[in Japanese]

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[in Japanese]

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Pivmecillinam (PMPC), semisynthetic penicillin for oral use, was studied clinically and following results were obtained.
1) Twenty-eight patients with acute simple cystitis treated with the drug 200 mg/day for 4 days, clinical results were excellent in 23 cases and moderate in 5 cases. Six patients with chronic simple cystitis treated with the drug 400 mg/day for 7 days, clinical results were excellent in 4 cases, moderate in 1 case and poor in 1 case. Eight patients with complicated urinary tract infections treated with the drug 400 mg/day for 7 days, clinical results were excellent in 2 cases, moderate in 2 cases and poor in 4 cases. Overall effectiveness amounted to 88.1%.
2) Pivmecillinam was clinically effective in patients infected by Gram-negative bacteria except Pseudomonas aeruginosa.
3) No side effects were observed in all cases.
The effectiveness of PMPC for acute simple cystitis was compared with that of talampicillin (TAPC) ampicillin (ABPC), amoxicillin (AMPC) and pivampicillin (PVPC) reported previously and PMPC was assessed as the most useful agent in these. Then, pivmecillinam should be chosen firstly as a chemotherapeutic agent for acute simple cystitis.

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Cefuroxime (CXM) was administered for 1 week to spinal cord injury patients with chronic complicated urinary tract infection and the transitional change of micro-orgamisms was observed. Bacterial counts and identification of isolated organisms were performed daily on the mid-stream urine for 1 week. MIC was also determined on the strains before and after CXM treatment. The results with 83 strains from 28 patients are as follows:
1. CXM's efficacy appears in line with MIC of strains. With the cases given 0.75g twice daily intramuscularly, all the 14 strains with MIC lower than 50μg/ml were eradicated, but 2 of the 14 strains were found re-growing, with only bacteriostatic action noted (in region of minimal inhibitory action). With the group of the cases given 1.5 g twice daily, all the 15 strains with MIC lower than 200 μg/ml were eradicated from urine 1-3 days after start of treatment (in region of bactericidal action).
2. At dose of bactericidal action CXM responded effectively with no relationship to organism species or bacterial count before CXM treatment.
3. Dose response was noted between the cases given 1.5 g daily and those given 3.0 g daily. 4. From the above result, we can presume appropriate doses in accordance with the disease conditions.
From above observation, combined with correlation between organism species, becterial count, MIC of strains, etc., CXM's efficacy was assessed quantitatively and objectively.

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The authors have carried out the laboratory and clinical studies of cefamandole (CMD).
The results are as follows:
The sensitivity was measured by plate dilution method on 26 strains of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and 14 strains of Salmonella typhimurium isolated from patients.The distribution of sensitivity of S. aureus was 0.39, -3.13 μg/ml and the peak of distribution was 1.56 μg/ml. The distribution of sensitivity of E. coli was 0.78->100 μg/ml, and K. pneumoniae, 1.56->100 μ g/ml. The distribution of sensitivity of Salmonella typhimurium was 6.25->100 μg/ml and its peak was 6.25 μg/ml.
CMD were given intravenously for 30 and 60 minutes at a single dose of 25 mg/kg body weight to 6 children.
The serum mean levels of CMD were 105.3 μg/ml at 30 minutes, 15.1 μg/ml at 1.5 hours, 1.6 μg/ml at 2.5 hours after drip infusion for 30 minutes, respectively, and 34.7, 5.2, 0.6 μg/ml at 1, 2, 3 hours after drip infusion for 60 minutes, respectively. And the serum level at 4 hours after administration was not detected.
The mean urinary excretion rates were 73.3% in the drip infusion for 30 minutes and 60.7% in its for 60 minutes, up to 8 hours after administration.
Half life was 26 minutes.
CMD was effective in 18 of 21 cases of bacterial infections.
No side effects were observed except for 2 cases with elevation of serum transaminase.

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In order to evaluate efficacy and safety, cefamandole, a new cephalosporin, was given intravenously to 12 children with respiratory tract infections (11 cases) and urinary tract infection (1 case), who ranged in age from 2 months to 5 years old.
Cefamandole sodium was administered 74-112 mg/kg/day in three or four equally divided doses by one-shot injection.
The overall efficacy rate was 83.3% in 12 cases, i. e., good in 8, fairly good in 2, and poor in 2 cases.
No adverse reaction was noted on any of our 12 cases.

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Passage of cefamandole sodium, a new cephalosporin, into the CSF was studied in experimental staphylococcal meningitis in rabbits, and the following results were obtained.
1) Blood concentrations, CSF concentrations and CSF/serum ratios after an intravenous injection of 100 mg/kg were as follows (an average of the results obtained in 5 rabbits); 30 minutes 198μg/ml, 5.4μg/ml and 2.7%; 1 hour 81.2μg/ml, 4.7μg/ml and 5.8%; 90 minutes 28.9μg/ml, 2.9μg/ml and 10.0%; 2 hours 6.6μg/ml, 1.6μg/ml and 24.2%. These CSF concentrations were almost comparable to those of other cephalosporins, but because of higher blood concentration of cefamandole sodium, CSF/serum ratios were lower at 30 and 60 minutes, respectively.
2) Based on the concentrations in blood and CSF obtained in other 6 rabbits at 15-minute interval following an intravenous injection of 100 mg/kg, half-life (T 1/2) and area under the curve (AUC) were calculated. Peak CSF concentration was attained at 30 minutes after injection, i. e., 22.65μg/ml, and T 1/2 of blood concentration 23.2 minutes, T 1/2 of CSF concentration 28.6 minutes and T 1/2 of CSF/serum ratio 1.23, respectively. AUC CSF/serum ratio percentage was 13.6% (15-60 minutes), 13.5% (15-90minutes), 13.7% (15-120 minutes) and 14.0% (15-150 minutes), and no increase was noted with the lapse of time.
3) These results suggested that the passage of cefamandole sodium into the CSF is relatively good but the disappearance of the drug from the CSF is rapid.
4) In order to obtain a therapeutic success in the treatment of bacterial meningitis, maintenance of a closer contact of the causative organism with the drug for a certain period of time is considered to be important, although an effective CSF concentration is a prerequisite. Consequently, when evaluating the effectiveness of an antibiotic in the treatment of bacterial meningitis, the determination of T 1/2 of CSF concentration is an important requirement. Considereration of T 1/2 will be required in the dosage of the antibiotic.
5) When Haemophilus influenzae meningitis is going to be treated with cefamandole sodium, it should be injected intravenously 50 mg/kg 8 times daily in order to secure a definite clinical response. However, further studies will be necessary, including the problem of adverse reactions.

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In order to evaluate effectiveness of cefamandole sodium, a new cephalosporin, in the treatment of bacterial infections of children, fundamental and clinical studies were carried out and the following conclusions were obtained.
1) The MIC of cefamandole sodium was compared with that of cefazolin for 15 strains of Staphylococcus aureus and 32 strains of Escherichia coli. There was a slightly higher sensitivity of the former bacteria to cefazolin and of the latter bacteria to cefamandole sodium, respectively. Cefazolin was slightly more effective against 6 strains of Klebsiella pneumoniae, but cefamandole sodium was more active against 3 strains of Salmonella typhi, one strain of Salmonella group B, 8 strains of Proteus mirabilis, 2 strains of Proteus morganii and one strain of
Proteus vulgaris. Only cefamandole sodium had antimicrobial activity against some of the 3 strains of Enterobacter and 5 strains of Serratia marcescens. However, neither drugs showed almost any activity against one strain of Proteus rettgeri, 2 strains of Citrobacter and 10 strains of Pseudomonas aeruginosa. Although the MIC of cefamandole sodium and of cefazolin was higher than 100μg/ml for one-fourth and one-third of the 43 strains of Klebsiella pneumoniae biovar. oxytoca, respectively, cefamandole sodium had definitely a higher antimicrobial activity against other bacterial strains. Besides, the MIC for one strain of Haemophilus influenzae was 0.8μg/ml of cefamandole sodium, 50μg/ml of cefazolin and 0.2μg/ml of ampicillin.
2) Blood concentrations of cefamandole sodium were determined in two children following oneshot intravenous injection of 20-25 mg/kg or a 30-minute continuous drip infusion of 20.3-23.8 mg/kg. Peak concentrations were induced 30 minutes after one-shot injection (average: 37μg/ml) and at the end of the drip infusion (average: 70μg/ml). Half-life of reduction was 26.1 and 26.6 minutes, respectively.
3) Passage of the drug into CSF was determined in 3 patients with non-bacterial meningitis. Although the CSF concentrations were either lower than 1μg/ml or undetectable in two patients, they were 6.2-6.7μg/ml 60-80 minutes after an intravenous injection of 76.9 mg/kg in the third patient. Comparable levels were obtained following an intravenous injection of the same dose of ampicillin, which was done approximately at the same time.
4) Twenty-six patients with the following bacterial infections were treated with daily doses of cefamandole sodium of 52.2-107mg/kg in 3-4 divided doses, which was given either by one-shot injection or 30-minute continuous drip infusion; pneumonia (12 cases), lacunar tonsillitis (1), suppurative lymphadenitis (1), suppurative mastoiditis (1), sepsis (2), suppurative osteomyelitis (1), staphylococcalscald skin syndrome (1), subcutaneous abscess (1), urinary tract infection (5) and Salmonella enteritis (1). The overall efficacy rate was 88.5%; excellent in 11 cases, good in 12 and failure in 3. Treatment failures comprised each one case of mastoiditis associated with cholesteatoma, pyelonephritis accompanied by a prominent vesico-ureteral reflux and Salmonella enteritis.
5) Adverse reactions were noted in 5 among 26 cases, i. e., 19.2%, which included one case of skin rash, 2 cases of eosinophilia and elevation of GOT in 2. In addition, one patient with aseptic meningitis who was treated with a massive dose of cefamandole sodium developed a burning sensation after one-shot injection and was noted to have fever, rash and eosinophilia in 9-day course of treatment. Further evaluation will be necessary as to the use of a massive dose of the drug.
6) Based on the above results, it was considered that cefamandole sodium is a poent new anti -biotic especially in the treatment of acute bacterial respiratory tract infections in children.

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Cefamandole (sodium salt) was administered to total 32 cases of bacterial infectious diseases of children, and in 3 cases, there were investigated of these absorption and excretion. The results are as follows;
1. Blood levels: Cefamandole was given intravenous dose of 25 mg/kg to 3 children. The blood level of 15 minutes after intravenous injection was 140.4μg/ml in average, and 0.3μg/ml in average at 4 hours after intravenous injection. T 1/2 was 13.9 minutes.
2. Urinary concentration: Within 6 hours after intravenous injection, 51.8% of the drug was recovered in average from the urine and the urinary concentration reached to 3, 050μg/ml in average (0-2 hours), 1,262μg/ml in average (2-4 hours), 41μg/ml in average (4-6 hours) after injection.
3. Clinical results: The drug was given 109 mg/kg/day (t.i.d. or q.i.d.) by intravenous route. The duration of administration was 11 days in average. The overall efficacy rate was 97%. In bacteriological results, excellent in 2, failure in 1, out of 3 strains. As side effects vascular pain was observed in 3 cases at the intravenous injection, and eosinophilia in 2 cases.

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Laboratory and clinical studies of cefamandole (CMD), a new semisynthetic cephalosporin, were investigated and following results were obtained.
1) Absorption and excretion study following 25mg/kg intravenous administration was carried out in pediatric patients. In 6 cases, mean serum levels of 116.7±24.0μg/ml, 62.1±19.2μg/ml, 12.2±2.7 μg/ml, 2.9±1.1μg/ml, 0.6±0.6μg/ml and 0.1±0.2μg/ml obtained after 15, 30 minutes, 1, 2, 4 and 6 hours administration. In 4 cases, mean urinary recovery of 68.2±17.2% (0-8 hours) was obtained. The mean half life of serum level was 0.36±0.08 hours.
2) The transfer of cefamandole was poor in infants with meningitis.
3) Cefamandole was given to 22 children with acute pyelitis (1 case), acute pneumonia (19 cases), and meningitis (2 cases). The dosage was 80.0-284.2 mg/kg/day, and it was divided into 4-6 times and given intravenous or intravenous drip. The duration of administration was from 3 to 17 days. The overall efficacy rate in 22 cases was 95.2%, i.e., excellent in 5, good in 15, poor in 1, and unknown in 1. In bacteriological examination, there were eradication of the organisms in 9 (52.9%), decrease in 4, unchange in 4 out of 17 strains.
4) Any noticeable adverse reaction was not observed.

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Clinical trials were carried out with cefamandole (sodium salt) in pediatric infections. Results were as follows;
1. CMD was applied to 13 patients with pneumonia, 1 patient each with submandibular abscess, urinarytract infection and bacterial meningitis.
2. Results were excellent in 1 and good in 13 patients, being overall efficacy rate 93.3%.
3. Slight elevations of GOT and GPT were observed in 1 patient. No other serious side effects were observed or reported.

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Ampicillin-cloxacillin (Viccillin S ‘Meiji’) by intravenous drip infusion was used in gynecological infections, with the following satisfactory results.
1) The drug was markedly effective in 2 out of 6 cases, effective in 4, being the efficacy rate 100%.
2) No abnormal laboratory findings and side effects were observed in our study.

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Clinical studies on apalcillin (APPC), a new broad spectrum semisynthetic penicillin developed in Japan, were carried out, and the following results were obtained.
APPC was administered to three patients with serious biliary tract infections by intramuscular or intravenous injection at daily dosage of 2.
Therapeutic responses were excellent in all cases, and no side effects and abnormalities of laboratory findings were observed.
APPC was considered to be an excellent drug for the treatment of biliary tract infections.

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A 35-year-old male went fishing at the Agano River side in the suburbs of Toyosaka City, in August 1977. He was admitted to the hospital then with the chief complaints of high fever and severe headache on the 5th day of illness.
Following the intravenous drip infusion of 12g piperacillin for 61/2 days, he became afebrile within 2 days and recovered rapidly.
Bacteriological examination disclosed none of significant data.
Serum agglutinin reaction for leptospirosis, however, was positive in a titer up to 1: 2,560 to L. hebdomadis, except for L.icterohemorrhagiae, L.autumnalis, L.australis and L.canicola.

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