Pharmacokinetic and clinical studies on ceftizoxime in the perinatal period

Pharmacokinetic and clinical studies were carried out on the use of ceftizoxime (CZX) in the perinatal period. The results obtained are summarized below. 1. Mean maternal serum concentrations of CZX reached 57.3 micrograms/ml at about 15 minutes after a single intravenous injection of CZX 1 g and then gradually decreased to 13.1 micrograms/ml in 1 hour and 55 minutes, 3.59 micrograms/ml in 4 hours and 20 minutes and 0.11 microgram/ml in 17 hours and 51 minutes. CZX in umbilical cord serum was at detectable concentrations soon after administration and peaked to 23.5 micrograms/ml in 32 minutes. Although the concentrations in umbilical cord serum gradually decreased thereafter, they were higher than those in maternal serum at 3 hours and more after an injection and was 0.41 microgram/ml at 17 hours and 51 minutes. The CZX in amniotic fluid became detectable a little later than CZX in umbilical cord serum. The concentration of CZX in amniotic fluid was below 1.00 microgram/ml at 30 minutes after administration. Concentrations then gradually increased to 21.3 micrograms/ml in 1 hour and 55 minutes and, even in 17 hours and 51 minutes, they were as high as 9.44 micrograms/ml. 2. In the clinical evaluation, CZX was given to a total of 7 cases, i.e., 1 of amnionitis, 2 of puerperal endometritis, 1 of puerperal fever, and 3 of pyelonephritis. The treatment showed satisfactory results, i.e. excellent result was obtained in 1 case, good in 5 and poor in 1 with an clinical efficacy rate of 85.7%. Microbiological examinations resulted in the isolation of 5 bacterial strains of 4 species and 1 fungal strain from 5 cases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic and clinical studies on aztreonam in the perinatal period in obstetrics and gynecology

Pharmacokinetic and clinical studies on aztreonam (AZT) in the perinatal period in obstetrics and gynecology were performed with the following results. 1. Concentrations of AZT in maternal serum, umbilical cord serum, amniotic fluid and neonatal serum were determined after 1 hour intravenous drip infusion of 1 g. The maternal serum concentration was 32.2 micrograms/ml at 26 minutes after administration, gradually decreasing thereafter to 13.2 micrograms/ml at 2 hours 33 minutes, 4.9 micrograms/ml at 3 hours 21 minutes and 2.9 micrograms/ml at 5 hours 3 minutes. Umbilical cord serum concentration was 17.0 micrograms/ml at 36 minutes after drip infusion and still remained at 4.0-16.1 micrograms/ml at 5 hours after administration. Amniotic fluid concentration was 9.9 micrograms/ml at 3 hours 21 minutes after drip infusion and showed 3.3 micrograms/ml at 16 hours 26 minutes after administration. Most of the maximum serum concentrations of newborns between 3 to 24 hours after delivery were not detectable, with only one case with 2.2 micrograms/ml at 9 hours after delivery. 2. AZT 1 or 2 g x 2/day was given by intravenous drip infusion to 12 cases of perinatal infections in obstetrics and gynecology for 5 to 8 days. Clinical efficacies were evaluated as excellent in 8 cases, effective in 2 and not effective in 2 with 83.3% efficacy rate. With respect to side effects, minor degree of urticaria was observed in 1 case. Another case showed a transient elevations of GOT, GPT and Al-P in laboratory tests.     

Transplacental transfer and clinical application of aztreonam

Preclinical and clinical studies on aztreonam (AZT) in the perinatal period were carried out and the results are summarized below. 1. Concentrations of AZT in maternal serum, umbilical cord serum and amniotic fluid were measured after intravenous injection of AZT 1 g and 2 g, and intravenous drip infusion of AZT 1 g. As results, the transfer of AZT into umbilical cord serum started to increase in 1 to 2 hours, and the transfer of AZT into amniotic fluid started to increase after an elapse of 2 hours. Upon the intravenous injection of 2 g, AZT concentration in amniotic fluid was as high as 27.1 micrograms/ml even at 10 hours 30 minutes after the injection, and it was still 6.9 micrograms/ml at 20 hours or more after the injection. 2. AZT 2 g/day (b.i.d.) was administered by intravenous drip infusion to 1 perinatal infection case with pyelonephritis. It was clinically effective and neither side effect nor abnormal laboratory test value was observed.     

Pharmacokinetic study of aztreonam transfer from mother to fetus

Aztreonam (AZT) was administered to 73 cases and its usefulness and safety were evaluated upon review of the transfer of the drug into maternal blood, umbilical cord blood and amniotic fluid. The result obtained are summarized as follows. 1. AZT was intravenously administered by single injection to obtain actual data. Based on the data, theoretical changes of drug concentrations in serum in mother were reviewed according to the lapse of time. Drug concentration in maternal blood showed its peak immediately after administration and gradually decreased thereafter. Umbilical cord blood concentration showed a lower peak, which was reached with a slight delay to the Tmax for maternal blood concentration, then decreased. The decrease, however, was more moderate than the decrease in maternal blood concentration and, according to the theoretical values, umbilical cord blood concentration was higher than maternal blood concentration at 2.23 or 2.24 hours after administration. AZT concentrations in amniotic fluid slowly increased after administration and were higher than umbilical cord blood concentrations at 1.68, 1.73 hours after administration, higher than maternal blood concentrations at 1.82, 1.85 hours after administration, and they reached their peak somewhat later. Subsequently, high concentrations of AZT in amniotic fluid were maintained for a long time. The result suggests that AZT is useful for prophylaxis and treatment of amniotic fluid infections. 2. Theoretical values were analyzed by applying two-compartment model and three-compartment model to the actually-measured values, and each parameter was compared. T 1/2 of AZT concentrations in maternal blood and in umbilical cord were 1.29 hours, 1.29 hours, 2.14 hours, 2.00 hours; Cmax 187.09 micrograms/ml, 184.15 micrograms/ml, 30.63 micrograms/ml, 30.66 micrograms/ml and AUC 153.25 micrograms.hr/ml, 153.40 micrograms.hr/ml, 123.19 micrograms.hr/ml, 123.09 micrograms.hr/ml respectively showing approximate values. Cmax values of AZT in amniotic fluid were 47.08 micrograms/ml, 47.74 micrograms/ml; AUC 948.03 micrograms.hr/ml, 1,028.70 micrograms.hr/ml also showing approximate values. However, volume of distribution of umbilical cord blood and amniotic fluid showed a difference according to compartment model. 3. It was considered from the above results that application of only two-compartment open model would make analysis possible when only T 1/2, Cmax and AUC values must be measured for mother-to-fetal transfer of a drug. 4. No subjective and objective side effects nor abnormal laboratory values were observed in any of these cases (both mothers and fetuses).     

Pharmacokinetic and clinical studies on flomoxef in the perinatal period in obstetrics and gynecology

Pharmacokinetic and clinical studies on flomoxef (FMOX) in the perinatal period in obstetrics and gynecology were performed and the results obtained are summarized as follows: 1. Concentrations of FMOX in maternal serum, umbilical cord serum and amniotic fluid were determined after intravenous injection of 1 g. The maternal serum concentration was 41.9 micrograms/ml at 16 minutes after administration, and gradually decreased thereafter to 1.36 micrograms/ml at 5 hours 19 minutes. The concentration of FMOX in umbilical cord serum was 17.5 micrograms/ml at 16 minutes after administration, then gradually decreased thereafter, was slightly higher than that in maternal serum after approx. 3 hours and was 2.88 micrograms/ml at 5 hours 19 minutes. The amniotic fluid concentration was 0.31 micrograms/ml at 16 minutes after administration, increased to 7.85-15.8 micrograms/ml at approx. 3 hours, and gradually decreased while maintaining relatively high levels. 2. One or two grams of FMOX were given by intravenous drip infusion twice daily to 17 patients with perinatal infections for 5 to 7 days. Clinical efficacies were evaluated as excellent in 7 cases and good in 10, suggesting that FMOX was effective in all cases. No subjective side effects were observed in any of the 17 patients. As to abnormal laboratory findings, a minor degree of elevation of GPT was observed in 1 patient and that of GOT.GPT in 1. No other abnormal changes in laboratory examinations were observed. Considering the above results, we conclude that FMOX is a useful antibiotic in perinatal infections.     

Experimental and clinical studies on latamoxef during the perinatal period

Fundamental and clinical studies on the perinatal use of latamoxef (LMOX) were performed, with the following results. Concentration of LMOX was examined in maternal serum, umbilical cord serum and amniotic fluid after intravenous administration of 2 g dose. Data were analyzed by the simulation curves using the two-compartment model. The peak level of LMOX in maternal serum was 218.4 micrograms/ml and half-life of the beta-phase was 1.9 hours. The peak levels of LMOX in umbilical cord serum and amniotic fluid were 37.4 micrograms/ml (1.4 hours) and 27.5 micrograms/ml (8.9 hours) after administration. The concentration of LMOX in amniotic fluid decreased in amount after the peak, but it still remained 21.9 micrograms/ml (16 hours) after administration. Above these results, it was concluded that the transfer of LMOX to umbilical cord serum and to amniotic fluid was sufficient. In clinical use, LMOX was administered to 30 pregnant patients with premature rupture of membrane. It showed excellent efficacy in preventing perinatal infection. Seven patients with perinatal infections were treated with LMOX and all of them had excellent efficacy. No side effects were observed in any of the cases studied.     

Fundamental and clinical studies on ceftazidime in the perinatal period

Fundamental and clinical studies were carried out on ceftazidime (CAZ) in the perinatal period, and the results obtained were summarized below. Following bolus intravenous injection of CAZ 2 g, maternal serum concentrations of CAZ were as high as 145.3 +/- 17.2 micrograms/ml (mean +/- S.D.) at about 10 minutes, and then gradually decreased to 46.7 micrograms/ml at 2 hours, 5.31 micrograms/ml at 5 hours and 4 minutes, and 1.54 micrograms/ml at 11 hours and 10 minutes. The CAZ was detected in umbilical cord serum immediately after the administration, and concentrations were 31.0 +/- 1.54 micrograms/ml at about 10 minutes. Although the concentrations gradually decreased thereafter, they were higher than those in maternal serum at 3 hours and later and was 3.00 micrograms/ml at 11 hours and 10 minutes. The CAZ was detected in amniotic fluid a little later than in umbilical cord serum, and concentrations of CAZ in amniotic fluid were as low as 1.50 +/- 0.67 micrograms/ml at about 10 minutes after the administration. Concentrations then gradually increased to 12.8 micrograms/ml at 2 hours and 26.5 micrograms/ml at 5 hours and 4 minutes, and even at 11 hours and 10 minutes, they were as high as 14.2 micrograms/ml. The above results demonstrated that the transfer of CAZ through placental barrier was very rapid and satisfactory. Also, CAZ showed good transfer into amniotic fluid, as well as sufficient retention, and was considered to be an effective antibiotic for prophylaxis of both fetal infections and amniotic fluid infections.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fundamental and clinical study on cefminox in the obstetrical and gynecological field

In order to assess clinical utility of cefminox (CMNX, MT-141), its transference into internal genital organ tissues and pelvic dead space was determined. In addition, transference of CMNX from maternal blood into fetal umbilical cord blood as well as into amniotic fluid was evaluated. In the clinical study, CMNX was administered in 4 cases. The following results were obtained. Transference into internal genital organ tissues; The concentration ratio of each tissue against serum concentration ranged from 25.3 to 42.7%, showing favourable transference as compared to other cephems. Transference into pelvic dead space; At 6 hours after intravenous injection of 1 g CMNX, its concentration in the pelvic dead space reached its peak of 38.8 micrograms/ml of the serum concentration, followed by gradual decrease. Transference into umbilical cord blood and amniotic fluid; Following intravenous injection of 1 g CMNX, its concentration in umbilical cord blood became almost similar to that of maternal blood at about 3 hours later, being 20 micrograms/ml. After that, it tended to decrease in accordance with the concentration in maternal blood. It appears that the drug persists for a more prolonged period in amniotic fluid. Clinical results: Clinically, CMNX was used in the treatment of 4 cases including 2 cases of lymphocystitis, 1 case of intrapelvic cellulitis and 1 case of postoperative wound abscess, and the results obtained were rated as excellent in 1 case, good in 2 cases and poor in 1 case with an efficacy rate of 75%. None of the cases treated experienced adverse reactions nor any laboratory abnormalities were observed.     

Study of imipenem/cilastatin sodium in the perinatal period

The placental passage and therapeutic efficacy of imipenem/cilastatin sodium (IPM/CS) were studied in the perinatal period. The results obtained are summarized as follows: 1. The mean biological half-life of IPM in maternal serum was 30 minutes. 2. The umbilical cord serum concentration of IPM was about 70% of that in maternal serum after 30 minutes. 3. A significant level of IPM was found in the amniotic fluid. The amniotic fluid concentration of IPM was over 1 micrograms/ml at 45 minutes after administration and equal to that in maternal serum at about 90 minutes. 4. In 4 patients, the time course of placental transfer of IPM was investigated. The level of IPM in amniotic fluid was higher than that in maternal serum at 90 minutes after administration and gradually increased afterward. 5. The level of IPM was 3.96 micrograms/g in the fetal membranes at 17 minutes after administration. 6. In the treatment of 12 patients with perinatal infections, the preparation showed excellent efficacies in 3 patients and good efficacies in 7 patients. 7. An adverse effect (vomiting) was observed in only one patient. In conclusion, this drug showed satisfactory placental transfer as well as sufficient safety and excellent efficacy in the treatment of perinatal infections.     

Pharmacokinetic and clinical studies on flomoxef in perinatal period

Pharmacokinetic and clinical studies on flomoxef (FMOX) in the perinatal period were carried out. The results are summarized as follows. 1. The concentration of FMOX in umbilical cord serum was about 10 micrograms/ml in about 30 minutes after 1 g one shot intravenous injection. Amniotic fluid concentration was 7 micrograms/ml in 41 minutes after administration. By 1 hour intravenous drip infusion, FMOX concentration in umbilical cord serum was about 5 micrograms/ml in 2-3 hours after administration. Amniotic fluid concentration of about 20 micrograms/ml was found in 1 case. 2. FMOX 1-2 g x 2-3/day was given by intravenous drip infusion to 7 cases of perinatal infection for 4-26 days. Clinical efficacies were evaluated a good for all cases. Neither side effect nor abnormal laboratory test value was observed. Consequently, FMOX was considered to be highly effective and safe for its clinical use in perinatal period infections.     

Pharmacokinetic and clinical studies of ceftizoxime in the perinatal period. The Chemotherapy Research Group for Mothers and Children

Pharmacokinetic and clinical studies of ceftizoxime (CZX) in the perinatal period gave the following results: 1. Peak concentrations of CZX in the maternal serum, umbilical cord serum and amniotic fluid in mothers after one intravenous injection of 1 g were, respectively, 70.2 micrograms/ml at 0 hour; 15.7 micrograms/ml at 0.5 hour; and 10-30 micrograms/ml at 3-6 hours. Concentrations of CZX in the neonatal serum were 0.87-13.5 micrograms/ml during 6-14 hours after parturition. The mean concentration of CZX in the milk in 1-8 hours after injection was less than 0.32-0.52 microgram/ml. 2. Good or excellent clinical efficacy was obtained in 28 of the 29 patients with perinatal infections, with an efficacy rate of 96.6%. Prophylactic effectiveness was obtained in 14 of the 15 patients, with an efficacy rate of 93.3%. 3. No side effects were observed in 44 cases. GOT and GPT values increased slightly in 1 patient. No abnormal values in total serum bilirubin or other parameters were found in any neonates after parturition. 4. The above results suggest that CZX is safe and effective for the treatment and prophylaxis of infection in the perinatal period.     

Pharmacokinetic and clinical studies of flomoxef in perinatal period

Pharmacokinetic and clinical studies of flomoxef (FMOX) in perinatal period were carried out and the following results were obtained. 1. Concentrations of FMOX in maternal serum, umbilical cord serum and amniotic fluid were determined subsequently to intravenous injection (4 cases) and intravenous drip infusion method (20 cases) of 1 g FMOX. Maternal serum levels were similar to those of healthy adults, and peak levels of umbilical cord sera and amniotic fluids were 12.0 micrograms/ml and 12.05 micrograms/ml, respectively, using intravenous drip infusion. The levels in amniotic fluids were higher than those in umbilical cord sera at 2 hours after treatment in either administration method. Parameters T 1/2 (beta) and AUC were 1.05 hours and 74.1 micrograms.hr/ml, respectively. 2. In the treatment of 4 cases with perinatal infection and in prophylaxis cases, clinical efficacies of FMOX were all good with 1 g twice daily treatment using intravenous drip infusion. No side effects nor abnormal laboratory test values due to the drug were observed in any cases. These results indicate that single intravenous drip infusion of FMOX 1-2 g twice daily is effective for the treatment and the prophylaxis of perinatal infections.     

Placental transfer and pharmacokinetic parameters of flomoxef during the perinatal period

Flomoxef (FMOX), a new oxacephem with low MIC values against not only Gram-negative bacilli (GNB) but also against Gram-positive cocci (GPC), was evaluated for its transfer into fetus, amniotic fluid, maternal milk, spinal fluid and urine during the perinatal period following a single intravenous drip infusion at a dose of 1 g for 30 minutes. The results obtained are summarized below. 1. High concentrations of FMOX were demonstrated in maternal serum, umbilical arterial serum and amniotic fluid with Cmax values of 48.0, 10.99 and 10.20 micrograms/ml, respectively. 2. Maternal urinary excretion rate was 65.4% in the first 6 hours after administration. 3. In contrast, maternal milk and spinal fluid levels were lower than 3 and 0.20 micrograms/ml, respectively. These results showed a good placental transfer of FMOX, which is very useful for various perinatal infections. No adverse effects were observed in mothers and neonates during the course of this study.     

Study on cefotiam in the perinatal period

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. The concentration of CTM in maternal serum was 38 micrograms/ml at 0.5 hour after an intravenous administration of 1 g. 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 neonates. 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 1-2 g per day.     

Pharmacokinetic and clinical studies of ceftizoxime in obstetrical and gynecological field (2)

Pharmacokinetic and clinical evaluations of ceftizoxime (CZX) in 3 obstetrical and gynecological clinics have substantiated the therapeutic usefulness of this drug in the relevant specialty. The results are summarized below. 1. The peak serum CZX concentration after drip infusion of 2 g given over 60 minutes was 115.3 micrograms/ml. The peak CZX concentration in the pelvic dead space exudate was 34.10 micrograms/ml which was attained 2.02 hours after beginning infusion. Half-lives of CZX in the serum and in the pelvic dead space exudate were 1.64 hours and 3.65 hours, respectively. 2. The passage of infused CZX to the umbilical cord serum was satisfactorily rapid, as evidenced by figures reaching 10 micrograms/ml or higher at 1 hour and 15 minutes and still as high as 3 micrograms/ml or higher at 6 hours after administration. 3. The passage of CZX to the milk of mothers receiving this drug was low, and no untoward effect on the infant was likely. 4. CZX would effectively prevent infections due to premature ruptures of membrane.     

Pharmacokinetic and clinical studies on aztreonam in perinatal period

Pharmacokinetic and clinical studies were carried out on aztreonam (AZT), a monobactam antibiotic with a high activity against Gram-negative bacteria. The results obtained are summarized as follows: 1. Following 2 g bolus intravenous injection, transfers of AZT to umbilical cord serum and amniotic fluid were found to be satisfactory. AZT level in amniotic fluid was higher than 1 micrograms/ml at 40 minutes after administration and it was at 3.7 micrograms/ml in 23.5 hours. 2. In the treatment of 9 patients with perinatal infections, clinical efficacies of AZT were judged excellent in 3 cases and good in 6 cases. 3. No side effects and abnormal laboratory findings due to the drug were observed in any case. These results indicate that AZT may be a useful antibiotic for the treatment of perinatal infections.     

A novel pharmacokinetic method for analysis of placental transfer of latamoxef in humans

A novel pharmacokinetic method was developed for analysing the behaviour of a drug in tissues. The absolute transfer ratio of a drug to a tissue was defined using the pharmacokinetic parameters obtained by this method. Composite data of latamoxef (moxalactam) concentration in maternal blood, umbilical cord blood and amniotic fluid following a 2g intravenous injection to pregnant women at delivery were analysed by this method to study the drug behaviour in pregnant women, fetuses and amniotic fluid. Latamoxef kinetics in pregnant women at full term were generally similar to that in previously reported healthy subjects. The concentration of latamoxef in umbilical cord blood peaked about 2 hours after dosing then decreased in parallel with the maternal blood concentration. The amniotic fluid concentration peaked about 7 hours after administration, then decreased slowly. The absolute transfer ratios to fetus and amniotic fluid were calculated to be about 2.5 and 0.37% respectively.     

Clinical evaluation of latamoxef in the perinatal period

Latamoxef (LMOX), a new oxacephem antibiotic with high activity against Gram-negative bacteria has been investigated for use in No. of 58 mothers in perinatal period, and obtained following results. Concentration of LMOX in maternal serum was 43.4 micrograms/ml at the 1 hour after intravenous administration of 1 g. In umbilical cord serum and amniotic fluid, LMOX showed good translation after intravenous administration of 1 g into the mother, but no adverse effect appeared in the neonate. LMOX is highly useful antibiotic in perinatal infections, and the safe dose of LMOX to the mother in perinatal period is 1--2 g per day considerably.     

Pharmacokinetic and clinical studies of imipenem/cilastatin sodium in the perinatal period

Pharmacokinetic and clinical studies on imipenem/cilastatin sodium (IPM/CS), a parenteral carbapenem antibiotic combination drug, were carried out in patients in the perinatal period. The obtained results are summarized as follows. 1. Concentrations of IPM and CS in umbilical cord blood, amniotic fluid and maternal blood were determined in 13 patients after 500 mg/500 mg of IPM/CS was administered by a drip infusion over a period of 30 minutes. Peak levels of both drugs in umbilical cord blood were about 30% of those in maternal blood. Although the levels gradually declined thereafter, the decline was slower in umbilical cord blood than in maternal blood and the levels became higher in the former than in the latter after 2 hours or more. The transfer of both drugs into amniotic fluid was slower than into umbilical cord blood. Peak levels were observed 5-6 hours after administration, averaging about 30% of that in the maternal blood for IPM and 45% for CS. 2. A 500 mg/500 mg dose of IPM/CS was administered to 10 patients with postpartum infections by a drip infusion over a period of 30 minutes or more twice daily in the morning and in the evening. Clinical responses were excellent in 6 patients and good in 4, with an efficacy rate of 100%. Bacteriologically, all of the 19 strains identified previous to the treatment were eradicated except for 1 strain. However, one new strain of Enterococcus sp. appeared in 1 patient. No side effects or abnormal laboratory findings were observed. These results suggest that IPM/CS will be useful for the treatment of various infections in the perinatal period.     

Ceftazidime: placental transfer and pharmacokinetic parameters in the third trimester pregnancy

Ceftazidime (CAZ), a newly developed cephalosporin with very high stability to beta-lactamase, was evaluated for its transfer into fetus and amniotic fluid in the third trimester pregnancy, following a single bolus intravenous injection at a dose of 1 g. In subjects with various conditions (background factors) standardized, concentrations of CAZ in maternal venous blood, venous and arterial blood in umbilical cord, and amniotic fluid were determined. High concentration of CAZ (10 micrograms/ml or higher) was found to be maintained in fetal blood and amniotic fluid for ca. 4 hours and ca. 8 hours, respectively, after intravenous injection, showing good placental transfer of CAZ. In view of MICs of CAZ, satisfactory clinical efficacy is expected in perinatal infections.