Imipenem (IPM) and fosfomycin (FOM) have been reported to possess a synergistic rela -tionship in their activities against both methicillin (DMPPC)-susceptible and -resistant strains ofStaphylococcus aureus.
However it was not concluded whether these antibacterial activities were bacteriostatic or bactericidal. The purpose of this report is to elucidate this point clearly. Activities of the 2 antibiotics against 15 strains S. aureus resistant to both DMPPC and FOM were investigated by means of the killing-curve method and electron microscopic studies.
MICs of DMPPC and FOM against these strains determined using the agar dilution method were >50 μg/ml and MICs of IPM by the broth dilution method ranged from 12.5 to 50 μg/ml.
The killing-curves with the following drug concentration combinations were examined in MUELLER-HINTON broth: 1. FOM 25 μg/ml, 2. FOM 25 μg/ml+IPM 1/2 MIC, 3. IPM 1MIC, 4.FOM 25 μg/ml+IPM 1 MIC and 5. FOM25 pg/ml+IPM 2MIC.
Morphological changes produced in 1 strain by 2 of the combinations, 2. FOM 25 μg/ml +1PM 1/2 MIC and 4. FOM 25 μg/ml- IPM 1MIC, were observed using scanning and transmis -sion electron microscopy.
The following results were obtained; (1) The synergisgic effects were found in 6/15 strains (40%) and no antagonistic effect was found.(2) Electron microscopic observation showed that IPM in combination with FOM caused lysis of the cells.
Conclutions: IPM in combination with FOM produced bactericidal and bacteriolytic effects on DMPPC-resistant S. aureus (MRSA).
This combination therapy should be evaluated for FOM resistant MRSA infections.

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Nine neonates were treated with aztreonam (AZT) and its clinical efficacy and side effects were evaluated. Six of the patients were treated with a combination of AZT and ampicillin. Ages of the patients ranged from 0 to 24 days, and their body weights ranged from 2,290 to 4,260 g. Doses of AZT ranged 18.8 to 23.7 mg/kg every 8 to 12 hours for 3 to 7 days. Three patients with infections including urinary tract infection, cervical abscess, and suspicion of sepsis, appeared to respond to the treatment of AZT alone. Among them, clinical results were excellent in 1, good in 2 patients. Those patients subjected to the combination therapy showed excellent response in 1 and good in 5. The drug was well tolerated, but 1 had diarrhea.
The pharmacokinetics of AZT was studied in 9 patients. Their ages ranged from 0 to 30 days, and body weights ranged from 2,000 to 4,000 g. Serum concentrations of AZT were 27.2 to 48.3 μg/ml at 1 hour after single 20 mg/kg intravenous bolus injection, and the levels were 3.4 to 15.5 μg/ml at 6 hours in 5 infants heavier than 2,500 g. Elimination half-lives of AZT ranged from 1.57 to 3.72 hours (mean 2.72 hours). Serum concentrations of AZT were 21.6 to 41.8 μg/ml at 1 hour after single 20 mg/kg intravenous bolus injection, and the levels were 10.2 to 17.0 μg/ml at 6 hours in 3 infants lighter than 2,500 g. The elimination half-lives of AZT were 3.63 to 4.86 hours (mean 4.31 hours). Serum concentration of AZT was 25.3 μg/ml at 1 hour after single 10 mg/kg intravenous bolus injection, and the level was 9.0 μg/ml at 6 hours in one infant of 3,200 g with congenital hydronephrosis. The elimination half-life of AZT was 4.62 hours. Urinary recovery rates in the first 6 hours after 20 mg/kg intravenous injection were 31.7 to 53.9% (mean 40.9%) in 4 patients heavier than 2,500 g and 9.5 to 41.6% (mean 28.4%) in 3 infants lighter than 2,500 g.

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Clinical and pharmacokinetic studies on aztreonam (AZT) were performed in neonates. The results are summarized as follows:
A total of 6 cases consisting of 5 mature and 1 low-birth-weight infants was clinically.evaluated.
AZT 20 mg/kg was administered 2 -33 times daily, via 1 hour intravenous drip infusion for 6-21 days. Concomitantly, vancomycin (VCM) 15 mg/kg was administered to 1 case 3 times daily, via 1 hour intravenous drip infusion for 3 days and ampicillin (ABPC) 20-50 mg/kg to 3 cases 3 time daily via 30 minutes intravenous drip infusion for 2-6 days.
Of the 6 bacterial infection cases (1 with sepsis and purulent meningitis, 2 with spesis, 2 with urinary tract infection and 1 with perirectal abscess), clinical effects of AZT were evaluated in 4 cases (2 each with sepsis and urinary tract infection) as “excellent” in all the cases. All of the causative organisms (Escherichia coli in 3 and Enterobacter cloacae in 1) were eradicated by the treatment with AZT.
Neither clinical side effect nor abnormal laboratory test value caused by AZT was observed.
MICs of AZT against 10 clinical isolates (Staphylococcus aureus 1, E. coli 4, Klebsieila pneumoniae 1, E. cloacae 1, Haemophilus influenzae 1 and Pseudomonas aeruginosa 2) from neonatal patients with bacterial infections were examined. As results, AZT showed very good antibacterial activity comparable or even superior to cefoperazone, cefotaxime, latamoxef;however, the activity against P. aeruginosa was inferior to imipenem.
AZT alone, or AZT in combination with ABPC or VCM was administered to a total of 17 cases consisting of 11 mature infants and 6 low-birth-weight infants and serum concentrations were determined. In addition cerebrospinal fluid concentrations were also determined in 2 cases.
The highest serum concentrations were detected immediately after the end of intravenous drip infusion and they were 41.5 pg/ml (12.6, -60.3 μg/ml) in the mature infants given 20 mg/kg and 39.4 pg/ml (16.5-77.6 μg/ml) in the low-birth-weight infants. A dosage of 45 mg/kg was administered to only 1 case of the low-birth-weight infant and the highest serum concentration immediately after the intravenous drip infusion was 129.5 μg/ml and a dosage of 50 mg/kg to a mature infant showed the highest serum concentration of 114.2 μg/ml.
The half-lives in the mature infant group administered with AZT at 20 mg/kg were2.03-8.73 hours and those in the low-birth-weight infants were between 1.62 and 5.51 hours showing a tendency to prolonged half-lives as day-ages of infants were lower. The half-life in the 45 mg/kg administration group was 3.62 hours and that in the 50 mg/kg group was 5.04 hours.
Cerebrospinal fluid concentrations of AZT upon administration of 50 mg/kg were 3.2 μg/ml at 7 hours after the administration and 1.7 μg/ml at 8 hours after the administration. Upon administration of 45 mg/kg, the concentration was 8.5 μg/ml at 6 hours after the administration.
These results and the characteristic properties of AZT with a very selective antimicrobial spectrum against only Gram-negative bacteria indicate that AZT can effectively be used alone after an identification of the causative bacteria through prompt diagnosis and skilful laboratory test, or when the probability of Gram-negative infection is high. However, in the early stage ofserious neonatal infections in which causative bacteria are unknown, it is advisable to use antibiotics with antimicrobial spectra against Gram-positive bacteria or against anaerobic bacteria such as ABPC.

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Clinical pharmacology and safety of aztreonam (AZT) in the neonatal period were investigated. The results obtained are summarized as follows.
1. Serum concentrations of AZT at 30 minutes after administration of 10 mg/kg were 22. 1-32.2 μg/ml and those of 20 mg/kg 22.5-75.9 pg/ml.
2. Serum half-lives of AZT were 3.5-6.6 hours in 0-3 day-old neonates, and 2.0-4.0 hours in neonates 4 day-old or older.
3. A dose response was evident between the 10 mg/kg administration group and the 20 mg/kg group.
4. Urinary recovery rates of AZT in the first 6 hours after administration ranged between 17.8 and 69.9%.
5. No clinical side effects were observed in the administration of AZT alone (6 cases), or in combination with ampicillin (9 cases). Thrombocytosis was observed in 1 case as an abnormal laboratory finding, but it returned to normal within 1 week after the completion of AZT administration.
6. AZT had a potent antimicrobial activity against Gram-negative aerobes and hardly induced β-lactamase. Furthermore, side effects were not observed in this study. Therefore, AZT is considered to be useful for the treatment of urinary tract infections and other serious infections caused by Gram-negative pathogens even in the neonatal period.

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Aztreonam (AZT) was studied for its pharmacokinetics, clinical effect and effect on intestinal bacterial flora in neonates, and the results obtained are summarized as follows:
1. Serum concentrations of AZT upon intravenous administration of 20 mg/kg were 38.6 μg/ml in 30 minutes, 30.6 μg/ml in 1 hour and 13.6 μg/ml in 6 hours. The T 1/2 was 3.73 hours. Ampicillin (ABPC) 25 mg/kg was concurrently used with AZT in 2 cases and serum concentrations of AZT in these 2 cases were 40.3 and 36.9 pg/ml in 30 minutes, 35.7 and 32.6 μg/ml in 1 hour, and 13.1 and 10.2 μg/ml in 6 hours, respectively. T 1/2's were 3.32 and 2.91 hours, respectively, and no interaction between the 2 drugs was observed.
2. AZT was administered to 21 neonates between 0 and 83 days of age and ABPC was concurrently administered to 18 of the cases. Clinical evaluation was made in 14 cases, where AZT was remarkably effective in 7 cases, effective in 6 cases and not effective in 1 case. Of the 21 cases, 1 case of diarrhea, 1 case each of eosinophilia, an increase in platelets, an increase in platelets and an elevation of GOT and a decrease in platelets were recorded.
3. With respect to effects of AZT on intestinal bacterial flora, fecal concentrations of AZT upon its single administration to 2 cases were low suggesting, there was little effect on the intestinal flora. Some effect on anaerobes, however, was recognized in 4 cases in which ABPC was concurrently used.

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In order to study serum concentration and urinary concentration (urinary recovery rate) of aztreonam (AZT), AZT was administered via intravenous bolus injection at dose levels of 10 mg/kg, 20 mg/kg and 50 mg/kg to 7 cases of 4 to 26 days old mature or premature infants nearing cure-stage of various bacterial infections upon the treatment with AZT. Clinical evaluation was made in 19 cases with therapy with AZT alone and 13 cases with combination therapy with AZT+ ampicillin (ABPC), with a total of 32 cases. The former group included 10 males and 9 females of 0 to 43 days of age and the latter group included 7 males and 6 females of 6 to 41 days of age. All the cases treated with AZT alone including 5 cases for prophylaxis were evaluable. In the 13 combination therapy cases, however, the effect of AZT was evaluable only in 3 cases excluding the cases in which ABPC-susceptible bacteria were the culprits.
1. Changes in serum concentrations and urinary recovery of AZT.
Pharmacokinetics of AZT in serum was examined in 5 matured infants at dose levels of 10 mg/kg in 2 cases and 20 mg/kg in 3 cases. Highest levels were observed with the first sampling at 30 minutes after administration in all the cases with values of 29.1 pg/ml with 10 mg/kg dose, and 37.8μg/ml and 55.5μg/ml with 20 mg/kg dose in cases with ages between 4 and 7 days and 1 case with age above 8 days, respectively. Half-life (T1/2) values were 3.42, 3.05 and 1.58 hours, respectively for the above three groups of patients. As is described here, the T1/2 value in the infant with age above 8 days was considerably shorter than the T1/2 values in infants of younger day-ages. Urinary recovery rates of administered AZT were between 10.4 and 52.6%, showing a large individual diversity. In addition to the above cases, one premature infant was administered with AZT(the dose level: 50 mg/kg) and examined for pharmacokinetic parameters at day-ages of 11 days and 19 days. Serum levels of AZT examined were the highest at 30 minutes after dosage (the first sampling) and were 106.8μg/ml at 11 days of age, and 90.4μg/ml at 19 days of age. Serum levels decreased to 16.2 and 9.6μg/ml, respectively, in 8 hours after dosage, at ages of 11 and 19 days. T 1/2 values were 2.62 and 2.35 hours, respectively. The urinary recovery rate in the first 4 hours after administration was 21.1% at the day-age of 11 days.
2. Clinical results
All the cases treated with AZT alone satisfied the criteria for clinical evaluation. The examined cases included purulent meningitis 1, bacteremia, septicemia (including a suspected case) 5, pneumonia 2, urinary tract infection 6 and prophylaxis 5, a total of 19 cases and AZTtreatment showed “good” or even better results in all the cases. Causative bacteria were identified in 13 cases (Escherichia coli 7,Klebsiella pneumoniae 5 and Pseudomonas aeruginosa1) out of 14 cases, excluding 5 prophylactic cases, and all of them were eradicated in the course of the treatment. Dosage levels of AZT were in a range between 36.9 and 152.7 mg/kg/day excluding the prophylactic cases, but, for bacteremia, septicemia and meningitis, dosages exceeding 100 mg/kg/day were given to 3 out of 6 cases. In the combination therapy of AZT with ABPC, it was possible to evaluate clinical efficacies of AZT in only for 3 out of 13 cases. All of the 3 cases were urinary tract infections and AZT showed “good” or even better results. Causative bacteria were P. aeruginosa,Morganella morganii+Klebsiella oxytocaandE. coli+Bacteroides fragilis and all of them were eradicated during the treatment. Dosage levels of AZT were in a range between 60.5 and 66.1mg/kg. Subjective or objective side effect was not observed in any case. As for abnormal laboratory test values, one prophylactic case of the therapy with AZT alone showed eosinophilia.

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Absorption and excretion of aztreonam (AZT) in neonates were studied and its clinical evaluation in 10 cases of neonates was perfomed using 1 hour intravenous drip infusion.
1. Serum concentrations of AZT in 7 neonates younger than 11 days of age were lower than those in infants.
2. Serum concentrations of AZT in 5 neonates given 20 mg/kg reached their peaks at the end of intravenous drip infusion with an average value of 45.8±10.41 μg/ml, and T 1/2 was 2.77±0.32 hours on the average.
3. Serum concentrations of AZT in 2 neonates given AZT 25 mg/kg reached their peaks at the end of intravenous drip infusion at 31.1 and 33.4 μg/ml with little difference from the 20 mg/kg group. Half-lives of serum AZT in the 2 cases were 1.87 hours and 3.23 hours, respectively.
4. Urinary excretion rates of AZT in 7 neonates younger than 11 days of age in the first 6 to 8 hours after the administration were 18.8 to 50.0%, or 31.7% on the average, which was lower than the average excretion rate found with infants.
5. All the cases given AZT showed clinical results rated better than “effective”. Effect of AZT was excellent on 3 UTI cases caused by Escherichia coli and Klebsiella pneumoniae, but bacterial replacement (superinfection) of Enterococcus faecalis was observed when AZT was administered.
6. Transient elevations of GOT and GPT were seen in 2 cases when AZT administration was continued at length. Clinical side effect was not observed.
7. The most appropriate dosage and administration scheme of AZT against Gram-negative infections in neonates seems to be 40-60 mg/kg/day, b.i.d. or t.i.d.

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Pharmacokinetic, bacteriological and clinical studies on aztreonam (AZT) were peformed in neonates. The results obtained are summarized as follows.
1. Plasma levels and urinary excretion of AZT were determined in 18 neonates with ages between 1 and 30 days (gestation periods were 36 to 40 weeks and birth weights were 1,890 to 4,300g) and in 2 infants with 54 and 60 days of age (gestation periods were 36 and 40 weeks, and birth weights were 2,300 and 3,300 g, respectively) upon one-shot intravenous injection of AZT 10 mg/kg (7 cases) or 20 mg/kg (11 cases) to the 18 neonates and 20 mg/kg to the 2 infants. Ampicilin (ABPC) 25 mg/kg was simultaneously injected to 5 cases of the neonates given AZT 20 mg/kg by one-shot intravenous injection and plasma concentrations of ABPC in these 5 cases were also studied.
Plasma concentrations in neonates at 0.5 hour after intravenous injection of AZT 10 mg/kg were 11.5 to 27.6 μg/ml (average 20.3± 5.5 μg/ml) and decreased with half-lives of 2.72 to 5.70 hours (average 3.81±1.28 hours), and the plasma levels at 8 hours after administration were 3.3 to 8.7 μg/ml (average 5.8± 2.5 μg/ml). In the cases given AZT at 20 mg/kg, plasma levels at 0.5 hour were 12.4 to 48.8 μg/ml (average 35.9± 11.6 μg/ml) and decreased with half-lives of 1.69 to 4.14 hours (average 2.94±0.76 hours) and AZT levels at 8 hours were 1.1 to 10.6 μg/ml (average 5.6±3.6 μg/ml). Urinary recovery rates in the first 8 hours after intravenous injection of the 10 mg/kg group were 15.5 to 61.9% (average 37.8±21.8%) and 16.3 to 62.2% (average 43.5±16.2%) for the 20 mg/kg group.
Plasma concentrations in infants after administration of AZT 20 mg/kg were 33.0 to 35.6 μ g/ml (average 34.3± 1.8 μg/ml) at 0.5 hour and decreased with half-lives of 1.76 to 3.77 hours (average 2.77± 1.42 hours) and AZT plasma levels at 8 hours were 1.4 to 5.8 pg/ml (average 3.6±3.1 μg/ml). Urinary recovery rates were 35.4 to 64.8% (average 50.1±20.8%).
These results suggested that AZT shows a dose-dependent, high plasma concentration even in the neonatal period, as well as good urinary excretion from an early stage of the administration. Although there were considerable individual differences, the peak values (at 0.5 hour) tended to be lower with the increase of day-age, but showing a tendency with somewhat higher peak levels in premature infants. The half-lives tended to be shorter with the increase of dayage, and they are particularly short in matured infants.
Also, plasma concentration changes and urinary recovery rates of AZT in the combination therapy of AZT and ABPC were compared with those in the AZT-monotherapy. The results indicated that the absorption and excretion of AZT were not significantly affected by the concomitant use of ABPC. In the same combination cases, the plasma concentration levels of ABPC were lower than those of AZT with considerable shorter half-life than AZT.
2. AZT alone or AZT in combination with ABPC (the latter until the identification of bacteria) were administered to 56 neonates in whom bacterial infections were presumed to be existing or onsets of bacterial infections were expected, in order to study clinical effect, bacteriological effect and side effect of AZT.
Upon monotherapy with AZT in 6 cases each with acute pneumonia and acute urinary tract infections, a totaling of 12 cases, the clinical effect was excellent in every case. The combination therapy with AZT and ABPC in 18 cases showed efficacies of “effective” or higher rating, namely, “effective” in 1 case of suppurative meningitis, “excellent” in 7 cases of acute pneumonia and 2 cases of acute upper respiratory tract infection, and “excellent” and “effective” in 3 cases and 5 cases, respectively, of intrauterine infection.

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Pharmacokinetic and clinical studies on aztreonam (AZT) were performed in neonates.
Serum concentrations and urinary excretion of AZT were determined in 12 neonates with ages between 0 and 7 days (birth weights were between 1,260 and 3,500 g) upon intravenous injection or 1 hour drip intravenous infusion of AZT at 20 mg/kg. Serum concentrations of AZT at 1 hour after i.v. administration were 54.0±12.5μg/ml, and half-lives were 6.01±0.70 hours. Serum concentrations of AZT reached their peaks at the end of drip infusion with levels of 42.1±17.6μg/ml in the d.i.v. group and half-lives were 6.40±1.88 hours. Urinary recovery rates in the first 12 hours after administration were 28.5±6.4% for the i.v. group and 32.3± 13.9% for the d.i.v. group.
AZT was administered to 12 neonatal patients (2 cases of sepsis, 2 cases of suspected sepsis, 3 cases of pneumonia, 2 cases of urinary tract infection and 3 cases for prophylaxis), and clinical effectiveness, bacteriological efficacy and adverse reactions were evaluated. Clinical efficacies in 9 cases except 3 cases with prophylactic use were excellent in 1 case, good in 5 cases, fair in 1 case, poor in 1 case and unknown in 1 case, thus the efficacy rate was 75%. Bacteriological effects in 3 strains with Gram-negative bacilli were eradicated in 2 strains and unchanged in 1 strain, hence the bacteriological eradication rate was 66.7%.
Increased GOT and GPT were observed in 1 case as abnormal laboratory test results, but the abnormality was not serious.
It was concluded that the clinical results of AZT are indicative of usefullness and the safety of the drug in the treatment of infections in neonates.

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Pharmacokinetic and clinical studies on aztreonam (AZT) in mature and premature neonates were carried out.
The results are summarized as follows.
The mean serum peak level of AZT after intravenous administration at a single dose of 20 mg/kg in 3 to 4 day-old-neonates was 36.6±2.39μg/ml at 1 hour after dosage. The mean serum level at 6 hours after dosage was 13.5±2.03μg/ml. The mean half-life time was 3.86±0.92 hours.
The mean urinary excretion rate was 25.1±5.18% in the first 6 hours after intravenous administration.
AZT was administered in 4 cases, but the effects could not be evaluated. No side effect was observed except an elevation of GOT.

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Serum concentration, urinary excretion and clinical application of aztreonam (AZT) were studied as follows:
1. Serum concentrations of AZT 1 hour after intravenous injection were 21.0 μg/ml in 1 case administered with approximately 10 mg/kg drug and 44.2 μg/ml on the average for 7 cases given approximately 20 mg/kg, indicating that serum concentrations are dose-dependent. Average serum half-life in 3 mature babies was 4.75 hours and that in 4 premature babies was 6.59 hours thus T 1/2 was longer in the latter. T 1/2 of 64 days of age newborn was 3.80 hours. Urinary recovery rates in 2 cases examined were 52.1 and 51.9%.
2. Daily dosages of AZT 39.9-63.3 mg/kg were intravenously administered to 10 newborns and prematures b.i.d. or t.i.d., 5 cases of which received AZT alone and the other 5 received AZT in combination with ampicillin (ABPC). Of the above 10 cases, AZT was given to 8 cases for treatment and to the other 2 cases for prophylaxis. Excluding 2 unascertainable cases, AZT showed good or better effectiveness in all the 6 cases in the treatment group, i.e., sepsis 1, suspected sepsis 1 and urinary tract infection 4 cases. All the identified pathogens (Escherichia coli 2 strains, Klebsiella pneumoniae 1 strain and Enterobacter 2 strains) were eliminated by the treatment. No onset of infection was observed in either of the 2 cases with prophylaxis.One of them was administered with AZT for 52 days consecutively but neither side effect nor abnormal laboratory test value was observed.
3. Side effect was not observed at all. One case each of minor degree of platelet increase and GOT elevation was recorded as an abnormal test value. The elevated GOT value continued to be high even after the completion of the administration and it was presumed to be due to the primary disease, heart failure.
4. As results of the above studies, AZT was considered to be effective and safe for neonatal infections caused by Gram-negative bacteria. It may be safer to initiate the treatment with AZT and ABPC in combination than with AZT alone before the identification of pathogen and to change the therapy to single administration of either AZT or ABPC when the pathogens are identified. With respect to method of administration, AZT 20 mg/kg 2 or 3 times a day appeared to show expected efficacy for the newborns with in 7 days after birth.

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One-shot intravenous injection of aztreonam (AZT), a monobactam-class β-lactam antibiotic, 20 mg/kg was administered to 4 neonates and 2 premature infants, a total of 6 cases, and plasma and urinary concentrations and urinary recovery rates were determined. Also, one-shot intravenous injection averaging 70.9 mg/kg/day of AZT alone was given to 0- to 43-day neonates and premature infants in b.i.d. to q.i.d. for an average of 8 days for the treatment (6 cases) and prophylaxis (11 cases) of infections. Furthermore, a combination therapy of AZT and ampicillin (ABPC) was applied to 0- to 79-day neonates and premature infants for the treatment (28 cases) and prophylaxis (18 cases) of infections. Average daily dosage of AZT 46.6 mg/kg was given by one-shot intravenous injection or by drip infusion in b.i.d. or t.i.d. for an average of 8 days. Average daily dosage of ABPC 78.6 mg/kg was given in the same daily frequency, route and average duration as AZT. Thus, clinical effects, prophylactic effects against infection, bacteriological effects as well as side effects and clinical laboratory test values were studied with the following results.
1. When AZT 20 mg/kg was administerd to 1 case each of 6- and 7-day neonates by oneshot intravenous injection, the plasma concentrations were the highest at 5 minutes after the administration in both cases. Specifically, they were 62.9 and 72.7 μg/ml with AUCs of 216.6 and 231.6 μg·hr/ml and half-lives of 2.80 and 2.97 hours, respectively. When AZT 20 mg/kg was administered to 5- and 6-day premature infants by one-shot intravenous injection, the plasma concentrations were the highest at 15 minutes after administration in the former and 5 minutes in the latter, at va·hr/ml, respectively, and larger than AUCs of the above-mentioned neonates. Half-lives were 5.74 and 4.87 hours, respectively and longer than those of the above-mentioned neonates. When AZT 20 mg/kg was administered to 8- and 13-day neonates by one-shot intravenous injection, the plasma concentrations were the highest at 30 minutes after administration in the former and 5 minutes in the latter, at values of 43.4 and 76.9 μg/ml, respectively. AUCs were 202.9 and 189.8 μg·hr/ml, respectively, and they were smaller than those of the above-mentioned neonates and premature infants. Half-lives were 3.11 and 2.00 hours and they were similar to or longer than those of the 6- and 7-day neonates.
2. Urinary concentrations were determined in the same cases as the determination of the plasma concentrations. The concentration was the highest in urine samples collected during 0 to 2 hours or 2 to 4 hours after administration showing values ranging 338 to 1,053 μg/ml and 48.6 to 75.3% of the administered drug was recovered in the first 8 hours in 5 out of 6 cases and in 6 hours in remaining 1 case after the administration. These recovery rates did not indicate significant differences in different day-ages determined.
3. Clinical effects of AZT against bacterial infections in the monotherapy were “excellent”for 2 of 6 cases and “good” for 3 and “good”; for the remaining 1 case. AZT showed prophylactic effect in every one of the 11 cases in which AZT administration was intended for the prophylaxis of infections. Meanwhile, clinical effects of AZT and ABPC in combination against bacterial infections were “good” for 25 cases, “fair” for 2 cases and “poor” for 1 case and the efficacy rate was 89.3%. In every case of the 18 cases in which administration of the drugs were intended for the prophylaxis of infections, the drug combination was prophylactically effective.
4. Bacteriological effects of AZT in the monotherapy were determined against 2 strains of Escherichia coli and a mixed infection of E. coli and Klebsiella pneumoniae and it was found that these bacteria were eradicated.

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Pharmacokinetics and clinical evaluation of aztreonam (AZT) in the neonates and premature infants were studied with the following results:
1. Serum concentrations of AZT in 60 minutes intravenous drip infusion of AZT 20 mg/kgto 6 cases of neonates with 2 to 22 days of age were 45.5±0.87 μg/ml immediately after the completion of intravenous drip infusion, 37.8±1.62 μg/ml 1 hour after, 31.2±1.92 μg/ml 2 hours after and 19.7±2.36 μg/ml 4 hours after, respectively. Serum half-life was 3.61±0.53 hours on the average.
2. Urinary excretion rate 6 hours after intravenous drip infusion was 26.4±6.36% on the average.
3. Clinical evaluation was given to 1 sepsis case of 7-days of age and it was effective.There was no abnormal clinical or laboratory finding considered to be associated with AZT.

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Aztreonam (AZT) was administered to immature infants, neonates and infants for preclinical and clinical studies.
1. Sufficient serum concentrations were obtained upon 1-hour intravenous drip infusion of AZT 40 mg/kg to infants with biliary atresia. The average T 1/2 was about 1 hour and urinary recovery rates were in a range between 35.2 and 61.3%. Biliary recovery rates were 0.03-0.4%.
2. AZT was given to 5 cases for prophylaxis and the results showed its prophylactic effect in 3 cases.
3. AZT is effective against Gram-negative bacteria and its efficacies in the treatment of
4 infection-cases were “excellent” in 2 cases and “effective” and “somewhat effective” in 1 case each.4. Neither side effects nor abnormal laboratory test values were observed in any of the 9 cases given AZT.

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Pharmacokinetic and clinical studies on aztreonam (AZT) in pediatric surgery were performed and results obtained are summarized below.
1. Plasma and urinary levels of AZT were measured in 6 neonate patients following dripinfusion for 1 hour of AZT (dose of AZT: 20 mg/kg). Plasma levels reached their peak (42.3-50.4 μg/ml) at the end of infusion or in 1 hour thereafter except in case 2. In case 2, plasma level reached its peak (36.6 μg/ml) at 2 hours after the end of infusion. Plasma levels of AZT decreased rapidly after reaching their peaks, and plasma half-lives (T 1/2) were 1.85-2.84 hours. Urinary recovery rates were 15.7-65.3%.
2. Bile levels of AZT were determined in 8 patients with biliary atresia following 1 hour drip-infusion of AZT (dose of AZT: 20 mg/kg for 4 patients, 40 mg/kg for the other 4 patients). In the 20 mg/kg group, peak levels of AZT in bile were noted 2 hours after the end of infusion, and they were 3.7-7.1 μg/ml. Recovery rates in bile in the first 6 hours after the end of infusion were 0.34-0.9%. In the 40 mg/kg group, peak levels of AZT in bile were found at 2 hours and 2-4 hours after the end of infusion, and they were 4.9-8.8 μg/ml. Recovery rates in bile in the first 6 hours after the end of infusion were 0.03-0.33%.
3. AZT and ampicillin were administered to 6 patients as prophylaxis against postoperative infections. Another patient with postoperative cholangitis was given AZT alone. No infectious complications, or clinical or laboratory adverse reactions due to the administration of AZT were observed in the patients upon the prophylactic use. In the patient with cholangitis, clinical effect was good but the organism in his bile was not eradicated.
It is conculuded that AZT is an effective and safe antibiotics in pediatric surgery.

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Pharmacokinetics and clinical study of aztreonam (AZT) in neonates and premature infants were conducted with the following results:
1. Pharmacokinetics
(1) Serum concentrations of AZT at 30 minutes after one-shot intravenous injection of 10 mg/kg and 20 mg/kg to neonates including premature infants were 20.6-26.6μg/ml and 38.5-46.4μg/ml, respectively, and decreased thereafter. A dose response was observed in the serum concentrations with administration of AZT 10 mg/kg and 20 mg/kg.
(2) Serum half-lives (T 1/2) tended to be shorter in both mature and premature infants as their day-ages increased and T 1/2 tended to be prolonged in premature infants compared with mature infants.
(3) Changes in serum concentration upon one-hour intravenous drip infusion of AZT 20 mg/kg were very similar to those upon one-shot intravenous injection.
(4) Urinary excretions in the first 6 hours after one-shot intravenous injection of AZT 10mg/kg or 20 mg/kg tended to increase in mature infants as they grew and showed excretion rate of 26.2-54.3% but those in premature infants did not show any specific tendency with rate of 17.5-45.1%. Urinary excretions upon intravenous drip-infusion showed a tendency very similar to those upon intravenous injection.
2. Clinical studies
(1) Clinically evaluable cases of AZT treatment were 88 cases (91 diseases), in which pathogenic organisms were identified in 56 cases (Group A), i.e., sepsis 9, purulent meningitis 2, pneumonia 8, urinary tract infection (UTI) 33 and others. Total efficacy rate was 98.2% including “excellent” (39), “good”(16) and “fair”(1). Number of cases in which pathogenic organisms were unknown (Group B) was 11, i.e., suspected sepsis (4), pneumonia (3) and intrauterine infection (4) and the efficacy rate was 100% with “excellent”(4) and “good” (7). Thus, both group A and B showed excellent results. AZT was also given to 24 cases for prophylaxis and all the cases showed prophylactic effect of AZT.
(2) Bacteriologically AZT was deemed effective in 53 cases out of 56 (Group A) with identified pathogens “eradicated”(51) and “unchanged”(2), thus the bacterial eradication rate was 96.2%.
(3) A minor degree of loose feces was observed in 1 (1.3%) of 80 cases as a side effect. Abnormal laboratory test values found were eosinophilia (3 cases), elevation of GOT and GPT (2), platelet-increase (1), elevation of GOT (1), and thrombocytopenia·elevation of GOT·GPT·LDH (1). Every one of these was of a minor degree and transient.
From the above pharmacokinetics and clinical results, standard dosage of AZT to neonates and premature infants should be in a unit dose of 20 mg/kg, twice daily to those with ages between 0 and 3 days, and 2 to 3 times daily to those with ages 4 days and above, by intravenous injection or intravenous drip infusion.

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Pharmacokinetics and clinical effects were studied in a combination therapy with aztreonam (AZT) and ampicillin (ABPC) in neonates and premature infants. The results obtained are summarized as follows.
1. Pharmacokinetics
(1) Average serum concentrations at 30 minutes after one-shot intravenous injection of AZT 20 mg/kg and ABPC 25 mg/kg to a 4-7 days age-group of neonates were 41.3 (AZT) and 30.5 (ABPC) μg/ml, respectively. They gradually decreased to 14.7 and 2.7 μg/ml at 6 hours after the administration, but the concentration of AZT was always higher than that of ABPC.
(2) Serum half-lives (T 1/2) in the 4-7 days age-group were 3.61 hours for AZT and 1.42 hours for ABPC, thus T 1/2 of AZT was longer. However, T 1/2 of AZT was scarcely affected in the concomitant administration of ABPC.
(3) Urinary excretion of AZT in the concomitant administration to the 4-7 days age-group was 52.7%, which was the same or a little higher comparing to that in AZT alone administration.
2. Clinical studies
(1) AZT and ABPC were concomitantly administered to 160 cases and 133 cases were evaluated for efficacy. Pathogenic organisms were identified in 29 cases (Group A) and the efficacy rate was 86.2% (25/29). The number of cases in which pathogenic organisms were not identified (Group B) was 50 and in this group, the efficacy rate was excellent, 94.0% (47/50). AZT and ABPC were concomitantly administered to 54 cases for prophylaxis and in all the cases the administrations showed prophylactic effect.
(2) Bacterial changes were confirmed in 21 of the 29 cases in which pathogenic organisms were identified initially and all of these 21 cases showed bacterial eradication, i.e., the bacterial eradication rate in the treatment was 100%.
(3) There were 2 cases in which side-effects were observed among the analyzed 152 cases (1.3%). The side effects found were 1 case each of diarrhea and eruption. Abnormal laboratory values were found in 23 cases (15.9%), i.e., eosinophilia (9 cases), platelet-increase (4), elevation of GOT (4), elevation of GOT and GPT (3) and others (3).
From the above pharmacokinetics and clinical results, the combination therapy of AZT and ABPC is considered to be one of the useful empiric antibiotic-therapies when pathogenic organisms are unknown in the infections of neonates and premature infants.

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