In vitro and in vivo antibacterial activity of ceftizoxime (CZX), a new cephalosporin antibiotic, was studied using clinical isolates of gram-negative bacteria. The results are summarized as follows.
1. The MIC levels of CZX against Escherichia coil, Klebsiella pneumonia, Serratia marcsscens, Citrqbacter freundii, Proteus mirabilis, Proteus vulgaris, Proteus morganii and Proteus rettgeri were much lower than those of cefazolin (CEZ) and cefoxitin (CFX).
2. CZX was stable against β-lactamases of cephalosporinase type extracted from E. coil, E. cloacae, P. aeruginosa, P. vulgaris, P. morganii, P. rettori, S. marcescens and C.freundli, but it was slightly hydrolyzed by β-lactamases from Pseudomonas cepacia and Bacteroidss fragilis.
3. CZX was more effective than CFX, CEZ and carbenicillin against experimental infections with E. coil, K. pneumoniae and S. marcescens in mice.

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The in vitro and in vivo antibacterial activity of ceftizoxime (CZX), a new cephalosporin antibiotic, was studied in comparison with cefazolin, cefamandole, cefuroxime, cefoxitin, cefmetazole, cefotiam and cefotaxime.
Ceftizoxime was found effective against both gram-positive and gram-negative bacteria, with particularly profound activity against gram-negative bacilli. The compound showed a greater activity than all other seven antibiotics against strains of indole-positive Proteus and Serratia which were poorly susceptible to the previously introduced cephalosporins. Ceftizoxime was also active against such non-glucose-fermenting species as P. cepacia, A. calcoaceticus and F. meningosepticum but was slightly less active than cefotaxime against P. aeruginosa. Strains of S. aureus were less susceptible to the compound than to cefazolin, cefamandole and cefuroxime.
Ceftizoxime proved to be as remarkably stable as cefotaxime, cefuroxime, cefmetazole and cefoxitin to inactivation by β-lactamases (penicillinase type and cephalosporinase type) elaborated by such organisms as E. coli, K. pneumoniae, P. mirabilis, P. vulgaris and C. freundii. However, it was slightly labile as cefotaxime to enzymes produced by some E. coli strains, possibly falling under class V of the RICHMOND classification.
Experiments in mice demonstrated antibacterial activity of ceftizoxime against infections, essentially consistent with the findings for its in vitro antibacterial activity. The compound exerted a greater protective effect than cefazolin, cefoxitin and cefotiam against E. coli, Serratia or Klebsiella infection. Against infection by Citrobacter freundii, it was practically as effective as cefoxitin and showed higher ED₅₀ values than cefotaxime and cefotiam.

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The antimicrobial activity of ceftizoxime (CZX) was studied in comparison with that of other cephalosporins (CEPs) and other antibiotics against 1, 191 clinical isolates of Streptococcus, Haemophilus, Eacherichia, Enterobacter, Citrobacter, Serratia, Proteus, Pseudomonas, Achromobacter, Flavobacterium, Acinetobacter, Akaligenes, Comamonas, Peptococcus, Peptostreptococcus, Clostridium, Bacteroi des and Fusobacterium obtained from patients during the years of 1978 and 1979.
A marked antibacterial activity of CZX was demonstrated against gram-negative bacilli; CZX was remarkably more active than cefazolin (CEZ) against a great proportion of the isolates of these species. CZX exhibited a greater activity than ABPC against H. influenza. strains, and those resistant to ABPC also proved susceptible to CZX. Noticeably conspicuous activity of CZX was observed against strains of E. coli, C. diversus and four Ptoteus species other than P. morganii. This antibiotic proved to be substantially more active than other β-lactamase resistant CEPs (CMZ, CFX and CXM) against Serratia strains and noticeably active against isolates of Pseudomonas cepacia and P. putrefaciens. Against P. aeruginosa isolates, the antibacterial activity of. CZX was greater than that of CBPC or SBPC, slightly inferior to that of CPZ and considerably modest as compared to CFS.
CZX produced a marked antibacterial effect against streptococcal isolates, especially those of S. pyogenes and S. pneumoniae as well as group G Streptococci. It was found fairly active against anaerobic grampositive organisms whereas gram-negative anaerobes proved rather poorly susceptible to this antibiotic.

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The stability of, ceftizoxime (CZX) against types Ia, Ic, II, III (TEM), IV and V (oxacillin-hydrolyzing) β-lactamases was compared with those of other new cephalosporins as the relative Vmax values measured by the macroiodometric method.
CZX was found to be nonhydrolyzable by the all types of β-lactamase except the type V that destroys the drug slightly. Furthermore, interrelationships were investigated between the MICs of CZX and other cephalosporins to β-lactamases-producing bacteria and the affinities of the drugs to the enzyme that were determined as the Ki values by modified acidometric method, since gram-negative bacteria producing β-lactamases as an epienzyme seemed to become resistant not only due to the hydrolysis of drugs but also depending upon unknown barriers directed by β-lactamases which does not destroy β-lactams but binds them and prevents passing through the periplasmic space to the sensitive site. It was revealed that CZX is not only stable but also possesses a large Ki value to the type III (TEM) β-lactamase, suggesting that the drug is indifferent from a majority of R (bla) plasmids coding the production of such kind of β-lactamase. In fact, the transfer of 51 different R (bla) plasmids to Escherichia coli CSH2 resulted in no change of the drug-susceptibilities from the plasmid-free parent strain. Whereas, the MICs of 6059-S and cefoxitin, which possess 100-fold and 5-fold higher affinities to the TEM-type β-lactamase, elevated to 10-and 4-fold, respectively, by the plasmid transfer, even tiough they are not hydrolyzed at all.

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Penicillin-binding proteins (PBP) are elucidated as the target enzymes of β-lactam drugs, which are necessary for the final biosynthetic step of murein in the bacterial cell wall. Ceftizoxime (CZX), a novel cephalosporin possessing the methoxyimino radical on the 7-Z (2) position and no side chain on the 3 position, manifests strong affinities to the 1a, 1b and 3 fractions of PBP of Escherichia coli and Vibrio cholerae.Since the 1b fraction has been understood as an essential enzyme for the murein-biosynthesis required for cellelongation and CZX is the most potent inibitor for the 1b fraction ever known, its bactericidal activity is expected to be significant. In fact, the drug exhibits stronger bactericidal effect on E.coli cells than cefazolin (CEZ) and cefotaxime (CTX). Furthermore, it was demonstrated that E.coli cells grown in the presence of a subinhibitory dose of CZX are easily killed by the complement in mammalian sera and easily phagocytized by cultured macrophages derived from mice. Although that phenomenon is common in the 7-Z (2)-methoxyimino derivatives of cephalosporin, CZX is more prominent than cefuroxime and CTX in this respect.

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The in vitro antibacterial activity of ceftizoxime (CZX) against anaerobes was measured. CZX was found to have a powerful antibacterial activity against anaerobic gram-negaive bacilli, especially against Bacteroides fragilis which is most frequently isolated from clinical materials and yields the β-lactamase. The activity of CZX was bactericidal. CZX was stable to the β-lactamase given frorri B. fragilis and was not hydrolyzed by it. CZX was found not to show a distinct effectiveness on the experimental mice infection caused by B. fragilis.

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The bacteriological evaluation on ceftizoxime (FK749) was performed in comparison with other antibiotics, cefotiam, cefmetazole, cefazolin, carbenicillin, piperacillin, and geotamicin as control antibiotics.
The following results were obtained.
1) Ceftizoxime showed broad antibacterial spectrum against gram-positive and gram-negative bacteria.
2) Antibacterial activity of ceftizoxime against clinical isolates of E. coil, K. pneumoniae, Enterobacter sp., indole positive Proteus, S. marcescens, P. cepacia, A. calcoaceticus, and H. influenzae was stronger than that of control antibiotics.
3) The MIC value of ceftizoxime was not affected by inoculum size, pH in the medium, and addition of horse serum.
4) Therapeutic effect of ceftizoxime against gram-positive and gram-negative bacteria except of P. aeruginosa was the most excellent than that of the control antibiotics, but with multiple injection of ceftizoxime, 7 times as effect as with once injection against P. aeruginosa.

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Ceftizoxime (CZX) is a distinctive new parenteral cephalosporin antibiotic with a broad antibacterial spectrum which is more potently active against a wide variety of gram-negative bacilli, including the opportunistic pathogens such as Citrobacter and Enterobacter species and Serratia marcescens, than cefotiam, cefoperazone and cefmetazole. The activity of CZX against Escherichia coli, Klebsiella pneumonia., indole-positive and-negative Proteus species, Haemophilus influenza. and Streptococcus pyogenes was by far superior to that of the four other antibiotics. These test organisms were not resistant to CZX. The antibacterial activity of CZX against Pseudomonas aeruginosa was almost the same as that of ticarcillin but was inferior to that of gentamicin and cefoperazone. The bactericidal activity of CZX against E. coli, K. pneumoniae was more potent than that of the four other antibiotics. CZX, like cefmetazole, was extremely stable to β-lactamases.
In studies in mice, the therapeutic effect of subcutaneous injection of CZX against various infections due to gram-negative bacilli was by far superior to that of, cefotiam, cefoperazone and cefmetazole, was almost the same as that of cefotiam and cefmetazole against Staphylococcus aureus infection and that of ticarcillin against P. aeruginosa infection.

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Antibacterial activity of ceftizoxime against ampicillin resistant clinical isolates of Escherichia coil was compared with those of other newly developed cephalosporins. CZX was the most active against strains possessing R-plasmids specifying ampicillin resistance and those whose resistance was chromosomally determined.
The susceptibility of ampicillin-sensitive E. coli to CZX was not decreased by transduction of ampicillinresistance specifying plasmids. However, most of the transconjugants acquired a high level of resistance to cefoperazone and cefamandole and a moderate level to cefotiam.
CZX was highly stable to both penicillinase and cephalosporinase type β-lactamases including R-plasmid mediated β-lactamase. Its level of resistance to β-lactamases was comparable to cefoxitin, cefmetazole and cefotaxime, slightly superior to cefuroxime and much superior to cefotiam, cefamandole and cefoperazone.

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Effects of ceftizoxime, cefotiam and cefmetazole on the morphology of E. coil at the sub-inhibitory concentrations were compared with a scanning electromicroscopy. When E. coil NIHJ JC-2 and No.5 (clinical isolate) were exposed to ceftizoxime at 1/8 the MIC, the viable counts decreased rapidly 1 hour after the exposure. However, no decrease of the viable counts was observed when cefotiam and cefmetazole were examined under the same condition.
The filamentous, spheroplast-like and lysia cells were observed 0.5 or 1.0 hour after exposure to ceftizoxime at 1/8 the MIC. Elongation of cells and formation of spheroplast-like structure on the cell surface were observed when cefotiam and cefmetazole were used, while the morphological alterations were much less than that of ceftizoxime.

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The pharmacokinetic profile of ceftizoxime (CZX) was studied and compared with that of cefotiam, cefmetazole, cefotaxime, cefazolin and cefamandole in mice, rats, dogs and monkeys after a single parenteral dosing.
CZX achieved high concentrations in the serum and tissues after parenteral dosing. The serum concentrations of CZX were higher than those of the other antibiotics in large animals (dogs and monkeys), but were lower in small animals (mice and rats). About 80% of CZX was excreted unchanged in a 24-hr period urine of all species tested. The biliary excretion of CZX was low, 3.7% in rats.
Pharmacokinetics were analyzed by the two compartment open model using data on serum concentrations in animals after a single intravenous (i. v.) injection. The active substance in urine samples was CZX itself, but, small amounts of an active metabolite were detected only in rat bile samples.
CZX was stable in biological fluids such as serum, urine and tissue homogenates, but cefotaxime was unstable in rat tissue homogenates. The serum protein binding of CZX in all speces was the lowest of all the antibiotics, i. e. 31% for humans, 17% for dogs and 32% for rats.

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The immunological properties of ceftizoxime (CZX) were compared with those of cefazolin (CEZ), cephalothin (CET) and penicillin G (PCG)
CZX showed a sensitizing activity as evidenced by the elicitation of specific hemagglutinating antibodies and PCA antibodies in rabbits immunized with protein conjugates or solution of this antibiotic, as do conjugates of CEZ, CET and PCG. When CZX solution was injected into rabbits, antigenicity of CZX was weaker than that of CET and PCG, similar to that of CEZ. CZX produced specific IgE type antibodies when injected intraperitoneally with suspension of its protein conjugates and Alum into mice. Producing activity of IgE type antibodies by CZX was weaker than that of PCG, similar to CEZ. CZX had weak cross-reactivity with CEZ, CET and PCG. Binding extent of CZX with human serum albumin was 3.4 moles/protein mole, similar to CEZ (3. 5 moles) and lower than that of CET (15.3 moles) under incubation at 37°C for 24 hours, pH 7.0. The extent of in vitro direct COOMBS' reaction of CZX was similar to CEZ and was weaker than that of CET and PCG.

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New cephalosporin, ceftizoxime (CZX) was evaluated in the treatment of 49 cases composed mainly of respiratory tract bacterial infection (41 cases) including 24 cases of pneumonia.
Ceftizoxime was administered at a daily dose of two grams divided into 2 intravenously or by drip infusion, diluted with glucose or saline solution.
As a result, in pneumonia cases, it was evaluated that 20 cases out of 24 (83%) were effective; excellent results were noted in 9 cases (38%). Poor and fair effects were observed mainly in cases associated with lung cancer. In bronchial infection such as chronic bronchitis and bronchiectasis, good results were noted in 13 cases (76%) out of 17 cases. Poor results were limited incases of pulmobary malignabcues complicated with lung infection. It was well effective in all cases (7 cases) of uriary tract infections.
Measurements of minimal inhibitory cobcentration (MIC) of this drug to clinically islated patbogens in this study demonstrated that this drug was extremely sensitive to gram-negative bacteria.
Skin eruption and/or elevation of alkaline phosphatase in 3 cases were observed as side effect of ceftizoxime during this trial.
It could be concluded from this study that ceftizoxime was highly useful and it may be used for the trcatment of respimtory tract bacterial infections.

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Pharmacokinetics and clinical effects of ceftizoxime (CZX), a new cephalosporin antibiotic, were investigated.
In 6 normal adults, intravenous administration of CZX in a dose of 1 g by drip infusion over 1 or 2 hours yielded a mean peak serum concentration of 69.0 or 30.6 μg/ml, respectively, at the end of infusion, and the mean serum levels at 4 hours after the end of infusion were 3. 4 and 1. 6 μg/ml, respectively. The biological halflife of the compound was estimated to be 1.33 hours by 1-hour drip infusion and 1.06 hours by 2-hours drip infusion. The drug was recovered in the urine by as much as 56.2% of the dose given in the first 2 hours after start of 1-hour drip infusion or similarly by 51.0% after start of 2-hours drip infusion. The subjects exhibited mean urinary recovery rates of 82.5% and 86.1%, respectively, in 6 hours.
As to the clinical evaluation, 24 patients with various infections (13 cases of urinary tract infection, 7 cases of respiratory tract infection, 3 cases of cholecystitis and 1 case of peritonitis) were treated with CZX receiving 1 to 4 g per day intravenously. Of 13 cases of urinary tract infection, the treatment produced a moderate improvement in 8, a slight improvement in 2 and no appreciable amelioration in 2 while the therapeutic response was unestimable in 1 patient. Of 7 patients with respiratory tract infection, 3 showed an excellent response, 3 a good response and 1 fair response. Two cases of cholecystitis and 1 case of peritonitis showed moderately effective and an overall effectiveness rate was 78.3%. Side-effects encountered were diarrhea in 2 cases, drug fever in 1 case and rash in 1 case.

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To evaluate the clinical efficacy of Ceftizoxime (CZX, FK 749), the treatment was made with the drug in 16 patients including 1 with pneumonia and 15 with urinary tract infections. Response was excellent is 9 patients and good in 6.
The MICs of Ceftizoxime against E. coli, K. pneumonia. and P. mirabilis, which were isolated from urine of patients with cystitis and pyelonephritis, were considerably lower thah those of cefazolin and similar to those of cefotiam.
Side effect noted was eosinophilia in 2 patients.

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Ceftizoxime therapy was performed in 7 cases of pulmonary infections including 5 cases with acute pneumonia, one with acute broncho pneumonia and one with pulmonary tuberculosis who was tentatively diagnosed as acute pneumonia on the first examination.
In every case, ceftizoxime was administered 1g in 300 ml of 5% xylitol by drip infusion method twice a day for 8 to 15 days. Minimum inhibitory concentrations (MIC) of clinically isolated organisms (may be causative) were determined for ceftizoxime and cefazolin, and radiographic examination of the chest was made as well as other laboratory examinations including routine haematology and urinalysis. The overall clinical efficacy of each case was rated on a five-step scale (marked, moderate, slight, poor and unevaluable) according primarily to degree of improvement in chest X-ray photograph and bacteriological effect from sputum and also by reference to other laboratory findings, subjective symptoms including adverse reactions.
Clinical response was marked in one case and moderate in 5 cases, whereas unevaluable case in one with pulmonary tuberculosis. A substantial contraction or disappearance of opacities on chest X-ray photograph was attained following ceftizoxime therapy in all cases except one case of pulmonary tuberculosis. MICs of Haemophilus influenza., Haemophilus parainfluenzae, Streptococcus pneumonia. and Enterobacter isolated as causative organisms from sputum were 0.025 to 1.56μg/ml at the inoculum size of 10⁶ cells/ml and 0.05 to 3.13μg/ml at 10⁸/ml. All these organisms disappeared following ceftizoxime therapy.
Adverse reactions occurred in one case; fever and anxiety developed on the 6 th day of ceftizoxime therapy, which subsequent feeling of chest distress, anorexia, diarrhea, nausea and vomiting, which all disappeared on the next day of the drug discontinuation.

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Ceftizoxime, a new parenteral cephalosporin antibiotic, was given to 14 cases with respiratory tract infections. Ceftizoxime was administered 0.5 to 2 grams twice a day by intravenous drip-infusion from 3 to 35 days. Pathogens isolated before treatment of ceftizoxime were mainly gram negative bacilli including Klebsiella pneumoniaand Haemophilus influenza and Peptococcus in one case of lung abscess.
Clinical responses of ceftizoxime were excellent in two cases, good in one case and fair in three cases out of seven cases with pneumonia; and good in each three cases with chronic bronchitis and infected bronchiolitis, and fair in one case with lung abscess, showing no failed cases except one unevaluable case with pneumonia who died of congestive heart failure.
Two cases of adverse effects due to ceftizoxime were observed. One case complained of pain of vein at the site of injection on the 17th day and ceftizoxime was discontinued. Another case complained of numbness of lower leg at each time of injection. Transient elevations of serum transaminase were noticed in two cases during ceftizoxime therapy.
Ceftizoxime was considered to be a useful tephalosporin antibiotic in the treatment of respiratory tract infections caused, by gram negative bacteria.

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Laboratory and clinical investigations on ceftizoxime were performed and the results obtainecl were as follows:
1) Susceptibility of clinically isolated strains to ceftizoxime was tested by the agar plate dilution method and compared to susceptibility to several antibiotics of cephalosporin, penicillin and aminoglycoside derivatives.
The minimum inhibitory concentrations of ceftizoxime for 50% inhibition of E. coil, K. pneumoniae, H. influenzae, S. marcescens and Enterobacter were less than 0.05μg/ml, 0.05μg/ml, 0.05μg/ml. 0.2μg/ml and 0.1μg/ml respectively.
2) Of 17 patients treated with ceftizoxime for respiratory tract infection (14 cases) and other infections, clinical results were effective in 16 patients.
Leucopenia and drug fever were observed in each one case by the administration of this drug.

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On a new semisynthetic derivative of cephalosporin, ceftizoxime (CZX), an in vitro study was conducted to compare its antimicrobial activities with those of other antibiotics which had been in clinical use Its clinical efficacy was also evaluated in patients with respiratory tract infections, and in 3 of them serum levels of the drug concentration were estimated and followed until 2 hours after the end of drip infusion of 2 grams of the drug.
One hundred and eighty four patient strains of gram-positive and-negative microorganisms were used for determination of inhibitory concentrations (MICs) of ceftizoxime, and the MICs determined were compared with those of cefazolin, sulbenicillin, dibekacin and amikacin.
Against 20 patient strains of Staphylococcus aureus the peak among MIC distribution was found at 1. 56μg/ml and this value was twice as much that of cefazolin, but one fifth of that of sulbenicillin.
Of 42 strains of Escherichia coli tested, the growth of 35 strains was inhibited at 0.39 μg/ml or less of ceftizoxime and the peak among MICs distribution was found at 0.025μg/ml or less, and ceftizoxime was shown to be the most active agent against E. coil among the drugs tested. Furthermore, it was known that almost all of CEZ-resistant strains of E. coli were susceptible to 0.39 μg/ml or less of ceftizoxime.
Of 49 strains of Klebsiella pneurnoniae tested, 42 strains were inhibited at 0.20 μg/ml or less of ceftizoxime and the peak value among distribution of MICs was 0.025 μg/ml and against Klebsiella pneumoniae the agent was most active as compared with any other drugs employed for comparison. About a half of the strains of Klebsiella pneumoniae which had been shown to be refractory to CEZ was found susceptible to 0.1 μg/mlorlessofceftizoxime.
Against patient strains of β-lactamase producing Enterobacter cloacae, ceftizoxime was demonstrated to be still active and the growth of 6 out of 7 patient strains was inhibited at 0.2 μg/ml or less of the agent. Antimicrobial activity of ceftizoxime against Enterobacter cloacae was most potent as compared with those of the other drugs examined.
In contrast to the results above mentioned, ceftizoxime was found to be not so active against patient strains of Pseudomonas aeruginosa. The peak among MICs distribution was found between 25 and 50 μg/ml, and this value was 4 or more times less than that of sulbenicillin, but was 4 or 5 times as much as that of dibekacin or amikacin.
Against 8 strains of Acinetobacter calcoaceticus, a species of glucose non-fermentative gram negative bacilli, the pattern of MICs distribution of ceftizoxime was similar to that obtained against Pseudomonas aeruginosa.
In 3 patients with no abnormalities in renal function tests, serum concentrations of ceftizoxime were de termined at the end of 2 hours drip infusion of 2 g of the drug and serum levels were followed through 2 hours thereafter. The mean serum concentration was 139.7 μg/ml at the end of infusion, and was 119.3μg/ml and 71.0μg/ml at 30 minutes and 2 hours thereafter respectively.
Twenty patients with respiratory tract infections were treated with ceftizoxime. Four patients were omitted from evaluation of efficacy of the drug because in 2 of them the underlying disease, lung cancer, was in so far advanced state that evaluation might be inadequately made and in other 2 patients diagnosis was made as pulmonary tuberculosis during the treatment. Sixteen patients on whom evaluation was made consisted of 6 patients with pneumonia, 4 with lung abscess, 1 with emphysema, 2 with diffuse panbronchiolitis, and 3 with secondary pulmonary infection to lung cancer. The drug was given by intravenous drip infusion with daily dose of 4 g in 14 patients or of 2g in the remaining 2 patients.

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Ceftizoxime, a newer cephalosporin antibiotic, was applied to 10 patients of respiratory tract infoggias including 7 cases of pneumonia, 2 cases of chronic bronchitis and one case of infected bronchiectasis. Two grams twice a day of ceftizoxime were injected by intravenous drip-infusion or bolus injection for 7 to U days.
Of 10 respiratory tract infections, excellent response was obtained in 4 cases, good in 4 cases, fair in one case and one case was poor. Three cases isolated H. influotzas responded satisfactorily.
No adverse effect was observed in all cases.
Ceftizoxime seems to be useful cephalosporin in respiratory tract infection.

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A clinical trial of ceftizoxime, a new parenteral cephaloeporin antibiotic, was carried out on 15 patients with respiratory tract infections.
To reveal the efficacy of low dose, short period of ceftizoxime treatment, 0.5 to 1 g was administered twice a day for 7 to 14 days by intravenous drip infusion method to the patients including 7 cases of pneumonia, 6 of acute bronchitis and 2 of panbronchiolitis. As a result, clinical response was excellent in 14 cases and fair in one case with a secondary infection of lung cancer. The following organisms were isolated from sputum of 5 cases; Staphylococcus aureus in 2 cases, Streptococcus pneumoniae in 1, Proteus vulgaris in 1 and Klebsiella aerogenes and Enterobacter cloacae in 1. All of these organisms were eradicated by ceftizoxime therapy.
A slight transient elevation of transaminase and drug fever were observed in each one case as side effects.
Ceftizoxime was considered to be a useful antibiotic for the treatment of respiratory tract infections.

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Ceftizotime (CZX, FK 749), a new parenteral cephalosporin antibiotic, was used in 15 cases with respiratory tract infections.
Ceftizoxime was administered to 10 cases of pneumonia, 2 cases of chronic bronchitis, and each one case of lung abscess, secondary infection of pulmonary silicosis and middle lobe syndrome, in the dose of one gram twice a day by intravenous drip-infusion dissolved in 100 ml of 5% glucose.
Out of 14 cases who were evaluated clinical effectiveness, nine cases were good, one case was fair and 4 cases were poor.
Exanthema was found in one case with middle lobe syndrome, and it was disappeared after discontinuing the administration of the drug. A transient elevation of transaminase in two cases was also restored to normal values after discontinuing the administration of the drug.
Ceftizoxime seemed to be useful cephalosporin antibiotic in the treatment of respiratory tract infections.

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Ceftizoxime (CZX, FK 749) was examined on its in vitro activity against clinically isolated strains. Ceftizoxime was found to be more active against most strains of Escherichia coli and Klebsiella pneumoniaethan CMZ, CTM and CEZ. And its activity was quite the same against strains of Pseudomonas aeruginosa compared with that of SBPC.
Ceftizoxime was given to 25 patients; 10 with respiratory tract infections, 11 with urinary tract infections and 4 with other infections. The drug was administered one-shot intravenously or intravenously by drip infusion, and intramuscularly with an exception.
1) Efficacy rate was counted 90% in respiratory tract infections, and 91% in urinary tract infections. The overall efficacy rate was 79%.
2) Bacteriological effect was as follows: Out of nine isolates of E. coli, seven were eliminated but two were replaced. Two strains of S. pneumoniae were all eliminated. One strain of Pseudomonas aeruginosa was eliminated but the other one was replaced.
3) No clinical side-effects were observed, except slight transient elevation of GPT was noted in one case.

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Laboratory and clinical studies on CZX, a new cephalosporin antibiotic, were carried out and the following results were obtained.
1. Clinical gram-negative isolates tested against CZX showed far superior susceptibilitiy to CEZ in special reference to E. coli, Klebsiella and Proteus.
2. CZX was administered in doses of one and two grams to six healthy male adults by drip infusion over two hours. Two grams of CEZ were also given in cross over method.
Dose response was found between the serum levels obtained in one and two grams of CZX administration.
Serum levels of CZX after two grams drip infusion were lower and the elimination from serum was faster than those of CEZ. Both recovery rates from urine and urinary levels of CZX were higher.
Serum levels, and biliary and urinary excretion of CZX were determined following intramuscular injection in dose of 40mg/kg to three normal rats. Both of rates of biliary and urinary excretion were considered to be satisfactorily high.
3. Clinically, one patient with biliary tract infection was treated with CZX, and responded well, without showing any side effect.

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Basic and clinical studies were made of ceftizoxime (CZX) with the results summarized as follows:
1) Antibacterial activity
CZX was show; to be reliably effective against, E. coil, Klebsislla, Enterobacterand Serrgtia, with its MIC values, being remarkably low especially when the inoculum size was small.
2) Absorption and excretion
The concentrations of CZX in the blood and wine were determined following the intravenous administration of 1 g in 3 healthy volunteers. Its half-life was shorter than that of CEZ and longer than that of CET. An average of 91.496 of the administered dose was recovered in urine within 6 hours after administration.
3) Clinical results
The drug was used in 1 case of bacteremia, 1 case of pneumonia, 5 cases of urinary tract infection, 2 cases of bile duct infection and 1 case o perjtoniti? and proved to be effective in 9 of these 10 cases (excepting 1 caseoftlirinary tract infection). The dosage was 1 to 2 g per day. Side-effects were encountered in none of the treated cases.

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Ceftizoxime was demonstrated to be far stronger in its antibacterial activity against Escherichia coli, Klebsiella pneuntoniae, Proteus mirabilis, indole-positive Proteus, Enterobacter cloacae and Serratia marcescensthan cephaloridine, cephalothin, cefazolin and cefotiam.
In healthy adults the administration of ceftizoxime in a single i. m. dose of 500 mg yielded peak blood levels of 12.0-16.0μg/ml in 30 minutes and the half-life was estimated to be 1.42-1.80 hours. Within 8 hours following the administration 64.3 to 83.2% of the administered dose was recovered in urine. When probenecid, in a dose of 500 mg, was administered 30 minutes before an i. m. dose of 500 mg ceftizoxime, elevated peak blood levels of 12. 5-23.4μg/ml were attained and the urinary recovery rate for initial 8 hours after dosing was decreased to 52.2-68.0%.
A total of 23 cases of bacterial infection, comprising 1 case each of sepsis and cervical lymphadenitis, 9 cases of respiratory tract infection, 2 cases of biliary tract infection and 10 cases of urinary tract infection, were treated with ceftizoxime. The results were rated as excellent in 9 cases, as good in 8 cases, as fair in 3 cases, as poor in 1 case and as unassessable in 2 cases.
The use of the drug was attended by pyrexia and elevation of transaminase in one instance each Otherwise no serious adverse reactions were seen in none of the cases studied.

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Laboratory and clinical studies on ceftizoxime, a newly developed cephalosporin antibiotic, were carried out.
Ceftizoxime showed a greater antibacterial activity against E. coil and K. pneumonia, than cefazolin, cefotiam and cefmetazole, and against S. marcescens than cefotiam and cefmetazole. The compound also proved to be noticeable against E. cloacae, the activity being greater than that of sulbenicillin and ticarcillin, whereas against P. aeruginose, it showed a 4 higher MIC value and hence was less active than those two drugs, Hqwever, therewas evi4ence, of synergism of the effect of ceftizoxime when combined with gentamicin or with dibekacin, against 21 of the 27 strains, of P. aeruginosa tested, thus suggesting possible clinical effectiveness in the treatment of P. aeruginosa infection.
Five patients with urinary tract infection were treated with ceftizoxime, of whom 4 responded with a significant glinical improvement.No side effects were encountered in any of these patients studied.
The results have indicated that the drug may be promising in antimicrobial chemotherapy.

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Ceftizoxime was administered to a total of 9 patients, including 6 cases of pneumonia and 3 cases of chronic urinary tract infection. Clinical efficacy was good in 5 cases, fair in 1 case, poor in 3 cases. Bacteriological efficacy was eliminated in 2 cases, decreased in 2 cases, replaced in 2 cases, unchanged in 2 cases and undetermined in 1 case. Adverse reaction to ceftizoxime was not revealed.

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Following results werepbtained by bacteriological, pharmacological and clinical, studies on ceftizoxime.
In vitro antibacterial activities of seftizqxime to clinically isolated, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae and Serratia marcescens were sgperiar to other cephaloaporins except of Pseudomonas aeruginosp.
Serum concentration and urinory excretion, of ceftizoxime were with cefmetazole following intramuscular injection of each half a gram by cross-over method, in six normal volunteers. As a result, half lives in serum of ceftizoxime and cefmetazole were 1. 6 hours and 1. 2 hours respectively. Urinary excretions for six hours following injection of ceftizoxime and cefmetazole were 72.6% and 77.6% respectively.
Peak levels in sputum of ceftizoxime fellowing drip-infusion of 1 to 2 grams were 3.25 to 10.8μg/ml at the dose of 2 grams, and 0.96 to 5.8μg/ml at the dose of one gram. These levels in sputum of ceftizoxime seem to be, favorable compared to other ceplporins.
Clinical response to ceftizoxime in one septicemia due to E. coil was satisfactory. Of 11 cases with respiratory tract, infection, one case was excellent, 8 cases were good and 2 cases were poor. Of five cases with urinary tract, infection, one case due to P. vulgaris was excellent, 2 cases were good and 2 cases were poor. Of three cases, with biliary, tract infection, 2 cases were good and one case was poor.
No adverse reaction was observed clinically, In the laboratory findings, transient elevation of transaminase in 2 cases, eosinophilia in 3 cases and anemia in one case were observed.

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The susceptibility of 25 strains of B. fragilis, 13 strains of B. thetaidaomicron and 5 strains of B. vulgatus to ceftizoxime was determined. The MIC₈₀ (mic which inhibits 80 96 of the strains tested) was 1.56μg/ml for B. fragilis, 12.5μg/ml for B. theiaibtaomicron, and 6.25μg/ml for B. pulgatus.
Serum concentrations in 13 aged volunteers after intravenous injection 1 g of ceftizoxime were compared to those of younger volunteers. The average serum level at 15 minutes after injection and serum half-life were 80.1μg/ml and 3.68 hours in the aged group, and were 64.3μg/ml and 1.39 hours in the younger volunteers. The serum level at 12 hours after injection was Calculated to be 5.3μg/mi in the aged group. On the basis of these results, intravenous injection of 1g of ceftizoxime twice a day would be a recommendable schedule for moderate to severe systemic infection of the aged.
Ceftizoxime was given to 12 patients and evaluation was feasible in 11 patients (one with septicemia, liye with urinary, tract infection, four with respiratory tract infection and one with phlegmone). Nine patients showed satisfactory response. The patients with urinary tract infection responded satisfactorily to intramuscular injection of half a gram of ceftizoixime given twice a day. The patient with septicemia due to, E. coil resistant to CEZ and ABPC showed favorable response to ceftizoxime. Two patients who failed to respond were the one with fungal pneumonia and another with urinary tract mixed infection due to P. aeruginosa and Enterococcus.
No adverse reaction was observed.

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A clinical study of ceftizoxime, a new cephaloaporin antibiotic, was carried out with the following results. Nine cases of various respiratory infections (including 6 cases of pneumonia, 2 cases of bronchiectasis and one case of acute bronchitis) were treated by intramuscular or drip infusion with 2, 000mg-4, 500mg per day of ceftizoxime given in 2-3 divided doses for 3-17 days.
The clinical response of the patients was satisfactory in 7 (6 cases of pneumonia and one case of bronchiectasis) and poor in 2 cases of bronchiectasis.
In all pneumonia cases, the causative organisms, including Klebsiella pneumoniae, Haemophilus influenzae, Serratia, Enterobacter, E. coli, Proteus mirabilis, disappeared from the sputum after treatment.
In two cases of bronchiectasis, H. influenzae was eliminated but Pseuthmumas aeruginosa was replaced.
The pharmacokinetics of this antibiotic were studied in two cases with chronic bronchial infection. After drip infusion of 2g of ceftizoxime for one hour, the peak of the serum concentration was 67.0μg/ml in the diffuse panbronchiolitis and 130μg/ml in the case with bronchiectasis. In the bronchiolitic case, the half life of the antibiotic in the blood was 1.27 hours. The penetration into the sputum of ceftizoxime was good and the level was sustained between 1.64-2.24μg/ml for 7 hours. In the case of bronchiectasis with renal failure, the half life in serum was 5.8 hours and the concentration in the sputum was 1.3μg/ml at the end of infusion, increased continuously, and reached to 20.0μg/ml after 5.5 hours.
No remarkable side effects were noted except eruptions in one patient, appeared at the 4th day of the treatment, which disappeared spontaneously after discontinuing the drug.

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Clinical effectiveness and adverse effects of ceftizoxime, a new cephalosporin antibiotic, were studied in 12 patients with the respiratory tract infections receiving 1 to 3g b. i. d. by drip infusion. There were 9 cases of lower resniratory tract infection. 2 cases of nneumonia and 1 case of lung abscess.
The treatment was markedly effective in 3 patients, moderately effective in 3, slightly effective in 2 and ineffective in the remaining 4, thus producing slight to marked clinical improvement in 67% of the cases studied.
The ceftizoxime therapy was effective in all 5 cases of respiratory tract infection with H. influenza whereas it failed to bring about any significant bacteriological improvement in any of 4 cases of respiratory tract infection by glucose non-fermentative gram negative bacilli.
In a case of pneumonia due to S. marcescens refractory to other antimicrobial chemotherapy, a bignificant clinical improvement was achieved by administration of ceftizoxime, 3 g b. i. d.
None developed any serious adverse effects.
The results indicate usefulness of ceftizoxime in the treatment of respiratory tract infection.

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Ceftizoxime, a newer cephalosporin derivative, was given in 20 patients with 4, cases of pneumonia, 3 cases of bronchitis, 2 cases of cholecystitis, one case of phlegmone of tongue, and 10 cases of pyelonephritis. In patients of pyelonephritis, ceftizoxime was given 0.5 gram twice a day and in other infection, was one grain or 2 grams twice a day intravenously or by intravenous drip-infusion.
As a result, one case of phlegmone, three cases of bronchitis, two cases of pneumonia and two cases of cholecystitis showed satisfactory response. The 7 patients with pyelonephritis responded satisfactorily.
Pathogenic organisms were disappeared in 3 cases of E. coil, 2 cases of Micrococcus, and each one case of S. pneumoniae, Enterococcus, Enterobacter, K. pneumoniae and P. mirabilis.
No adverse reaction due to ceftizoxime was clinically observed in all cases, but one case demonstrated a transient elevation of serum GOT.

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Clinical studies were made on ceftizoxime (CU), a new injectable cephalosporin antibiotic, and the following results were obtained.
1. Noticeably low minimal inhibitory concentrations (MICs) were observed for ceftizoxime against clinical isolates of E. coli (20 strains), K. pneumoniae (18 strains), S. marcescens (14 strains) and P. cepacia (49 strains), the activity against the P. cepacia being particularly marked as compared to other antibiotic. None of these clinical isolates was found resistant to ceftizoxime, with an MIC over 100μg/ml.
2. A total of 13 courses of ceftizoxime therapy were performed in 12 patients with infections. The treatment produced a marked clinical improvement in 1 case, a moderate improvement in 9 cases, a slight improvement in 1 case and no improvement in 1 case while the clinial response could not be assessed in the remaining 1 case (effectiveness rate: 83.3%). Of 8 cases which were refractory to other antimicrobial chemotherapy, 6 responded with clinical improvement to the ceftizoxime treatment. Eruption and a slight elevation of serum transaminase were noted as side-effects in 1 case each.
It would follow from the results that ceftizoxime is a new antibiotic with potential usefulness not only against infections by gram-negative bacilli but in cases refractory to other drugs as well.

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Ceftizoxime, cefotiam and cefazolin were administrated intravenously in daily dose of 500mg/kg for 10 days to rabbits and the nephrotoxicity of ceftizoxime was compared with that of cefotiam or cefazolin. As the results, the eviclence of renal damage due to these three cephalosporins, as judged by protein and Ted blood cell in urine, the levels of serum creatinine and histological change of kidneys, was hardly observed in all rabbits. Therefore, it was impossible for, us to distinguish the degree of nephrotoxicity in ceftizoxime from that of other two cephalosporins under these experimental conditions.

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Ceftizoxime has been studied clinically, and the following results were obtained.
1. Ceftizoxime was administered to 38 patients: 23 respiratory tract infection, 8 urinary tract infection, 2 sepsis, and 5 other infection.
2. Ceftizoxime was given intravenously or intramusculary at a daily dose of 1.0 to 6.0g to the patients with normal renal function, or at a daily dose of 1.0g to the patients with reual insufficiency.
3. Clinical response was excellent in 3 patients, good in 27, fair in 1, poor in 3 and undetermined in 4, with normal renal function, or at a daily dose of 1.0g to the patients with reual insufficiency.
4. Drug fever was observed in 3 patients and exanthema in 1.
Laboratory tests revealed the elevation of GOT and GPT in 2 patients, the elevation of Al-P in 1 and ebsinophilia in 2.
No severe side effects were observed with this drug.

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Ceftizoxime concentrations in serum and urine were determined in 5 healthy adult volunteers and 14 patients with impaired renal function after 0.5g of the drug was injected intravenously.
Average serum half life was 1.3 hours in healthy volunteers, 1.4 hours in the patients with Ccr values of more than 60 ml/min, 2.5 hours in the patients with Ccr values of 60 to 30 ml/min, 8.1 hours in the patients with Ccr values of 30 to 10 ml/min, and 26.6 hours in the patients with Ccr values of less than 10ml/min.
In these patients undergoing haemodialysis, average serum half life was 3.2 hours. As for urinary recovery rate within the first 6 hours, average value was 95% in healthy volunteers, 78% in the patients with Ccr values of more than 60 ml/min, 71% in the patients with Ccr values 60 to 30ml/min, 21% in the patients with Ccr values 30 to 10 ml/min.
From the above data obtained, the linear equation of Ke=0. 0285+0.00478·Ccr was established between creatinine clearance and elimination rate constant of ceftizoxime. Using the above mentioned equation, modified dose intervals and nomogram of loading dose and maintenance dose were prepared at the same intervals both in the patients with normal renal function and those with impaired renal function.

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Ceftizoiaine was used in a total of 6 cases of moderately severe or severe infections in the held of internal medicine, 5 of respiratory tract infection and 1 of a fever of nnknown origin. The results in this series were good in 3 cases, fair in 2 cases and Unknown in one case.
No subjective symptoms occurred as adverse reactions by the drug. In one case the treatment with the drug was associated with a slight elevation of BUN, but it was uncertain as to whether or not this abnormality was attributable to the drug.
Although no conclusive statement can be made from this study of a small group of cases, it can be said at least that the drug may be anticipated to prove of clinical benefit in the treatment of moderately severe or severe infection.

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Ceftizoxime (FK 749), a new cephalosporin derivative developed by Fujisavii Research Laboratories was examined on its activity; against bacteria isolated from human infection foci, as well as on its distribution in rat's body. Some clinical trials were also carried out. The results obtained were as follows:
1) Antimicrobial activity: The activity of ceftizoxime against S. aureus strains was similar tu that of cefotaxime, being somewhat weaker, than those, of cefazotlin, cefuroxime, cefotiam and cefmetazole, and P. aeruginosa strains showed higher susceptibility to ceftizoxime, similarly to cefotaxime, than to other cephalosporin derivatives. Ceftizoxime was found to be the most potent drug against P. mirabills strains among the cephalosporin derivatives tested.
2) Distribution in the rat's body The distribution pattern of ceftizoxime in the rat's body after intramuscular injection of 100mg/kg was similar to those of cephalciridine, cephalothin and cefazoliri, although its level was much higher than those of other cephalosporins.
3) Clinical trials: Ceftizoxime was administered 1-2g×2/day by drip infusion for 3.5-13 days, to eight patients (UTI 4, RTI 2, cholecystitis 1, and FUO 1). Six pf the patients responded well to the treatment, and one (pneumonia by, Pseudomonas) fairly; while no response was seen in the patient of cholecystitis with bile-stone. Neither side effects nor abnormal laboratory findings attributable to the drug were observed. These results obtained suggest that ceftizoxime should, be one of the excellent cephalosporin derivatives newly developed.

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Fundamental and clinical studies were performed on ceftizoxime.
Peak seithivity leveleto the drug of clinical isolates of S. aureus, B. coil, Klebsiella, P. mirabilis, P. vulgaris, P. aeruginosa were found at 1.56, <0.1, <0.1, <0.1, 0.1, 25 and <0.1μg/ml, respectively. The drug was thus demonstrated to be less active against S. aureus than CEZ but far greater than CEZ in its antibacterial activity against gram-negative bacilli.
Blood levels of ceftizoxime yielded by the i. v. drip infusion of 1g for 1 hour in healthy adults averaged 49.2μg/ml just after completion of administration, 25.7μg/ml at 30 minutes, 17.7μg/ml at 1 hour, 6.9μg/ml at 3 hours and 2.5μg/ml at 5 hours, with T1/2 being estimated at 1.432 hours. T1/2 of cefotiam as measured under the same conditions was 0.988 hour. Following the administration of 1g of ceftizoxime by i. v. drip infusion for 1 hour 86.7% of the administered dose was recovered in urine within 24 hours.
Fourteen cases of respiratory infection and 7 cases of urinary tract infection were treated with ceftizoxime administered by i. v. drip infusion at a daily dosage of 1 to 4 g for 5 to 22 days. Clinical response to this drug was excellent in 2 cases, good in 7 cases, fair in 3 cases and poor in 2 cases of respiratory tract infection and excellent in 3 cases, good in 3 cases and poor in 1 case of urinary tract infection. Bacteriologically, the result of the treatment was good in 10 cases, poor in 1 case and uncertain^ in 3 cases of respiratory tract infection and good in 2 cases, fair (partially effective) in 1 case, poor in 2 cases and uncertain in 2 cases of urinary tract infection. Of 21 cases, the use of the drug was attended with a transient, slight elevation of GOT and GPT in 3 cases and of BUN in 1 case. Otherwise no noticeable side-effects were encountered.

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1. The peaks of MIC distribution of ceftizoxime (CZX) against E. coli, K. pneumonia, P. mirabilis and S. marcescens were <0.1μg/ml. Most of the strains of P. vulgaris, E. cloacae, P. cepacia and Acinetobacter were inhibited by 50μg/ml or lower of CZX. These results were much better than those of cefazolin and a little better than those of cefotaxime.
2. The peak blood levels of CZX after intravenous drip infusion of 1 g for 2 hours were 17.6-33.0μg/ml (26.9μg/ml on average) at the completion of infusion, and the urinary recoveries during 6 hours were 75-98%(88.7% on average).
3. Clinical response of CZX in 11 cases with respiratory tract infection and one case with sepsis was excellent in 6 cases, good in 3 cases, fair in 2 cases and failure in one case. No side effect and no abnormal laboratory finding was observed in any case.

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The clinical effects of ceftizoxime (FK749), a new cephalosporin antibiotic, was studied in nine cases. All of the cases accompanied with various kinds of underlying disease. Clinical efficacy was observed in 3 out of 4 cases of respiratory tract infection, and in 2 out of 4 cases of urinary tract infection. However a case of liver abscess complicated with acute myelocytic leukemia was failed. GOT and GPT elevated in one case of urinary tract Infection with hyperthyroidism, but returned to normal levels after discontinuation of the drug.
In a case of liver abscess with severe acute myelocytic leukemia, the patient complained of numbness, palpitation and dyspnea during ceftizoxime administration. This may be due to underlying disease itself.
Ceftizoxime seemed to be a useful antibiotic against various bacterial infections.

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Patients wit4 infections of the respiratory tract were treated in a clinical trial of ceftizoxime, a new antibiotic, to assess its efficacy and levels of antimicrobial activity in serum and pleural effusions.
1. Of 17 patients receiving ceftizoxime alone, 94% responded with a significant clinical improvement.
2. Two patients experienced an adverse reaction which subsided following discontinuation of the medicament, requiring no particular treatment.
3. A slight elevation of serum transaminases occurred in 3 cases, increased eosinophil counts in 2 and elevation icif serum alkaline phosphatase in 1 during the ceftizoxime therapy.
4. Intravenous drip infusion of ceftizoxime in a dose of 1 g yielded a peak serum concentration of about 50μg/ml immediately after the end of infusion and a peak level of 3. 3-11.1 pginfl in the pleural effusionat about 3 hours after the end of infusion.
5. The ratio of peak pleural, effusion level to peak serum level was determined to be 10.0-21.0% for ceftizoxime, compared to, 2.8-11.9% for CEZ, thus indicating an obviously better distribution of ceftizoxime into tae pleural cavity.

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Laboratory and clinical studies were performed on ceftizoxime, a new semisynthetic cephalosporin antibiotic, and the results were as follows.
1. Antimicrobial activity MICs of ceftizoxime against various clinical isolates were determined. With an inoculum size of 10⁸ cells/ml, percentages of strains susceptible to 12.5μg/ml or less were 94.9% for S. aureus, 12.5% for S. faecalis, 98.6% for E. coli, 97.4% for K. pneumoniae, 10096 for K. oxytoca, 8.9% for Enterobacter sp., 71.4% for S. marcescens, 76.1% for Proteus sp., 50% for Citrobacter sp., and 0% for P. aeruginosa. With 10⁶ cells/ml MICs of ceftizoxime were much more potent than those with 10⁸cells/ml and most strains of E. coli, K. Pneumoniae and K. oxytoca were inhibited by 0.20μg/ml or less.
2. Serum and liquor concentration Serum concentrations of ceftizoxime were measured in patients being treated with ceftizoxime. In two patients given lg of ceftizoxime intravenously serum concentrations were 1.9, 29.0μg/ml before iv injection; 39.0, 90.0μg/ml at 15 min.; and 6.0, 36.5μg/ml at 4 hr. after injection respectively. In a patient given 2g of ceftizoxime by drip infusion, serum concentrations were 2.0μg/ml before infusion; 62.5μg/ml at the end of infusion; and 8.8μg/ml 6 hr. after infusion. Liquor concentrations of ceftizoxime 1 hr. after i. injection of lg were 6.0 and 4.7μg/ml in the same patient, and liquor/serum ratio was 0.22.
3. Clinical efficacy Three patients with pneumonia, 2 with SBE, 1 with lung abscess, 1 with sepsis, 1 with purulent meningitis, 1 with periostitis, and 1 with relapsing UTI were treated with ceftizoxime in daily doses of 2-6g for 3-31 days. Clinical response was excellent in 2, good in 5, fair in 1 and poor in 2 patients. Bacterial effect was very good, especially against gram-negative bacilli. Colonization of P. aeruginosa was seen in one patient.
Exanthema and diarrhea were noticed in one patient each and GOT and GPT increased in one patient.

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Serum concentrations of ceftizoxime, a new cephalosporin, were determined in patients undergoing heinodialysis.
The drug was given in an intravenous dose of 500 mg for 3 minutes and serum concentrations were measured in 6 patients during dialysis and in 4 of the same patients during and between dialysis periods.
Mean serum concentrations of ceftizoxime during dialysis 15 minutes, 2 and 6 hours after intravenous injection were respectively 38.1, 15.7 and 8.1μg/ml, and mean serum half-life was 4.93 hours.
In contrast, mean serum concentrations of the drug between dialysis 15 minutes, 6 and 24 hours after intravenous injection were respectively 41. 3, 33.2 and 21.3μg/ml and mean serum half-life was prolonged to 28.95 hours.
Urinary excretion of ceftizoxime was also measured simultaneously in the four patients at various intervals after i. v. injection.
The urinary concentrations of the drug were 61μg/ml or higher, which were considered effective for clinical use.

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Laboratory and clinical studies on ceftizoxime (FK 749), a newly developed cephalosporin derivative, were carried out with the following results.
The in vitro antibacterial activity of ceftizoxime against 22 standard strains and 763 routine clinical isolates including gram-positive cocci, Enterobacteriaceae glucose non-fermentative gram-negative bacilli and Haemophilus species was compared with that of cefazolin, cefotiam, cefamandole, cefmetazole, ampicillin and piperacillin. Ceftizoxime was less active against Staphylococcus aureus and Staphylococcus epidermidis than cefazolin, cefotiam, cefamandole, cefmetazole but was the most active of the antibiotics tested against Exherichia coli, Klebsiella aerogenes, Enterobacter cloacae, Enterobacter aerogenes, Citrobacter freundii, Protaus vulgaris, Pr. mirabilis, Pr. rettgeri, Pr. inconstans, Serratia marcescens, Haemophilus parainfluenzao and H. influenzae. Ceftizoxime was also given to ten healthy adult volunteers in single doses of 250 and 500 mg in a cross over study.
Mean peak serum levels were 14.3μg/ml at a dose of 250 mg and 27.0μg/ml at a dose of 500mg. Urinary recovery rate for both doses was about 80 per cent for 6 hours after the end of intravenous drip infusion.
Peak serum levels of ceftizoxime were 84-101μg/ml after intravenous drip infusion of 1 gram, and 90-210μg/ml after intravenous drip infusion of 2 grams. Urinary recovery rates were 68.3-95. 6 per cent.
Peak sputum levels of ceftizoxime were 0.29-1.8μg/ml in the 6 patients with chronic bronchitis after intravenous drip infusion of 1-2 grams.
Biliary level of ceftizoxime after intravenous drip infusion of 2 grams was about 0.07μg/mI. HaemoPhilus influenzae in the sputum of a patient with chronic bronchitis began to decrease from the initial 10⁸ cells/nil to 10⁴ cells/ml for the first 10 hours after intravenous drip infusion of 1 gram, and peak sputum level was 0.29μg/ml in this patient. This organism was eliminated from the sputum on the second day of treatment.
Pseudomonas aeruginosa isolated from the sputum was stable at about 10⁵ cells/ml throughout the treatment period.
Twenty-eight patients with pulmonary, pleural, urinay, biliary or peritoneal infection were treated with ceftizoxime by intravenous drip infusion. Twenty one of the 27 patients responded satisfactorily to the tettment and the effectiveness rate was 77.8%.
One strain of Streptococcus pneumoniae, 1 of β-Streptococcus, 7 of H. influenzae, 2 of E. coli, 2 of Kl. aerogenes, 1 of Ent. aerogenes and 2 of Ps. aeruginosa were eliminated and the bacteriological efficacy rate was 83.3%. Serum transaminase value increased slightly in one patient.

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Ceftizoxime is a new semisynthetic cephalosporin antibiotic, which possesses the syn isomer of the methoxyimino and the aminothiazol groups at the 7 poiition of the cephem ring without the 3-substituent. Clinical and laboratory study has been made of ceftizoxime in order to evaluate its usefulness mainly in respiratory infections.
Antibacterial activity of ceftizoxime was superior to the other broad-spectrum cephalosporin antibiotics against the respiratory pathogenic bacteria. The geometric mean MICs of ceftizoxime were 0.0186°g/ml against Haemophilus influenzae, 0.0461°g/ml against Streptococcus pneumonia., >0.05°g/ml against Klebsiella pneumonia., 15.4°g/ml against Pseudomonas aeruginosa, >0.05°g/ml against Escherichia coli, and 0.09°g/ml against Enterobacter sp. Beta-lactamase stability of ceftizoxime was established, utilizing β-lactarnase-producing ampicillin-resistant Haemophilus influenza.(4 strains) and Haemophilus parainfluenzae (1 strain).
Ceftizoxime concentration of tissues in rats after intramuscular injection of 20 mg/kg was in the order: Kidney >Serum >Liver >Lung.
The half-life of ceftizoxime in a patient with normal renal function was 1. 39 hr or 1.58 hr. The ratios of maximal sputum level to peak serum concentration ranged from 1. 35% to 4. 66%(mean 2.95%) in patients with respiratory infections.
Eighteen respiratory infections and three urinary tract infections were subjected to clinical evaluation of ceftizoxime, indicating favorable clinical response, i. e., the rates of clinical therapeutic efficacy were83.3% and 100%, respectively. One of them showed reversible, slight elevation of alkaline phosphatase. The safety of this cephalosporin antibiotic was good.
From the above results, it was concluded that ceftizoxime is one of the most effective' and useful antibiotics for the treatment of respiratory bacterial infections, particularly for those due to Haemophilus influenzae and/or Streptococcus pneumoniae.

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1. Antibacterial activity
Ceftizoxime proved to be somewhat less active against Staphylococcus aureus than cefazolin (CEZ) but its activity against gram-negative bacteria, especially against Escherichia coil, Klebsiella pneumonia., Protein and Sarrolia, was greater than that of CEZ by several tubes in the serial 2-fold dilutions. The antibiotic also showed activity against Pseuclomonas aerugitsoso.
2. Clinical trial
Ceftizoxime was also studied in the treatment of 11 patients with bicterial infections. Ceftizoxime treatment; produced an excellent, clinical improvement in 2 cases, a moderate improvement in 7 and no clinical benefit in 2.
3. Side-effects,
One patient complained of a transient nausea which, however, could not be obviously associated with the administration of ceftizoxime. No significant adverse findings were noted in the laboratory examinations that included liver function tests, renal function tests, routine hematologic examination and blood biochemical tests.

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Fundamcntal studies of ceftizoxime, a new cephalosporin antibiotic for injoction use, were made and the following results were obtaioed.
Antibacterial activity of the drug was slightly lower than that of cefazolin against S. aursus but was much higher against, gram-negative rodS such as E. coli. When the inoculum size of 10⁶ cells/ml was used, a concentration of the drug lower than 0.1μg/ml inhibited the growtb of 22 out of 33 strains of E. coli and that Iower than 0.39μg/ml 28 strains, respectively. The MIC of 20 strains of group B Streptoeoceus to ceftizoxime was determined with the inoculum size of 10⁸ cells/ml; 17 strains had an MIC of 0.1μg/ml, eacb one strain of 0.05, 0.2 and 3.13μg/ml. respectively.
Average concentfations of the drug in CSF following a single intraveuous injection of 100 mg/ kg into 5 rabbits with staphylococcal meningitis were as follows; a maximum level was obtained 30 min. after the injection. i. e. 6.42 0.78μg/ml; 6.06±1.13μg/ml (1 hr.); 4.03±0.8μg/ml (2 hrs.); and 2.94±0.75μg/ml (3 hrs); respectively. The CSF/ serum ratio of AUC was 5.8%(15-60 min), 8.9%(15-120min) and 11.4%(15-180min), and the T1/2 of the CSF conce Ptration 122.3min. ahd the CSF/serum ratio of T1/2 4.16, respectively.
When the above results were compared with those of cefotaxime which had already been reported, it was found that ceftizoxime had a slightly lower AUC ratio but a signlficantly longer T1/2. When the clinical experiences of cefotaxime in the treatment of bacterial meningitis and also its antibacterial activities against E.coli and group B Streptococus described above and H. influenzae and S. pneumoniae reported in nationwide surveys were taken into. consideration, it was conchdded that ceftizoxime is apotent new antibiotic worth trying in the. treatment of bacterial meningitis.

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Ceftizoxime, a new antimicrobial agent, was evaluated experimentally and clinically. The results obtained were as follows.
1) Serum and skin concentrations of ceftizoxime in rabbits
The subjects consisted of adult rabbits ranging from 2.5 kg to 3.5kg in weight.
Twenty mg/kg of ceftizoxime were admitted intravenously in one shot. The highest serum concentration was 41.0μg/ml at 10 minutes after injection, and the value at 4 hours after injection was 0.9μg/ml. The skin concentration reached peak at 10 minutes after injection indicated 35.8μg/g, and the level declined and was negligible by 4 hours.
2) Serum and skin concentrations of ceftizoxime. n adult patients
The subjects consisted of 3 adult patients who were operated “full thickness skin graft” under general anesthesia. One gram of ceftizoxime was injected intravenously in one shot. The peak concentration in the serum was 58.8μg/ml at 10 minutes after injection and showed 28.5μg/ml 30 minutes after injection. The skin concentration one hour after injection was 21.0μg/g. These specimens were obtained from excess parts of removal full thickness skin for grafting.
3) Clinical studies
Five patients with wound infection who were within normal limits on laboratory data, were treated with 1.0 g of ceftizoxime twice a day intramuscularly or intravenously.
Causative organisms were disappeared in two cases, and diminished in one case.
No side effect was observed in these cases.

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