Influence of cefroxadine (CXD) dry syrup on intestinal bacterial flora was studied in mice infected with 4 species of bacteria, namely,Escherichia coli, Enterococcus faecalis, Bacteroides fragilis and Bifidobacterium breve, and in pediatric patients having infections in the respiratory tract and cutaneous/soft tissues. The results were summarized as follows:
1. CXD dry syrup was administered for 5 consecutive days to mice infected with the 4 species. No considerable changes were observed in levels of bacteria in the feces and in different parts of digestive tracts.
2. Eleven pediatric patients were orally administered with 30-54 mg/kg of CXD dry syrup a day for 7-15 consecutive days. Symptom of diarrhea was noted in 2 patients.
3. Dominant species of the intestinal flora such as E. colt, Brfidobacterium, and Bacteroides sometimes decreased in patients treated with CXD dry syrup. In general, however, decreases in numbers of these bacteria were insignificant.
4. Changes of intestinal flora in patients treated with CXD dry syrup were apparently smaller than those treated with ampicillin and were similar to those treated with cephalexin or amoxicillin.

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We studied the concentration of ampicillin (ABPC) into middle ear effusions after administration of bacampicillin (BAPC).
Nine patients with acute purulent otitis media were given orally single doses of the drug at a level of 10 mg/kg, and concentrations of ABPC which is the active antibiotic metabolite of BAPC were determined in middle ear effusions periodically after the administration. Bacteria present in effusions were identified, and their ability to produce β-lactamase was also determined.
ABPC concentrations in middle ear effusions were inversely related to the ability of bacteria detected from the intratympanic cavity to produce β-lactamase. ABPC concentrations in middle ear effusions from which only β-lactamase negative organisms were detected were higher by 5.2-and 2.3-fold at 60 and 120 minutes after the administration of BAPC, respectively, than those in effusions from which β-lactamase positive organisms were detected. ABPC concentrations achieved in middle ear effusions in cases where only β-lactamase negative organisms were detected exceeded MIC₈₀'s of the drug against main causative bacteria of acute purulent otitis media such as Streptococcus pneumoniae, Streptococcus pyogenes, and Haemophilus influenzae. Because only 10% or less of these species produces β-lactamase, BAPC appears to be one of the highly effective drugs in the treatment of this disease.

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Some of new cephem antibiotics, particularly the so called the third generation cephalosporins, are reported to be potent inducers of,β-lactamases and to be responsible for developing microbial cross-resistance to multiple β-lactam antibiotics and occassionally to the aminoglycosides (SANDERS and SANDERS, 1983). In Japan, third generation cephalosporins such as cefotaxime, cefoperazone, ceftizoxime, and latamoxef became available in 1981, and cefmenoxime in 1982. Therefore, it is of interest to investigate changes, if any, in the antimicrobial activity of cefotiam (CTM) against various Gram-positive and negative bacteria, particularly to determine whether its antimicrobial activity has been reduced since 1982.
Susceptibilities of clinical isolates of S. aureus (1,776 strains), S. epidermidis (2,247), S. pneumoniae (160), S. pyogenes (108), E. faecalis (1,930), E. coil (2,024), K. pneumoniae (1,913), Proteus spp.(950), E. aerogenes(823), Serratia marcescens (1, 160), Citrobacter spp. (303), Pseudomonas aeruginosa (2,824), and H. influenzae(396) to CTM were studied. It was found that susceptibilities of these clinical isolates to CTM were not altered from 1981 to 1985, except S. marcescens. In 1985, susceptible strains of S. aureus, S. epidermidis, S. pneumoniae, S. pyogenes and E. faecalis were 93.8, 93.4, 100, 100 and 0%, respectively. Those of E. coii, K. pneumoniae, Proteus spp., H. influenzae, P. aeruginosa, S. marcescens, E. aerogenes and Citrobacter spp.were 97.9, 97.7, 89.4, 94, 0, 10.8, 45.9 and 74.5%, respectively. The rate of susceptible strains of S. marcescensdecreased from 34.7 to 10.8% since 1981 to 1985. This increased resistance of S. marcescens might be due to the clinical use of third generation cephalosporins since 1982, because the development of cross-resistance to multiple antibiotics by third generation cephalosporins has been reported to be more prevalent in S. marcescens, P. aeruginosa and Enterobacter spp. (SANDERS and SANDERS, 1983).

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Ceftriaxone (CTRX), a new injectable cephem antibiotic agent, was evaluated bacteriologically and clinically for its efficacy and safety in the pediatric field by a study group organized with pediatricians from all over the country. The following are a summary of the results of the evaluation.
1. Antibacterial effects:
The inhibition of growth was attained for over 90% of strains of K. pneumoniae, H. influenzae and Salmonella spp. at the concentration of 0.10 μg/ml and of strains of S. pneumoniae and E. colt at the concentration of 2.0 μg/ml. The CTRX was proved to have excellent antibacterial effects.
2. Absorption and excretion:
Thirty minutes after one shot intravenous administration with 10, 20, 40 and 50 mg/kg of CTRX, its serum levels were 73, 124, 169 and 190μg/ml, respectively, a clear tendency of dose-response relationship being noticed. The serum levels decreased only gradually and stayed as high as 10 to 20 μg/ml even after 12 hours. The half-lives of the drug were 5.5, 6.3, 6.0 and 4.7 hours for the 4 different dose levels, respectively.
Following the intravenous injection with 10, 20 and 40 mg/kg, the urinary excretion rates were 55, 52 and 54%, respectively. Following the one shot intravenous administration or by the drip infusion for 30 minutes with about 50 mg/kg, CTRX levels in the cerebrospinal fluid ranged from 1 to 20.3μg/ml in case of purulent meningitis (5 to 10μg/ml in most cases).
3. Clinical results:
A total of 322 cases was enrolled. The efficacy of CTRX was evaluated in 295 cases out of the 322, excluding drop-outs and the cases which did not meet the protocols.
The clinical efficacy rate was 94% of 191 cases where the causative bacteria were identified, CTRX being “excellent” in 108 cases and “effective” in 72. In the remaining 104 cases where the causative bacteria were not identified, the efficacy rate was 92%, CTRX being “excellent” in 42 cases and “effective” in 54. Furthermore, the efficacy rate was 89% of 18 cases infected with more than one kind of bacteria. The drug showed “excellent” or better effectiveness in 88% of 75 cases which had not responded to other antibiotics.
Bacteriologically, 174 out of 216 strains (93%) which were judged to be causative bacteria disappeared with the use of CTRX. Eightyfive percent of 53 strains which had not responded to other antibiotics disappeared by the CTRX treatment.
4. Adverse reactions and over-ranged clinical laboratory parameters:
Adverse reactions like diarrhea, loose passage and urticaria appeared in 28 cases out of 322 (8.7%). In clinical laboratory tests, increase in GOT, eosinophilia, increase in GPT, thrombocytosis, etc. were observed in 38 cases (48 symptoms).
5. Optimal clinical dose in children:
The optimal clinical dose in children was 20 mg/kg twice a day by intravenous injection or by drip infusion.
The dose was adjusted according to types and severities of diseases.
The drug was considered to be a useful cephem antibiotic in the pediatric field especially because of the time-saving and cost-effective twice-a-day administration which was enabled due to the fairly long half-life, the broad antibacterial spectrum, the good transfer to the cerebrospinal fluid and the high safety. The administration to newborn babies, once-a-day administration and adverse reactions will have to be studied further for this new antibiotic agent.

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Newly developed lenampicillin (LAPC) which is a prodrug of ampicillin (ABPC), and ampicillin (as the control) were each administered to 6 healthy male volunteers, aged from 21 to 25 years (mean 22.4years) and weighing 57-78kg (mean 67.0kg) to study the effect of LAPC and ABPC on fecal bacterial flora. Each drug was given orally 3 times daily (after meals) with each dose of 250 mg for five days. Changes of the fecal bacterial flora caused by the antibiotic were investigated by determining fecal bacterial counts on the 3rd day before the treatment, 0 (the start of treatment), 3rd and 5th days (the final day of treatment) during treatment, and 3rd, 5th and 10th days after the treatment. Fecal concentrations of LAPC and the metabolites (ABPC, 2-aminobenzyl penicilloic acid (ABPA) and 5S-ABPA) for the LAPC group and ABPC for the ABPC group were assayed. A single dose of 500 mg of LAPC was administered orally after breakfast to additional 6 healthy male volunteers and concentrations of LAPC, metabolites (ABPC, ABPA and 5S-ABPA) in the entire stool were determined daily for 5 successive days after the administration. Clinical adverse reactions and abnormal laboratory-findings caused by either drug were studied in the 18 volunteers. The results obtained are summarized as follows.
1. In the bacterial flora of the 6 volunteers to whom LAPC was administered (the LAPC group), the number of isolated E. coil showed no tend of decrease. Mean bacterial counts obtained 3 days before the treatment and at the day of the treatment were 10⁹ and 10⁸ cells/g, respectively. These values were compared to the counts obtained on the 3rd and the 5th days during the treatment and were found to be about 10²-folds as high as the latter. The decreased counts observed on the 3rd and the 5th days did not last and counts increased again to similar levels observed before the treatment. Klebsiella sp. was isolated from 1 or 2 samples before the treatment. It was isolated from as many as 5-6 cases with mean bacterial counts of 10⁷, 10¹¹ cells/g during and up to 5 days after the treatment. The frequency of isolation then decreased to 4 cases on the 10th day after the treatment. Citrobacter sp. was isolated from 4 cases on 2 different days of examination before the treatment and from only 1 to 2 cases by the examinations after the start of the treatment. The frequency of isolation of Citrobacter sp. transiently decreased on the 5th day during the treatment compared to the other days of examination. Proteus sp. and Citrobacter sp. were isolated sporadically. Mean counts of Enterobacteriaceae on 3 days before the treatment and the 0-day of the treatment were 10⁹ and 10⁸ cells/g, respectively, and when compared to the count obtained at the 3rd and the 5th day of the treatment, they were higher by 10². The high counts were accounted for by the increase of E. colt and Klebsiella sp., and when the treatment was done, they decreased back to similar levels observed before the treatment. Other Gram-negative rods such as Aeromonas sp., Pseudomonas sp. and Acinetobacter sp. were isolated. Their levels did not change much by the treatment.
Gram-positive bacteria, Staphylococcus sp., decreased slightly on the 3rd and the 5th days during the treatment and returned to the level found before the treatment. Mean bacterial counts of Enterococcus sp. were 10⁷-10¹⁰ cells/g without much change throughout the period of examination, as were those of Micrococcus sp. Candida sp. was transiently isolated from all cases on the 3rd day of the treatment but their counts did not increase much.
Bacteroides sp., an anaerobe, was isolated at a relatively constant level with mean counts of 10¹¹-10¹² cells/g during the study.

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Ceftazidime (CAZ) was evaluated for its pharmacokinetics and clinical usefulness in neonates and premature infants. The results obtained were summarized below.
1. Following intravenous injection of CAZ 10 or 20 mg/kg to neonates and premature infants, dose response was observed in serum concentrations ranging from 5.1 to 21.9μg/ml at 6 hours after the injection.
2. The serum half-life tended to be longer in premature infants than in neonates; the half-life being longer for an infant with lower day-age.
3. Urinary recovery rates during the first 6 hours after single administrations of 10 mg/kg of CAZ tended to be higher in neonates than in premature infants, and higher rates were observed in older infants. However, no noticeable difference was observed after the administration of CAZ 20 mg/kg.
4. Clinical efficacy was evaluated in 99 neonates and 55 premature infants (156 infections), daily doses ranging from 21.1 to 246.4 mg/kg.
5. Out of 105 cases of common infections, mainly 44 cases with causative organisms identified (including 17 of sepsis, 7 of pneumonia, 4 of purulent meningitis, 11 of urinary tract infections) were examined for the clinical efficacy. The efficacy of CAZ was excellent in 21, good in 18, fair in 1 and poor in 4, with the efficacy rate of 88.6%. In the remaining 61 cases, i.e., 37 with causative organisms unknown and 24 with signs of intrauterine infections, the efficacy rate was 95.1%. Other than these cases, additional 51 cases were given CAZ solely for prophylaxis of infections, and the results were found satisfactory. On the whole, clinical efficacy rate of CAZ was 94.9% in 156 cases.
6. Out of the 44 cases examined for bacteriological responses, 38 were evaluated as ‘eradicated’, 3 ‘persisted’ and 3 ‘unknown’ with eradication rate of 92.7%. Replacement of organisms (superinfection) was observed in 3 cases.
7. Out of 179 cases in which adverse effects were assessable, adverse effects were observed in a total of 4 cases (2.2%), i.e., 3 cases of diarrhea (1.7%) and 1 case of rash (0.6%), and abnormal laboratory findings were observed in a total of 14 cases (7.8%), i.e., increase in eosinophiles count in 8 (4.5%), elevation of GOT in 3 (1.7%), increase in platelet, elevation of GOT. GPT, and elevation of GOT-GPT·BUN in 1 case each (0.6%). None of them were severe and they were transient. Elevations of bilirubin and cases of positive PIVKA II associated with CAZ were not observed.
From the above results, the desired dosage of CAZ to neonates and premature infants should be in the unit dose of 20 mg/kg, 2 to 3 times daily to those with ages between 0 and 3 days, and 3 to 4 times daily to those with ages 4 days and above, by intravenous injection or intravenous drip infusion, with the maximum daily dose of 150 mg/kg, depending on symptoms.

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Seventeen newborn and young infants including 6 premature infants were treated with ceftazidime (CAZ) and the clinical efficacy and side effects were evaluated. Ages of the patients ranged from zero to 55 days, and their body weights ranged from 1.35 to 3.87 kg. Doses of CAZ ranged 10-50 mg/kg every 6 to 12 hours for 3 to 14 days. Twelve infants with infections including meningitis, sepsis, pneumonia and urinary tract infections, were considered to have responded to the CAZ treatment. Among them, results were excellent in 2, good in 9 and fair in 1 patient. The drug was well tolerated, but 1 had diarrhea and 3 patients had eosinophilia among the 17 patients.
The pharmacokinetics of CAZ was studied in 22 patients including 11 premature infants. Their ages ranged from 1 to 60 days, and body weights ranged from 0.85 to 3.96 kg. Serum concentrations in 7 patients ranged from 24.2-38.5μg/ml at 30 minutes after single doses of 10 mg/kg intravenous bolus injections and 4.36-12.4μg/ml at 6 hours. Mean elimination half-lives of the drug were 3.20 hours in 2 patients under 7 days of age and 2.31 hours in 5 patients from 7 days of age or older. In 8 patients, serum concentrations ranged 32.6-57.9μg/ml at 30 minutes and 8.10-20.7μg/ml at 6 hours after single doses of 20 mg/kg. Elimination half-lives were 3.53 hours in 4 patients under 7 days of age and 2.79 hours in 4 patients from 7 days of age or older. Excretion rates into urine within 8 hours ranged from 57.9 to >100% in 9 patients given single dose of 10 mg/kg each. Excretion rates of the drug into urine after a 20 mg/kg of dose each were 66.8-78.1% within 6 hours in 3 patients and 64.2-86.4% within 8 hours in 4 patients.
In 1 patient with bacterial meningitis given 50 mg/kg of the drug every 8 hours, the cerebrospinal fluid level at 2 hours after a dose on the 2nd day of treatment was 8.65μg/ml. In another patient with bacterial meningitis given 33 mg/kg of the drug every 6 hours, its levels at 1 and 2 hours after the doses were 5.87 and 4.98μg/ml, respectively, on 3rd day of treatment.

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Ceftazidime (CAZ) was evaluated for its safety and efficacy in 27 newborns. Four confirmed cases of bacterial infections were cured by the CAZ therapy (efficacy rate 100%). The CAZ was assessed as effective in sepsis (2) and urinary tract infections (2). Main pathogens which responded to CAZ were Escherichia coli, Enterobacter cloacae and Acinetobacter anitratum.
As adverse effects, elevations of GOT and GPT (1 case) were found to be associated with the CAZ therapy.
Half-lives of the serum levels in mature infants were 1.93-3.52 hours, and those in low birth weight infants were 2.92-4.17 hours. Penetration into the cerebrospinal fluid in 1 case of viral meningitis was satisfactory.
The data suggest that CAZ is a safe and effective injectable antibiotic when used in newborn with infection caused by CAZ-susceptible bacteria.

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Fundamental and clinical evaluation of ceftazidime (CAZ) were carried out in neonates and premature infants, and the results obtained are summerized below.
1. Serum concentrations of CAZ after administration of 20 mg/kg were satisfactorily high regardless of the route of administration; bolus intravenous injection or 1-hour intravenous drip infusion. Like other cephem antibiotics, half-lives tended to be shorter as day-ages of subject became higher.
2. Although there were some differences in urinary recovery rates between different dosage groups, they were generally high.
3. Clinical efficacy was either excellent or good in all 21 assessable cases.
4. In 23 cases examined for adverse effects, diarrhea was observed in 1 case, and elevation of GOT and GPT, in another case.

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Pharmacokinetics and clinical efficacy of ceftazidime (CAZ) were evaluated in neonates. The results obtained are summarized below.
1. After a bolus intravenous injection of 20 mg/kg CAZ to neonates, peak serum concentrations ranged 55.1-97.4μg/ml with the mean half-life of 2.26 hours in neonates with birth weight of 2,500g or more, and 59.3-60.7μg/ml with half-lives ranging from 3.98 to 4.22 hours in neonates weighing less than 2,500g at birth. In the time-course observation, it was noted that the half-life at 2 days after birth was longer than half-lives observed on 4 and 9 days after birth.
2. Four cases were given CAZ for treatment, and 3 cases for prophylaxis of infections, and the clinical efficacy was either excellent or good in all of the cases. Neither adverse effects nor abnormal laboratory findings were observed except rash in 1 case.
3. Intestinal flora was examined in 5 cases. It was found that the effect of CAZ was less than that of LMOX, although some delay was seen in the growth of intestinal flora.
4. There was no vitamin K deficiency in any of 6 cases examined.

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Ceftazidime (CAZ) intravenous injection was evaluated from fundamental and clinical aspects in neonates, and the results obtained are summarized below.
1. Following a 60-minute intravenous drip infusion of CAZ at 10mg/kg, the peak serum level was 19.8μg/ml at 30 minutes after the completion of the infusion(half-life: 2.75 hours).
2. Following 30 to 60-minute intravenous drip infusions of CAZ at 20mg/kg, the mean peak serum levels of CAZ were 33.1-33.0μg/ml. Mean levels at 6 hours were 5.2-6.7μg/ml (half-life: 1.6,-4.1 hours).
3. Following 30 to 60-minute intravenous drip infusions of CAZ at 25-30mg/kg, peak serum levels were 51.7-64.6μg/ml (half-life: 1.6-2.05 hours).
4. Dose response relationship was clearly observed in peak serum levels after intravenous drip infusion, and half-lives of serum CAZ levels in neonates aged 0-10 days tended to be longer than those in infants.
5. Following intravenous administration of CAZ at 20-30mg/kg, urinary excretion rates during the first 6 hours were 18.7-66.5%, and the rates were low in neonates compared to those in infants and children.
6. Following a 60-minute intravenous drip infusion of CAZ at 28.7mg/kg, the cerebrospinal fluid level was 5.0μg/ml at 3 hours, the ratio of cerebrospinal fluid level to serum level was 22.5%.
7. Eleven neonates were subjected to the present study. Clinical efficacy of CAZ was excellent in sepsis caused by A. anitratus, which showed higher sensitivity to CAZ compared with other cephem antibiotics of the third generation. In all of the other cases, including those of pertussis and acute urinary tract infections and in the prophylaxis of amniotic infection, clinical efficacy of CAZ was excellent or good.
8. S. epidermidis, E. coli and A. anitratus, identified from cultures of pharynx, urine or blood, were rapidly eliminated during the CAZ treatment.
9. Doses of CAZ used in the present study were 29-133mg/kg/day, mostly in the range of 40-60mg/kg/day. Durations of treatment ranged from 3 to 10 days. Neither systemic nor local adverse effect was observed, nor was any abnormality observed in laboratory findings.

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Ceftazidime (CAZ) was administered to 34 full-term and premature infants aged 0-27 days with various bacterial infections in a dose of 10 or 20mg/kg by intravenous bolus injection, and plasma concentrations and urinary recovery rates in these subjects during recovery periods were studied. Because of the small number of the cases recruited, neonates were not divided into the full-term and the premature group, but into 3 groups based on day-age: 0-3 days, 4-7 days, and 8 days or older. Concentrations and rates of transfer of CAZ into cerebrospinal fluid (CSF) were determined in 2 cases, and biliary concentrations in another case.
A clinical evaluation of CAZ was performed in 12 male and 6 female infants aged 1 day to 4 months and 19 days, including 2 each with purulent meningitis, pneumonia and pyelonephritis, 3 with septicemia, 1 each with speticemia suspected, cholangitis, osteomyelitis, bronchopneumonia, staphylococcal scalded skin syndrome, and acute enterocolitis and 3 for prophylactic use.
1. Plasma concentrations and urinary recovery rates of CAZ
(1) The intravenous bolus injection at 10mg/kg (Fig. 11).
Peak plasma concentrations of CAZ were obtained at the first collection (30 minutes) of blood samples or 1 hour in all 3 groups, ranging from 23.3 to 26.9μg/ml with no significant variations, plasma concentrations then slowly decreased, and were still 6.04-9.88μg/ml even at 6 hours after the administration. The half-lives of CAZ in plasma tended to be shorter in older day-age neonates, with mean half-lives being 3.59, 2.50 and 2.50 hours for the youngest.
(2) The intravenous bolus injection at 20mg/kg (Fig. 12).
Peak concentrations were obtained at the first collection of blood samples in all 3 groups (0-3 days: 15 minutes, the others: 30 minutes), being 54.8, 39.9 and 43.8μg/ml, respectively, then slowly decreased and were still 10.4-15.7μg/ml even at 6 hours after the administration. Inter-age differences in half-lives were marked, i. e., 3.6 hours in 0-3-day group, 3.48 hours in 4-7-day group and 2.75 hours in 8-day or older group.
(3) Urinary recovery rates were about 40-60% without reference to day-age neonates.
2. CSF concentrations
About 50mg/kg of CAZ was given to each of 2 cases. The CSF concentration was 1.29μg/ml (transfer ratio: 4.5%) in Case 1 of meningitis due to E. coli, and it was in a range between 3.5 and 7.2μg/ml in Case 2 of meningitis due to H. influenzae with transfer ratio exceeding 10% even after the acute phase, and the ratios obtained in 5 measurements were high, in a range 13.8 to 89.1%.
3. Biliary concentrations
Biliary concentrations were determined only in 1 case. They ranged from 0.67 to 10.2μg/ml with transfer ratio being as high as 6.1-81.9%. No effect of the day of sampling was observed.
4. Clinical results
Clinical evaluations were made in 18 cases administered with CAZ 39.7-210.8mg/kg/day in 2-4 doses. In all the cases examined including those considered serious, i. e., purulent meningitis (2 cases), septicemia (3) and osteomyelitis (1), clinical efficacies were excellent or good. In 14 cases excluding 1 case of osteomyelitis and 3 for prophylactic use, causative organisms were identified, and E. coli (6 strains), S. aureus (4), H. influenzae (1), P. aeruginosa (1), E. cloacae (1), S. marcescens (1), S. viridans (1) and K. pneumoniae (1) were all eradicated within the treatment period.
5. Dosage and dosing frequency
In almost all of the cases treated with CAZ 20mg/kg, the plasma concentrations remained about 10μg/ml even at 6 or 8 hours after the administration, and even in the cases treated with 10mg/kg, they ranged from 4.73 to 14.6μg/ml at 6 hours.

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Evaluations of ceftazidime (CAZ) in a few different categories were carried out in neonates.
Single doses of 20mg/kg of CAZ were administered to 8 neonates (day-age range: 1-26) and 3 infants (day-age range: 45-119) by bolus intravenous injection. Mean serum concentrations of CAZ at 15, 30 min., 1, 2, 4 hours and 6 hours were 51.6±9.2, 48.1±8.7, 47.9±7.8, 38.2±6.5, 20.2±4.0μg/ml, and 15.3±5.8μg/ml, respectively, in the neonates, and 51.1±10.3, 44.7±6.8, 35.5±4.1, 21.4±2.0, 8.6±1.0μg/ml and 3.5±0.8μg/ml, respectively, in the infants. Mean half-lives of CAZ in serum were 2.87±0.77 hours in the neonates and 1.39±0.10 hours in the infants, and mean urinary recovery rates in the first 6 hours were 60.5±16.0%, and 76.8±39.6% in the neonates and the infants, respectively. When individual differences are taken into consideration, no significant difference exists among 30-minute serum concentrations of neonates of different day-ages, and these concentrations were not significantly different from those in infants and older children. Half-lives of CAZ in sera decreased rapidly with the advances of the day-ages of the neonates, and the half-life at an age of 1-month should be similar to that in older children.
The CAZ was administered to 2 cases of suspected sepsis, 7 of acute pneumonia, 1 of acute pyelonephritis, 1 of cellulitis, and 2 of idiopathic respiratory distress syndrome, and clinical efficacies were excellent in all the cases except for 2 cases excluded from the assessment. S. pyogenes (1), E. coli (1) and S. aureus (1) suspected as causative organisms were eradicated by the treatment with CAZ. Neither clinical adverse effects nor abnormal laboratory findings were observed in any case.
From the above results, CAZ is considered to be an antibiotic with high efficacy and safety in the treatment of neonates.

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The pharmacokinetics of ceftazidime (CAZ) were investigated in neonates.
The following was a summary of the results obtained.
1. Mean peak serum levels of CAZ reached at 15 minutes after intravenous administrations at single doses of 10mg/kg were 31.7μg/ml in 1-day-old neonates and 31.4μg/ml in a 13-day-old neonate. Mean serum levels at 6 hours after administrations were 8.97μg/ml and 5.26μg/ml in the 1-day-old and the 13-day-old, respectively. Mean half-lives of CAZ in sera were 3.29 hours in the 1-day-old and 2.24 hours in the 13-day-old. In a 4-day-old neonate, the serum level of CAZ reached a peak of 25.4μg/ml at 1 hour and was 5.75μg/ml at 6 hours; the half-life was 2.41 hours.
2. peak serum levels of CAZ reached at 15 minutes after intravenous administrations at single doses of 20mg/kg were 46.3μg/ml in a 3-day-old neonate and 80.6μg/ml in a 7-day-old neonate. The serum levels at 6 hours after administration were 12.2μg/ml and 10.4μg/ml, in the 3-day-old and the 7-day-old, respectively. Half-lives of CAZ in sera were 3.02 hours in the 3-day-old and 2.08 hours in the 7-day-old. In 4-day-old neonates, mean serum levels were 52.5μg/ml at 15 minutes and 14.6μg/ml at 6 hours after administration and the half-life was 2.76 hours.
3. In a 5-day-old neonate, serum levels of CAZ immediately after the completion of an intravenous drip infusion for 30 minutes at a single dose of 20mg/kg were 75.7μg/ml and 16.4μg/ml at 5 hours after the completion of infusion; the half-life of serum CAZ was 2.33 hours. In a 6-day-old neonate, serum levels were 45.8μg/ml at the completion of an infusion, 47.1μg/ml at 1 hours, and 15.1μg/ml at 5 hours; the half-life was 2.47 hours.

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Ceftazidime (CAZ) was evaluated in the treatment of infections in neonates and premature infants.
1. In 1 mature neonate (age: 14 days) administered with 30.3mg/kg of CAZ by a single bolus intravenous injection, the serum concentration of CAZ was 50μg/ml at 30 minutes after the dosing, and the elimination half-life was 1.38 hours. The urinary recovery rate of administered CAZ during the first 6 hours was 52.9%. In 6 neonates (mean gestational period: 37.8 weeks, mean birth weight: 2,508g, mean age: 3.7 days) administered with ca. 20mg/kg of CAZ by single bolus intravenous injections, the mean serum concentration of CAZ was 63.6μg/ml at 30 minutes after the dosing, and the half-life was 3.78 hours. In 3 out of the above 6 neonates, the mean urinary recovery rate of CAZ during the first 6 hours was 59.8%.
2. Five neonates and 2 infants with infections were given 18.4-65.9mg/kg of CAZ b. i. d.-q. i. d. by intravenous injections. One of these cases was excluded from an evaluation for clinical efficacy, because CAZ was given only for 2 days. In the remaining 6 cases, clinical efficacy was excellent in 1 case of urinary tract infection (E. coli+E. faecalis), good in 3 cases of pneumonia (P. aeruginosa+K. pneumoniae: 1, P. aeruginosa: 1, and causative organism unknown: 1), and poor in 1 case of sepsis (S. aureus). In 1 case of asphyxia neonatorum contaminated with meconium, CAZ was used prophylactically, resulting with no infection.
3. No clinically adverse effect was observed. Also no abnormality was observed in laboratory analyses in the 6 cases. One case was excluded from laboratory examinations because a combination therapy with another antibiotic was performed.

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Ceftazidime (CAZ) was administered to 24 neonates and premature infants aged 0-31 days in a dose of 10 mg/kg or 20 mg/kg by an intravenous bolus injection, and plasma concentration, urinary concentration and urinary recovery rate during the first 6 hours after the administration were determined. The CAZ was also administered to a total of 43 patients consisting of neonates, premature infants and infants at ages ranging from 0 day to 1 year 9 months (21 suffering or suspectedly suffering with various bacterial infections, and 22 treated for prophylaxis of infections), by intravenous bolus injections in a mean daily dose of 59.6 mg/kg in 2 to 4 divided doses for 9 days on the average. The clinical efficacy, prophylactic effects and bacteriological response were evaluated. Adverse effects of the drug were examined in 65 cases including 22 drop-out cases, and in some of them, abnormal laboratory findings were also examined. The results obtained are summarized as follows:
1. Patients given 10 mg/kg of CAZ were divided into 5 groups on the basis of age: 0-3 days, 4-7 days, 8-14 days, 15-21 days, and 29 days and older, and mean peak plasma concentrations of CAZ were 40.7, 43.1, 37.1, 38.0 and 35.6 μg/ml, respectively, at 5 minutes after administration, with no significant difference. Mean AUC values were higher in younger-age groups, i.e. 189.9, 170.8, 159.1, 135.3 and 134.4 μg·hr/ml for the 5 different day-age groups, respectively, and mean half-lives of CAZ in plasma tended to be longer in youngerage groups, i.e. 3.16, 3.05, 2.84, 2.44 and 2.43 hours for the 5 groups, respectively. Patients given 20 mg/kg of CAZ were divided into 4 groups also on the basis of age: 0-3 days, 4-7 days, 8-14 days, and 15-21 days, and mean peak plasma concentrations for the 4 day-age groups were 72.9, 73.3, 70.0 and 78.4 μg/ml, respectively, at 5 minutes after administration, without any difference among these groups. Mean AUC values were 429.9, 327.3, 279.3 and 302.1 μg·hr/ml for the 4 groups, respectively, with the highest AUC in the youngest-age group. Dose response was observed in mean peak plasma concentrations and mean AUCs when 10 mg/kg and 20 mg/kg dose groups were compared for similar day-age patients. Mean half-lives of CAZ in plasma were 4.01, 3.51, 3.00 and 3.07 hours, the longest being in the youngest-age group.
2. Urinary concentrations ranged from 97.9 to 1,330 μg/ml in the 10 mg/kg dose group, and from 21.2 to 2,280 μg/ml in the 20 mg/kg dose group during 0-2, 2-4, and 4-6 hours after administration. In the 10 mg/kg dose group consisting of patients aged 0-3 days, 4-7 days, 8-14 days, 15-21 days, and 29 days and older, mean urinary recovery rates during the first 6 hours after administration were 56.7, 70.3, 85.8, 91.7 and 86.0%, respectively. In the 20 mg/kg dose group consisting of patients aged 0-3 days, 4-7 days, 8-14 days and 15-21 days (except for 1 patient aged 0 day with urination only in 4-6 hours which showed a low concentration of 21.2 μg/ml), mean urinary recovery rates were 83.2, 50.3, 76.0 and 68.8%, respectively.
3. In 21 cases of various bacterial infections or suspected infections, clinicial efficacy was 85.7%, and in 22 cases treated for prophylaxis of infection, efficacy was confirmed in all cases. Bacteriological responses were examined in 7 cases and causative organisms were “eradicated” in 4 cases and “unchanged” in 3 cases.
4. No adverse effects were observed in 65 cases consisting of 43 cases assessed for clinical or prophylactic efficacy and 22 drop-out cases. As to abnormal laboratory findings, eosinophilia was observed in 2 cases (3.6%).

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Fundamental and clinical studies of ceftazidime (CAZ) were performed in pediatric surgery. The results obtained were summarized below.
1. Serum and urinary levels of CAZ were measured in 5 patients following injection (CAZ: 10 or 20 mg/kg, intravenous bolus injection). Highest levels in serum were observed within 30 minutes, 30.4 μg/ml and 49.5-62.9 μg/ml with 10 mg/kg and 20 mg/kg doses, respectively. Then serum levels of CAZ decreased gradually except in 1 case with a metabolic disease, and serum half-lives (T 1/2) were 1.19-1.88 hours for the high doses. The highest levels in urine were observed in 0-2 hours, and the urinary recovery rate was 59-100%.
2. The bile levels were also measured in 3 patients who underwent radical operations of congenital biliary atresia (CBA). Highest levels of CAZ in bile, 4.47-9.66 μg/ml, were noted in 0-2 or 2-4 hours following injection. Recovery rates for 8 hours were 0.11, 0.17 and 0.20% for the 3 patients.
3. The CAZ was administrated to 7 patients for prophylaxis of the postoperative infection (5 cases) or to treat ascending cholangitis in CBA (2 cases). Clinical results were good in 4, fair in 1, poor in 1 and unknown in 1. No clinical and laboratory side effect due to the administration of CAZ was observed.
It is concluded that CAZ is a safe and effective antibiotic in pediatric surgery.

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Efficacy and safety of ceftazidime (CAZ) in women during the perinatal period and their neonates were evaluated by a perinatal co-research group, and the results obtained were summarized as follows.
1. Following an intravenous bolus injection or a drip infusion of CAZ from 1g to 2g, CAZ was transfered to maternal serum, umbilical cord serum and amniotic fluid rapidly and effectively.
2. In 31 cases of perinatal infections, clinical efficacy was excellent in 10 cases, good in 18 and poor in 3, with an efficacy rate of 90.3%. In 85 cases given CAZ for prophylaxis of infections accompanying premature rupture of the membrane or following cesarean section, prophylactic effects were noted in 81 cases (efficacy rate: 95.3%).
3. Neither adverse effects, nor abnormal laboratory findings were observed in any case. Also, no abnormalities in total serum bilirubin were observed in any neonates.
4. From the above results, CAZ is considered to be a safe and useful drug for infections in women in perinatal period, usually in a unit dose of 1g twice daily, or if necessary, 2g twice daily.

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In a chemotherapy of perinatal infections, the safety of mothers and their neonates and the transfer of a drug to amniotic fluid and fetus as well as its bacteriological efficacy are some of the important factors. In the present study, the authors have carried out a pharmacokinetic evaluation on the transfer of ceftazidime (CAZ), a new cephalosporin, to amniotic fluid and umbilical cord serum, and also a clinical study on its efficacy and safety in 3 cases of perinatal infections.
Transfer ratios of CAZ to umbilical serum and to amniotic fluid were 25.3-46.5% and 0.6-17.5% (of maternal serum), respectively, after 1 g of CAZ was administered by bolus intravenous injection, and 24.3-85.8% and 1.6-17.5% (of maternal serum), respectively, after 2g of CAZ was administered by bolus intravenous injection. These levels were high enough to expect that CAZ is an effective antibiotic both for treatment and prophylaxis of intrauterine fetal infections.
Out of the 3 cases treated with CAZ, clinical efficacy was good in 2 cases which did not respond to other antibiotics. CAZ was considered to be clinically effective, although the number of cases treated was small.
No abnormalities were observed at all either in subjective symptoms or objective findings in laboratory findings such as hepatic and renal functions of mothers, or neonates. This confirmed the high safety of CAZ.
As earlier reports indicate, CAZ has a broad-spectrum of antibacterial activity against various bacteria including Gram-negative organisms and anaerobes, and shows a good transfer into intrauterine tissues, and high clinical efficacy in the field of obstetrics and gynecology.
From the above results, CAZ is considered to be a useful antibiotic in the perinatal infections. Its transfer through the placenta is effective and its safety has been confirmed in both fetus and neonates.

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Ceftazidime (CAZ), a newly developed cephalosporin with very high stability to β-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 1g.
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 (10μg/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.

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Pharmacokinetic studies and clinical evaluations of ceftazidime (CAZ) were carried out in perinatal mothers and infants, and following results were obtained.
The CAZ was promptly absorbed after intravenous injection or intravenous drip infusion in pregnant women, producing dose-related peak serum levels.
Placental transference to the fetus was good. After intravenous injection or intravenous drip infusion of 1.0-2.0g of CAZ, drug concentration in umbilical serum and amniotic fluid exceeded MICs of CAZ against main pathogenic organisms. Levels of CAZ in umbilical serum ranged 0.2-15.6μg/ml after 1.0g intravenous injection or intravenous drip infusion, and 0.7-27.2μg/ml after 2.0g intravenous injection, and those in amniotic fluid were 1.4-21.3μg/ml after 1.0g administration and 2.0-27.0μg/ml after 2.0g administration. According to the above results, it is possible to successfully prevent or treat perinatal infections by twice a day administration of CAZ at 1.0-2.0g/dose.
Clinically, CAZ was effective in the treatment of perinatal infections and the prophylaxis of intrauterine amniotic infection without any side effect.
Moreover, newborn infants delivered from mothers receiving CAZ treatment did not have any abnormalities in laboratory test.
The penetration of CAZ into mother's milk was low, thus the transfer of CAZ from milk to newborn infants should be low.
The above results demonstrated that CAZ is a clinically useful antibiotic for the prophylaxis and the treatment of perinatal infections.

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1. Following an intravenous injection of ceftazidime (CAZ) 1g, the ratio of transfer of the drug into a fetus was 59.9%, and umbilical serum concentrations of the drug reached the peak of 18.2μg/ml at 1.5 hours, and were slightly higher than maternal serum concentrations at 2.93 hours and after, with the half-life of 1.37 hours, the same as in maternal serum.
2. Following an intravenous injection of CAZ 1g, concentrations of CAZ in mother's milk at 2 hours after injection were 1.16μg/ml on the 4th day of the treatment of CAZ, and 0.86μg/ml on the 7th day.
3. The CAZ was administered to cases of premature rupture of membrane. The prophylactic efficacy against puerperal infections in mothers was 92%, and that against fetal infections in neonates was 96.7%.
The CAZ was also administered after cesarean section, and the prophylactic efficacy against postoperative infections was 93.3%.
4. Neither subjective/objective adverse effects nor abnormal laboratory findings for which CAZ was suspected were observed in any mothers or neonates.
From the above results demonstrating satisfactory maternal transfer into fetuses and the high degree of safety in fetuses and neonates, as well as its high antibacterial activity, CAZ is considered to be a useful drug for the treatment of perinatal infections.

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Fundamental and clinical studies were carried out on ceftazidime (CAZ) in the perinatal period, and the results obtained were summarized below.
1. Following bolus intravenous injection of CAZ 2g, maternal serum concentrations of CAZ were as high as 145.3±17.2μg/ml (mean±S. D.) at about 10 minutes, and then gradually decreased to 46.7μg/ml at 2 hours, 5.31μg/ml at 5 hours and 4 minutes, and 1.54μg/ml at 11 hours and 10 minutes.
The CAZ was detected in umbilical cord serum immediately after the administration, and concentrations were 31.0±1.54μg/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 3.00μg/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±0.67μg/ml at about 10 minutes after the administration. Concentrations then gradually increased to 12.8μg/ml at 2 hours and 26.5μg/ml at 5 hours and 4 minutes, and even at 11 hours and 10 minutes, they were as high as 14.2μg/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.
2. In the clinical evaluation of CAZ which was given to a total of 11 cases, i. e., 2 of amnionitis, 8 of puerperal endometritis and 1 of pyelonephritis, treatments showed satisfactory results, i. e., excellent in 6, good in 4 and poor in 1 with an efficacy rate of 90.9%.
As to bacteriological examination, 18 strains (15 species) of bacteria were isolated from 9 cases. After CAZ administration, 8 strains were eradicated and 1 strain persisted among 9 strains each of aerobic and anaerobic bacteria with eradication rate of 88.9%.
Neither subjective/objective side effects nor abnormal laboratory findings were observed in any of the cases (mothers and babies) treated with CAZ.

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Ceftazidime (CAZ), a new cephem antibiotic with high activity against Gram-negative bacteria, has been investigated for use in mothers in perinatal period, and the results obtained are summarized below.
1. Into maternal serum, umbilical cord serum and amniotic fluid, CAZ showed good transfer after intravenous administration of 1g or 2g into mothers, and no adverse effect appeared in their neonates.
2. The CAZ is a very useful antibiotic for the prophylaxis and the treatment of perinatal infections at a dose level of 1-2g per day.

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