The susceptibility of Serratia marcescens isolated in 1973 and that isolated from urinary tract infection in 1975, was determined against each of 20 antimicrobial agents, and the following results were obtained.
1. Serratia marcescens isolated from urinary tract infection in 1975 was resistant to many antimicrobial agents compared with the strains in 1973.
2. Generally, the majority of Serratia marcescens was susceptible to amikacin, gentamicin and KW-1062, while 35 percent of the strains in 1975 was multiple resistant to gentamicin, KW-1062, dibekacin and tobramycin.
3. Almost all strains of Serratia marcescens were resistant to β-lactam antibiotics, while penicillins were slightly more active than cephalosporins.
4. The susceptibility to antimicrobial agents was different between pigmented strains and nonpigmented strains.

View full abstract

R-74, 1, 4-di (2-methyl sulphonyloxy-ethylamino) -1, 4-dideoxyerythrite-dimethylsulphonate, is an alkylating agent whose antitumor properties were originally determined by tests against transplanted tumors. In the present study attention has been focused primarily to compare the antitumor effect between R-74 and typical alkylating agent cyclophosphamide (CTX). Mouse leukemia P-388 and L-1210, EHRLICH ascites carcinoma, sarcoma-180 and NF sarcoma solid tumor, responded to treatment with R-74, and some schedule dependency was observed. R-74 was intraperitonealy injected every day for 10 days from 24 hours after the intraperitonealy injection of leukemia P-388 into CDF1 mice, all treated animals survived more than 60 days at a dose of 10 mg/kg/day. CTX was most effective on leukemia P-388 with a dose of 27. 6 mg/kg producing an increase in median survival time of >400%, and 4 out of 7 mice survived over 60 days. The effects of R-74 on leukemia L-1210 and EHRLICH ascites carcinoma were almost equally effective with that of CTX. The effects of three therapeutic schedules (daily for 7 days, daily for 4 days, and every other day for 7 days) with R-74 were evaluated on mouse leukemia L-1210 and P-388. It was found that daily treatment for 4 days was most effective against leukemia P-388, but no remarkable schedule dependency was observed on leukemia L-1210. R-74 was intraperitonealy injected every day for 7 days from 24 hours after the subcutaneous transplantation of small piece of sarcoma-180 or NF sarcoma solid tumor by a trocar, and the agent was found to be equally effective in the treatment of sarcoma-180 and NF sarcoma solid tumor. The toxicities of R-74 were evaluated by comparing the weight of spleen and thymus between treated and untreated mice. It was observed that the weights were decreased according to the increasing of dosage. Thus, R-74 was equally or more effective with CTX but lymphatic toxicities must be considered.

View full abstract

Bleomycin depo was administrated 12 times to 10 patients with malignant lymphoma, including 4 cases of Hodgkin's disease, 4 reticulum cell sarcoma, 1 lymphosarcoma and 1 giant follicular lymphoma. It was also given to 4 patients with lung cancer, 1 esophagus cancer, and 1 keratoacanthosis. Eight patients with malignant lymphoma were treated with combination therapy of BLM depo, 6-mercaptopurine, cyclophosphamide, procarbazine and prednisone. Other 2 were treated with BLM depo only. Five patients with lung cancer and esophagus cancer were also treated with BLM depo only. In effective cases of malignant lymphoma, enlarged lymphnodes shrunk rapidly after administration of 15 to 45 mg of BLM depo and remission obtained in 10 of 12 cases. BLM depo was also effective in 3 of 4 patients with lung cancer but not effective for keratoacanthosis. The mean duration of remission was 4. 2 months without consolidation therapy. It was vigorously, prolonged by consolidation with VEMP therapy during remission in 4 cases. Fever developed in 6 of 17 patients. Pulmonary dysfunction, suggesting fibrosis, occurred in 2 of 17 cases but it was not fatal.

View full abstract

Fosfomycin was administered orally in 42 cases with acute or chronic urinary tract infections.
1. The clincal results were excellent or good in all of 15 cases with acute simple urinary tract infections.
2. Out of 27 cases with urinary tract infections complicated or after surgery, very satisfactory results were obtained, that is, excellent in 14 cases, good in 7 cases, and poor in 6 cases. As to the excellent efficacy rate, the cases after surgery were especially superior to the complicated cases. It was remarkable that the excellent effect was observed even in the infections with Proteus, Klebsiella, Pseudomonas, or Serratia. No correlation was observed between MIC of Fosfomycin R against pathogens and bacteriological responses in complicated cases.
3. One patient complained of diarrhea, and no severe side effects were encountered.
4. Nowadays, the organisms resistant to antibiotics in common use are detected increasingly in chronic urinary tract infections. Fosfomycin-Ca may be thus expected in the treatment of these infections.

View full abstract

The purpose of this study is to make the precise observation of the severe ototoxic interaction following the long-term combined administration of furosemide, one of the new potent diuretics, and aminoglycoside antibiotics (kanamycin, streptomycin and gentamicin), and to make clear the mechanism of the ototoxic interaction using rabbits. In order to confirm the mechanism, the concentration of kanamycin in body fluids (inner ear perilymph, serum and cerebrospinal fluid) after single injection of kanamycin with or without furosemide is studied, and histopathological findings of the kidney with long-term administration of drugs are carried out. The results obtained are as follows.
1. Severe outer hair cell damage has been shown to occur in rabbits following the combined administration of furosemide and aminoglycoside antibiotics (kanamycin and streptomycin). At the doses used no damage of the outer hair cells was detectable with furosemide or aminoglycoside antibiotics alone.
2. The kanamycin concentration in each of above-mentioned fluids was very high in the group receiving furosemide and kanamycin as much as that in the group receiving kanamycin alone.
3. Histopathological examination of the kidneys showed severe tubular necrosis in rabbits that received both furosemide and aminoglycoside antibiotics compared with rabbits that received furosemide or aminoglycoside antibiotics alone.
4. The mechanism of the ototoxic interaction following combined administration of furosemide and aminoglycoside antibiotics was discussed from the antibiotic concentration in body fluids and from the renal histopathological points of view.
5. Severe damage occurred in not only the inner ears but also kidneys when both furosemide and aminoglycoside antibiotics were administered to rabbits in even small dosage. Therefore, the administration of both drugs may be dangerous in patients.

View full abstract

An experimental pyelonephritis model was prepared in rats by infecting E. coli C-11 ascendently from the urethral orifice 3 days after the intraperitoneal administration of 150 mg/kg of 2-bromoethyl-amine hydrobromide. In this model, the lesion was confined to renal papillary tips, and BUN value in the blood was remarkably increased. Three days after infection of E. coli, 20 mg/kg doses of CTZ, CEZ and CER, respectively, were administered intramuscularly to rats induced pyelonephritis, and the levels of each drug in sera, kidneys and livers were determined.
The results showed that the decreasing tendencies in serum and tissue levels of CTZ with time-course showed similar patterns to those in normal rats. On the other hand, the decrease in serum and tissue levels of CEZ and CER was hardly observed.
The urinary excretion of CTZ, CEZ and CER was compared after intramuscular administration of 20, 40 and 80 mg/kg doses. It was found that the mean urinary, excretion rates in 24 hours after administration were 87-90% in CTZ, while they were 38-49% in CEZ and 33-42% in CER. These data indicated that urinary excretion in experimental pyelonephritis rats was much less disturbed in case of CTZ than in CEZ and CER.
Four patients with uremia, operated ureterostomia bilateralis, were administered intramuscularly with 1 g of CTZ and CEZ, respectively, by the cross-over method, and the serum levels and urinary excretion rates of each drug in 6 hours after administration were compared. The results showed that the urinary excretion rates of CTZ were higher than those of CEZ in all cases.
The relationship between the above results and the clinical effects of CTZ against urinary tract infections were discussed.

View full abstract

It is well recognized that urinary tract infection caused by Pseudomonas aeruginosa is difficult to treat and manage because of the drug resistance and an existence of urinary stream disturbance in such cases. So that a large dose chemotherapy using such as carbenicillin (CBPC) and sulbenicillin (SBPC) against Pseudomonas infections is used to be applied recently. In order to evaluate an appropriate chemotherapy for Pseudomonas infections in the urinary tracts, especilly pyelonephritis, the following studies have been performed on experimental pyelonephritis in rabbits.
1. MICs and MBCs of CBPC and gentamicin (GM) against Pseudomonas aeruginosa NCTC 10490 (standard strain) and Pseudomonas aeruginosa isolated from urinary tract infections (UTI strain) were measured by agar dilution method and by SILVERBLATT & TURCK's method. It was proved that the difference between MIC and MBC of the drugs against the bacterias ranged from twice to 16 times.
2. Experimental pyelonephritis in rabbits was produced by inoculation with both strains of Pseudomonas aeruginosa into unilaterally obstructed ureter. The animals were sacrificed 24, 48, 72 hours and a week after the inoculation. Occurrence of acute pyelonephritis in rabbits was proved 48 hours after the inoculation from histopathological and bacteriological points of view.
3. Concentration of CBPC and GM in the serum, urine and renal tissue 1, 3, 5 hours after the intramuscular administration in acute pyelonephritic rabbits was measured by thin layer cup method. It was suggested that tissue level of the drugs in acute pyelonephritic kidney was recorded higher and decreased more gradually than that in the normal kidney.
4. The animals 48 hours previously inoculated with the bacterial strains were treated by intramuscular injection of CBPC or GM once a day for 7 days. Doses of the drugs were 40, 200, 400 mg per kg for CBPC and 1. 6, 8. 0, 16 mg per kg for GM. The animals were sacrificed on next day of the cessation of the treatment. Histopathological findings demonstrated complete healing in rabbits treated by CBPC showing dose response. However, dose response was not reflected and consequently the results were poor in efficacy in UTI strain inoculated animals treated by GM, while good to excellent results were obtained in standard strain inoculated animals.
5. The fact came into the light the tissue level of the drugs in the pyelonephritic kidney revealed higher than MBC in rabbits who obtained perfect histopathological and bacteriological healing. MBC is thought to be more important than MIC for a marker of the treatment of acute pyelonephritis induced by Pseudomonas aeruginosa.
6. OEP-HA titer was measured in 10 normal rabbits and in 3 rabbits inoculated with standard strain of Pseudomonas aeruginosa but not medicated. OEP-HA reagent was supplied by Prof. HOMMA of the Institute of Medical Science, the University of Tokyo. Microtiter method was applied. OEPHA titer showed lower than 40 × in normal controls. On the other hand, it began to rise 24 hours after the bacterial inoculation and reached range from 160 to 320 ×. Elevation of OEP-HA titer was kept for 6 months after, the inoculation. Measurement of OEP-HA titer is useful for diagnosis of Pseudomonas aeruginosa infection in the urinary tract.

View full abstract