[in Japanese]

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A double-blind comparison of josamycin propionate granule for oral suspension (JM-P) and that of erythromycin ethylsuccinate (ES-EM) was performed on their efficacy and safety in the treatment of scarlet fever inpatients, and the following results were obtained.
1. A total of 159 patients was randomly assigned to two groups of almost equal size: 79 cases to JM-P and 80 to ES-EM groups. Among them, 8 cases medicated with JM-P (10%) and 11 with ES-EM (14%) were removed from analysis because of not filling prerequisites. Medication was 30 to 40 mg (potency) /kg per day for 7 days.
2. No item of background factors was significantly different (P> 0.05).
3. Global efficacy data showed no significant difference between the two groups (P> 0.05). The rate of improvement (excellent plus moderate) was 70% with JM-P and 58% with ES-EM. The rate would become 64% with JM-P (50 out of 78 cases) and 53% with ES-EM (40 out of 76), if 14 among 19 cases removed were taken into account, in which medication was earlier terminated by change to other drugs.
4. The rate of disappearance of pharyngeal streptococci before the 3rd day was 40% with JM-P (23 out of 57 cases) and 39% with ES-EM (19 out of 49), showing no significant difference between them (P>0.05).
The rate of detection of pharyngeal cocci after termination of drug administration was not significantly different between the groups (P>0.05).
5. The rate of defervescence was not significantly different between the two groups (P>0.05). Days for disappearance of eruption and of pharyngeal reddening suggested a trend favorable to JM-P.
6. Global evaluation was shown significantly correlated with the efficacy criteria selected: days for disappearance of pharyngeal streptococci, days for defervescence, days for disappearance of eruption and days for disappearance of pharyngeal reddening in the order cited, except for a nonsignificant correlation between global evaluation and days for disappearance of pharyngeal reddening in the ES-EM group.
7. Changes in ASLO and CRP values before and after medication were similar in both groups. However a slight trend favorable to JM-P was observed.
8. A case medicated with JM-P showed definite rise in SGOT and SGPT values, which did not reveal any clear correlation with medication. As to side effects, a case was encountered who complained a slight abdominal pain during medication of ES-EM.

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[in Japanese]

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(1) Macrophage monolayers, taken from peritoneal cavity of mice pretreated with schizophyllan, were infected with M. tuberculosis SCHACHT, and the fate of tubercle bacilli within the cultured macrophages was followed up for 96 hours. The growth of the phagocytized tubercle bacilli within the macrophages taken from schizophyllan-treated mice proved to be markedly suppressed, as compared with that within control cells.
(2) The mice infected with tubercle bacilli were treated with schizophyllan alone or in combination with ethambutol and/or rifampicin, and the viable bacterial number in lungs of mice was estimated by the quantitative culture method.
1) The viable number of tubercle bacilli in lungs of mice treated with 2.5 mg/kg or 5.0 mg/kg of schizophyllan alone was shown to be remarkably smaller than that of control mice.
2) The administration of 10 mg/kg of ethambutol alone showed slight effects. However, a remarkable increase of the inhibitory activity was observed by the combined therapy with schizophyllan.
The treatment with 20 mg/kg of ethambutol alone gave moderate effects, and more marked effects could be obtained in combination with schizophyllan.
3) The combined therapy with 5 mg/kg of rifampicin and 5 mg/kg of schizophyllan seemed to be more effective than the monotherapy. However, no remarkable difference of effect could be seen between the monotherapy with 10 mg/kg of rifampicin and the combined therapy with schizophyllan, the former alone showing a marked effect.
4) The triple combination therapy with 5 mg/kg of schizophyllan, 20 mg/kg of ethambutol and 10mg/kg of rifampicin appeared to give the most excellent results among the combinations tested in this experiment.

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[in Japanese]

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Preliminary administration of stem-bromelain in combination with antibiotics exerted a marked prolongation on survival time of mice infected by Str. hemolyticus, Dipl. pneumoniae or Ps. aeruginosa. That is to say, on streptococcosis in combination with penicillin V, on pneumococcosis in combination with ampicillin and on pseudomonosis in combination with gentamicin, the bromelain showed significant prolongation on survival time of mice.

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The authors reported in the previous paper that CB-PC enhances the ability of PMN to phagocy tose and kills Pseudomonas aeruginosa. The present paper is concerned with further studies.
(1) The effect of three other antibiotics, differing in mechanism of action, on the enhancement of the activity of PMN is as follows;
a) Sulbenicillin (SB-PC), as well as Carbenicillin (CB-PC), enhanced the PMN activity at a concentration of 1/16 MIC or more.
b) Colistin enhanced the activity at MIC.
c) DKB proved ineffective even at MIC.
(2) The bactericidal activity in the supernatant, reduced by sonication of the PMN, was recovered by the addition of CB-PC to the test medium.
(3) The culture filtrates of PMN-resistant strains of Ps. aeruginosa inhibited the phagocytosis and killing of E. coli by PMN, but that of the PMN-sensitive strains did not inhibit it.

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[in Japanese]

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The antimicrobial activity of paromomycin (Aminosidine)(PRM (AMD)) against tubercle bacilli was examined in vitro, and the susceptibility of kanamycin (KM), capreomycin (CPM) or viomycin (VM) resistant strains to PRM (AMD) was investigated. Fifty one strains in total tested were isolated from the in-patients affected with pulmonary tuberculosis. KIRCHNERag ar containing 10% albumin was used for the examination.
(1) The strains resistant to 10 mcg/ml of KM were susceptible to PRM (AMD). However, some of the strains resistant to 100 mcg/ml of KM showed decreased susceptibility to PRM (AMD).
(2) The strains resistant to CPM or VM were not always susceptible to PRM (AMD), and the strains resistant to 100 mcg/ml of CPM or VM were less susceptible to PRM (AMD) than the strains resistant to 10 mcg/ml of CPM or VM.

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Cephapirin, a new derivative of cephalosporin, was investigated in comparison with cephaloridine and cephazolin, especially on antimicrobial activity and the inactivating enzyme of the drug produced by microorganisms.
(1) Cephapirin was strongly effective against gram-positive and gram-negative cocci, and grampositive bacilli.
(2) Fifty-four strains of Staphylococcus aureus isolated clinically were sensitive in the range of 0.02-0.78 mcg/ml of cephapirin and its peak was 0.19 mcg/ml. None of cephapirin-resistant strains of Staphylococcus was detected in the test strains including penicillin-resistant strains.
(3) Fifty-five strains of Escherichia coli isolated clinically were sensitive in the range of 0.78 100 mcg/ml of cephapirin and its peak was 6.25 mcg/ml.
(4) Cephapirin-resistant strains of Escherichia coli and Serratia marcescens produced inactivating enzymes of cephapirin in the culture broth. The enzymes (β-lactamase) were extracted from their culture filtrates by ammonium sulfate. The enzymes showed substrate specificity for cephapirin, cephaloridine and penicillin G.

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1. The antibacterial activity of cephapirin (CEP) is strongest against staphylococci. CEP is active against Escherichia coli, Salmonella, Shigella, Klebsiella and some of other Gram-negative bacteria. The activity is almost similar to that of cephalothin (CET), weaker than cephaloridine (CER), and stronger than cephalexin (CEX).
2. The antibacterial activity of CEP against Pseudomonas and Proteus, except P. mirabilis, is very weak as same as CET, CER and CEX, that 97% of the strains tested grew in media with 100 mcg/ml CEP.
3. Cross resistance was observed between CEP and CER or CEX in most strains isolated clinically. Some strains of Klebsiella isolated were sensitive to CEP and resistant to CET.
4. CEP was stable against penicillinase produced by staphylococci, but easily be decomposed by cephalosporinase produced by Gram-negative bacteria.
5. The therapeutic effects of CEP and CET for infections with Staphylococcus and E. coli were almost similar at larger doses, but CEP was superior to CET at small doses.

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We determined the antibacterial activity of cephapirin against many strains of following various pathogens by plate-dilution method. We used 593 strains of hemolytic streptococci, enterococci, Staphylococcus aureus, Haemophilus group, several species of Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter and various species of anaerobes isolated from clinical materials in our laboratory during 1972. We compared the antibacterial activity of this drug with cephalothin and cephaloridine.
1) To hemolytic streptococci and Staphylococcus aureus cephapirin is less active than cephaloridine, but to Haemophilus group is more active than cephaloridine.
2) Cephapirin has similar antibacterial activity to cephalothin.

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Microbiological evaluation of cephapirin was made by comparing with three known antibiotics of the cephalosporin family, cephalothin, cephaloridine and cefazolin, as to in vitro antimicrobial activity including antimicrobial spectrum, sensitivity of clinically isolated strains of bacteria, stability against beta-lactamase and in vivo therapeutical effect in experimentally induced infections in mice.
(1) Cephapirin has virtually the same antimicrobial spectrum as cephalothin, cephaloridine and cefazolin. In the antimicrobial activity, cephaloridine was found superior to the others, cephapirin being virtually equal to cephalothin and cefazolin, when tested with Gram-positive organisms, while the four were comparable to each other when tested with Gram-negative ones.
(2) Clinically isolated staphylococcal strains were sensitive in the range of 0.09-25 mcg/ml to cephapirin, in the range of 0.09-25 mcg/ml to cephalothin, in the range of >0.011-12.5 mcg/ml to cephaloridine and in the range of 0.09-25 mcg/ml to cefazolin.
Clinically isolated E. coli strains, on the other hand, were sensitive in the range of 3.12->100 mcg/ml to cephapirin, cephalothin and cephaloridine, and in the range of 1.56->100 mcg/ml to cefazolin.
In the sensitivity of clinically isolated staphylococcal strains cephapirin was well correlated with cephalothin and cefazolin, while in the case of E. coli strains cephapirin was found to have a good correlation with cephalothin.
(3) Influence of factors on MIC was investigated. Culture pH, human serum and inoculum size were found to effect on MIC of cephapirin.
(4) Cephapirin was found stable as same as cephalothin against beta-lactamase produced by E. coli.
(5) In therapeutical effect on infections in mice caused by Gram-positive organisms such as Staphylococcus aureus Smith, No.13 and Diplococcus pneumoniae type III, cephaloridine was found best, followed by cephapirin, then by cephalothin. The same order of effectiveness resulted when tested on the infections caused by Gram-negative organism E. coli.

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The clinical study on cephapirin (CEP) which was administered to the patients with pulmonary infection was done. CEP was given intravenously with 500 ml of D5/W in 2 hours.
1. In the cases with 5 g administration of CEP, the highest concentration of the drug in blood was seen at the end of intravenous infusion, and its T1/2 was 0.35 hour on average.
2. The drug concentration in sputa of the patients with bronchiectasis was 1.6 mcg/ml at highest when 3 g of CEP were given. The ratio of the level to that of the blood at the highest concentration was 0.01.
3. Sixteen patients with infection in the lower respiratory tract were treated with 3-10g daily of CEP (bronchopneumonia 6, middle lobe syndrome 1, lung abscess 2, bronchiectasis 4, chronic bronchitis 1, bacterial pneumonia complicated with lung cancer 2). CEP was markedly beneficial in 4 cases, beneficial in 3 cases, slightly beneficial in 3 cases and not beneficial in 6 cases.
4. Regarding the adverse reactions, increasing of serum transaminase level was seen, in 3 cases with 4 g administration per day (SGOT 89 u and SGPT 85 u at highest). Otherwise, the side effect was not remarkable. The increased level of SGOT and SGPT got down to normal by discontinuing the administration.

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Concentration in the serum and urinary excretion of cephapirin were studied. After injection of cephapirin intravenously (20 mg/kg) to rabbits, the concentration of the drug in serum decreased with a half-time of 20 minutes, and after intramuscular injection about one hour. About 50% of the drug injected was excreted in urine within 6 hours. Concentration in the serum of other cephalosporin group drugs were estimated comparatively.

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Cephapirin was given by intramuscular injection, 2 g per day, dissolved in sterile water or lidocaine hydrochloride solution, to 19 patients with inflammatory biliary tract disease and 5 patients with gastric cancer, intussusception, retroperitoneal cyst, appendicitis and tumor of the thyroid gland. The results in 19 cases of the biliary tract diseases were good in 14 cases (73.7%), fair in 1 and unchanged in 4, in 5 cases of non-biliary-tract diseases, good in 3, fair in 1 and undecided in 1.
Bacteriolozical examination was carried out on 18 cases. In 11 cases, cultures were positive for Escherkhlac oil, F romm, Pseudomonaas eruginosa, E nterobacteriaceae, A kaligenesf a ecalis, Enterococcus and Staphylococcuse pidermidisi n bile as simple or mixed infection.
No side effect was observed in all cases except localized pain by the intramuscular injection.

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A new aminoglycoside antibiotic amikacin (BB-K8) was produced by acylation of kanamyc: n A with L (-)-γ-amino-α-hydroxy-butyric acid (HABA). Amikacin showed high and broad antibacterial activity against gram-positive and gram-negative bacteria. It should be noted further that amikacin as well as gentamicin showed strong antibacterial activity against Pseudomonas aeruginosa. According to the fact that P. aeruginosa strains resistant to either gentamicin or butirosin were sensitive to amikacin, the biochemical mechanism of amikacin-resistant P. aeruginosa is suggested to be different from that of gentamicin or butirosin resistance in P. aeruginosa. Antibacterial activity of amikacin was compared with that of gentamicin C1, DKB and 6'-N-methyl DKB using kanamycin-resistant strains, indicating that these drugs were effective.

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[in Japanese]

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The pharmacological actions of BB-K8, a new semisynthetic aminoglycoside antibiotic in which 1-NH of kanamycin was replaced with 4-amino-2-hydroxybutyric acid, were investigated.
Summary of pharmacological actions and minimal effective doses (MED) of BB-K 8 were as follows: fall on blood pressure of the rabbit (20mg/kg), bradycardia on ECG of the rabbit (50mg/kg), inhibition on excised guinea-pig atrium (2×10-4g/ml), inhibition on excised frog heart (10-8g/ml), acceleration on permeability of rabbit abdominal skin vessels (100mcg), stimulation (2×10-4g/ml) and inhibition (5×10-4g/ml) on excised rabbit intestine, inhibition on excised tracheal muscle of the guinea-pig (10-8 g/ml) and inhibition on excised rat uterus (5×10-4g/ml for nonpregnant uterus and 10-4g/ml for pregnant uterus). No effect on respiration of the rabbit, on excised rabbit ear vessels or on excised guinea-pig intestine was observed at doses up to 80mg/kg, 10-1g/ml and 2×10-8g/ml, respectively.
Its actions were similar to other aminoglycoside antibiotics and MED were larger in general. These MED also were much larger than minimum inhibitory concentrations and maximum blood levels in clinical uses. Therefore, it is concluded that BB-K8 is one of the antibiotics with less pharmacological actions.

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[in Japanese]

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1) Minimal inhibitory concentration of amikacin (BB-K8) was determined on 84 strains isolated from urinary tract infections by the plate dilution method. Many strains of Escherichia coil, Staphylococcus aureus and Pseudomonas tested were inhibited at the concentration of 6.25 mcg/ml or less.
2) In one case with normal renal function, the blood level reached the maximum (25.5 mcg/ml) 30 minutes after intramuscular administration of 200 mg amikacin.
3) The urinary recovery was 82.8% during 6 hours after injection in one normal subject.
4) Thirty-one cases with the complicated urological infections were intramuscularly treated with amikacin 100-400 mg per day. These were 20 cases of chronic pyelonephritis, 7 cases of chronic cystitis and 3 cases of acute prostatitis. Good results were obtained in 20 cases.
5) Side effects were observed in 6 of 31 cases throughout the treatment. Some elevation of serum transaminase was observed in 5 cases and tinnitus and headache in one case. There was no case with abnormal audiogram.

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The bacterial and clinical experiments for ophthalmic use of amikacin (BB-K8) were performed. The results were summarized as follows:
1) Minimum inhibitory concentrations of BB-K8 for various organisms concerning to ocular infection were 25-100 mcg/ml for KOCH-WEEKS bacillus, 0.39-0.78 mcg/ml, for MORAX-AXENFELD diplobacillus, 12.5-50 mcg/ml for pneumococcus, 0.39 mcg/ml for Corynebacterium diphtheriae, 0.78 mcg/ml for gonococcus, 3.13-50 mcg/ml for streptococcus, 0.19-3.13 mcg/ml for staphylococcus and 3.13-6.25 mcg/ml for Pseudomonas aeruginosa.
2) Twenty strains of Ps. aeruginosa were sensitive at 1.56-50 mcg/ml with the peak of distribution at 3.13 mcg/ml.
3) Twenty strains of Staphylococcus aureus were sensitive in the range of 0.78-50 mcg/ml.
4) The peak of blood level (13.9 mcg/ml) after intramuscular injection of 100 mg BB-K8 at a dose was attained in half an hour, and reduced gradually unto 6 hours.
5) The ocular penetration of BB-K8 in the rabbit eye was studied following local and systemic application. The penetration level into both of the outer and inner parts of the eye was highest after subconjunctival injection, followed by intramuscular injection and instillation.
6) Various ocular suppurative diseases, such as external hordeolum, internal hordeolum, lid abscess, corneal infiltration, corneal ulcer, orbital phlegmon and panophthalmitis were cured by BB-K8 treatment, intramuscular injection of 100 mg once or twice a day.
7) No side effect was observed in all 18 cases.

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