Azthreonam is a novel monocyclic β-lactam antibiotic with excellent activity against a broad range of gram-negative microorganisms. The in vitro antibacterial activity of Azthreonam is summarized as follows:
(1) Azthreonam showed almost equal activity to CTX but was more effective than GM against gram-negative bacteria including E. coli, C. freundii, E. cloacae, S. marcescens, Proteus spp., H. influenzae, N. gonorrhoeae and K. pneumoniae. This compound also demonstrated activity against P. aeruginosa and P. cepacia. However it was generally less active than CTX and GM against gram-positive bacteria.
(2) Azthreonam was resistant to hydrolysis by various bacterial β-lactamases. However it was slightly hydrolyzed by chromosome-mediated oxyiminocephalosprinase (CXase).
(3) Azthreonam showed low inducer activity of β-lactamase production in gram-negative bacteria.
(4) Azthreonam was also resistant to hydrolysis by renal dehydropeptidases 1 which were isolated from both swine and human kidneys.
(5) The MICs of Azthreonam were little affected by the inoculum size, serum concentration and pH in medium.

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Azthreonam is the first synthetic monobactam. The activity of Azthreonam to gram-positive bacteria was weak, although it manifested higher or same growth inhibitory effect on E. coli, K. pneumoniae, every species of genus Proteus, C. freundii, S. marcescens and H. in fluenzae than 3rd generation oxime-type cephem antibiotics. Azthreonam showed antipseudomonal activity as strong as cefsulodin to P. aeruginosa, the activity, however, was moderate to P. cepacia and P. maltophilia.
Since Azthreonam possessed a high binding affinity to the penicillinbinding protein (PBP) 3 and 1A of E. coli, S. marcescens etc., bacterial filamentaous cells were induced in vitro in the presence of this drug. Azthreonam, however, was expected marked bactericidal activity in vivo because of its synergy of bactericidal effect with the serum complement and macrophages.
In cases of mixed infections by gram-positive and gram-negative bacteria, combination of Azthreonam and semisynthetic β-lactamase-tolerant penicillins, i. e. cloxacillin, flucloxacillin etc., was recommended because of their mutual compensation of antibacterial spectra.

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Antibacterial activities of Azthreonam were examined and compared with those of cephem antibiotics against 921 strains of bacteria, including S. aureus, β-haemolytic streptococci (group A, C and G), group D streptococci (S. faecalis, S. faecium and S. avium), H. influenzae, C. freundii, E. cloacae, S. marcescens, M. morganii, Providencia (P. rettgeri, P. stuartii and P. alcalifaciens), Pseudomonas (P. aeruginosa, P. maltophilia, P. putida and P. cepacia), Bacteroides (B. fragilis and others), Flavobacterium and Acinetobacter, which were isolated from clinical materials in the period of 1982 to 1983.
The results can be summarized as follows.
1. S. aureus, β-haemolytic streptococci (group A, C and G) and group D streptococci (S. faecalis, S. faecium and S. avium) were resistant to Azthreonam at the concentration of 6.25μg/ml at least.
2. Azthreonam showed strong antibacterial activities against Proteus group. Especially, the activity of Azthreonam was more potent against M. morganii than those of third generation cephem antibiotics tested.
3. Azthreonam also showed strong antibacterial activities against H. influenzae (including β-lactamase producing strains), S. marcescens and P. aeruginosa.
4. Azthreonam showed weak antibacterial activities against C. freundii, E. cloacae, P. maltophilia, Acinetobacter, Flavobacterium and Bacteroides.

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Azthreonam, a new monobactam antibiotic, had a potent antibacterial activity in vitro against gram-negative bacilli, especially E. coli, K. pneumoniae, Proteus spp., S. marcescens and P. aeruginosa, but was not active against gram-positive bacteria. Azthreonam was extremely stable to all types of β-lactamases; nine distinct types of β-lactamases (Richmond's classification) and β-lactamase from B. fragilis.
Azthreonam had also a potent therapeutic activity in mice experimentally infected with gram-negative bacilli, when given subcutaneously to mice. In addition, the therapeutic effect of Azthreonam correlated well with the MICs with an inoculum size of 10⁶ cells/ml, but not with an inoculum size of 10⁸ cells/ml.

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The in vitro and in vivo activities of Azthreonam, a new β-lactam antibiotic belonging to the recently discovered group of monobactams, were compared with those of Latamoxef (LMOX), Cefmenoxime (CMX) and Cefoperazone (CPZ). The following results were obtained.
1. The antibacterial activity of Azthreonam against gram-negative bacteria was higher than those of LMOX and CPZ and similar to that of CMX. However, Azthreonam had no activity against gram-positive cocci and anaerobic bacteria.
2. In the sensitivity distribution of clinical isolates, Azthreonam was more active than LMOX, CPZ and CMX against gram-negative bacteria, including Pseudomonas aeruginosa but was less active than CMX and CPZ against Haemophilus spp.
3. There was little or no inoculum effect on the MICs or MBCs of all antibiotics tested. The influence of inoculum size upon growth curve was also studied. The bactericidal activity of all antibiotics tested decreased by increasing the inoculum size. In the effect of the inoculum size on the protective effects for systemic infections in mice, a large inoculum resulted in a lower activity of all drugs tested, but Azthreonam was more active than the other antibiotics.
4. Azthreonam showed dose-dependent bactericidal action against Escherichia coli, Klebsiella pneumoniae, and P. aeruginosa.
5. There was no major difference between MIC and 20 h-MLC, but there was difference between MIC and 3 h-MLC or 6 h-MLC.
6. In the protective effects of Azthreonam on systemic infections in mice, Azthreonam was more effective than LMOX, CMX and CPZ against E. coli, Serratia marcescens and P. aeruginosa. Against infections with K. pneumoniae, Azthreonam was slightly less active than CMX and CPZ and was less active than CMX and LMOX against Proteus morganii.
7. The morphological response of E. coli and P. aeruginosa to Azthreonam was investigated by phase contrast microscopy. Azthreonam initially caused the formation of filaments. On continued incubation, lysis of the filaments occurred. Azthreonam showed very high affinity for PBP 3 of E. coli.

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Antibacterial evaluation of Azthreonam was made against anaerobic bacteria compared with several other β-lactams, such as cefotaxime, cefoxitin, cefoperazone, ticarcillin and so on.
Azthreonam was shown to be inactive to both Bacteroides fragilis and Clostridium difficile with MICs of 50μ/ml to 200μ/ml, but active to some species such as B. ureolyticus, black pigmented Bacteroides, B. bivius, Propionibacterium acnes, Fusobacterium nucleatum and anaerobic cocci.
Azthreonam was stable to the β-lactamases from B. fragilis and B. bivius as wellas cefoxitin.
Both B. fragilis and B. bivius formed filaments in broth containing 1/2, 1, 2 and 4 MIC of Azthreonam.
Combined effect of Azthreonam and ticarcillin was observed against some strains of B. fragilis and B. thetaiotaomicron. The prophylactic effect of Azthreonam was shown against mice experimental intraabdominal sepsis due to a β-lactamase nonproducing Escherichia coli and a β-lactamase producing B. fragilis.
The outgrowth of C. difficile was not observed in the caecal contents of mice administered 2 or 4mg/day of Azthreonam subcutaneously.

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Azthreonam is a novel synthetic monocyclic β-lactam antibiotic. It had excellent activity against gram-negative aerobes including members of the Enterobacteriaceae, Haemophilus influenzae and Pseudomonas aeruginosa, but poor or little activity against anaerobes and gram-positive aerobes.
The MIC₅₀ values of Azthreonam against the clinical isolates of Proteus mirabilis and indole-positive Proteus species were 0.005 to 0.015μ/ml, indicating that Azthreonam was 4 to 128-fold more potent than other cephalosporins. It was also highly active against Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens and H. influenzae. The MIC₅₀ values of Azthreonam against those isolates were 0.04, O.03, 0.07, O.12, 0.11, 0.31 and 0.04μ/ml, respectively. Furthermore, Azthreonam was as active as Cefsulodin against P. aeruginosa and was 2 to 3-fold more active than Cefoperazone and Minocycline.
Type of or pH of growth medium and the addition of horse serum had no effect on the activity of Azthreonam, but the inoculum size slightly affected its activity as other cephalosporins.
Combinations between Azthreonam and other antibiotics showed additive effects from the viewpoint of complementary spectrum and Azthreonam did not interfere with the activities of other antibiotics against gram-positive or anaerobic bacteria.
Azthreonam showed an unusually high stability to most of bacterial β-lactamases, but was only slightly hydrolysed by type II penicillinase and β-lactamases produced by K. oxytoca and P. cepacia.
The protective effect of Azthreonam against intraperitoneal infection model in mice by P. aeruginosa was superior to Cefoperazone but inferior to Ceftazidime. Azthreonam also exhibited potent activity against urinary tract infection caused by P. mirabilis, respiratory tract infection caused by K. pneumoniae, and inflammatory pouch infection caused by P. aeruginosa.
The protective effect of Azthreonam against intraperitoneal infection model in mice by P. aeruginosa was superior to Cefoperazone but inferior to Ceftazidime. Azthreonam also exhibited potent activity against urinary tract infection caused by P. mirabilis, respiratory tract infection caused by K. pneumoniae, and inflammatory pouch infection caused by P. aeruginosa.

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The tissue level of Azthreonam and the stability of Azthreonam in the tissue homogenates were investigated by a cup plate method by using Escherichia coli ATCC 27166 for the test organism and Mueller Hinton Agar Modified (Eiken) medium.
The following results were obtained:
1) Azthreonam showed an excellent stability in rat tissue homogenates (lung, liver, kidney and spleen) and in human tonsil homogenate for 7 days at 5°C and for 24 hr. at 20°C.
2) Azthreonam potency was considerably decreased in human gallbladder homogenate. It was found that Azthreonam stability depends on the samples of gallbladder. The microbiological assay should be performed as soon as possible for the biological specimens such as human gallbladder.

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Microbiological assay methods for the determination of monocyclic β-lactam antibiotic SQ 26, 776 (AZT) in body fluids were studied. Escherichia coli A TCC 27166 was used as the test organism. The medium prepared according to Nikkoki medium i made clear inhibition zones, and the quantitation limit by this method was 0.078μg/ml. The AZT concentration of serum was determined with the standard solutions supplemented with 5% of pooled human serum, and Moni-Trol I and Consera were substituted for pooled human serum. AZT in serum was detected at a concentration of 0.625μg/ml when serum samples were treated by methanol extraction. For the determination of AZT in urine samples the standard solutions were prepared with 10% urine solution. A calibration curve prepared with 1% phosphate buffer (pH 6.0) was available for the determination of AZT in bile as the samples were diluted 1:20 with 1% phosphate buffer (pH 6.0).
Antimicrobial activities in serum and bile were stable at-20°C for 3 days and in urine for 30 days. The regression analysis of AZT determination in 101 serum samples and 90 urine samples by microbiological and liquid chromatographical methods gave the functions y=0. 9957 x+3.2441 (r=0.9605) on serum and y=0.8656 x+89.5609 (r=0.9780) on urine. x, y and r mean the values assayed microbiologically and liquid chromatographically, and the correlation coefficient, respectively.

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The pharmacokinetics of Azthreonam (SQ 26, 776), a new parenteral monobactam antibiotics, were investigated in 3 healthy volun teers and 11 patients with renal insufficiency after a single 1.0g intravenous administration. Serum and urinary concentrations of Azthreonam were determined by high pressure liquid chromatography. In patients with various degree of renal insufficiency, the mean serum half-life (β), which was 1. 8 hours in healthy volunteers, became longer in parallel with the degree of renal dysfunction measured by creatinine clearance. Similarly, the urinary recovery rate was decreased as renal function declined. There was a significant linear correlation between the creatinine clearance and the elimination rate constant (r=0. 964, P<0.001). Finally, it is considered that administration dose and interval should be determined according to the creatinine clearance in patients with renal insufficiency.

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One gram of Azthreonam was intravenously injected to patients with benign prostatic hypertrophy before they went to operating room and Azthreonam concentrations in serum and prostatic tissue which were obtained during their surgery were bioassayed. Serum concentrations were higher than that obtained from normal volunteers. Prostatic tissue concentrations well correlated with serum concentrations in a ratio of 0.282±0.156.

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The fundamental properties of Azthreonam (AZT), one of the new monobactam antibiotics, were studied.
MIC values of AZT against clinical isolates were compared with those of Cefazolin, Latamoxef and Cefotaxime. MIC values of AZT was 100μ/ml or more against S. aureus and was inferior to MICs of the other antibiotics. MICs of AZT, however, was the best against Serratia and P. aeruginosa. When MICs of AZT was compared with those of Cefotaxime against E. coli and K. pneumoniae, they were almost equivalent against the former and high at one level against the latter but superior to those of other two antibiotics.
The peak of blood level reached 15 minutes after the intravenous administration at 100mg/kg in all 4 rabbits with S. aureus meningitis and the average peak level was 269±44.3μg/ml. The drug level in the cerebrospinal fluid reached the peak in 45 minutes after drug administration in the all (10.0±2.16 μg/ml in average). The drug level ratio between serum and cerebrospinal fluid was 3.7%, and the serum half-life was 35.9 minutes in average. The cerebrospinal fluid half-life was 88.5 minutes in average. The ratio of the half-life in the cerebrospinal fluid to that in the serum was 2.47. AUC cerebrospinal fluid/serum ratio was 4.28%, 6.53% and 7.81% for 15-60 minutes, for 15-120 minutes and for 15-480 minutes, respectively, after the drug administration. AZT transfer efficiency into the cerebrospinal fluid was in the middle among the β-lactams. If AZT alone is used in the treatment of purulent meningitis, it is the only way to allocate AZT as the second choice drug to be used after identifying the pathogen due to its antibacterial spectrum, but when a concomitant administration of AZT with Ampicillin covers the mutual demerits on their spectra, it is considered that AZT will be shifted into the first choice. Therefore, it may be worthwhile to study AZT concomitant therapys with other antibiotics.

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Intraocular penetration of Azthreonam (AZT), which was developed as a new monobactam antibiotic, was examined in rabbit and human eyes. In albino rabbits, after the intravenous administration of 50 mg/kg of AZT, concentration of AZT in the aqueous and vitreous were examined. In human subjects, 1 g of AZT was administered intravenously before surg ery of lens extraction in 25 cataract patients. The concentration of AZT in the primary aqueous was determined between 10 th to 120 th minutes after drug administration.
To detect the AZT concentration in each sample, high performance liquid chromatography was used.
The results obtained were as follows:
1. The maximum concentration of AZT in the aqueous and vitreous of rabbit eyes was 1.9±1.0μg/ml and 0.6±0.2 μg/ml 30 minutes after the injections, respectively. The drug concentration decreased rapidly in the aqueous, however, that in the vitreous considerably remained even after 240 minutes.
2. AZT concentration in the aqueous of human eyes, maintained its level more than 1.0μg/ml, from 10 to 80 minutes after the injection and then 0.5μg/ml up to 120 minutes.
3. No side effects were observed in cases of cataract patients.

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Acute Toxicity Study of Azthreonam (AZT), a newly developed monobactam antibiotics, was studied in mice and rats.
LD₅₀ values of AZT were as follows: >10, 000mg/kg in both sexes of mice and rats by p. o.; 3, 906mg/kg (male) and 5, 368mg/kg (female) in mice, and 3, 578mg/kg (male) and 3, 154mg/kg (female) in rats by s. c.; 2, 897mg/kg (male) and 3, 722mg/kg (female) in mice, and 2, 549mg/kg (male) and 2, 964 (female) in rats by i. p.; 1, 963mg/kg (male) and 2, 068mg/kg (female) in mice, and 2, 882mg/kg (male) and 3, 149mg/kg (female) in rats by i. v.
In the oral administration, general signs such as diarrhea, soft feces or yellowish soft feces were observed in both species, and no death occurred. At necropsy, dilatation of the caecum was found in mice.
In the subcutaneous or intraperitoneal administration, general signs such as decreased locomotor movement, hypothermia, collapse and rough hair were observed in both species, and yellowish soft feces and emaciation in rats. At necropsy, discoloration of the liver, dilatation of the caecum and hemorrhage of the stomach were observed in dead animals of both species, and enlargement and discoloration of the kidney in surviving rats.
In the intravenous administration, general signs such as convulsion, dyspnea and sedation were observed in both species, and reddening of extremity, tail and pinna, and swelling of the extremity in rats. At necropsy, congestion of the lung was detected in dead animals of both species, and enlargement and discoloration of the kidneys in surviving rats.

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A 35-day subacute toxicity study on Azthreonam (AZT), a newly developed monobactamantibiotic, was conducted by intravenous injection in Sprague-Dawley rats. The followingdose-related changes in clinical laboratory examinations were detected in the animals received AZT: lower serum GOT level (100mg/kg or more), soft and yellowish discoloration of feces (270mg/kg or more), lower levels of hemoglobin and serum GPT (750mg/kg or more), swelling and reddening of extremity after injection, increased water intake, decreased RBC count and death of 8 males and 9 females in highest dose group (2, 000mg/kg). Pathological examination revealed increased liver weight (100 mg/kg or more), hypertrophy of hepatocyte (270 mg/kg or more), increased spleen weight withsuch histopathological changes as hyperactivity of extramedullary hematopoiesis, hypertrophy of white pulp and hyperactivity of germinal center (750 mg/kg or more). The above dose-related changes except death of animals were returned to normal after 35 days cessation of treatment.

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A 35-day subacute toxicity study on Azthreonam (AZT), a newly developed monobactam antibiotic, was conducted by subcutaneous injection in Sprague-Dawley rats. The following dose-related changes in clinical laboratory examinations were detected in the animals received AZT: slightly increased water intake (150 mg/kg or more), decreased RBC count (300 mg/kg or more), subcutaneous edema and hemorrhage at the injection site, lower levels of Al-P, GPT, glucose, total protein, albumin and Ca (600 mg/kg or more). Organ weight analysis showed increased weights of liver, caecum, carcass (300 mg/kg or more), kidney (600 mg/kg or more) and spleen (1, 200 mg/kg or more). Histopathologic examination revealed vacuolation in the renal proximal tubular epithelial cells, subcutaneous inflammation at the injection site (600 mg/kg or more) splenic extramedullary hyperhematopoiesis and hypertrophy of hepatocyte (1, 200 mg/kg or more). Other than mentioned above, depressed growth, decreased thymus weight, hyperplasia of erythropoiesis in the bone marrow and each of two deaths out of ten of both sexes, which showed vacuolation of hepatocyte and renal proximal tubular epithelium, and necrosis of renal proximal tubule (pars recta), were observed in the animals received 2, 400 mg/kg of AZT. The above dose-related changes except dead animals were returned to normal after 35 days cessation of treatment.

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Fertility study on Azthreonam (AZT), a newly developed monobactam antibiotic, was conducted by intravenous injection in Sprague-Dawley rats.
AZT was administered for 63 (males) and 14 (females) days before mating, during the mating period, and during the early stage of gestation in females (from day 0 to 7 of gestation). A total of 5 males (one in the 100 mg/kg group, another in the 270 mg/kg group and 3 in the 750mg/kg group) died. There were no effect on body weight and food intake, while water intake increased in the early stage of administration (270 mg/kg or more). Hematological examination revealed decreases in WBC and hemoglobin (750 mg/kg), while biochemical examination demonstrated a decrease in Al-P level and an increase in albumin level (100 mg/kg or more), a decrease in creatinine level and an increase in Cl^- level (270 mg/kg or more), and a decrease in GPT level (750 mg/kg).
The increase in weight of caecum (100 mg/kg or more) and increases in weights of liver, kidneys and spleen (270 mg/kg or more) were observed.
Female showed the increase in weight of caecum (100 mg/kg or more) and a decrease in food intake in the early stage of treatment (750 mg/kg). However, AZT had no influence on general symptoms and water intake.
No influence were also observed in estrous cycle and copulation, insemination and fertility indices.
Observations of fetuses revealed no influence on the number of corpora lutea, mortality of fertilized eggs before implantation, the number of implantations, incidence and time of embryonic death, the number of live fetuses, sex ratio, body length, tail length and body weight of live fetuses, placental weight and degree of ossification. AZT showed no effect on external, visceral and skeletal malformations and skeletal variations, either.
Thus, the maximum no-effect dose level of AZT on the reproduction in male and female rats and their fetuses in the present study, was estimated to be 750 mg/kg.

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Teratological study on Azthreonam (AZT), a newly developed monobactam antibiotic, was conducted by intravenous injection in Sprague-Dawley rats. AZT was administered to female rats from day 7 to 17 of gestation.
Food intake was decreased after the initiation of administration and increased after delivery (270 mg/kg or more) and water intake was increased from the initiation of administration till after delivery (750mg/kg).
At necropsy on day 20 of gestation and day 21 of lactation, the increase in weight of caecum was observed in all administration groups.
There were no changes to the fetuses on the number of implantations, the number of live and dead fetuses, body weight, body length, tail length, external, visceral and skeletal malformations, skeletal variations, and degree of ossification.
In F 1 animals, no changes were observed as to the live birth index, viability index, weaning index, sex ratio, body weight, postnatal physical developments, external, visceral and skeletal malformations, organ weights, functional developments, behavioral developments, emothional activity, learning ability and reproductive performance.
Thus, the maximum no-effect dose level of AZT in the next gen eration in the present study, was estimated to be 750mg/kg.

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Perinatal and postnatal study on Azthreonam (AZT), a newly developed monobactam antibiotic, was conducted by intravenous injection in Sprague-Dawley rats. AZT was administered to female rats from day 17 of gestation throughout day 20 after delivery.
Body weight gain was decreased from day 14 of lactation until weaning in dams (270mg/kg or more). Food intake showed a transient decrease after administration (100mg/kg or more) and an increase after delivery (750mg/kg). Water intake increased after administration (270mg/kg or more). An animal in the 750mg/kg group showed a delayed delivery and died on day 23 of gestation. This animal presented vacuolation of hepatocytes and tubular epithelium. At necropsy on day 21 of lactation, the increase in weight of caecum (all administration groups) was observed.
No changes were observed as to live birth index, viability index, weaning index, sex ratio, body weight, postnatal physical developments, external, visceral and skeletal malformations, organ weights at the age of 21 and 84 days, functional developments, behavioral developments, emotional activity, learning ability and reproductive performance.
Thus, the maximum no-effect dose level of AZT in the next generation in the present study, was estimated to be 750mg/kg.

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The antibacterial activity of Azthreonam, a new monobactam antibiotic, was examined against 144 clinical isolate organisms using the plate dilution method with inoculum size of 10⁶ cells/ml. The peak MICs of the drug were 0.1μg/ml for E. coil, Klebsiella, P. mirabilis and P. morganii, 0.8μg/ml for S. marcescens, and 1.56 μg/ml for P. aeruginosa.
Pharmacokinetics of Azthreonam in 6 healthy male volunteers were investigated. One gram intramuscular dose of the drug yielded peak serum level of 55μg/ml at 1 hr., T_1/2 of 2.15 hrs., AUC of 216μghr/ml and urinary excretion of 70.1% within 8 hrs. According to intravenous 1g dose of the drug yielded peak serum level of 157.5μg/ml at 5 min., T_1/2 of 1.98 hrs., AUC of 229μghr/ml and urinary excretion of 72.8% within 8 hrs. These data were measured by bioassay method and similar results were obtained with HPLC method.
Twenty seven patients with infections were treated with Azthreonam administered by intravenous drip infusion 1.0g b. i. d. for 5-14 days. Excellent response was obtained in 15 of these patients, good in 8, fair in 2 and poor in 2. The efficacy rate was 85.2%. No clinical side effect occurred and abnormal laboratory findings was observed in 3 patient such as elevated transaminase, eosinophilia and reduced RBC, Hb, Ht.

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Clinical study on Azthreonam (SQ 26, 776; AZT), a new monocyclic β-lactam antibiotic were performed and the following results were obtained.
1. AZT was administered to 8 cases with pneumonia, 2 cases with diffuse panbronchiolitis and 1 case with lung abscess at a dosage of 2-6 g/day by intravenous drip infusion for 5-14 days.
2. Clinical response of AZT was excellent in 1 case, good in 7 cases, fair in 1 cases and poor in 2 cases.
3. Transient elevation of serum GOT, GPT was observed in 3 cases.

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Azthreonam was administered to a total of 30 patients; 29 with RTI (bacterial pneumonia 13, bronchiectasis 7, chronic bronchitis 5, lungabscess 2, and pyothorax and DPB each 1) and with 1 UTI. Of 29 RTI cases, 16 patients were over 60 years old and 27 patients with severe or moderate infectious disease.
Overall clinical efficacy rate was 73.3% (22/30). Total dosis and administration route of Azthreonam vs. clinical efficacy including excellent and good were as follows: 1-19g, 50% (2/4); 20-29g, 62.5% (5/8); 30-39g, 70% (7/10); 40-69g, 100% (7/7); over 70g, 100% (1/1) and D. I., 60% (9/15); I. V., 100% (11/11), I. M., 50% (2/4).
In 20 strains and others (normal flora) found in sputums, 4 strains (30.8%) of P. aeruginosa out of 13 strains, 2 strains of K. pneumoniae out of 3 strains and all of normal flora were eradicated. Four strains (30.8%) of P. aeruginosa persisted and each 1 strain of K. pneumoniee and P. aeruginosa replaced to Acinetobacter.
In 1 UTI case out of the 30 cases, slight elevation of S-GOT and S-GPT was observed, but on other adverse reaction was noted.
A case of lung abscess (82 years old, female), administered 3g of Azthreonam 2 times a day for 30 days, was excellent and without adverse reaction.

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Azthreonam, one of monobactams which is a new type β-lactam antibiotic possessing monocyclic β-lactam rings in their structures and is totally synthesized from L-threonine was administered to 16 patients with respiratory infections (6 with acute pneumonia and 10 with chronic bronchitis) to evaluate its safety and efficacy.
Azthreonam was administered at 1 g/dose twice daily to 10 patients, and at 2 g/dose twice daily to 6 patients. The total dosage was a minimum of 14 gram to a maximum of 84 gram.
The clinical efficacy was excellent in 2 patients, good in 9 and poor in 5. The efficacy rate was 68.8% when excellent and good ranks were summed up.
Regarding its usefulness, Azthreonam proved excellent in one patient, useful in 10, and non-useful in 5, and the ratio of excellent and useful ranks was 68.8%.
Fever occurred in 2 patients as a side effect. Abnormality in GOT, GPT and Al-P were observed in 3 patients in the clinical test findings. Out of the 3, one patient Showed an increase of BUN and serum creatinine Simultaneously.
Of 9 patients infected with GNR, the pathogens cleared in 3 patients, reduced in 5, and did not change in one. Azthreonam was found to be an effective and safe drug in the treatment of these respiratory infectious diseases.

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Azthreonam was evaluated for its clinical efficacy in 24 patients, namely, 1 with pharyngitis, 1 with acute bronchitis, 5 with chronic bronchitis, 3 with pneumonia, 1 with bronchiectasis with its secondary infection, 1 with lungtumor with pulmonary infection, 2 with acute cystitis, 6 with chronic cystitis, 2 with acute pyelitis, 1 with perinephritis, 1 with sepsis and subcutaneous abscess in the lumbogluteal area.
The clinical response obtained was excellent in 4 patients, good in 13, fair in 1 and poor in 6. Out of 16 strains assumed to be causative organisms, 8 strains of organisms were eradicated, 1 persisted and the others were replaced.
There was no side effect following the treatment with Azthreonam. Laboratory abnormality was a slight elevation of GOT and GPT in 1 case.

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Azthreonam, a new monocyclic β-lactam antimicrobial agent, was intravenously administered to 24 patients with respiratory tract infection including 13 bacterial pneumonia, 3 lung abscess, 6 diffuse panbronchiolitis and 2 bronchiectasis. The daily doses were 2 g or 4 g in two. divised dose. The results were as follows:
1) Concerning its overall clinical efficacy, 7 patients obtained excellent response, 13 good response, 2 fair response and 2 poor response. An overall efficacy rate was 83.4%.
2) In 15 cases of the 16, causative organisms isolated, various gram-negative bacteria were pathogens. Among them, 9 cases (56. 3%) were eradicated their pathogens after treatment. However, for P. aeruginosa and Acinetobacter, bacteriological effects were poor in our cases.
3) Abnormal laboratory values were noted in 6 cases as increased transaminase and Al-P but in 5 cases increased values were transient. The other side effect, nausea, was tolerated during administration.
From these results, it is concluded that Azthreonam have a clinical benefit for gram-negative bacterial infections in respiratory tract.

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The clinical efficacy of Azthreonam (SQ 26, 776), a newly developed synthesized monobactam, was evaluated in the treatment of n patients with some bacterial infections to the respiratory tracts; the most of them had some underlying diseases. The quantitative culture of bacteria revealed that certain pathogens including H. influenzae, P. aeruginosa were isolated from the expectrated sputum in all of these patients.
The drug was given intravenously by drip infusion 2 to 4 grams daily in 2 divided doses. Bacterial examination revealed that primarily isolated bacteria could be completely eradicated in 6 cases (54%) after treatment. The overall assessment of clinical effectiveness based on the improvement of clinical symptoms and the disappearance of inflammatory reactions was found to be excellent or good in 7 cases among them (64%).
Azthreonam, therefore, is expected to be a remarkable therapeutic antibiotic for the treatment of intractable respiratory tract infections especially caused by Gram negative bacilli.

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The MICs of Azthreonam (SQ 26, 776) against 121 bacterial strains from patients' sputa were compared with those of Cefazolin, Cefmetazole, Ceftizoxime and Latamoxef on Enterobacteriaceae and with those of Piperacillin and Cefsulodin on Pseudomonas aeruginosa, and the efficacy of Azthreonam in the treatment of two patients with pneumonia which had not been cured by some other antibiotics was evaluated.
The results of in vitro tests revealed that Azthreonam was as highly active against Escherichia coli, Klebsiella sp., Enterobacter sp. and Serratia sp. as Ceftizoxime and was more active than Cefazolin, Cefmetazole and Latamoxef. The antipseudomonal activity of Azthreonam was less than that of Cefsulodin but more than that of Piperacillin.
Two grams of Azthreonam per day was given to the patients by intravenous drip infusion. Clinical response to the treatment was good and infiltrative shadows on the chest X-ray films disappeared in both patients. In one patient, drug fever occurred during the treatment, but body temperature became normal soon after cessation of the drug. No other side effects were observed.

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The concentration in sputum and plasma and clinical investigations against RTI were examined on Azthreonam (AZT), a new monobactam.
One gram of AZT was administered to the 4 patients twice a day at 9 a. m. and 6 p. m.
The concentration of AZT in plasma showed 106.3μg/ml at the end of drip infusion and showed to 1.79μg/ml of top level in sputum after 6 hours and kept more than 1.10μg/ml untill 24 hours after.
AZT was administered to a total of 14 patients with RTI including four cases of pneumonia, six cases of acute exacerbation of chronic bronchitis, one case each of pneumonia with mediastinitis, pneumonia with pyothorax and two cases of diffuse panbronchiolits.
The following nine potential pathogens were recovered from the sputum at a start of the treatment with AZT and eight strains were all eradicated but one S. aureus was eradicated with Penicillin.
The clinical response to the treatment with AZT was excellent in eight cases, good in five cases and fair in one case (efficacy=92.8%).
No side effect was observed.
The cases of slight elevation of GOT, GPT and GOT, GPT, Al-P and eosinophilic leukocyte were observed.
From the above results, it is concluded that AZT is effective and useful antimicrobial agent.

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Azthreonam is a new parenteral β-lactam antibiotic from a new antibiotic class, monobactams. This antibiotic has little activity against gram-positive organisms and anaerobes, but shows exceptional activity against aerobic gram-negative rods including Pseudomonas.
Azthreonam was parenterally administered to five patients with respiratory tract infection, two patients with acute pyelonephritis, and a leukemic patient with unknown origin of fever. These patients received the drug for 5 to 49 days in doses of 1 to 4g/day. Four of these patients responded well in the therapy. None of 8 patients was observed any side effect due to Azthreonam.

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Azthreonam was studied in 12 patients: 8 with respiratory tract infections and 4 with urinary tract infections, and the following results were obtained.
Azthreonam was used intravenously at a dose of 0.5g to 2.0g twice a day in principle.
Clinical response of Azthreonam was excellent in 1 patient, good in 8, fair in 2 and poor in 1. Fever occurred in one patient as the side effect of this antibiotic, and no abnormality of laboratory tests caused by the drug was observed.

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Azthreonam were administered to 25 episodes in 23 patients with various infectious diseases. Clinical efficacy was assessed in 24 episodes. In a case of pleural empyema and two cases of subcutaneous and decubital infections caused by S. aureus and S. faecalis, any clinical effects were not obsereved. In four cases of biliary tract infection good effects were obtained in three cases, but response was not obsereved in another case. Causative organisms in 17 patients with urinary tract infections were 7 strains of E. coli, 4 of K. pneumoniae, 2 of P. aeruginosa, each one of P. inconstans and P. mirabilis. No causative bacteria was isolated in the 4 cases because of preliminary treatment of other antibacterial drugs. MIC of Azthreonam against 11 causative organisms were equal to or below 0.1μg/ml, excluding 12.5μg/ml and over 100μg/ml of P. aeruginosa. Underlying diseases were complicated in 13 cases of 17 urinary tract infections, bacteremia were demonstrated in 4 cases and supposed in the other 2 cases. ExcelIent response were obsereved in two cases, good response were in 12 cases. Clinical efficacy rate was 82% in urinary tract infection. In 3 cases, S. faecalis were isolated in urine after eradication of causative bacterias. Rush and fever as the adverse effect of Azthreonam were obsereved in two cases. Leucocyte migration inhibition tests against Azthreonam were positive in both cases.

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The authors report on the results of their clinical investigation of Azthreonam (AZT), newly developed monobactam antibiotic.
The antibacterial activity of AZT was compared to that of cefoperazone (CPZ), cefotaxime (CTX), cefmetazole (CMZ) and cefazolin (CEZ) in a total of 132 clinical isolated gram-negative bacilli of E. coli, K. pneumoniae, E. cloacae, Proteus sp. S. marcescens and P. aeruginosa.
AZT was the most active against Proteus sp. and E. cloacae and exhibited almost the same antibacterial activity as CTX against E. coli, K. pneumoniae and S. marcescens, additionally AZT showed the same MIC against P. aeruginosa as CPZ.
Clinical evaluation was carried out in 14 patients with respiratory tract infections (RTI) and 3 patients with urinary tract infections (UTI). Response was good in 9 (64.3%) out of 14 RTI cases and good in all UTI cases.
As a side effect, slight elevation of GOT and GPT was observed in 2 cases, but adverse reaction returned to normal range following the completion of administration.

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We conducted microbiological and clinical studies on Azthreonam (AZT, SQ 26, 776), a novel β-lactam synthetic antibiotic.
Antimicrobial activity of AZT against various clinical isolates, such as S. aureus, S. pneumoniae, E. coli, K. pneumoniae, P. mirabilis, Indole (+) Proteus, H. influenzae, P. aeruginosa, S. marcescens and Enterobacter spp., was compared with those of CMX, LMOX, CPZ, CMZ and CAZ.
AZT was highly active against Gram-negative organisms, especially E. coli, Klebsiella, Indole (+) Proteus and Serratia, however, was relatively inactive against Gram-positive cocci such as S. aureus and S. pneumonia
AZT was administered to 5 patients with respiratory tract infection and 1 patient with urinary tract infection and 1 patient with FUO.
The dosage was 2.0 to 4.0g/day given in divided doses 2 times daily for 5 to 16 days. The clinical response was excellent in 2 cases, good in 3 cases and poor in 2 cases. The success rate was 71.4%.
As side effects, slightly elevation of GPT was found in 1 patient.

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In four cases, clinical effects of Azthreonam, a new monobactam antibiotic, on five episodes of respiratory tract infections due to P. aeruginosa were studied. The clinical effects of two episodes were evaluated good, those of two were fair and that of one was poor. The MIC of three strains were determined, and those of two were more than 100μglml. Compared with other reports, this phenomenon is thought to be rather rare, and this fact may explain lower effectiveness of Azthreonam than other reports. In one case with allergy to PIPC, CBPC and others, the administration of Azthreonam resulted in no side effects. We conclude that Azthreonam can be useful in the treatment of respiratory tract infections due to P. aeruginosa.

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Azthreonam is a new monobactam antibiotic with antibacterial activity against gram-negative bacilli.
The antibacterial activity in vitro of Azthreonam was determined against 79 strains of clinical isolates comparing with those of Cefoperazone and Cefotaxime. Azthreonam was more active than Cefoperazone and as active as Cefotaxime against Escherichia coli and Klebsiella with MICs below 0.2μg/ml. Against Pseudomonas aeruginosa it was more active than Cefotaxime and as active as Cefoperazone.
Azthreonam was administered to four patients (Pneumonia 1, Acute pyelonephritis 3) 1g twice a day by drip infusion for 4 to 9 days. Their clinical course showed that Azthreonam was effective to all of them. Adverse effects that may be attributed to the administration of Azthreonam were not observed except one case with eruption.
However, in this case, it could not be clarified whether the eruption was caused by this drug or not.

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Azthreonam (SQ 26, 776) is a new monobactam antibiotic which showed the highest antibacterial activity against gram-negative bacteria. However, Azthreonam is less active against gram-positive and anaerobic bacteria.
Azthreonam was used in the treatment of 4 cases of uncontrollable Pseudomonas aeruginosa infection of lower respiratory tract: 3 cases of diffuse panbronchiolitis and one case of chronic bronchitis. The ages of patients ranged from 37 to 74 years (mean 49 years), and there were 2 males and 2 females.
Azthreonam was administered by intravenous drip infusion. The dose of Azthreonam was 2.0g, 12-hourly and the duration of the treatment varied 6 to 18 days (mean 12.3 days) and the total doses ranged from 24 to 72g (mean 47.5g).
Clinical responses were fair in one case, poor in 3 cases and not evaluated in one case. Bacteriological responses were not evaluated in one case and poor in 3 cases.
Laboratory abnormalities were observed in one patient consisting of temporary slightly elevated GOT, Al-P, LAP and r-GTP, but no severe side effect was found.

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One gram of Azthreonam was administered twice daily to four patients with RTI and four patients with UTI. Seven patients were clinically evaluable.
Satisfactory response was observed in 3 patients with pneumonia. One patient with chronic bronchitis due to P. aeruginosa did not respond satisfactorily. Three patients with complicated UTI, infected with mixed gram positive cocci and gram negative rods failed to respond to Azthreonam.
No adverse reaction was observed.

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Clinical efficacy and adverse effects of Azthreonam, a new monobactam antimicrobial agent, were studied in 21 patients with respiratory tract infections receiving 2 to 4g b. i. d. by drip infusion. Among them, 16 cases were respiratory tract infections, 3 cases were pneumonias and 2 cases were lung abscesses.
The clinical effects were excellent in one, good in 12 cases, fair in 3 cases and poor in 5 cases. The efficacy rate was 62%.
As for adverse reactions, fever was observed in one case, which was improved promptly on withdrawal of Azthreonam. In 3 cases, slight abnormality in liver function tests, in one, slight leukopenia and eosinophilia were seen.
In conclusion, Azthreonam is an effective and safe antibiotic in the treatment of respiratory tract infections caused by Gram-negative bacteria including P. aeruginosa.

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Azthreonam was used in 7 patients with broncho-pulmonary infections and 1 with urinary infection. Daily doses of Azthreonam ranged from 1 to 2 g.
Clinical effects in 2 cases of acute pneumonia were assessed as poor.
In 3 cases of diffuse panbronchiolitis, fair response were observed in 2 cases and poor in 1 case.
In 2 cases of chronic bronchitis, clinical response were good.
In 1 case of simple urinary infection, clinical response was good.
Causative organisms were H. influenzae (1 case), K. pneumoniae (1 case), E. coli (1 case) and P. aeruginosa (3 cases).
After Azthreonam, K. pneumoniae and E. coli were eradicated, and H. influenzae was replaced to S. pneumoniae.
In 3 cases of P. aeruginosa, 1 case was eradicated, 1 case suppressed and 1 case persisted.
Fieberung with eosinophilia was noted in 1 case and S-GOT and S-GPT elevation was noted transiently in another case.

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Antibacterial activity, pharmacokinetics and clinical effects of Azthreonam, a synthetic morbactam antibiotic for parenteral use was studied.
1) Antibacterial activity
MIC's of Azthreonam for 50 clinical isolates of E. coli, K. pneumoniae and P. aeruginosa were det, mined and compared with those of Piperacillin (PIPC), Cefmetazole (CMZ), Cefoperazone (CP2 Ceftazidime (CAZ) and Latamoxef (LMOX).
Antibacterial activity of Azthreonam against E. coli and K. pneumoniae was most excellent in tlseries. It was somewhat less active than CAZ against P. aeruginosa, but even with PIPC and CP
2) Pharmacokinetics
The serum and urinary concentrations of AZT were determined in 5 healthy volunteers after 1, (mg intravenous administration. Influence of Probenecid on the serum concentration and urina recovery rate were also investigated.
The serum concentration of AZT at 5 minutes after administrarion averaged 94.1±14.6/semi, a then the concentration decreased with the half-life (β-phase) of 1.36 hours. The urinary recow rate up to 8 hours averaged 55.8±6.5%.
When 1, 000 mg of Probenecid was administered orally 30 minutes before the intravenous admir tration of 1, 000mg of AZT, the serum concentration of AZT at 5 minutes after administration a raged 99.3±22.6g/ml.
And serum half-life and urinary recovery were 1.59 hours and 56.5±5.3% respectively. The values were not significantly different from those without administration of Probenecid. From thresults, it is suggested that AZT is filtrated from the glomerulus mainly.
The serum and urinary concentrations of AZT and LMOX were investigated in 5 healthy volunte after 1, 000 mg intravenous administration by the cross over method.
The serum concentration of LMOX were found to be higher than those of AZT after dosing. Jserum half-life and AUC of AZT and LMOX were 1.36 hours and 1.13 hours, 68.8μg·hr/ml and pg-hr/ml, each. The urinary recovery of AZT and LMOX in 8 hours after dosing were 55.8±6. and 90.3±5.2%, each. These values indicates that LMOX gives higher serum and urinary conc tration than those of AZT.
3) Clinical results
AZT was administered to 3 patients including 1 case of pneumonia, 1 case of cholecystitis an case of urinary tract infections, at a daily dose of 2 grams for 3 to 9 days. The clinical respc was good in 1 case and poor in 2 cases.
In the course of clinical study, no adverse reactions and abnormalities of laboratory data for A were observed.

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Azthreonam, a novel monocyclic β-lactam compound, was administered to 14 patients with various infectious diseases (UTI 6, diabetic foot 1, RTI 7) in order to evaluate its clinical efficacy. The clinical effect was excellent in 5, good in 3 and poor in 6 patients. The efficacy rate was 57.1%.
Azthreonam exhibited good antimicrobial activity against E. coli, K. pneumoniae, E. aerogenes, S. marcescens and E. cloacae except P. aeruginosa.
No side effects were observed. However, a transient increase in WBC and eosinophiles was seen in each patients, respectively (patient No.1 and No.13). An abnormal elevation of GOT and GPT was also!seen in one patient (patient No.12).

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Antibiotic efficacy of Azthreonam (AZT) was determined in the clinical isolates of various microorganisms. They were compared with those of Cefoperazone (CPZ) and Ceftizoxime (CZX). AZT has an excellent MICs against E. coli, P. vulgaris and P. mirabilis as same as CZX. CZX was the best against K. pneumoniae. AZT was the intermediate among these three antibiotics. MICs of AZT against P. aeruginosa were in a range from 3.13μg/ml to 25.0μg/ml in 88% of the strains tested. MIC pattern of AZT was similar with that of CPZ. Twelve percent of these strains were resistant to AZT. AZT has slightly stronger MICs against E. cloacae and S. marcescens than other two drugs. MICs of AZT were 25μg/ml or more in S. aureus and inferior to CPZ and CZX.
AZT provided excellent clinical results. That is, AZT was excellent or good in 8 out of 10 patients, such as 4 out of 5 patients with pneumonia, all two patients with cystic bronchiectasis and all two patients with pyelonephritis. AZT was effective in 3 out of 4 patients with Pseudomonas infection. AZT caused fever in one patient. But there is less definite relation between fever and AZT administration. There was neither subjective/objective symptoms nor changes in the clinical test results.

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Azthreonam, one of the monobactam β-lactam antibiotic, was studied to determine clinical efficacy and safety by the intravenous route in 23 patients with respiratory infections (14 chronic bronchitis and 2 pneumonia), 5 with septicemia and 2 with urinary tract infections.
Included were patients in which gram-negative bacteria were identified as the pathogen as well as patients in which infections caused by gram-negative bacteria were uncertain. Many patients were considered difficult to refractory even for reasons such as failure to respond to previous treatment, presence of delayed infection and finally advanced age. The therapeutic results were good in 16 of 23 patients with respiratory infections (efficacy rate 70%), in all 5 patients with septicemia and in both patients with urinary tract infections. No side-effects were observed. The GOT and GPT values were elevated in 2 patients and the BUN in one. All elevated values were transient.
The above results suggest that Azthreonam is a useful antibiotic for the treatment of respiratory infections caused by gram-negative rods and for the treatment of gram-negative septicemia. There is a need to study dosage levels and periods for efficacy in the treatment of respiratory infections caused by Pseudomonas. Azthreonam is an efficacious antibiotic that deserves further evaluation.

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A new antibiotic, Azthreonam, was administered for 7 days at daily doses of 2.0g to 10 cases, including 2 cases of acute bronchitis, 1 case of acute cystitis and 7 cases of chronic pyelonephritis.
The results obtained were effective in 4 cases. The total efficacy rate was 40.0%.
Neither side effects nor abnormal laboratory findings were observed in any of these cases.

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Azthreonam, a new monocyclic β-lactam antibiotic, was investigated on its antimicrobial activity, absorption, excretion and clinical effects with the following results.
(1) MIC₈₀ values of Azthreonam against CEZ-resistant (MIC>100μg/ml) isolated pathogens E. coil, K. pneumoniae and P. mirabilis were 12.5, 0.78 and 0.39μg/ml respectively.
(2) The serum level reached its peak 1 to 2 hours after the intramuscular administration of Azthreonam 1.0 g to three healthy adults. The mean values of the three cases at 0.5, 1, 2, 4 and 6 hours were 26.7, 47. 2, 52. 9, 21.2 and 12.6μg/ml respectively.
The urinary level was as high as 1, 616-3, 840μg/ml up to 4 hours after the injection and the urinary recovery rate of Azthreonam in 6 hours was 53.4% on an average.
In the meantime, the serum level of the patient in the complication of carcinoma of the gallbladder and sepsis with normal renal function reached 87.6μg/ml at the end of 1 hour intravenous drip of Azthreonam 1.0g and declined there after with 1.60 hours half-life to 2.1μg/ml after 8 hours. The urinary level reached its peak, 2, 021μg/ml in 0-2 hours and the urinary recovery rate in 8 hours was 62.5%. The bile concentration was checked by separately taking the sample at 1.5-2 and 2-4 hours with the values of 20. 4 and 26.8μg/ml respectively.
(3) One gram of Azthreonam was intravenously injected two times daily to a total of 12 internal infection cases-sepsis (1), bacterial pneumonia (2), chronic bronchitis (2), acute pyelonephritis (1), acute prostatitis (1), acute cystitis (2) and chronic cystitis (3) and Azthreonam was effective or excellent for 11 cases. The one slightly effective case was a bacterial pneumonia. No significant side effect was reported through the study.

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Azthreonam (SQ 26, 776), a synthetic monocyclic β-lactam antimicrobial agent belonging to the monobactam family and having a specific activity against aerobic Gram-negative bacteria, was administered to 21 patients with respiratory tract infections. The patients consisted of 5 patients with pneumonia, 2 with acute bronchitis, 10 with chronic bronchitis, 3 with bronchiectasis and 1 with bronchopulmonary cysts.
The effect on causative organisms was evaluated as eliminated in 11 cases, decreased in 4 cases, unchanged in 2 cases and unknown in 2 cases.
The clinical effect was evaluated as excellent in 2 cases, good in 12 cases, fair in 1 case and poor in 5 cases. One case was put out of discussion because of its severe complication. The overall clinical effectiveness was therefore 70% (14/20).
The side effect was not observed in any cases, but the abnormal values of bloodchemical examination were observed in 4 cases (19.0%). From these results it appears that Azthreonam is a valuable antimicrobial agents against the patients with respiratory tract infection especially with Gram-negative bacilli.

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Azthreonam, the new single-ring β-lactam antibiotic was administered to 14 aged patients with infectious diseases to evaluate the clinical efficacy and side effects. The patients were 7 with acute pneumonia, one with lower respiratory tract infection, 3 with urinary tract infection, 2 with sepsis and one with cholangitis.
Azthreonam provided the good result in 6 patients, fair in 3, and poor in 5. The efficacy rate was 42.8%, and it increased to 64.3% when fair patients were included into the effective cases. Bacteriologically, three strains of E. coli and one strain of E. agglomerans were eliminated by Azthreonam administration. But P. mirabilis was replaced by S. aureus. S. pneumoniae was found in 2 patients after Azthreonam administration.
GOT and GPT levels elevated in one patient, neutrophile reduced in one, platelet reduced in one, and eosinophile increased in one patient. All these changes returned to normal after the withdrawal of Azthreonam.
Azthreonam was considered to be a useful antibiotic for the treatment of the aged patients with infectious diseases caused by gram-negative bacteria.

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Azthreonam (SQ 26, 776), a novel monocyclic β-lactam compound, was applied to the treatment of 16 patients with respiratory tract infections.
The drug was administered intravenously at a daily dose of 2-4 g, divided into two doses.
The results obtained were: excellent in one case, good in six cases, slightly good in six cases, ineffective in one case, unassessable in two cases.
No side effects were observed.
The results suggest that the drug is safe and comparatively useful in the treatment of respiratory tract infections due to gram-negative bacilli.

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Azthreonam (SQ 26, 776), a new monocyclic β-lactam (monobactam) antibiotic, was administered to 15 patients with infections in the field of internal medicine, and its effectiveness and safety were evaluated.
Azthreonam was administered to a total of 15 patients consisting of 7 cases of respiratory tract infections, 6 cases of digestive tract infections and 2 cases of urinary tract infections. Organisms isolated were H. influenzae (1), K. pneumoniae (3), P. vulgaris (1), E. coli (2), S. epidermidis (1), Acinetobacter (1), Salmonella (1) and Normal flora.
Clinical efficacy was evaluated as excellent or good in 5 cases (5/7) with respiratory tract infections, 5 cases (5/6) with digestive tract infections and 2 cases (2/2) with urinary tract infections. The overall efficacy rate was 80% (12/15).
No serious side effects were observed.
From these results it appears that Azthreonam was evaluated to be a effective and safe P-lactam antibiotic against infections in the field of internal medicine.

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Azthreonam, a monocyclic β-lactam antibiotic newly developed by Squibb Co., was examined on its antibacterial activity, absorption and excretion in vivo, as well as on its clinical availability. The results obtained were as follows:
1) Antibacterial activity: The MIC of Azthreonam against Gram-negative bacilli isolated from clinical infection foci were estimated and compared with MIC of Cefotaxime (CTX), Cefoperazone (CPZ), Cefuroxime (CXM), Latamoxef (LMOX) and Cefmetazole (CMZ).
Most strains of E. coli and Klebsiella sp. showed MIC lower than 0.05μg/ml of Azthreonam similarly to CTX, being lower than MIC of other antibiotics examined. P. mirabilis strains were divided into two groups according to their sensitiveness to Azthreonam; one being more sensitive, and the other less sensitive to the drug than to other antibiotics.
As for the strains of E. aerogenes, S. marcescens, P. vulgaris. P. rettgeri, and P. morganii, Azthreonam was found to be most potent among the antibiotics examined. Azthreonam showed activity against P. aeruginosa, too, similarly to CPZ, being four-to eightfold stronger than CTX and LMOX, while E. cloacae strains were less sensitive to Azthreonam than to LMOX.
2) Absorption and excretion: A patient of 62 years of age having cholecystitis was administered with 1g Azthreonam by i. v. drip infusion. One gram of the drug dissolved in 100 ml phys. Saline was infused in one hour. The blood level of the drug was 110μg/ml at the end of the infusion, descending thereafter, but still keeping the level of 10.5μ/ml even after six hours. The bile of the patient obtained by the duodenal drainage showed concentrations of 17μg/ml (A-bile), 66μg/ml (Bbile), and 450μg/ml (C-bile) of the drug. The urinary recovery rate of the drug in six hours was 66.4% of the dose.
3) Clinical trials: Twenty-one patients with various infections (RTI 8, UTI 2, BTI 8, septicemia 2, the rest 1) were treated with 2-4 g/day of the drug; two of them by i. m. injection, and others by i. v. drip infusion.
Seventeen of the patients were assessable for the clinical effectiveness of the therapy; i. e. excellent 2, good 9, fair 1, and poor 5; the efficacy rate being 64. 7%. The clinical results obtained should be appreciable, as almost all of the treated patients had some underlying diseases which might have mitigated the efficacy of the antibiotic therapy.
No side effects were observed, except for two cases; one complained local pain at the site of i. rn. injection, and another showed exanthema accompanied by slight neutropenia.
Those results obtained should suggest that Azthreonam is a new antibiotic of use for infections caused by Gram-negative bacilli.

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