In this study, 120 mg of micronomicin (MCR) was given to 15 cases intended for cholecystectomy intra-muscularly by a single injection or 5 consecutive injections (in the evening of day-2, morning and evening of day-1, morning of day 0, and 1 hour before operation) or intravenously by 1-hour drip infusion, and levels of MCR in serum, B bile and gallbladder tissues were determined by means of HPLC and bioassay.
1. The serum level of MCR 30 minutes after consecutive injections (8 cases) was 11.86±1.90μg/ml, significantly higher than that after the single injection, 7.08±0.93 μg/ml.2. The highest bile level of MCR after consecutive injections was 10.0μg/ml. The average level in 4 detectable cases, 6.33±2.06 μg/ml, came up to 50% of the serum level and was higher than that after the single injection, 3.53±1.39 μg/ml.
3. The gallbladder tissue level of MCR after consecutive injections was 4.5μg/g at the highest and 2.51±0.73μg/g on the average in 5 detectable cases. This was equivalent to 20% of the serum level and higher than that after the single injection, 1.63±0.26 μg/g.
4. The MIC of MCR could be determined against 8 of 10 strains detected in B bile. Against E. coli and K. pneumoniae, main causal bacteria of bile duct infections, it was as low as 0.39 to 0. 78μg/ml. Levels of MCR in bile and gallbladder tissues determined in this study exceeded by far the above MIC. From these results, it can be expected that clinical administration of MCR at 2 doses of 120 mg daily for 3 days or more will give rise to a sufficiently antibacterial effect against Gram-negative bacilli.

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The pharmacokinetics of sisomicin (SISO) were determined in 3 patients including a case with mild renal dysfunction after intravenous infusion over 1 hour of a single dose of 50 mg. The peak serum concentra-tion was ranged from 3.3 to 3.9μg/ml with about 2 hours of half-life in patients with normal renal function and 4.5 hours in a patient with renal impaired function. This result suggested that dosage regimen should be adjusted in patients with renal impaired function.
Clinical response was evaluated in treatment of 16 cases with chronic complicated UTI. SISO was administered intravenously over 1 or 1.5 hours at a daily dose of 100 or 150 mg. An overall excellent or moderate effect was seen in 68.8% of treatment cases with the evaluation by the UTI committee's criteria. As for clinical laboratory abnormal values, a slight but reversible increase of BUN was observed in 1 case.
In conclusion, intravenous administration of SISO appeared to be effective and useful method for treat-ment of complicated UTI.

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Antibiotic sensitivity of H. influenzae collected from 8 hospital laboratories in the Sendai area during Jan. and Apr., 1984 were determined. One hundred and eighty-seven strains of H. influenzae isolated from different infectious sites were tested for their susceptibility to several representative antibiotics. Twenty-six strains (13.9%) of the isolates were β-lactamase positive and none of these strains could be serotyped be-cause of a lack of capsules. It was remarkable that β-lactamase positive strains were rather common in infants under 1 year of age (4 from 23 strains, 17.4%).
Minimum inhibitory concentrations (MICs) of antibiotics against H. influenzae revealed that most β-lactamase negative strains were highly sensitive to both ampicillin and amoxicillin (AMPC), while their MICs to β-lactamase positive strains were widely distributed from 1.56 (3.13) to more than 100μg/ml. BRL 25000, a formulation of AMPC and clavulanic acid, inhibited the growth of all β-lactamase positive strains at concentrations of 1.56μg/ml or less.
Among cephalosporins, the sensitivity to drugs did not differ between β-lactamase negative and positive strains. It was also noteworthy that 7 strains (3.8%) of the isolated H. influenzae were resistant to chloram-phenicol, and 2 of them were β-lactamase positive. The most active drug against H. influenzae, therefore, seemed to be the third generation of cephalosporins, especially cefmenoxime which was extremely active to all the strains tested.

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The concentration transferred to human serum and tissues in oral region after the administration of cefmenoxime (CMX) were investigated. The results were obtained as follows:
1. The mean values of CMX-concentrations in serum at 15, 30, 60, 120 and 180 minutes after the intra-venous administration of 20 ml of 5% glucose solution containing 1 g of CMX were 84.1, 52.7, 28.2, 12.7 and 8.81μg/ml, respectively.
The half-life times of serum concentration at T 1/2α and T 1/2β were 0.55 and 1.05 hours, respectively.
2. The mean concentrations transferred to gingiva at 15 (1 case), 30, 60 and 120 minutes after the intravenous administration of the same dose of CMX were 49.2, 14.1, 9.93 and 3.48 μg/g, respectively.
Moreover, the ratios (tissue concentration to serum concentration) were also 67.50, 27.95, 38.46 and 32.28% at each time, respectively.
3. CMX was administered intravenously for postoperative treatments of 13 patients, resulting in good effect from the laboratory data and clinical findings.
No side effects were obtained.

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Bacterial isolates from the patients with pulmonary infections have been collected over these 3 years,in collaboration with investigators at 13 hospitals in various parts of Japan for the study on frequency of isolation of pathogens among the patients and their drug susceptibilities. Possible causative pathogens mainly isolated from sputum in patients with lower respiratory tract infections during period from September 1983 to March 1984, were collected.
The frequency of bacterial isolates from the sputum and their drug susceptibility on H. influenzae among the various pathogens are discussed. The kinds of bacterial species isolated from the patients with respira-tory tract infections associated with chronic bronchitis, chronic capillary bronchitis or bronchiectasis and their relative frequency of isolation were as follows; Total numbers of bacterial isolates collected from various hospitals were 220 strains in 1981, 168 strains 1982 and 258 strains in 1983. H. influenzae was always isolated with highest frequency of 50.5% in 1981, 45.8% in 1982 and 40.7% in 1983, and followed by P. aeruginosa (24.1%), S. aureus (8.2%), S. pneumoniae (7.3%) and K. pneumoniae (5.9%) and E. coli (4.1%) in 1981; P. aeruginosa (30.4%), S. pneumoniae (11.9%), S. aureus (4.8%), K. pneumoniae (3.0%) and E. coli (1.8%) in 1982; P. aeruginosa (26.7%), S. pneumoniae (10.1%), S. aureus (7.8%), K. pneumoniae (3.5%) and E. coli (3.5%) in 1983.
The drug susceptibility test of H. influenzae to ampicillin (ABPC), piperacillin (PIPC), mezlocillin (MZPC), sulbenicillin (SBPC), gentamicin (GM), amikacin (AMK), cefotiam (CTM), cefmetazole (CMZ), cefoperazone (CPZ), cefotaxime (CTX), ceftizoxime (CZX), cefmenoxime (CMX) and latamoxef (LMOX) was done by using agar micro-broth dilution methods. H. influenzae was most markedly susceptible to cephems of the third generation, especially to CMX, CZX and CTX by which about 95% of H. influenzae tested were inhibited the growth under the concentration with ≤0.10μg/ml of the drugs. Furthermore, annual changes in sus-ceptibility of H. influenzae to various antibiotics was analyzed over the period from 1981 to 1983.
The frequency of S. pneumoniae isolated from patients with chronic bronchitis or bronchiectasis was about 10% in this survey. However, in the case of respiratory infections associated with bacterial pneumonia, the frequencies were as follows; 24.8% (77 cases/311 cases) in 1981, 17.7% (44 cases/248 cases) in 1982, and 11.0% (39 cases/355 cases) in 1983. The frequency of isolation of S. pneumoniae decreased every year.
All drugs tested were found remarkably active against S. pneumoniae; 100% of S. pneumoniae were inhibited apparently by all drugs at the concentration of 6.25μg/ml. Of the cephem antibiotics of the thirdgeneration, CTX, CZX and CMX were most active. More than about 95% of S. pneumoniae were inhibited by these antibiotics at the concentration of 0.05 μg/ml. ABPC and PIPC, among penicillins, produced a noticeable antibacterial effect; all the strains tested were inhibited by these penicillins at the concentration of 0.05μg/ml.
In 1982, S. aureus was most frequency isolated 31.5% from patients with bacterial pneumonia, followed, in order, H. Influenzae 16.7%, K. pneumoniae 14.8%, S. pneumoniae and P. aeruginosa 13.0%, respectively. And also in 1983, S. aureus was most frequently isolated 27.3%, followed, in order, H. infiuenzae 22.7%, P. aeruginosa 18.2%, S. pneumoniae 11.4% and K. pneumoniae 4.5%. The frequency of S. aureus isolation increased from 11.0% in 1981 to 31.5% in 1982, and to 27.3% in 1983.

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Twenty infectious episodes were caused mainly by Gram-negative rods in 16 patients with a disorder of the hemopoietic tissue. The ages of the patients ranged between 20 and 76 years. Cefotaxime (CTX) was used alone in 9 infectious episodes (group I) and in combination with other antibiotics in the remaining 11 infectious episodes (group II). The following results were obtained.
1. A good response to CTX was noted. The clinical and bacteriological success rates were 100% and 83% in group I, and 82% and 100% in group II, respectively.
2. Bleeding was not clinically found during and after treatment of any infectious episodes with CTX. No change in PT and aPTT was noted during CTX treatment, either. CTX was thus evaluated to be an effective and safe cephem antibiotic in the treatment of infectious episodes secondary to a disorder of the hemopoietic tissue, which is usually accompanied by a marked hemorrhagic tendency.

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Doxycycline (DOXY) was administered to 45 male patients with nongonococcal urethritis. The dose was 200mg b. i. d. and the duration of administration was 14 consecutive days in principle.
The results were as follows:
1. C. trachomatis was detected from urethral swab by culture confirmation test and/or direct specimen test. Of 45 patients with nongonococcal urethritis, 25 were positive with C. trachomatis. The positive rate was 56%.
2. In the C. trachomatis positive group, the clinical efficacy was excellent in 15 patients, and fair in 4 out of 19 patients which could be studied about the clinical effect after administration. The total efficacy rate was 79%.
The efficacy in 11 patients of the C. trachomatis negative group was excellent in 7 patients and fair in 4, the total efficacy rate being 64%.
3. Microbiologically, inclusion bodies disappeared in 7 days of administration in all 9 patients which were positive with C. trachomatis by culture confirmation test.
In 19 patients which were positive by direct specimen test, elementary bodies of C. trachomatis disappeared within 7 days in 13 patients (76%) and within 14 days in all patients.
4. As to side effect, mild epigastralgia was observed in 1 patient, but medication could be continued when the dose of DOXY was reduced by half.
Clinical laboratory tests were investigated in 15 patients before and after administration and no abnormal alteration was observed.

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Thirty male patients with nongonococcal urethritis and 7 female patients nongonococcal cervicitis were treated with 200mg doxycycline (DOXY) daily over a period of 7 days. The microbiological cure rate in infections with C. trachomatis was 92.9% with the clinical effectiveness rate being 92.9%.
The clinical effectiveness rate in nonchlamydial urethritis was 63.6%. There were no statistically demonstrable difference in clinical outcome between the group of the C. trachomatis positive patients and the C. trachomatis negative patients, both treated with DOXY.
Side effects were observed in 2 cases (5.4%) who complained of gastrointestinal disorder, but no dizziness was observed.

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Twenty male patients with urethritis caused by C. trachomatis were subjected to the clinical study of treatment with doxycycline (DOXY) 100mg twice daily for 14 days. C. trachomatis was identified from urethral swab, both by direct fluorescein-conjugated anti-C. trachomatis species-specific monoclonal antibody technique (CTFA) and by culture using HeLa 229, in all cases before treatment. Almost complete agreement between CTFA and culture was obtained in the urethral swabs taken before treatment and after the 7th day of treatment. Disagreement between CTFA and culture especially CTFA-positive, culture-negative cases were observed at the third day of treatment. During the treatment course there might be the period where C. trachomatis antibody can be detected, but C. trachomatis can not be isolated by culture. After the 7th day of treatment C. trachomatis could not be identified neither by CTFA, nor by culture in all 20 cases, even after 2 to 5 weeks after the completion of the treatment. No notable side effect was experienced. Above results lead to the conclusion that treatment with DOXY 100mg twice daily for 14 days is effective against male urethritis by C. trachomatis.

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The clinical effectiveness of doxycycline (DOXY) in the treatment of chlamydial infections was studied by giving it to 14 patients composed of 9 with nongonorrheal urethritis and 5 with cervicitis, all caused by Chlamydia trachomatis. DOXY was given in an oral dose of 100mg twice daily for 4 to 19 days. The total dosage ranged from 800 to 3,800mg. The overall clinical efficacy as assessed on the basis of both bacterial response and relief of subjective or objective symptoms was excellent in all of 12 evaluable patients. Two patients for whom we failed to perform postdose bacteriological examinations were excluded from evaluation. No side effect related to dosing of DOXY developed.

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This report summarizes the results of joint studies in pediatrics on aztreonam, the first monobactam antibiotic for practical use.
1. Pharmacokinetics was studied in 53 cases administered with 10, 20, 40 and 50mg/kg of aztreonam (AZT) by intravenous injection and 20 cases with 10, 20, 30, and 40mg/kg by drip infusion.
All the cases had normal hepatic and renal functions at the administration. T 1/2 was in a relatively fixed range of 1.35-1.56 hours in intravenous injection cases and 1.30-1.55 hours in drip infusion. One hour after commencing administration of standard 20mg/kg, the serum concentrations were 50.18±4.24μg/ml in intravenous injection and 116.33±10.18μg/ml in drip infusion and even 6 hours after the end of the administration, they were 5.80±1.16μg/ml and 3.38±0.58μg/ml, respectively.
The cerebrospinal fluid penetration was studied on suppurative meningitis (5 cases) and nonbacterial meningitis (3 cases). The penetration was generally good with sufficient concentration for meningitis caused by E. coli and H. influenzae. Amount of the penetration decreased as the cases were improved.
2. Twenty-nine (29) cases were excluded and 262 cases of total 291 were clinically assessed, and the pathogen-isolated 167 cases of 262 were principally analyzed. Efficacy of AZT was “excellent” for all 3 cases of E. coli sepsis and 1 case of N. meningitidis meningitis and “good” for 1 case of H. influenzae meningitis.
The effective rate was 94.6% for 37 pneumonia cases, 94.7% for 76 UTI cases and 88.5% on the whole including as many as 98 “excellent” cases. However, the effective rate for 21 enteritis cases was only 52.4%. Similar trend was observed in the pathogen-unknown group and overall effective rate of total 267 cases was 86.8%.
3. The clinical effect by pathogen was 97.7% for 44 E. coli cases and 97.1% for 34 H. influenzae cases, showing excellent results for the GNB group. AZT was also effective for 8 out of 11 P. aeruginosa cases.
4. With regard to microbiological effect by pathogen, AZT showed a high rate of bacterial elimination for GNB, primarily 98.1% for E. coli and 100% for H. influenzae followed by 76.9% for P. aeruginosa. However, it was only 30.0% for Salmonella. Excluding the Salmonella cases, GNB elimination rate was 93.5%.
5. Clinical and microbiological dose response was not clear partly because, same as the previous studies, the effective rate of AZT was high. It was considered, however, standard dose of 20mg/kg×3-4 times a day was recommendable.
6. AZT was administered to the 53 cases which had not been responsive to more than 3 days administration of other antibiotics and 27 cases showed “excellent” result, 13 cases “good” with total effective rate of 75.5%. Causative microorganisms eliminated by AZT were E. coli (5/6), H. influenzae (5/5), P. aeruginosa (4/6) and K. pneumoniae (3/3). On the whole, bacteria were eliminated in 26 of total 32 GNB strains, decreased in 2 and unchanged only in 4. There was 1 S. aureus strain, which was unchanged. The bacterial elimination rate of AZT administered to the cases previously treated by penicillins was 88.9% and to the cases previously treated by cephalospolins was 66.7%. Clinically successful cases were sepsis (2/3), suppurative meningitis (2/2), pneumonia (12/16), respiratory tract infection (9/10) and UTI (13/16).
7. Side effects were only rash (3 cases) and diarrhea (2 cases) with little digestive disturbance. Coagulopathy was not encountered. There were no significant abnormal laboratory findings same as available cephalosporins.
8. It was recognized that AZT is an effective and safe antibiotic for the GNB infections in pediatrics.

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Aztreonam (AZT) was evaluated for its safety, clinical efficacy and pharmacokinetics in children. AZT was effective in all the 16 children with Gram-negative bacterial infections. The diagnoses included acute bronchitis and pneumonia (11), UTI (2), UTI with bacteremia (1), purulent meningitis (1) and acute mucositis (1). The etiologic agents were H. influenzae (10), B. catarrhalis (1), N. meningitidis group C (1), E. coli (3) and P. aeruginosa (2).
The serum half-life was approximately 1.2 hours after intravenous bolus injection. Penetration into the inflamed cerebrospinal fluid was good not only in acute purulent meningitis but also in viral meningitis.
From the present study, AZT is a safe and effective antibiotic when used in children with Gram-negative bacterial infections.

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Fundamental and clinical results of AZT in pediatrics were as follows.
1. Pharmacokinetics of AZT was studied for 1 case with resulting high serum concentration and a halflife of approximate 1 hour.
2. AZT was administered to 10 patients with bacterial infections with 100% clinical efficacy and 62.5% bacterial elimination. Side effect was 1 case of diarrhea.
3. There were no abnormal laboratory or coagulation test findings nor vitamin K deficiency, platelet hypofunction or effects on intestinal bacterial flora. AZT was considered to be high in safety.
4. The administration of 20mg/kg AZT 3 times a day was considered to be an effective treatment for pediatric Gram-negative infections.

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The fundamental and clinical studies of aztreonam (AZT) were performed. The results were as follows:
1. The MICs of AZT for E. coli and Salmonella sp. which were recently isolated in the pediatric field were less than 0.78μg/ml. AZT also was effective against ABPC/PIPC-resistant bacteria. The MIC of AZT for V. parahaemolyticus was less than 1.56μg/ml.
2. The peak serum levels of AZT which were occurred just after the 1 hour drip infusion of 10-30mg/kg were 60.5-136.8μg/ml, and at 6 hours after infusion the serum levels were 1.3-6.1μg/ml; therefore, the dose response was proved. The mean half-lives (T 1/2) were between 1.21 and 1.36 hours.
3. The excretion rates in urine up to 6 hours after intravenous drip infusion were between 32.7 and 77.5%.
4. The ratio of the cerebrospinal fluid concentration to serum in the child with purulent meningitis was 3.5% at 1 hour after the intravenous injection at the dose of 69mg/kg, and the ratios of the subdural fluid levels to serum were 31.3-37.5%.
5. The levels of AZT into the feces by the multiple dosage were 0-840μg/g.
6. Twenty-five pediatric patients with acute infections had been treated by intravenous injection or drip infusion at the doses of 49-120mg/kg/day (almost 50-100mg/kg/day) for 4 to 13 days.
The efficacy rate of excellent+good was 84% and that of excellent+good+fair was 96%.
7. The efficacy rate of excellent+good was 100% in all cases with upper/lower respiratory tract infection, bronchopneumonia, and acute urinary tract infection caused by Gram-negative rods.
8. The clinical efficacy was observed in all cases with acute bacterial enteritis. Although AZT was clinically effective against Salmonella enteritis, bacteriological efficacy on the causative organisms was not observed in some cases.
9. Although AZT was bacteriologically effective in 1 patient with typhoid, it did not alleviated fever.
10. AZT showed activity to 9 strains isolated from the culture of throat swab, urine and feces.
11. No side effects were clinically observed in all cases, while slight elevations of laboratory findings were observed in 4 cases.

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Fundamental and clinical studies were carried out with aztreonam (AZT), a new monocyclic β-lactam antibiotic, in pediatric infections.
Results were as follows.
1. The mean half-lives in the vein blood were 1.09 hours, 1.18 hours, 1.22 hours after injection, when the doses were 10, 20 and 40mg/kg, respectively. Dose response was observed.
The average recovery rates in the urine between 0 and 6 hours were 40.2%, 42.3%, 50.8% when the doses were 10, 20 and 40mg/kg, respectively.
2. The antibacterial activity of AZT against 16 clinical isolates were determined in comparison with those of ABPC, CPZ, LMOX and CTX.
Against 8 clinical isolates of E. coli and 3 of H. influenzae, the activity of AZT was equal or superior to that of CPZ, LMOX and CTX, and way by far superior to that of ABPC.
3. Twenty-three pediatric patients received AZT in doses ranging from 48 to 79mg/kg divided 3 times a day; 12 cases of urinary tract infection, 9 cases of respiratory tract infection and 2 cases of bacterial enterocolitis. The rate of clinical effectiveness was 100%.
4. No side effect was observed. Slight elevation of GOT and GPT were observed in 2 cases, increase of platelet count in 2. All were considered to be transient and mild.

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Fundamental and clinical studies on aztreonam (AZT), a new monobactam antibiotic, were performed in the pediatric field.
1. The MICs of AZT were assessed against the clinically isolated strains in the pediatric infections. AZT showed an excellent antibacterial activity against Gram-negative bacteria, i. e., against E. coli (20 strains), K. pneumoniae (9), P. mirabilis (16), P. vulgaris (5), P. aeruginosa (10), S. typhimurium (4) and H. influenzae (11); the MICs of AZT against the above strains were less than 0.39μg/mI, 0.10μg/ml, 0.024μg/ml, 0.024μg/ml, 6.25μg/ml, 0.10μg/mI and 0.10μg/ml, respectively. However, antibacterial activity of AZT against Gram-positive bacteria was inferior to that against Gram-negative bacteria, i. e., against the strains of S. aureus (16) and S. pyogenes (4), those MICs were more than 400μg/ml and 3.13μg/ml, respectively.
2. Serum concentrations and urinary excretion of AZT were measured in 2 children aged 7 and 11 years after a single intravenous injection at the dose of 20mg/kg.
The mean serum concentration of AZT followed by the injection 62.5μg/ml at 1/4 hour, 28.5μg/ml at 1/2 hour, 16.5μg/ml at 1 hour, 12.0μg/ml at 2 hours, 3.6μg/ml at 4 hours and 1.1μg/ml at 6 hours, respectively. The mean half-life (β-phase) was 1.24 hours. The mean urinary concentrations after the injection were 5,000μg/ml in 0-2 hours, 1,650μg/ml in 2-4 hours and 611μg/ml in 4-6 hours and the mean urinary recovery rate up to 6 hours was 61.2%. These results in our studies were considered to be comparable with those reported in adults.
3. In our clinical studies, AZT was administered to a total of 14 cases, i. e., acute pneumonia (4 cases), acute pyelonephritis (4), acute enteritis (5) and acute sppurative cholangitis (1).
Clinical effect of AZT was excellent or good in 13 cases except fair in 1 case with acute enteritis and the efficacy rate (excellent and good) was 92.9%. With regard to bacteriological effect, all the strains of H. influenzae (3), E. coil (2), P. mirabilis (1) and P. vulgaris (1) were eradicated, but, S. typhimurium (4) was not eradicated. Neither side effect nor abnormal laboratory findings were observed during the study.

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Clinical usage of aztreonam (AZT), a newly synthesized antibiotic which belongs to monobactam, was evaluated for its efficacy and safety in 22 patients aged from 1 month-old to 13 year-5 month-old with bacterial infections and the following results were obtained.
1. AZT was administered to 4 patients with pyelonephritis and 10 patients with tonsillitis at a daily dosage of 40.4-120.9mg/kg and to 5 patients with clinical sepsis associated with agranulocytosis caused by intensive antileukemic therapy at a daily dosage of 142.4-471.4mg/kg, divided into 3 or 4, by intravenous injection or by 30 minutes drip infusion. The clinical results of these 19 evaluable patients were as follows: excellent; 10 cases, good; 5 cases, fair; 2 cases, poor; 2 cases. The over all efficacy rate was 78.9% and that of pyelonephritis and tonsillitis was 100.0%.
2. No clinical side effects were observed in any 23 patients, including a patient who proved to be suffering from Mycoplasma pneumoniae infection, and no abnormal laboratory findings caused by AZT was noticed.
3. The MICs of AZT against 9 strains isolated from patients with pyelonephritis and those with tonsillitis were as follows: MICs against all of 3 strains of K. pneumoniae were less than 0.05μg/ml. MICs against 2 out of 4 strains of H. influenzae were less than 0.05μg/ml and those of the remaining 2 strains were 0.10μg/ml. MIC against 1 strain of S. aureus was 1.56μg/ml. MIC against 1 strain of S. epidermidis was more than 100μg/ml. Bacteriological effect was evaluated about 2 patients with pyelonephritis caused by E. coli and K. pneumoniae, respectively, and about 3 patients with tonsillitis caused by H. influenzae. Eradication of causative bacteria was proved in all 5 patients.
4. These data described above suggest that AZT is a new useful antibiotic in the treatment of patients with urinary tract infection caused by Gram-negative bacteria and that it can be used in some patients with upper and lower respiratory tract infections with extreme attention to the possibility of participation of Gram-positive bacteria, to which this drug is ineffective, as the causative organisms.

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Pharmacokinetics, in vitro, and in vivo effect of aztreonam (SQ 26,776, AZT), a newly synthesized monobactam antibiotic, were investigated in pediatric patients.
The pharmacokinetics were studied in 12 children without renal or hepatic impairment, each of whom received single 10, 20 and 40mg/kg intravenous doses of drug. Serial samples of serum and urine were assayed for AZT. Serum pharmacokinetics of AZT were described by an open, linear, two-compartment kinetic model. After intravenous administration, AZT was eliminated primarily by urinary excretion of unchanged drug (60.4%). The average biological half-lives of AZT in serum were 1.33 (10mg/kg, n=1), 1.69±0.40 (20mg/kg, n=8), and 1.51±0.61 (40mg/kg, n=3) hours.
The antibacterial activity of AZT against E. coli and P. aeruginosa was equal or slightly stronger than that of CPZ, LMOX, and CTX. It had no antimicrobial activity against Gram-positive cocci.
In vivo effect of AZT was evaluated in 13 children with various infections. The result was excellent in 7 cases, good in 1 case, fair in 3 cases and poor in 1 case, with effective ratio of 66.7%. Exanthema or elevation of GOT and GPT were noticed in 3 patients.

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The authors have carried out the laboratory and clinical studies of aztreonam (AZT) and obtained the following results.
The antibacterial activities of AZT against the clinical isolates of E. coli, K. pneumoniae and P. aeruginosa were measured by the agar dilution method with inoculum size of 10⁶cells/ml. The susceptibility distribution of E. coli to AZT ranged from 0.025 or lower to 1.56μg/ml, and the peak of distribution was 0.05μg/ml. The peak of susceptibility distribution of K. pneumoniae was 0.025μg/ml or lower, and the distribution of P. aeruginosa ranged from 0.1 to 100μg/ml higher and the peak of distribution was 3.13μg/ml.
After intravenous bolus injection of 20mg of AZT in 4 children, the mean peak serum level was 117±35.1μg/ml at 15 minutes after injection, and half-life time was 1.42 hours. The mean urinary excretion rates was 63.2±30.6% up to 6 hours after bolus injection of 20mg/kg of AZT.
AZT was given 11 cases with bacterial injection. Daily doses of AZT were from 41.7 to 94.9mg/kg.Clinical results obtained were excellent and good responses in 8 of 11 cases (72.7%). No side effect was observed.

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Clinical studies of aztreonam (AZT) were performed in 10 pediatric cases. One transient pyuria case with 10³/ml E. faecalis detected in urine was excluded from clinical evaluation, because the presence of infection was unclear.
Results were as follows:
1. AZT was effective on 1 patient with meningitis (causative organism: H. influenzae), who was treated with 41.7mg/kg 4 times a day.
Results of administration of 58.1-78.9mg/kg 3 or 4 times a day by intravenous injection for 1 E. coli sepsis-and-pyelonephritis complication case and 7 pyelonephritis cases (causative organisms: E. coli in 1, E. coli+E. faecalis in 1, E. faecalis in 1, P. aeruginosa in 3 and unknown in 1) were excellent in 4, good in 2 and poor in 2 cases. The pathogens of the 2 poor cases were E. faecalis and P. aeruginosa, respectively. Six of the pyelonephritis cases had vesicoureteral refluxes as an underlying condition.
2. Clinical and microbiological effects of AZT were considered to be closely correlated with its MIC values.
3. No side effect was recognized. Though abnormal laboratory findings were obtained in 4 cases, including elevations of GOT·GPT in 2 cases, GPT elevation in 1 case and plateletcount increase in 1 case. All of these abnormalities were minor and transient.
4. The serum concentrations of AZT for a two-month-old patient with pyelonephritis were 65, 50, 35, 22.8 and 12.4μg/ml at 1/2, 1, 2, 4 and 6 hours, respectively and T1/2 was 2.42 hours after injecting AZT 20mg/kg by intravenous injection.
5. The concentrations of AZT in the cerebrospinal fluid for a patient with meningitis (causative organism: H. influenzae) were examined 30-150 minutes after intravenous injecting 41.7mg/kg AZT on the 2nd, 3rd, 4th, 5th, 6th, 8th and 15th days after commencing the treatment with recorded levels of 7.0, 4.4, 6.1, 4.4, 3.3, 2.9 and 1.9μg/ml, respectively (bioassay method). The concentration gradually decreased with the recovery of the patient, but it was still more than 30 times higher than the MIC for the pathogen.
According to the above results, AZT is considered to be a useful new antibiotic for pediatric infections.

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Aztreonam (AZT) was given intravenously to 20 children with the following acute bacterial infections: 13 cases of bronchopneumonia, 5 cases of urinary tract infection, 1 case of cervical lymphadenitis with acute tonsillitis and 1 case of acute enteritis.
Clinical effectiveness was obtained in 17 cases of 20 cases and bacteriological effectiveness in 10 strains out of 11 strains.
No side effect was observed except for 2 cases with eruption, 1 case with slight elevation of GPT, 1 case with slight elevation of GOT and 1 case with slight elevation of GOT and GPT.
From the above clinical results, it is apparent that AZT is a useful antibiotic for treating pediatric patients with various kinds of bacterial infections.

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The penetration of aztreonam (AZT), a new synthetic monobactam, into cerebrospinal fluid (CSF) and the clinical studies for bacterial infections were carried out. The following results were obtained.
1. The concentrations of AZT in CSF were less than 0.31μg/ml and 0.42μg/ml, respectively, at 1 hour after intravenous administration of 34mg/kg and 71mg/kg in 2 cases of aseptic meningitis at the acute stage.
The concentration of AZT in CSF was 6.9μg/ml at 1 hour after intravenous administration of 100mg/kg in 1 case of purulent meningitis at the acute stage and was 0.62-0.98μg/ml even at the recovering stage. At each stage, its concentration was more than the minimum inhibitory concentration of E. coli (0.10, <0.05μg/ml; at inoculum size of 10⁸, 10⁶ cells/ml).
2. Clinical efficacy of AZT was good in 2 cases of purulent meningitis, excellent in 1 case of septicemia, excellent in 5 cases of urinary tract infection, excellent in 1 case and good in 3 cases out of 4 cases of gastroenteritis, excellent in 4 cases and poor in 2 cases out of 6 cases of pneumonia and bronchitis, excellent in 2 cases and good in 1 case out of 3 cases of tonsillitis.
3. No side effects and no abnormal laboratory findings were observed except 1 case of mild diarrhea out of 21 cases.

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Efficacy and safety of aztreonam (AZT) for 31 cases of infections of children were studied with the following results.
1. Clinical efficacy of AZT for 22 respiratory tract infections, 5 urinary tract infections and 2 gastro-intestinal infections was “excellent” for 19 cases (65.5%), “good” for 9 cases (31.0%) and “poor” for 1 case (3.4%) with an overall effective rate of 96.6%.
2. Microbiological effect of AZT for 19 isolated strains (15 cases) was 100% in disappearance of the Gram-negative bacteria and 89.5% on the whole.
3. With regard to side effect of AZT in 31 cases, there was a slight elevation of GPT in 1 case and eosinophilia in 2 cases.
4. It was considered from the above results that AZT is a useful and safe antibiotic for infections of children.

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Laboratory and clinical studies were performed as follows on aztreonam (AZT), a new monobactam antibiotic.
1. Pharmacokinetics
Serum concentrations of AZT were measured in 1 patient given 20mg/kg by intravenous bolus injection. The peak concentration was 100μg/ml at 15 minutes, and T 1/2 was 1.85 hours.
2. Clinical efficacy
AZT was administrated intravenously to 10 patients in doses of 59.2-170.7mg/kg (average 76.1mg/kg) t. i. d. for 3-8 days (average 5.3 days); 5 with pneumonia, 1 with bronchitis, 1 with lymphadenitis, 1 with sepsis (suspected) and 2 with urinary tract infections. The overall efficacy rate was 80%, i.e., efficacy was excellent in 5, good in 3, fair in 1 and poor in 1.
Bacteriological efficacy was excellent, i.e., 4 of 4 Gram-negative strains disappeared.
Any clinical side effects and laboratory abnormalities were not observed.
The above results suggest that AZT is a useful antibiotic for treating pediatric bacterial infections, especially due to Gram-negative bacteria.

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Aztreonam (AZT) is the first monobactam antibiotic that has significant activity in vitro against aerobic Gram-negative bacteria but not against Gram-positive or anaerobic bacteria.
The agent was used 120-200mg/kg in daily dose to treat 10 hospitalized cases of refractory infections in pediatric field. There were 3 cases of 1 pneumonia, 4 cases of urinary tract infections, 2 cases of pyogenic meningitis and 1 case of septicemia.
Seven aerobic Gram-negative bacteria were isolated from patients and 4 bacteria were eradicated by treatment. Clinical cure was achieved in 8 out of 10 cases without adverse reaction or drug toxicity.

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Serum and urinary concentrations and recovery rates of aztreonam (SQ26, 776, AZT), a newly developed antibiotic, were studied for a total of 20 pediatric cases by one-shot intravenous injections of 10, 20 and 40mg/kg to 3, 4 and 3 cases, respectively, and by intravenous drip infusion of 10, 20 and 40mg/kg to 3, 4 and 3 cases for 1 hour, respectively.
Clinical and bacterial effects of AZT were studied by administering 76.7mg/kg per day on average for a total of 36 cases of tonsillitis (6), pneumonia (13), otitis media and pneumonia complication (1), pleurisy (1), sinusitis (1) and UTI (14). The above daily dose was given t. i. d.(9 cases) or q.i.d (27 cases), by intravenous drip infusion for 30 minutes for one t.i.d case and by one-shot intravenous injection for 7 days for the remaining 35 cases. Also, side effect and laboratory values were examined for 43 cases including 7 dropouts.
1. Serum concentration of AZT in 10 pediatric cases were measured by dosing 10, 20 and 40mg/kg by one-shot intravenous injection to 3, 4 and 3 cases, respectively. In every dosage group, the serum concentrations were highest 5 minutes after the intravenous injection with average values of 91.0, 174.0 and 175.3mcg/ml, respectively. Dose response was observed between 10mg/kg dose group and 20, 40mg/kg dose groups, but it was not between 20mg/kg group and 40 mg/kg group. This was considered to be attributable to the individual case-fluctuations in the 2 groups and to a high concentration case of 240.0mcg/ml in the 20mg/kg group. Half-life of each dosage group was 1.55, 1.65 and 1.93 hours.
2. Serum concentrations of AZT in 10 pediatric cases at the dosage level of 10, 20 and 40mg/kg for 3, 4 and 3 cases, respectively, by 1 hour intravenous drip infusion were highest at the end of the administration with average values of 95.7, 126.0 and 170.7mcg/ml, respectively. There was a dose response among the 3 groups and the half-life of them were 1.02, 1.41 and 2.48 hours, respectively. A longer half-life of the 3rd group with 40 mg/kg administration than the other 2 groups was due to 1 particular case of 4.44 hours with unknown cause of such an exceptional extension.
3. Urinary concentration in the aforementioned one-shot intravenous injection groups was highest 2-4 hours after administration for 1 case each in 20 and 40mg/kg group and highest 0-2 hours after for the remaining 8 cases. Average concentrations in every 10, 20 and 40mg/kg group was highest 0-2 hours after the administration with 1,908.0, 1,711.3 and 3,940.0mcg/ml, respectively. Average recovery rates by 6 hours after administration were 65.9, 56.4 and 50.4%, respectively, with unknown cause of an exceptionally low case of 18.7% in the 20mg/kg group.
4. Urinary concentrations in any 1 case of the aforementioned intravenous drip groups was highest 0-2 hours after administration and average concentrations in 10, 20 and 40mg/kg groups were 1,157.3, 1,938.2 and 3,648.6mcg/ml, respectively. Average recovery rates 6 hours after administration were 50.5, 48.8 and 62.7%, respectively.
5. Clinical effect of AZT was “good” or “excellent” for 31 of 36 various bacterial infection cases with a favorable rate of 86.1%.
6. Microbiological effect was evaluable for 5 E. coil cases and 1 P. mirabilis case, a total of 6 cases and all of them disappeared.
7. No side effect was reported on 43 cases including the dropouts. With regard to the laboratory test, 1 case leukopenia and 2 cases eosinophilia were reported. No abnoraml findings were reported on Al-P, LDH, BUN, creatinine, but 4 cases each of independent GOT or GPT elevation and 1 case of concurrent GOT and GPT elevation were noted.

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Aztreonam (AZT) and ampicillin (ABPC) were independently administered to 6 and 7 rabbits respectively, with S. aureus meningitis. Additionally, AZT and ABPC were concomitantly given to 6 rabbits with S. aureus meningitis. Concentrations of AZT and ABPC in cerebrospinal fluid (CSF) and serum were determined by HPLC method, and the results in concomitant treatment were compared with those for single treatment of each agent. Results were as follows:
1. Maximum serum concentrations of AZT in concomitant treatment of AZT and ABPC were higher than those in single treatment of AZT. However, there was no significant difference between the 2 treatment groups with regard to maximum CSF concentration, percentage of AUC of CSF to serum, and T 1/2 of the CSF and serum concentrations of AZT. ABPC in the concomitant treatment did not influence the CSF concentration of AZT.
2. There was no significant difference in serum concentration of ABPC between concomitant treatment and the single one. However, the values of maximum CSF concentration, percentage of maximum CSF to serum concentration and percentage of AUC of CSF to serum in the concomitant treatment were lower than those in the single treatment of ABPC. With regard to T 1/2 of CSF concentration of ABPC, there was no remarkable difference between the 2 treatment groups. The above results suggest that the distribution of ABPC into CSF is suppressed in the concomitant treatment of AZT and ABPC.
3. AZT has no antimicrobial activity against Gram-positive bacteria. The CSF concentration of ABPC is suppressed in the concomitant treatment. Those facts suggest that AZT should be administered for meningitis cases after the identification of causative pathogens.

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Aztreonam (AZT), a new injectable monobactam antibiotic, was administered to 7 healthy male volunteers, aged 21-28 years (23 years, on average) and weighing 60.5-87.0 kg,(69.5 kg, on average) by one shot intravenous injection of 1,000 mg twice a day for 5 days. The effect of AZT on the fecal flora was studied 3 days before administration, on the day of the initiation, 3 and 5 days (end of the administration course) after the initiation, and 3, 5 and 10 days after the end of the administration. Fecal concentration of AZT was also studied. Also, fecal concentration and recovery rate of AZT in 4 healthy male volunteers aged 23-31 years (26 years, on average), weighing 59.5-70.5kg (65.6 kg, on average) were measured by injecting 1,000mg of AZT by intravenous injection only one time. Susceptibility of the bacteria isolated from the 7 cases receiving consecutive dosage to AZT, cefmetazole (CMZ), latamoxef (LMOX), cefoperazone (CPZ) and ceftazidime (CAZ) as well as side effect and laboratory values were examined with the following results.
1. In the fecal flora, the population of Enterobacteriaceae on average was 10⁷ cells/g feces on the day of the initiation and decreased by 2 logarithms to 10⁵ cells/g 3 days after the initiation, 10⁵ cells/g feces 5 days after the initiation with no bacterial isolation in 2 cases, 10⁷ cells/g feces on 3 and 5 days after the end of administration respectively with recovery of the population to the average population on the day of the initiation. However, it increased 10 days after the end of administration with the population of 10⁹ cells/g feces due to the isolation of one 10¹⁰ cells/g feces, which was an increase by 2 logarithms as compared with average population before the administration. It was also higher than the average population 3 days before the initiation of administration. Temporal decrease or disappearance of the bacteria were noted by the administration of AZT. As to other cases of Gram-negative bacilli, Pseudomonas sp. was detected from only 2 cases 3 days before the initiation of administration and on the day of the initiation, but there was an increase to 4 and 5 cases 3 and 5 days after the initiation respectively. Number of isolation returned to 2 cases, 3, 5 and 10 days after the end of administration respectively and it was same as the number before the initiation of administration.
As to Gram-positive Staphylococcus sp., average population was in the level of 10⁸ cells/g feces on the day of the initiation and it increased by 2 logarithms to 10¹⁰ cells/g feces 3 days after the initiation and was in the range of 10⁷-10⁹ cells/g 5 days after the initiation, 3 and 5 days after the end of administration, which was similar to the level at the time of initiation. At the end of the administration, number of isolation case decreased to 5 but this was not considered to indicate a decreasing trend due to 4 isolation cases detected 3 days before the initiation of administration. There was not a significant change in the population of Enterococcus sp. with 10⁷-10⁹ cells/g feces range on any day of the examination. The population of Candida sp. was in the level of 10⁸ cells/g feces both 3 days before the initiation and on the day of the initiation, but it showed a gradually-increasing trend with 10⁵, 10⁷ and 10⁸ cells/g feces 3 and 5 days after the initiation and 3 days after the end of administration, respectively. It was in the level of 10⁶ cells/g feces 5 days after the end of administration and there were 3 isolation cases 10 days after the end of administration and one of them showed a higher population than at the initiation by 3 logarithms.

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Aztreonam (E-0734, AZT) was administered to pneumonia and chronic respiratory tract infections. The results were as follows:
1. AZT was administered to 29 patients. Twenty-six cases were evaluable and 3 cases were excluded from evaluation of efficacy because 1 was Gram-positive infection, 2 were unclear symptom of infection.
2. Pneumonia was 4 cases. Chronic respiratory tract infections were 22 cases.
3. Clinical efficacy was judged as follows; excellent in 7 cases, good in 10 cases, fair in 5 cases and poor in 4 cases, then the efficacy rate was 65.4%. Efficacy rate in pneumonia, acute aggravation of diffuse panbronchiolitis and bronchiectasis with infection was 50%, 67% and 83%, respectively.
4. Bacteriological response was judged on 21 cases with eradication rate was 66.7%.
5. Bacteriological response classified by pathogen was as follows: All 6 isolates of H. influenzae, 2 in 6 isolates of P. aeruginosa, 4 in 5 isolates of H. parainfluenzae and all 3 isolates of K. pneumoniae were cleared. Total eradicated rate was 74.1%.
6. Eruption was observed in 1 case as side effect. Abnormal laboratory findings were observed in 4 cases. Elevation of GOT and GPT was in 3 cases. Increase of eosinophil and basophil was in 1 case.
7. AZT was considered to be a useful antibiotic for the treatment of respiratory tract infections, especially chronic respiratory tract infections, caused by Gram-negative pathogens.

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