancer. Materials from drain exudate were taken at intervals with sterilized paper discs and CFS concentrations were determined by the paper disc bioassay method with P. aeruginosa NCTC 10490 as the test organism.
Serum concentrations of CFS just after injection reached 135.4±66.1μg/ml, and they were 2.7±1.5μg/ml at 6 hours after injection. Concentrations in purulent exudates of patients with acute peritonitis increased quickly after intravenous bolus injections, and reached maximum levels relatively early after injection in cases 2 to 3 days after operation. In cases 10 to 13 days after operation, CFS levels were comparatively low and reached to peak levels at 4 to 5 hours after injection. Levels of CFS in purulent exudate tended to increase in proportion to the severity of symptoms, as did CFS levels in appendix wall.
Pseudomonas spp. were not isolated in this study, but MICs of CFS were mostly around 1.56 to 3.13μg/ml when clinically isolated Pseudomonas spp. were present at 10⁶ cells/ml. Levels of CFS in infected exudate were higher than the above MIC values against Pseudomonas spp. Therefore, CFS were a useful drug for the chemotherapy against pseudomonal infections.

View full abstract

Cases of premature rupture of the membranes (PROM) were subjected to bacteriological examination of lower genital organs and their clinical courses were analyzed.
The results obtained were summarized below.
1. From lower genital organs of cases examined at the 24th-36th week of pregnancy, Gram-positive or Gram-negative aerobes were detected at a high rate in both the group without PROM (-) and the group with PROM (+). From patients in the group with PROM + chorioamnionitis (CAM) anaerobes as well as aerobes were detected at especially high rates.
2. Many patients with PROM (+CAM) were administered with penicillin-antibiotics orally or parent-erally. Clinical analysis showed effectiveness of these antibiotics which were especially effective when administered intravenously. The oral administration produced inferior results to the injection judging from clinical results.
3. Patients with PROM and infection during the puerperal period were examined. They were found to include 15 cases of intrauterine infection and 6 cases of puerperal fever. Patients who started showing infectious symptoms at a later time than 8 hours after the onset of PROM tended to have a higher frequencies of infections. The rate of occurrence of cases requireing cesarean section was higher in this group than in the group where infectious symptoms started within 8 hours after PROM.

View full abstract

One gram of cefmenoxime (CMX) was administered to each of 10 patients by a one shot intravenous injection at the beginning of surgery. At 30, 60, 90, 120 minutes after the administration, concentrations of CMX in venous blood, bone marrow blood and bone tissue were assayed by the agar-well method.
CMX was smoothly transmigrated after the injection from venous blood to bone marrow blood and bone tissue, and effective concentrations higher than MIC₈₀ values were maintained for several hours.
CMX, therefore, appears to be a useful drug for the prophylaxis and the treatment of postoperative infections.

View full abstract

The penetration of cefmenoxime (CMX) into bile and gallbladder tissues was studied. A dose of 2g CMX was given intravenously to each of patients with gallstones.
Concentrations of CMX in the gallbladder tissues were 120.6±39.8μg/g in normal tissues about 2 hours after the administration and 128.3±52.3μg/g in inflamed tissues.
The penetration of CMX into gallbladder tissue tended to decrease in proportion to the severity of inflammation, but the difference between the 2 groups, normal and inflamed tissues, were not satistically significant.
The penetration of CMX into gallbladder tissue was presumed to increase in proportion to increase in the serum concentration of CMX.
The result indicated that the achievement of high concentrations of CMX in the serum is important in the treatment of bilialy tract diseases.

View full abstract

Concentrations of cefmenoxime (CMX) in peripheral venous serum, uterus and intrapelvic genital organs were determined by bioassay. The obtained results are summarized below.
1. When 1g of CMX was administed by an intravenous injection, peak concentrations in various tissues of female genital organs were as follow: 17.4 and 46.8μg/g in ovary and oviduct, respectively, and from 28.2 to 43.8μg/g in other genital organs.
2. These concentrations of CMX were maintained at higher level than minimal inhibitory concentrations against E. coli, Bacteroides and other organisms.
3. In these studies, CMX showed a satisfactory clinical efficacy and a potent antibacteriological effect in the treatment of infections in the field of obstetrics and gynecology.

View full abstract

Seven neonates and young infants were treated with cefotiam (CTM) in doses ranging from 8-25.6mg/kg every 6 to 24 hours for 1 to 14 days, and the clinical efficacy and side effects were evaluated. Among 5 infants with bacterial infections including bacteremia, perianal abscess, pneumonia, urinary tract infection and probable sepsis and meningitis, clinical responses were excellent in 1 and good in 4 patients. In the 7 patients, no side effect attributable to CTM was observed.
Serum concentrations of CTM were measured in 5 patients administered with 10 to 20mg/kg of CTM by bolus intravenous injection. Peak serum concentrations of 21.9 to 38.0μg/ml were noted in samples taken at 15 minutes after injection. Serum half-lives of the drug were 2.35 hours in 2 day-old neonate, 0.72 to 0.85 hours in 3 infants of 25 to 37 days, and 8.46 hours in an 18 day-old neonate with renal insufficiency.

View full abstract

Intravenous drip infusion (d. i.) of cefotiam (CTM) in neonates and infants produced the following pharmacokinetic and clinical results:
1. In a 2 and 3 day-old neonates group, blood concentrations at 1 and 5 hours after intravenous drip infusion of 20mg/kg of CTM were 33.0μg/ml and 12.3μg/ml, respectively. Thus high blood CTM levels were maintained in these cases.
2. In a 4 day-old neonate, blood concentrations after 1 and 6 hours were 20.5μg/ml and 5.8μg/ml, respectively. In a 8-13 day-old neonates group, blood levels after 1 and 6 hours were 12.2-18.5μg/ml and 0.7-2.4μg/ml, respectively. Compared to the corresponding values in the 2 and 3 day-old neonates, the blood CTM levels in this group were low.
3. Half-lives of CTM in the blood were 1.8-2.7 hours, 2.1 hours, 1.1-1.7 hours and 0.7 hour, in 2-3 day-old neonates, 4 day-old neonate, 8-13 day-old neonates and a 45 day-old infant, respectively. Half-lives tended to become shorter with increasing age.
4. The 6-hour urinary recoveries ranged between 20.3 and 62.3%. Transport of the drug into the spinal fluid was also observed.
5. The CTM was very effective in the treatment of 6 patients suffering from suppurative meningitis, septicemia, bronchopneumonia or UTI with ampicillin-resistant E. coli. The daily dose ranged between 41 and 175mg/kg.
6. The duration of the treatment was 5 to 18 days, with total doses of 0.72 to 16.25g. In only one case, a transient eosinophilia was noted. It was, however, normalized during the treatment. In all other cases, neither side effects nor abnormal laboratory findings were observed.

View full abstract

The effect of cefotiam (CTM) on neonates and premature infants was examined in basic and clinical studies.
Minimum inhibitory concentrations of CTM against 190 clinically isolated strains kept by this department were investigated. This drug was found to have a strong antibacterial effect against Escherichia coli, Klebsiella spp., Proteus mirabilis and Streptococcus agalactiae, Staphylococcus aureus and Staphylococcus epidermidis, although some strains were resistant.
The CTM was given to 0-3, 4-7, and ≥8 day-old premature infants and neonates by intravenous injection at the dose of 20mg/kg, and we studied changes in serum CTM levels over time. Mean serum CTM levels were 62.3μg/ml at 15 minutes and 16.4μg/ml at 6 hours after the injection, with the half-life of 3.6 hours, for the 0-3 day-old premature infants. They were 38.5μg/ml at 15 minutes and 10.1μg/ml at 6 hours, with the half-life of 2.9 hours, for the 0-3 day-old neonates. Those levels were 22.5μg/ml at 15 minutes and 2.9μg/ml at 6 hours, with the half-life of 1.9 hours, for the 4-7 day-old neonates, and 51.8μg/ml at 15 minutes and 1.0μg/ml at 6 hours, with the half-life of 1.1 hours, for the 8 day-old neonates.
The CTM was given to 0-3 and ≥8 day-old premature infants and neonates by 1-hour intravenous drip infusion at the dose of 20mg/kg, and changes in serum CTM levels after the infusion were followed. The 0-3 day-old premature infant (there was only one subject) had a peak serum CTM level of 21.0μg/ml 1 hour after the start of the infusion (that is, at the time of its completion), with the level decreased to 8.6μg/ml at 7 hours and the half-life was 5.4 hours. The mean peak serum CTM level in 0-3 day-old neonates were 36.7μg/ml at 1 hour, which decreased to a mean of 7.0μg/ml at 7 hours; the half-life was 2.3 hours. The ≥8 day-old neonate (1 subject) had 2 peaks of serum CTM levels, 28.4μg/ml at 30 minutes, deceasing to 21.7μg/ml at 1 hour, then increasing again to 23.7μg/ml at 2 hours, and decreasing to 1.9μg/ml at 7 hours, with the half-life of 1.7 hours after the completion of the infusion.
Rates of CTM excretion into the urine of these premature infants and neonates after the injection were examined. Although there were some differences in rates of CTM excretion with different day-ages, excretion rates at 6 hours after the end of the administration were about 10-20% for the 0-3 day-old group and about 40-50% for the ≥4 day-old group.
The CTM was given to 21 neonates and premature infants with bacterial infections. Clinical results were good or excellent in 20 of the 21 patients, and the efficacy rate was 95%.
The bacteriological effect of CTM was studied in patients with infection caused by one of 6 strains (2 strains of S. aureus, 2 of S. epidermidis, and 2 of E. coli). Five of the 6 strains were eradicated (the exception was S. aureus), so the efficacy rate was 83%.
Side effects of CTM were studied in 27 patients treated. Although no serious side effect was observed, diarrhea occurred in 1 patient, eosinophilia in 1, an elevated GOT level in 2 patients, elevated GOT and GPT level in 1 patient, and the protein induced by vitamin K absence or antagonist (PIVKA II) became detectable in 1 patient.

View full abstract

Cefotiam (CTM) was given to 25 mature and premature infants, ranging in age from 0 to 24 days, who have various nearly-healed bacterial infections. CTM was administered at the dose of 10mg/kg by intravenous injections or by 1-hour intravenous drip infusions, or at the dose of 20mg/kg by intravenous injections. Only a small number of subjects being examined, they were divided by their aged day into 3 groups; 0-3 days old, 4-7 days old and 8-24 days old. We compared the time courses of changes in serum and urine levels of CTM in these groups.
The clinical study was done with 8 male and 4 female infants ranging in age from 3 days to 4 months. One had septicemia, 4 had bronchopneumonia, 3 had urinary tract infection, 1 had colitis, 2 had abscess, and 1 had maxillary sinusitis.
1. Changes in serum and urinary levels of CTM
(1) Changes in serum levels after 10mg/kg intravenous injection.
Peak serum CTM levels of all 3 groups were achieved at 30 minutes after administration; the levels were between 11.7 and 23.6μg/ml; and differences were not significant. Serum levels then gradually decreased in all the groups to 0.5-7.0μg/ml at 6 hours after administration. Half-lives of serum CTM levels tended to be shorter in older infants; means were 2.7, 2.2 and 1.3 hours for the 0-3 day-old, the 4-7 day-old and the 8-24 day-old respectively.
(2) Changes in serum levels of CTM after 10mg/kg 1-hour intravenous drip infusion.
The 0-3 day-old and the 4-7 day-old had peak serum CTM levels, ranging from 16.3 to 35.8μg/ml, at the end of drip infusion. Half-lives of serum CTM levels tended to be shorter in older infants, with 3.2 hours for the 0-3 day-old and 2.0 hours for the 4-7 day-old groups.
(3) Changes in serum levels after 20mg/kg intravenous injection.
The 0-3 day-old and the 4-7 day-old had peak serum levels, ranging from 30.6 to 42.1μg/ml, at 30 minutes after administration, then serum levels of CTM in either group showed a gradual decrease to 2.5-11.4μg/ml at 6 hours after injection.
(4) Changes in urinary levels of CTM after intravenous injection and 1-hour intravenous drip infusion.
Proportions of CTM excreted in the 0-6 urine after administration of 10mg/kg CTM were 33.6-58.2% by intravenous injection and 22.3-34.0% by 1-hour intravenous drip infusion, respectively. On 1 patient given by intravenous injection of 20mg/kg, urinary excretion rate of 46.2% was observed in 8 hours after the injection.
2. Clinical results
The CTM was used in a total of 12 patients. The CTM was given by intravenous injection to 11 of the 12 patients (administration was by 30 minute intravenous drip infusion for the other patient), two or three times a day at doses of 42.1 to 133.9mg/kg/day for 3 to 13 days. Results were either good or excellent in all 12 cases; the efficacy rate was 100%. Causative bacteria were eradicated in 11 of the 12 patients (E. coli in 4 patients, S. aureus in 4, K. pneumoniae in 1, S. epidermidis in 1 and K. pneumoniae+S. aureus in 1). In the other case, bacteriological result was not clear.
The drug produced no adverse symptoms or side effects in any of the 12 patients, except an increase in GOT observed in 1 patient.

View full abstract

Pharmacokinetic and clinical studies were carried out regarding the use of cefotiam (CTM) in the treatment of infections in newborn infants.
1. Absorption and excretion
CTM was administered by bolus intravenous injection at a dose of 20mg/kg to 9 newborns ranging in age from 1 to 28 days (gestational age, 34-40 weeks; birth weight, 2,000-3,380g) and 6 infants aged 30 to 87 days (gestational age, 33-40 weeks; birth weight, 2,100-3,600g) and its serum concentration and urinary excretion were determined.
In the newborns, mean serum concentrations were 43.3μg/ml at 1/4 hour, 36.7μg/ml at 1/2 hour, 27.8μg/ml at 1 hour, 17.7μg/ml at 2 hours, 8.8μg/ml at 4 hours and 4.8μg/ml at 6 hours, and in the infants, they were 44.5μg/ml, 31.2μg/ml, 19.1μg/ml, 7.6μg/ml, 2.2μg/ml and 0.7μg/ml at the above sampling times, respectively.
Mean half-lives were 1.92 hours for the newborns and 0.96 hour for the infants, and mean urinary recoveries within 6 hours were 41.2% and 50.1% for the newborns and the infants, respectively.
Taking individual differences into account, serum peak levels (at 1/4 hour) in newborns were very similar to each other irrespective of age (days after birth), and did not appear to be greatly different from those in infants. Half-lives, however, became shorter with aging, and the half-life of the serum CTM level in infants of about 1 month old should be close to those in young children or school-age children.
From these observations, it is suggested to establish a standard regimen in which CTM is administered at a dose of 20mg/kg once or twice a day to newborns within 3 days after birth, twice or 3 times a day to those aged 4 to 7 days, and 3 or 4 times a day to those aged 8 days or older.
2. Clinical study The CTM was administered to 11 patients with acute pneumonia, 2 patients each with suspected septicemia and with bullous impetigo, 1 patient with purulent lymphadenitis, 3 patients with idiopathic respiratory distress syndrome and 1 patient with pneumothorax, and its clinical effect was investigated.
Excellent responses were observed in 12 of the 15 evaluated cases, good responses in 2, and a poor response in 1, thus an overall clinical effectiveness was 93.3%. Regarding the bacteriological response, 1 of 2 strains of S. aureus disappeared but the other persisted. One strain of E. coli was eliminated and 2 strains of K. pneumoniae reduced. Thus, the elimination rate was 40.0%.
No side effects were found clinically in any of the cases. As to abnormal laboratory values, elevations of GOT and GPT were noted in 3 cases, elevation of GOT in 2 cases, and eosinophilia in 1 case. These changes were slight and were normalized in all the cases except 2 in which a retest or a follow-up could not be conducted.
The above results suggest that CTM is useful and safe in the treatment of infections in newborns.

View full abstract

Pharmacokinetic and clinical studies on cefotiam (CTM) in mature neonates were carried out. The results were summarized as follows:
1. The serum peak level of CTM after intravenous bolus injection at a single dose of 10mg/kg was found at 15 minutes after the injection. The serum peak level was 32.9μg/ml in a 1 day-old neonate and it was 17.7μg/ml in a 4 day-old neonate. Serum levels at 6 hours after injection were 4.5μg/ml and 0.7μg/ml for the 1 day-old and the 4 day-old, respectively. Half-lives were 2.1 and 1.2 hours in the 1 and 4 day-old neonates, respectively.
Serum peak levels of CTM at 15 minutes after intravenous bolus injection at a single dose of 20mg/kg were 40.9μg/ml in a 1 day-old neonate and 36.5μg/ml in a 5 day-old neonate. Serum levels of CTM at 6 hours were 8.0μg/ml in the 1 day-old neonate and 2.3μg/ml in the 5 day-old neonate. Half-lives were 2.5 and 1.5 hours in the 1 and 5 day-old neonates, respectively. With each dosage, the younger showed extended half-lives. A dose-response relationship was observed.
2. In 2 cases of 2 day-old neonates given CTM 20mg/kg by 30-minute intravenous drip infusion, the mean peak concentration at the termination of the infusion was 25.1μg/ml. Even after 6 hours the concentration was found at 8.7μg/ml. Half-lives were 2.9 and 3.7 hours.
3. Urinary excretion rates of CTM in 1 to 5 day-old neonates were as low as about 20% in any of cases subjected to a 10mg/kg intravenous bolus injection, a 20mg/kg intravenous bolus injection or a 20mg/kg 30-minute intravenous drip infusion.
4. It was possible to evaluate the efficacy of CTM in only 1 case of pneumonia. CTM was clinically and bacteriologically effective in this case. No abnormal clinical symptoms and findings were observed in all of the 5 cases.

View full abstract

Using cefotiam (CTM) against infections in neonates and premature infants, we obtained the following results:
1. With intravenous administration of the drug to 2 cases each of pyoderma, pneumonia, and fetal infection, the drug was effective in all the cases except in 1 premature infant with pneumonia. Dose levels at individual injections were between 18.6 and 27.8mg/kg, per dose, with an exception in 1 case of pyoderma (36.4-54.5mg/kg), and 2 to 4 doses per day were given to each patient.
2. For prophylactic purposes, the drug was administered to 1 case of turbid amniotic fluid and 3 cases of massive aspiration syndrome, and no infection was observed in any case.
3. In a total of 11 cases consisting of the above mentioned 10 cases and an additional case which had been excluded from the evaluation because of the detection of P. aeruginosa, neither side effects nor abnormal laboratory values were recognized.
4. In 5 cases of 4 to 31-day old infants, CTM concentrations in blood were measured after one-time intravenous injection of the drug at a dose level of about 20mg/kg. Blood concentrations of CTM were low in 1 case with levels of 14.4 and 4.5μg/ml at 30 minutes and 2 hours after the intravenous injection, respectively, whereas they were high in another case with readings of 82 and 65μg/ml. In the remaining 3 cases, however, 30-minute and 2-hour values were between 41 to 52, and 13.5 to 22.8μg/ml, respectively. Half-lives of blood CTM levels were 0.91 to 2.94 hours, and they showed a tendency to be longer in those whose body weights at the time of birth were lower and also in the case of a 4-day old infant. The urinary recovery rate up to 6 hours after an intravenous injection was measured in 1 case to be 57.8%.
5. Adding some literature studies to the above results, we consider that CTM is a useful antibiotic agent in neonatal infections, and that usually good results can be obtained with intravenous administration 3 times daily with each dose level of 20mg/kg.

View full abstract

Single doses of cefotiam (CTM) by bolus injection of 20mg/kg of CTM were given to 17 neonates and premature babies (11 prematures) and plasma and urine CTM levels as well as urinary recovery rates of CTM were determined.
The CTM was also evaluated clinically with regard to therapeutic and protective effects, bacteriological efficacy as well as safety.
A mean daily dose of 56.6mg/kg of CTM was given intravenously in 2 to 4 divided doses for an average of 8 days to 11 neonates and prematures consisting of 1 case with pneumonia, 2 suspected septicemia, 3 urinary tract infections and 5 for prophylaxis against infections.(In the 6 babies evaluated for clinical effects, a mean dose of 59.8mg/kg/day of CTM was given for an average 9 days).
The findings of these studies are summarized below:
1. The mean peak plasma level of 2 cases of 4-7 day-old neonates was 32.3mcg/ml 5 minutes after injection. The mean AUC was 96.6mcg·hr/ml, and the mean half-life was 2.12 hours.
In 3 of the 4 neonates of 8-14 day-old group, the mean peak plasma level of 55.6mcg/ml was obtained after 5 minutes.
The mean AUC was 63.0mcg·hr/ml and the mean half-life was 0.82 hour. Compared to the 4-7 day-old group, AUC was smaller and half-life was shorter in this group.
2. In premature infants, plasma CTM levels were determined in 2, 1, 1, 5 and 2 cases of the 0-3, 4-7, 8-14, 15-21 and 22-28 day-old infants, respectively.
In the 8-14 day-old group and one of 15-21 day-old group, peak plasma levels were obtained after 15 minutes. Peak plasma levels in the remaining groups, were attained after 5 minutes. Peak plasma levels in the 5 groups were 40.7, 48.4, 33.9, 38.1 and 45.3mcg/ml, respectively.
Mean or individual AUC's obtained after excluding markedly varying values from the respective groups were 122.0, 96.2, 65.2, 72.8 and 60.4mcg·hr/ml, respectively. With the increasing age, the AUC tended to decrease.
Mean or individual half-lives were 2.31, 1.47, 1.28, 1.41 and 0.96 hours, respectively, showing a tendency to decrease with increasing age.
3. In 6 neonates, high urinary levels continued up to 6 hours after administration.
Mean 6-hour urine recoveries in the 4-7 and 8-14 day-old groups were 16.6% and 43.0%, respectively.
The value of the latter group resembled reported values in children.
4. Urinary levels of CTM in the 11 premature infants remained high up to 6 hours.
Mean or individual urine recoveries of the 0-3, 8-14, 15-21 and 22-28 day-old groups were 19.2, 89.3, 44.4 and 38.2%, respectively.
Only one premature infant of 8-14 day-old was tested and the CTM recovery rate was similar to that of adults showing very high CTM recovery.
Urinary recoveries of the 15-21 and 22-28 day-old groups were similar to those of children. The recovery rate of the 0-3 day-old premature infants was low like that of the 4-7 day-old neonates.
5. The CTM produced either good or excellent response in 5 of the 6 patients and fair response in the remaining 1 patient. In any of the 5 patients given prophilactic doses of CTM, no signs or symptoms of infection were observed after treatment.
6. Neither side effects nor abnormal laboratory findings were observed in any of the 11 babies treated.

View full abstract

Pharmacokinetics and clinical studies on cefotiam (CTM) in pediatric surgery were performed and the results obtained are summarized below.
1. In neonates without congenital heart disease (CHD), serum levels of CTM were rapidly increased following injection of CTM (20mg/kg, one shot intravenous administration) and the peak values were found at 15 minutes. Six hours later, CTM almost disappeared from the blood. In:the patient with CHD, however, CTM was retained in the serum and the urinary excretion was poor.
2. The CTM was administrated prophylactically to prevent postoperative infections in 10 patients. Eight of 10 had no episodes during postoperative period. Wound infection, however, was found in 2 patients. No clinical and laboratory side effects were caused by CTM.

View full abstract

Pharmacokinetic studies and clinical evaluations of cefotiam (CTM) were carried out in perinatal mothers and infants and following results were obtained.
The drug was promptly absorbed after intravenous injection or intravenous drip infusion in pregnant women, producing dose-related peak serum levels.
Placental transfer to the fetus was effective. After intravenous injection or intravenous drip infusion of 1-2g of CTM, drug concentration of the umbilical cord blood, amniotic fluid and fetal blood exceeded MICs of the drug against main pathogenic organisms. By administration of the dose of 1-2g twice a day, therefore, perinatal infections should be successfully prevented or treated.
Clinically, CTM was effective in the treatment of perinatal infections.
Moreover, newborn infants delivered from mothers receiving CTM treatment had drug concentrations higher than MICs of CTM against main pathogenic organisms. Blood CTM concentrations in infants, however, did not remain high very long after birth, and these infants did not exhibit any abnormalities in laboratory tests.
Penetration of CTM into mother's milk was ineffective, thus the transfer of CTM from milk to newborn infants was negligible.
These results demonstrated that CTM is a clinically useful antibiotic for the prophylaxis and the treatment of perinatal infections.

View full abstract

Patients, who had undergone cesarean sections, and those who had experienced premature rupture of membranes, received cefotiam (CTM) and the clinical efficacy and the safety for mothers and fetuses were investigated. At the same time, pharmacokinetic analysis was done to study the maternal fetal transfer. Following results were observed.
1. In cases of premature rupture of membranes, the maternal-fetal transfer ratio after intravenous administrations of CTM was 50.3% at a dosage of 1g. Maternal and fetal serum concentrations of CTM were maintained higher levels than the MIC80 (0.78μg/ml) against major pathogens excluding anaerobics of gynecologic-obstetric infections and were maintained up to 5.87 hours and 6.15 hours in mothers and fetuses, respectively.
2. The CTM was administered once every 12 hours at a dosage of 1g to 38 cases up to the 3rd or 4th day of puerperium after the rupture of membranes. Also, the CTM was administered up to times of delivery to another 20 cases, in one of which the fetus developed pneumonia. The maternal-fetal prophylactic effect was recognized in 98.3% (57/58) of cases.
3. Forty-three cesarean section cases received CTM at a dosage level of 1g by one-hour intravenous drip infusion in the following manner: after surgery to the 4th day, twice a day; from the 5th to the 7th day, once a day. Postoperative prophylactic effect against infection was achieved in all the cases.
4. In 1 case, a slight transient elevation in the maternal GOT was observed.
5. Neonatal jaundice with total bilirubin levels higher than 15.0mg/dl was observed in 19 neonates (32.8%) in the group in which premature rupture of the membranes had occurred. However, the cause/effect relationship between CTM and the total bilirubin levels is unclear.
The maternal-fetal transition of CTM was excellent, and the safety toward the fetus and neonate was high. When an antimicrobial activity and pharmacokinetics are considered, CTM will be a useful drug in the treatment of perinatal infections.

View full abstract

Pharmacokinetic and clinical studies of cefotiam (CTM) were carried out in pregnant women. The results obtained are summarized below.
1. The concentration of CTM in amniotic fluid increased gradually up to 14. 7μg/ml at 4. 5 hours after administration and gradually declined thereafter. This amniotic fluid concentration was sufficiently higher than reported MIC₉₀'s of CTM against E. coli strains.
2. Passages of CTM to embryo, fetus and fetal appendages were minimal.
3. The passage of CTM to milk was minimal.
4. The CTM was used in the treatment of 6 pregnant patients with pyelonephritis and unknown fever and 1 with puerperal pyelonephritis. Clinical responses were positive in 85.7% (6/7).
5. The CTM was used 7 patients with rupture of the membrane and 2 patients with operation for the purpose of prophylaxis and it was effective in 77.8% (7/9).
6. Neither noteworthy adverse reactions nor abnormal laboratory data in our patients or neonates were observed throughout the studies.

View full abstract

Pharmacokinetic and clinical studies on cefotiam (CTM) in the perinatal period were performed and results obtained are summarized below.
1. Concentrations of CTM in maternal serum, umbilical cord serum and amniotic fluid were examined after a bolus intravenous administration at a dose of 1g.
Data were analyzed using simulation curves drawn by the two-or three-compartment open model.
The peak level of CTM in maternal serum was 86.6μg/ml and the half-life of the β-phase was 0.91 hour.
Peak levels of CTM in umbilical cord serum and amniotic fluid were 20.8μg/ml at 0.1 hour and 9.2μg/ml at 3.2 hours after the administration, respectively.
The concentration of CTM in amniotic fluid decreased after reaching the peak, but it was still as high as 1.6μg/ml even at 12.0 hours after the administration.
These results clearly demonstrated that the transfer of CTM to umbilical cord serum and to amniotic fluid was efficient in protection of perinatal infections.
2. In a clinical trial, CTM was given to 11 patients with perinatal infections. Clinical efficacies were evaluated as excellent in 2 patients, good in 8 patients and poor in 1 patient.
No adverse effects were observed in any of the patients studied.
In conclusion, CTM was useful and safe antibiotic for the treatment of infections in the perinatal period.

View full abstract

Cefotiam (CTM), a new cephem antibiotic with high activity against Gram-positive and Gram-negative bacteria, has been investigated for use in 60 mothers in perinatal period, and following results were obtained.
1. The concentration of CTM in maternal serum was 38μg/ml at 0.5 hour after an intravenous administration of 1g. A good transport of CTM into umbilical cord serum and amniotic fluid was observed after the intravenous administration into the mother. No adverse effect appeared in the neonatus.
2. The CTM is highly useful antibiotic in perinatal infections, and the safe dose of CTM to the mother in perinatal period is considered to be 1-2g per day.

View full abstract