The physico-chemical properties, antibacterial spectrum, antibacterial activity, distribution of MICs against clinical isolates and in vivo activity of KW-1062 proved to be similar to those of gentamicin. Safety evaluation of KW-1062 in animals revealed that its toxicity is lower than that of gentamicin, especially on the eighth cranial nervous system and the kidney.
Clinical trials with KW-1062 were carried out on the basis of the above pre-clinical studies and the results were reported at the new drug symposium of the 23 rd East Japan branch general meeting of the Japan Society of Chemotherapy. The cases collected and analyzed by the symposists on that occasion consisted of 136 patients with internal diseases and 388 with surgical ones and KW-1062 was found to be effective in 73. 5% and 74. 7% of these cases respectively. Of 566 patients subjected to KW-1062 treatment, 14 experienced side effects and 48 had abnormal values in their laboratory findings. Taking it into consideration that the subjects of this therapy were far advanced in age and suffering from intractable infections associated with complications and underlying diseases, we think of these results as fairly satisfactory.

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In vitro and in vivo antibacterial activities of KW-1062, a new aminoglycoside antibiotic, were examined using various species of bacterial strains isolated from clinical specimens. The results are summarized as follows :
(1) The MIC levels of KW-1062 against E. coli, S. marcescens, K. pneumoniae and Proteus sp. were almost the same as those of GM and much lower than those of DKB and KM.
(2) The MIC levels of KW-1062 against gram-positive bacteria, including S. aureus, S. epidermidis and S. pyogenes, were almost the same as those of GM.
(3) The MIC levels of KW-1062 against P. aeruginosa were the same or less than those of GM, and slightly higher than those of DKB. Cross resistances among these three drugs were found to be well correlated.
(4) The mode of action of KW-1062 was considered to be bactericidal.
(5) Therapeutic effect of KW-1062 against experimental infection of mice with E. coli was nearlythe same as that of GM and more active than that of DKB. However, in vivo antibacterial activity of KW-1062 against P. aeruginosa infection was slightly lower than that of DKB but slightly higher than that of GM.

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In vitro and in vivo antibacterial activity of KW-1062, a new aminoglycoside antibiotic, was studied on gram-positive and gram-negative bacteria in comparison with that of gentamicin (GM), dibekacin (DKB), tobramycin (TOB) and amikacin (AMK).
KW-1062 was found to exhibit a broad antibacterial spectrum against gram-negative and gram-positive. bacteria. The antibacterial spectrum of KW-1062 was quite similar to that of GM. Acute toxicity of KW-1062 was slightly weaker in mice than that of GM.
The serum concentration of KW-1062 maintained lower peak level and decreased more slowly than, GM.

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We tested the antibacterial activity of KW-1062 against various pathogens isolated from clinical materials from July 1975 to June 1976 and compared the activity with gentamicin, tobramycin, dibekacin, amikacin, kanamycin and streptomycin. We used 471 strains of Haemophilus influenzae, H. parainfluenzae, E. coli, Klebsiella, Serratia, Enterobacter, Proteus vulgaris, Pr. mirabilis, Pr. morganii, Pr. rettgeri, Pr. inconstans, Pseudomonas aeruginosa, Neisseria gonorrhoeae and N. meningitidis, and estimated the minimum inhibitory concentrations of each antibiotic by agar dilution method.
Antibacterial activity of KW-1062 against pathogens tested is quite as similar as that of gentamicin, and the cross-resistance was observed between these two drugs. KW-1062 has also the similar antibacterial activity as tobramycin or dibekacin, and we observed the cross-resistance among a great part of strains tested between KW-1062 and tobramycin or dibekacin, but we could not find the cross-resistance between this antibiotic and amikacin, kanamycin or streptomycin.
KW-1062 showed a good antibacterial activity against strains of various pathogens excluding Pr. rettgeri, but resistant strains were observed among strains of Enterobacteriaceae, especially Pr. morganii, Pr.inconstans and Serratia.

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The antibacterial activity of KW-1062, a new aminoglycoside antibiotic, was compared with that of gentamicin (GM), tobramycin (TOB), dibekacin (DKB) and kanamycin (KM). The results obtained are as follows :
1) KW-1062 exhibited a broad antibacterial spectrum. Its activity was much the same as that of GM. Against a few species of gram-positive bacteria, it was found to be more active than TOB, DKB and KM.
2) The antibiotic had a similar activity to GM, TOB and DKB against clinical isolates of S. aureus, E. coli, Ps. aeruginosa, Proteus sp., K.pneumoniae and Serratia sp. Cross resistance between KW-1062 and GM was observed.
3) In vitro antimicrobial activity of KW-1062 was influenced to the same degree as gentamicin, by medium pH, the presence of equine serum and the inoculum size of S. aureus, E. coli and Ps. aeruginosa.
4) KW-1062 as well as gentamicin exhibited a rapid bactericidal action against E. coli and Ps. aeruginosa.
5) KW-1062 showed nearly the same in vivo activity as gentamicin against the experimental Ps. aeruginosa and Serratia infection in mice.
6) KW-1062 was found to be synergistic with semi-synthetic penicillins.

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For the purpose to seek an optimal method for dosing KW-1062, a new aminoglycoside antibiotic, in the infection due to Pseudomonas aeruginosa, gram-negative rod bacteria, both in vitro and in vivoantibacterial actions of KW-1062 were examined, and the following items were clarified.
1) The time of onset of the bactericidal action and the bactericidal potency of KW-1062 depended on its concentration.
2) Ps. aeruginosa was damaged by KW-1062, however, it began to regrow, when the drug was free, as fast as intact cells after a lag time.
3) The maximal therapeutic efficacy of KW-1062 was obtained following its single administration.

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In vitro and in vivo evaluation of KW-1062, a new aminoglycoside antibiotic, was performed in comparison with gentamicin. KW-1062 showed in vitro antibacterial activity against gram-positive and gramnegative bacteria as well as gentamicin. Several antibacterial features of KW-1062 such as influence of medium pH and inoculum size, effect of addition of serum, binding to serum albumin, development of resistance, and bactericidal activity were shown to be almost identical with those of gentamicin. KW-1062 exhibited stronger activity than gentamicin against some clinical isolates of Ps. aeruginosa which seemed to produce 6'-N acetylating enzyme. The in vivo protective activity of KW-1062 was similar one with gentamicin in mice infected with certain strains of the gram-positive and gramnegative bacteria.

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The pharmacological actions of KW-1062, a new aminoglycoside antibiotic, were investigated. Summary of pharmacological actions and minimal effective doses (MED) of KW-1062 was as follows : fall of blood pressure of the rabbit (10 mg/kg), inhibition of respiration of the rabbit (50 mg/kg), bradycardia of rabbit ECG (100 mg/kg), inhibiton of isolated guinea pig atrium (5×10^-5 g/ml), stimulation of permeability of rabbit skin vessels (10 dug) and inhibition of isolated rabbit and guinea pig intestine (10^-4 g/ml), of isolated guinea pig trachea (10^-4 g/ml), and of isloated nonpregnant and pregnant rat uteri (2×10^-5 and 2×10^-6 g/ml). No effect on rabbit ear vessels was observed in a concentration up to 2×10^-1 g/ml. The actions and MED were similar to those of gentamicin. In nerve-muscle preparation of rat diaphragm, contraction by indirect stimulation was inhibited at a concetration of 5×10^-4 g/ml. ED₅₀ in which moderate paralysis was elicited in mice was calculated as approximately 200 mg/kg (sc). No potentiating effects of KW-1062 on ether anesthesia and Pentobarbital sleep were observed. KW-1062 did ont protect the Pentetrazol convulsions. The increase in body weight, volume of urine, urinary excretion of sodium and potassium, and urinary findings in the rat applied KW-1062 in doses from 12. 5 to 100 mg/kg subcutaneously once a day for 7 days were similar to normal values and those of the control group, except that application of 100 mg/kg showed tendency of inhibition of body weight increase and decreased excretion of sodium.

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Distribution, fate and excretion of KW-1062, a new aminoglycoside antibiotic, were investigated in rats and mice. When rats were intravenously and intramuscularly injected KW-1062 at a dose of 5 mg/kg, biological half lives were 8. 23 and 37. 26 min, respectively. The biological half life of KW-1062 in the injected site of muscle was 20. 56 min. KW-1062 was well absorbed from muscle and rapidly eliminated from blood. The serum level and organ levels were proportionally increased with the doses applied, and all organ levels were lower than the serum level. KW-1062 was hardly absorbed from intestine. The total amount excreted in 24 hr urine of the rat was 70% of the injected amount. The cord blood levels were 36. 79 to 66. 55% of maternal serum levels in the pregnant rats. The fetal organ levels were very low. Approximately 10. 57 and 19. 16% of KW-1062 were bound to human plasma and to bovine serum, respectively.

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Absorption, distribution, excretion and metabolism of KW-1062, a new aminoglycoside antibiotic, were studied in the test animals after subcutaneous or intramuscular administratration of 10 mg/kg.
KW-1062 was extremely well absorbed when given in mice, rats and dogs. The peak of plasma concentration of KW-1062 ranged from about 15 to 20 μg/ml at 15 or 30 minutes in animals. No plasma activity was noticed at 3 or 4 hours after administration. KW-1062 was distributed into various organs and the concentration in kidney remained very high for a long period of time. The other tissue concentrations of KW-1062 in animals were lower than the concentration of plasma. Most of the administered KW-1062 was excreted mainly through the urinary tract. The 24 hour urinary recovery rate was approximately 80% in rats and dogs. The biliary excretion rate in rats after intramuscular administration of 50 mg/kg was very small. No active metabolites were found in urine of rats and dogs, but only KW-1062 itself was excreted. The significant difference was not observed in the pharmacological results between KW-1062 and GM.

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Plasma and tissue concentrations of KW-1062 in rats, in comparison with gentamicin, were determined after multiple intramuscular administration of 10, 25 and 156 mg/kg for 5 or 10 days. Remarkable accumulation of KW-1062 after multiple administrations was observed in the kidney. The eliminaton of KW-1062 from the kidney was rather slow and the half-life was very long. No accumulation of KW-1062 in plasma was observed with multiple administrations, and the half-life was constantly about 20 to 30 minutes. Slight accumulation of KW-1062 was observed in other organs such as lung, liver and spleen. The elimination of gentamicin from the organs was in general slower than that of KW-1062.

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KW-1062, a new aminoglycoside antibiotic, was labeled with tritium and carbon-14 by hydrogen exchange reaction and biosynthesis, respectively.
³H-KW-1062 was administered intramuscularly in the rat was absorbed immediately to show the highest blood level at 15 min. Ninety six percent of KW-1062 was excreted in the urine and only 1% in the feces by 48 hrs. No urinary metabolite was found both in radioactivity and bioactivity.
Distrbution of KW-1062 was also investigated by autoradiography in mice. ¹⁴C-KW-1062 was located in the epiphysis temporarily, but in the cortex of the kidneys it distributed highly for prolonged time.

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Placental transfer of KW-1062, a new aminoglycoside antibiotic, has been studied in the pregnant rat or mouse intramuscularly administered ³H-or ¹⁴C-KW-1062 respectively. The results were as follows :
(1) The level of KW-1062 in the umbilical cord blood was 8% of the maternal blood level and the excretion half life in the umbilical cord blood was about 2. 5 hr, in contrast to 35 min. of that of the maternal blood.
(2) KW-1062 was hardly distributed into the amniotic fluid. The concentration of the antibiotic in the fetal membrane was rather high.
(3) KW-1062 was highly distributed into the fetal kidney and bone. The concentrations in the other tissues were decreased in the following order : heart, lung, umbilical cord blood, brain, liver.
(4) The distribution of KW-1062 in the pregnant mouse was similar to that in the male mouse. KW-1062 was highly distributed in the kidney, epiphysis, gallbladder and intestinal contents. Transfer into the ovary and uterus was good.

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Three series of animal tests were performed on 394 guinea pigs of Hartley strain to evaluate the ototoxicty and safety of a newly developed aminoglycoside antibiotic KW-1062.
Series I. Animal test for acute ototoxicosis. KW-1062 and Gentamicin (GM) were given to 41 guinea pigs i. m. at dose of 50 mg/kg, and 100 mg/kg, respectively for 28 days. Differential frequency pinna reflex test in range from 20 kHz to 200 Hz was carried out before the experiment and during the administration of the antibiotics for measurement of frequency range of pinna reflex loss. After the end of the experiment, individual animals underwent intravital perfusion fixation with Wittmaack's fixative according to the procedure previonsly reported. Bilateral temporal bones were removed en bloc and decalcified. After washing of the temporal bones in running water the bones were dehydrated and embedded in celloidin. Serial horizontal sections were prepared and every 5 th sections were stained with hematoxylin-eosin.
Series 2. Animal test for chronic ototoxicosis. KW-1062 was given to 39 guinea pigs i. m. at dose of 2. 5 mg/kg and 25 mg/kg, respectively for 3 months. Additionally distilled water was given to 20 guinea pigs at dose of 0.1 ml/100g for 3 months. The differential frequency pinna reflex test weekly carried out before and during the administration. After the end of the experiment histological sections of the temporal bones of the individual animals were prepared in the same way as in the series 1.
Series 3. a) Animal test for acute ototoxicosis in early period of gestation. KW-1062 was given to 15 pregnant guinea pigs i. m. at dose of 50 mg/kg and 100 mg/kg, respectively for 28 days since the first pregnant day. The pregnancy was confirmed by presence of sperms in vaginal smear. GM was given to 17 pregnant guinea pigs i. m. at dose of 25 mg/kg and 50 mg/kg, respectively for 28 days since the first pregnant day. Distilled water was given to 4 pregnant guinea pigs i. m. at dose of 0.1 ml/100g for 28 days since the first pregnant day. The differetial frepuency pinna reflex test was carried out on the pregnant guinea pigs before, during and after the administration until 2 nd week after delivery. The differential frequency pinna reflex test was also performed on 91 new born guinea pigs one and two weeks after birth. After the end of the experiment histological sections of the temporal bones of the individual animals were perpared in the same way as in the series 1.
b) Animal test for acute ototoxicosis in later period of gestation. KW-1062 was given to 27 pregnant guinea pigs i. m. at dose of 25 mg/kg, 50 mg/kg and 75 mg/kg, respectively for 28 days since the 6 th week of gestation. GM was given to 18 pregnant guinea pigs i. m. at dose of 12. 5 mg/kg and 25 mg/kg, respectively for 28 days since the 6 th week of gestation. Distilled water was administered to 4 pregnant animals i. m. for 28 days since the 6 th week. The differential frequency pinna reflex test was carried out on the pregnant animals before, during and after the administration until 2nd week after delivery. The differential pinna reflex test was also performed on 118 new born guinea pigs from the pregnant animals treated with the antibiotics one and two weeks after birth. After the end of the experiment histological sections of the temporal bones of the individual animals were prepared in the same way as in the series 1.
The results obtained are as follows ;
1) In animal test for acute ototoxicosis. The differential frequency pinna reflex test and histopathological examination revealed that KW-1062 is much less ototoxic than GM at dose of 50 mg/kg and 100 mg/kg, respectively. These data suggest that KW-1062 has much less ototoxicity to the end organs of the auditory and vestibular systems than GM.
2) In animal test for chronic ototoxicsis. The differential frequency pinna reflex test and histopathological examination revealed that there was almost no remarkable

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KW-1062 is an aminoglycosidic basic antibiotic like gentamicin with a molecular formula C₂₀H₄₁ N₅O₇, and the ototoxicity was examined with this antibiotic.
Sixty healthy guinea pigs of 300-400 g body weight were used. Fifty animals were given KW-1062 daily at a dose of 100-200 mg/kg for 14-27 r, days. Ten animals were the control group. The cochlear function was studied by Preyer's reflex of 0.5, 1, 2, 4, 8, 10 and 12 kHz. The vestibular function was measured by postrotatory nystagmus test with the constant angular velocity of 60°/sec and 180°/sec. The pathological changes in the inner ear were observed by the method of surface preparation after succinic dehydrogenase staining. The hair cells of the organ of corti and the vestibular organs were observed. In the crista ampullaris lateralis, especially, the central and peripheral hair cell numbers per unit square (0.01 mm²) were counted. The relationship between thus measured functional data and morphological changes was studied.
The following results were obtained.
1. The cochlear damages were very slightly found both in the functional and the morphological researches.
2. On the contrary, the vestibualr damages were severely found.
3. The postrotatory nystagmus decreased in different degrees depending upon the dose of KW-1062.
4. In the crista ampullaris lateralis the central part was more severely damaged than the peripheral part.
5. The impairment of the vestibular function well paralleled to the increased toxic signs demonstrated in the morphological preparation.

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Laboratory and clinical studies on KW-1062, a new aminoglycoside antibiotic, were carried out and the following results were obtained :
1. Serum levels of KW-1062 were measured in healthy adults and aged patients given 60 and 40 mg of KW-1062 following single administration. Serum levels of KW-1062 were 5. 27 and 5. 9 μg/ml, respectively, after one hour. Both peak levels were similar. However, its excretion in urine varied according to renal functions of the patients.
2. KW-1062 was given to 17 cases at a dose of 40 mg twice a day. All the cases were aged. Clinical results were good in 13 cases and unknown in one case. Good results were obtained in 4 cases, where no response had been observed to other antibiotics.
3. As side effects, vertigo and headache were observed in each one case. The administration had been stopped because of their side effects. No other abnormality was observed in biochemical tests.

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Eight patients with various intractable lung infections (9 cases) received daily 120 mg of KW-1062 divided into two or three doses by intramuscular route for 5 to 12 days. The effect was excellent in 1 case, good in 2, fair in 3 and poor in 3. The rate of effectiveness was 66. 7%. There were no changes attributable to KW-1062 in blood picture or in liver or renal function. Side effects such as impairment of the 8 th nerve were not noted.

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Laboratory and clinical studies on KW-1062 have been carried out, and the following results were obtained.
(1) The antibacterial activity of KW-1062 against Ps. aeruginosa was nearly the same as Gentamicin (abbr. GM) and Dibekacin (DKB), slightly weaker than Tobramycin (TOB) and slightly stronger than Amikacin (AMK). MICs of 47/50 clinically isolated strains were distributed at the range of 0.2-12.5 μg/ml.
(2) KW-1062 was administered clinically at the daily dose of 80 mg for 8-33 days to 7 cases of respiratory tract infections. The results obtained were effective in 3 cases of acute pneumonia (E. coli, Proteus morganii), and 1 case of chronic bronchitis (Ps. aeruginosa), but not in 2 cases of chronic bronchiolitis (Ps. aeruginosa) and pyothorax (Klebsiella pneumoniae).
(3) No side effect was noticed throughout the cases treated.

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In vitro antimicrobial activity and therapeutic effects of KW-1062 on respiratory tract infections were evaluated and the following results were obtained.
The MICs of the drug against clinical isolates of Klebsiella pneumoniae were slightly lower than those of DKB and nearly the same as those of GM. The drug was revealed to be less effective than GM or DKB against Pseudomonas aeruginosa.
Of 4 cases, treated with the drug, of respiratory tract infections with gram negative bacilli, an excellent bacteriological and clinical effect was observed in one case, but the 3 remaining cases showed negative clinical responses during the periods of the administration of the drug.

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KW-1062 was administered intramuscularly to 12 patients with biliary tract infections of various. types.
Clinical responses to KW-1062 therapy were excellent in 5 cases, good in 5 cases and not determined in 2 cases.
None of the patients experienced aggravation of their diseases on the therapy.
The therapy with KW-1062 was also evaluated bacteriologically.
All strains were eradicated except E. coli and Klebsiella.
Out of 19 strains of organisms isolated from bile before the therapy, 9 strains disappeared, 4 strains were reduced in number and 5strains persisted after the therapy.
No side effects were encountered during this study.

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On KW-1062, fundamental experiments and clinical application studies were performed.
1. In three healthy adults injected intramuscularly 100 mg of KW-1062 and gentamicin by crossover, the peak of averaged serum concentration was 5.3 pg/ml and 5. 4 pg/ml, respectively, and the each averaged half-life was 1. 72 hours and 1.65 hours. The averages of urinary recovery rate after 6 hours were 82. 6% and 96%, respectively.
In two patients with severely impaired renal function, the half-life was as long as 10 hours.
2. When KW-1062 was administrated to a patient with severely impaired renal function, any other active component than KW-1062 itself was not demonstrated in the urine of the patient.
3. Inactivation of KW-1062 by carbenicillin or sulbenicillin was found in in vitro during several hours when the mixed two drugs were incubated at 37°C.
4. Nephrotoxicity of KW-1062 in rabbits was less than that of gentamicin and dibekacin.
5. Clinical application of KW-1062 was attempted in a patient with cholecystitis and sepsis due to Escherichia coli, a patient with bronchopneumonia, and three patients with uninary tract infection due to Escherichia coli, Proteus mirabilis and Serratia.
The good response was shown in all patients except a patient with chronic cystitis due to Serratia. One who resulted in the failure of treatment had underlying diseases of RECKLINGHAUSEN's disease and diabetes mellitus, and indwelling catheter of urinary bladder.

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KW-1062 is a new aminoglycoside antibiotic with potent antimicrobial activity against gram-negative bacteria.
1. After a single intramusclar injection of 40 mg of KW-1062 to patients with impaired renal functions, serum levels were determined. In a patient with a creatinine clearance of 36 ml/min, the serum concentration reached to the peak after 2 hrs and fell down slowly to an undetectable level after 24 hrs. In patients with more severe renal insufficiency (Ccr. 0 and 8ml/min), however, the serum levels of KW-1062 after 24 hrs were still about a half of the peak levels. The fall in the serum concentration was observed during 5-hr haemodialysis in a patient with renal insufficiency.
2. KW-1062 was administered to 13 patients with respiratory tract infections (10 cases) and urinary tract infections (3 cases including a patient with renal insufficiency) and found to be effective in 11, fairly effective in one and non-effective in one. No significant adverse reactions were encountered.

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Laboratory and clinical studies on a new aminoglycoside antibiotic, KW-1062, were performed with the results which were summarized as follows.
1) By the thin-layer cylinder-plate method using B. subtilis ATCC 6633 as a test organism, KW-1062 was assayable to the lower limit of 0.1 μg/ml in serum.
2) Following a single intramuscular administration of KW-1062 in two adults, the serum peak level was 5. 8 μg/ml at a dose of 50 mg and 11.9 μg/ml at a dose of 60 mg, respectively. The agent was excreted in urine with the level up to 110 μg/ml and the recovery rate of 67. 5% within 16 hours, at a dose of 50 mg, and 240 μg/ml and 97. 8% at a dose of 60 mg.
3) Clinical response to the drug was excellent in a case of E. coli pyelonephritis and good in two cases of respiratory tract infection, i. e., bronchitis complicated with middle-lobe syndrome and deglutition bronchitis.
4) No side-effect was noticed in these three cases.

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1) The distribution of MIC values of KW-1062 against clinical isolates such as Serratia mercescens, Pseudomonas aeruginosa and Acinetobacter calcoaceticus was found to be similar to that of gentamicin and dibekacin.
2) KW-1062 was administered intramuscularly to two healthy volunteers at a single dose of 40mg. The serum level of KW-1062 reached the peak of 4. 6 μg/ml at one hour after administration. The urinary excretion rate for the first 6 hours was 65% in an average. These results obtained with KW-1062 were considered to be comparable to those obtained with gentamicin or dibekacin.
3) KW-1062 was administered to two patients with pneumonia and one patient with chronic pyelonephritis and found to be effective in all cases.
No particular side effects were observed.

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Clinical studies on KW-1062 were performed with the following results :
1) Antibacterial activity
MIC values of KW-1062 against 50 clinical isolates of E. coli, Kleb. pneumoniae, Prot. mirabilis and Ps. aeruginosa ranged from 1. 56 to 25, 0.78 to 3.12, 0.78 to 12. 5 and 0.39 to 100 μg/ml or more, respectively. Antimicrobial activity of KW-1062 against those strains was considered to be comparable to that of gentamicin, tobramycin and dibekacin.
2) Absorption and excretion in human subjects, and tissue levels in rats
After intramuscular administration of KW-1062 to healthy adults at a single dose of 40 mg or 60 mg, the serum level reached the peak of 4. 88 to 11. 38 μg/ml in one hour, and the concentration declined with half-life values of 1.67 to 2.10 hours. Urinary recovery was 65. 6 to 89. 4% of the dose within the first 6 hours. The serum half-life of KW-1062 in patients with renal insufficiency prolonged in proportion to the degree of impairment of renal function.
After intramuscular administration of KW-1062 to rats at a single dose of 10 mg/kg, the tissue level at the peak was highest in the kidney, followed by the serum, liver and lung in descending order. The concentration of KW-1062 attained in the kidney was still detectable 6 days after injection, and the drug level tended to be higher in the cortex than in the medulla.
3) Results of clinical trials
Two patients, one with chronic pyelonephritis and the other with chronic cystitis, were treated with KW-1062 at the daily dose of 80 mg for 10 to 13 days, but they did not respond to the drug. No particular untoward reactions were observed in these cases

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Some experimental and clinical trials were performed on KW-1062, a new aminoglycoside antibiotic, and the following results were obtained.
1. Antibacterial activities of KW-1062 were similar to those of gentamicin. There found cross resistance between two drugs.
2. Serum levels, urinary concentrations and the amounts of urinary excretion were determined at increasing dosing of KW-1062 to human volunteers. Dose response was shown in the values of serum levels. The rate of urinary excretion was very high.
3. There was no tendency of accumulation in serum level following successive dosings twice a day for 5 days.
4. In cross over study with KW-1062 and gentamicin, the values of serum level and urinary excretion were almost identical.
5. Two patients, one with infections of respiratory and urinary tracts and decubitus ulcer and the other with pneumonia, were treated with KW-1062. Perhaps because of various underlying diseases, the effect was insufficient. No side effect was observed.

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1. The antibacterial activity of KW-1062, a new product, was compared with that of GM, DKB and AMK against E. coli, K. pneumoniae and P. aeruginosa isolated from the blood.
1) Against E. coli and K. pneumoniae, the antibacterial activity of KW-1062 was as strong as that of GM and stronger than those of DKB and AMK.
2) Against P. aeruginosa, the activity of KW-1062 was as strong as that of GM, and stronger than that of AMK and weaker than that of DKB.
2. KW-1062 was poorly active against E. coli, K. pneumoniae and P. aeruginosa that were resistant to GM. In these organisms, cross resistance was observed between KW-1062 and GM. MIC of KW-1062 was 12.5 pg/ml against a strain of E. coli and 25 μg/ml or more against other strains.
3. A good in vitro bacteriostatic synergism was observed against P. aeruginosa with the combination of KW-1062 and SBPC.

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KW-1062 was used in the treatment of pneumonia and recurrent chronic bronchitis in a series of 16 cases, most of whom had various underlying diseases and cram-negative bacteria were isolated from sputa of 15 cases.
In 10 cases (63%) out of 16 cases, improvements in subjective symptoms and laboratory findings were observed, while 5 cases (31%) did not respond to KW-1062 therapy and one was aggravated during the therapy.
No side effects were encountered during this study.

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1) The antimicrobial activity of KW-1062 against E. coli, Klebsiella pneumoniae, Serratia marcescens and Pseudomonas aeruginosa was similar to that of gentamicin.
2) Five healthy volunteers were injected intramuscularly 40 mg of KW-1062. The mean serum level achieved the peak of 2.94 μg/ml at 30 minutes, and was trace at 6 hours.
The mean urinary recovery rate during 8 hours after administration was 83. 5%.
The peak serum levels after multiple administration were apt to be a little higher in the advanced age patients.
The sputum level after multiple administration was more than 1 μg/ml. Its rise was slower than that of serum level, and the sputum level remained considerably high.
3) KW-1062 was administrated to 15 patients suffering from respiratory tract infection (5 cases) and urinary tract infection (10 cases).
KW-1062 was effective in 3 cases out of 4 cases with respiratory tract infection due to Ps. aeruginosa.
Another patient with Serratia infection responded satisfactorily to KW-1062 therapy.
All three patients with acute urinary tract infection responded satisfactory. Among 7 patients with chronic urinary tract infection, KW-1062 was effective in 4 cases clinically and in 3 cases bacteriologicaly.
No adversed reactions were observed except a little elevation of GOT and GPT in 1 case. No hearing impairment and rash were encountered. KW-1062 is considered to be a useful antibiotic in the treatment of infections due to gram-negative rods, especially Ps. aeruginosa.

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1. Sensitivity of 36 strains isolated from patients to KW-1062 was compared with that of gentamcin, kanamycin and streptomycin.
The minimum inhibitory concentration (MIC) of KW-1062 against 10 strains of Pseudomonas aerusinosa distributed in the range from 6.25, μg/ml to 100, μg/ml.
The antibacterial activity of KW-1062 was almost similar to that of gentamicin against Pseudomonas aeruginosa, E. coli, Klebsiella and Serratia.
2. KW-1062 was administrated at daily dosage of 80 mg to 5 cases with urinary tract infections and one case with bronchopneumonia.
Clinical response to therapy was excellent in one case, good in 4 cases and poor in one case. Effective rate was 83.3%.
3. No significant side effects were experienced.

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Some investigations were made on the clinical application of KW-1062 and the following results were obtained.
1. Antibacterial activity of KW-1062 against Serratia was nearly the same as that of gentamicin. Cross-resistance between KW-1062 and gentamicin was observed in some of these strains.
2. The peak serum level of KW-1062 in a patient of renal sufficency with pyelonephritis was at 4.3 μg/ml 1 hour after intramuscular administration of 60 mg dose.
The urinary recovery of KW-1062 within 6 hours was 67.8% of the dose.
3. Clinical result of KW-1062 was effective in 9 (64.3%) out of 14 patients.
4. Elevation of S-GOT, S-GPT and BUN was encountered in some patients.However, these results might not be due to the administration of KW-1062, because antitumor agents or the blood transfusion had been applied to the patients suffering from underlying diseases such as malignant tumor, peritonitis or leukemia. No other adverse reactions were obseved.
5. KW-1062 was administered concurrently with cephalosporins or penicillins to the patients who did not respond to those drugs. Satisfactory clinical responses were observed in 2 cases. With regard to these combination therapy, further investigations are required.

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Six infectious episodes in patients with acute leukemia, which had been resistant to either CET, CEZ, CBPC or SBPC combined with GM or DKB, were treated with KW-1062 (240-360 mg/ day) combined with CEZ or CBPC. Two cases responded to the combination antibiotics therapy and the other 4 failed to respond. No side effect attributable to KW-1062 administration was noted.

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From basic and clinical studies on KW-1062, the following results were obtained.
1) Antibacterial activity of KW-1062 against various clinically isolated organisms, such as Staphylococcus aureus, E. coli, Klebsiella, Proteus sp. and Pseudomonas aeruginosa was tested.
The M. I. C. s of KW-1062 were almost distributed at less than 12. 5 μg/ml and those of 70% of organisms were less than 1. 56 μg/ml.
Antibacterial activity of KW-1062 was found to be similar to that of gentamicin or less than that of gentamicin.
2) KW-1062 were administered at a daily dose of 80 to 240 mg (6-35 days) to 7 patients comprising 6 cases of respiratory tract infections and one case of sepsis.
Excellent response was observed in one with sepsis and good effect was obtained in 4 oat of 6 patients with respiratory tract infections.
Transient hearing impairment and slight elevation of BUN were observed in one patient who was given a daily dose of 240 mg. No other side effects were encountered.

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Basic and clinical studies were made on KW-1062, a new aminoglycoside antibiotic developed by Kyowa Hakko Kogyo Co. The results obtained were as follows :
1) The MICs of KW-1062 against 46 strains of Pseudomonas aeruginosa were between 1.6 and 12.5 μg/ml, and those against 17 strains of Proteus mirabilis were between 0.4 and 6.2 μg/ml.
2) Intramuscular injection of 40 mg KW-1062 yielded a peak blood level up to 7.0 μg/ml in half an hour, the urinary recovery being 68.8% of the dosage in 8 hours; while only 0.26% was recovered from the bile in two hours.
3) Distribution of the KW-1062 into rats organs : The highest tissue concentration of the antibiotic was found in kidney, followed by serum, lung, spleen, and liver. The distribution pattern was similar to those found in other aminoglycosides.
4) Twelve clinical cases (urinary tract infections 6, respiratory tract infections 6) were treated with KW-1062 at a dosis of 80 mg-120 mg (i. m.) per day. Six cases responded well to the treatment.
Side effects were found in three of the cases, i. e. slight elevation of S-GOT and S-GPT, microhaematuria, and a slight drop of respiration rate in amyasthenia gravis case ;all of those adverse reaction & disappeared soon after cessation of dosing.

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1) KW-1062 was chiefly applied to 23 cases of various infectious diseases combined with underlying diseases, such as progressive cancer, diabetes mellitus and nosocomial infection due to resistant Staphylococcus aureus.
2) The clinical effectiveness rate of KW-1062 was 67% in all cases, and 50% in patients with urinary tract infections.
Bacteriological improvements were obtained in 64% of patients with respiratory tract infections and 60% in urinary tract infections.
3) Superinfection was observed in 8 cases in which appearance of fungi, gentamicin-resistant Pseudomonas aeruginosa, resistant Sta. aureus, etc. was noted.
4) Side effects were encountered in 7 cases (30%). Impaired sense of hearing or equilibrium was observed in 4 cases and hepatic impairment in one case.
No noticeable side-reactions were observed in renal function.

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KW-1062, a new aminoglycoside antibiotic was administered to 4 cases with urinary tract infection and the good results were obtained in all cases. In three cases with acute leukemia associated with suspected sepsis (the causative organisms were unknown), the effectiveness of KW-1062 was doubtful in one case, and failure in other two cases.
No significant side effects were noted throughout all cases. A dose of 240 mg of KW-1062 was admimistered intravenously for 51 days in one case without showing any renal impairment.

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1. KW-1062, a new aminoglycoside antibiotic, was compared with gentamicin (GM), dibekacin (DKB) and kanamycin (KM). KW-1062 inhibited 98% of St. aureus (51 strains), 84. 6% of E. coli (44 strains), 91.2% of Proteus sp. (31 strains), 82.4% of Kl. pneumoniae (42 strains), 33% of Ps. aeruginosa (17 strains) and 75. 6% of Serratia (68 strains) at a concentration of 6. 25, μg / ml. As a whole, the antimicrobial activity of KW-1062 was much stronger than that of KM and intermediate between those of GM and DKB.
2. Concentration of KW-1062 in serum was determined in four patients after intramuscular administration of 40 mg KW-1062. The peak serum level achieved at 30 minutes after drug administration was 7.4 μg / ml. The average level at 6 hours was 0.7 μg/ml.
3. KW-1062 was administered to six patients with pulmonary infections. Three patients responded in a satisfactory fashion to KW-1062. Three patients failed to respond satisfactorily to KW-1062. Untoward effects were seen in two patients. One patient developed a tremor of the upper limb at injection site. The other complained of tinnitus and hearing impaired. Both patients returned to normal after discontinuance of therapy.

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1. Antimicrobial activities
The in vitro activity of KW-1062 was compared with that of gentamicin against 23 stock cultures and 927 clinical isolates of gram-positive and gram-negative bacteria (81 Staphylococcus aureus, 57 Citrobacter freundii, 33 Salmonella, 81 Escherichia coli, 48 Shigella, 8 Erwinia herbicola, 81 Klebsiella aerogenes, 42 Enterobacter aerogenes, 39 Enterobacter cloacae, 162 Serratia marcescens, 26 Proteus vulgaris, 51 Proteus mirabilis, 22 Proteus rettgeri, 17 Proteus inconstans, 42 Morganella morganii, 24 Aeromonas hydrophila, 1 Plesiomonas shigeroides, 24 Vibrio parahaemolyticus and 88 Pseudomonas aeruginosa).
2. Tissue distribution of KW-1062 in male rats (wistar)
Tissue distribution investigation in rats administered 20 mg/kg i. m. revealed the high peak concentration in serum followed by kidney, lung and liver.
3. Absorption and excretion in man
KW-1062 and gentamicin were administered intramuscularly at a dose of 50 mg to three healthy adult volunteers by the cross-over method. Serum levels of KW-1062 reached the peak of 10. 0 to 14. 0μg/ml in 30 minutes to one hour. The level ranged from 0.5 to 1.5 μg/ml at 6 hours. The urinary recovery of KW-1062 averaged 81. 6% during 6 hours after administration. Both the peak serum level and the urinary recovery rate of KW-1062 were a little higher than those of gentamicin.
4. Results of KW-1062 treatment
KW-1062 was administered to three patients with respiratory tract infection (bacterial pneumonia, lung abscess and chronic bronchitis, respectively) at a daily dose of 120 to 160 mg for 7 to 8 days. One patient with bacterial pneumonia responded well to KW-1062 treatment.
5. No particular adverse reactions were encountered.

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Laboratory and clinical studies on KW-1062 were performed with following results :
1) MIC values of KW-1062 against 34 clinical isolates of Pseudomonas aeruginosa ranged from 1.56 to 6.25 μg/ml, and were found to be similar to those of gentamicin. Antimicrobial activity of KW-1062 against E. coli, Klebsiella sp. and Serratia marcescens was also comparable with that of gentamicin.
2) After intramuscular administration to rats at a single dose of 5 mg/kg, tissue levels at the peak were the highest for serum, followed in descending order by kidney and lung. The antibiotic level was not measurable for liver.
3) KW-1062 was administered intramuscularly to 5 patients with urinary tract infections (4 cases with acute cystitis and 1 case with chronic cystitis) of the daily dose of 80 mg in two divided doses. The clinical response to KW-1062 was excellent in 2 cases, good in 2 cases and poor in 1 case.
4) No untoward effects were observed in any cases.

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KW-1062 was found to be similar to gentamicin in in vitro activity against 25 Staph. aureus, 25 E. coli, 25 Prot. mirabilis, 24 Prot. morganii, 25 Pseudomonas aeruginosa and 22 Serratia isolated in pediatric field.
When administered intramuscularly, KW-1062 was rapidly absorbed and excreted into urine. In the patient with renal impairment, however, the peak serum concentration was enhanced and the excretion was markedly delayed.
Two patients were treated with KW-1062 at a dose of 2 mg/kg/day. The burn patient with Pseudomonas infection responded well to KW-1062 therapy. The other suffering from chronic pyelonephritis due to E. coli responded well bacteriologcally by KW-1062 therarapy. But the drug was changed to amoxicillin because of the relapse of fever. No praticular adverse reactions were encountered during this study.

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KW-1062 is a new aminoglycoside antibiotic with a broad spectrum of antimicrobial activity similar to that of gentamicin. The clinical studies on KW-1062 were performed in the pediatric field, and the following results were obtained.
1) KW-1062 was administered to 14 children with various bacterial infections and found to be effective in 13 cases of them. One patient with pneumonia due to Mycoplasma did not respond to KW-1062 treatment.
2) The patient with pyothorax responded satisfactorily to the intrapleural infusion therapy of KW-1062 combined with drip infusion therapy of cefazoline.
3) No adverse reactions were encountered.

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1. KW-1062 inhibited the growth of 90% of Pseudomonas aeruginosa (100 strains) recently isolated from clinical materials at the MIC range of 1. 56 μg/ml to 6. 25 μg/ml.
2. KW-1062 was administered intramuscularly to 12 children with various bacterial infections : 4 cases with bronchopneumonia, 1 case with pyothorax and suspected septicemia, 4 cases with acute urinary tract infections and 3 cases with lymphadenitis purulenta.
Clinically, 10 out of 12 cases responded well to the therapy. Causative or isolated bacteria disappeared or diminished significantly in 6 out of 7 cases, of whom bacteriological assessment was possible.
Both clinical and laboratory findings revealed no untoward reactions due to the drug.

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Laboratory and clinical experiments of KW-1062 were made in the field of pediatric, and the following results were obtained.
1) Clinical effect
One to 5 mg/kg of KW-1062 was administrated intramuscularly to 11 patients with acute bacterial infection.
Respiratory infection responded well in 6 out of 11 patients.
Urinary tract infection showed too an excellent clinical effect in 2 cases. The effect of KW-1062 was uncertain in a case with septicemia and a case with chronic granulomatous disease. In the former case, KW-1062 was switched to other antibiotics after 7 days, and in the latter case, the periproctal abscess was incised during the course of abscess therapy. KW-1062 was also administrated in a case with fever of unknown origin, and the diagnosis of this case was confirmed later as J. R. A.
2) C. S. F. level
KW-1062 was administrated 2. 5 to 3. 0 mg/kg intramuscularly to 3 patients with ventriculo-peritoneal stomy.
The serial estimation of drug concentration in C. S. F., which was obtained through the shunt valve, revealed 1.1 to 7.1 μg/ml in 2 out of 3 patients for 30 to 180 minutes after drug administration, while no significant elevation was found in C. S. F. in the remained patient.

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The authors have carried out the laboratory and clinical studies of KW-1062, and the results were obtained as follows :
The sensitivity was measured by the plate dilution method with 32 strains of P. aeruginosa, 16 strains of Klebsiella and E. coli isolated from patients.
The peak of KW-1062 distribution was at 1. 56, μg /ml for P. aeruginosa. The growth of P. aeruginosa was inhibited in 90. 6% at a concentration of less than 3. 13 Jug/ml, while that of Klebsiella was in 87. 5% at a concentration of less than 0. 39 ug/ml. The growth of E. coli was inhibited in all strains at a concentration of less than 3. 13 μg/ml.
KW-1062 was given at a single intramuscular dose of 2. 0 mg/kg b. w. to 4 children and of 1. 0 mg/ kg b. w. to 2 children.
The maximum blood levels reached at 30 minutes after administrations of 2. 0 mg/kg and 1. 0 mg/kg b. w., were 8. 25, μg/ml and 5. 35 μg/ml, respectively. The blood levels at 8 hours were 0. 23 μg/ml and 0.33 μg/ml, respectively.
The excretion rates of KW-1062 in urine within 8 hours were 58. 8-71. 7%.
KW-1062 was effective in all of 5 cases with pediatric bacterial infections. No side effects were observed.

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Experimental and clinical studies have been conducted and the following results were obtained :
1. Antibacterial activity of KW-1062 against 23 strains of clinically isolated gram-negative rods was almost equivalent to that of gentamicin.
2. Transfer of KW-1062 and gentamicin has been studied in experimental staphylococcal meningitis in rabbits. Although the serum concentration and pattern of its change was similar to that of gentamicin, gentamicin showed a higher transfer rate into CSF than KW-1062.
3. The following two cases caused by Ps. aeruginosa were treated with 4 mg/kg/day of KW-1062, which was divided into two doses. One patient who had cerebral palsy as an underlying disorder had recurrent urinary tract infections, and another mandibular cellulitis associated with AML. They responded satisfactorily to the drug and were entirely free from any adverse reactions.

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1. KW-1062, a new aminoglycoside antibiotic, was studied on antibacterial activities, absorption, excretion, metabolism and clinical application.
2. KW-1062 has a broad antibacterial spectrum against gram-positive and gram-negative bacteria, which is similar to that of gentamicin (GM).
3. The susceptibility of KW-1062 against clinically isolated strains from surgical focuses was determined, and the following results were obtained. Antibacterial activity of KW-1062 against Staph. aureus was similar to that of GM and tobramycin (TUB), and regarding the activity against E. coli, KW-1062 was similar to dibekacin and a little less than GM. The activity of KW-1062 against Proteus sp. was similar to that of GM, and against Klebsiella, it was almost equal to that of TUB and less than that of GM. Against Pseudomonas aeruginosa, KW-1062 was as active as GM.
4. Three : healthy adults were administered 40 mg of KW-1062 intramuscularly, and 30 minutes after dosing the serum level reached the peak, 2. 47 μg/ml. Urinary recovery of KW-1062 during 6 hours in these cases was 75. 8% on an average.
5. Tissue level of KW-1062 in rats was highest in the kidney and serum, but it was not detectable in the liver.
6. Bioautogram of the urine collected from healthy adults having intramuscular administration of 40 mg of KW-1062 showed no metabolites with antibacterial activity except KW-1062 itself.
7. Clinical response to KW-1062 in surgical infectious diseases was good in 4 cases, fair in 1 case and poor in 2 cases. A dose of KW-1062 was 40-80 mg/time. It appeared effective when intramuscular injection at this dose was given three times/day.
8. As a side effect, the elevation of GOT and GPT was observed in 1 case, but it was unknown if the elevation was due to KW-1062, because of combination with another antibiotic agent. Side effect which may have been caused by KW-1062 was not observed, including of this case.

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Basic and clinical tests of KW-1062 were made in surgical field and the following results were obtained.
1. Biliary excretion in rabbits was poor. The bile levels of KW-1062 were 1/5 to 1/6 of the peak serum level.
2. The penetration of KW-1062 into cerebrospinal fluid was as poor as that of gentamicin.
3. Nine patients with surgical infections were treated with KW-1062. Clinical response was excellent in 1, good in 5, fair in 1 and failed in 1 case. The assesment was impossible in 1 patient.
4. No adverse reactions on renal function and hearing were observed. Serum GOT level increased in one patient with colon cancer, but this could not be definitely attributed to drug administration.

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KW-1062 was tried on acute cases with various infections in the field of surgery, and effective responses were seen on 11 of all the 16 patients. Untoward side effects were experienced on 2 cases : an uncomfortable sensation in the chest immediately after an intramuscular injection on one case, and dermal rash on the other.
In addition, serum levels and urinary excretion were investigated in healthy male volunteers.
KW-1062 is a new promising antibiotic effective for acute infections, especially caused by gram negative rods including Pseudomonas aeruginosa in the field of surgery.

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KW-1062, a new aminoglycoside, was investigated on clinical effectiveness in the surgical infections.The results of these clinical trials were obtained as follows :
(1) Ten patients with surgical infections, almost mixed type, were administered 80mg or 160 mg of KW-1062 daily by the intramuscular or the topical route. This agent showed remarkable therapeutic results : eight of these patients (80%) responded satisfactorily.
(2) No noticeable untoward reactions were obtained except slight elevation of GOT, GPT, and BUN. These abnormalities returned immediately to the normal range after cessation of this agent.

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Basic and clinical studies were performed with KW-1062, a new antibiotic of aminoglycosides.
1. Twenty-four strains of E. coli isolated clinically showed a good sensitivity to KW-1062 since all the strains tested were sensitive to 12.5μg/ml or less, most of them being sensitive to 3.13μg/ml.The small number of strains did not permit definitive conclusions but Enterobacter, Serratia, Klebsiella and P. aeruginosa showed the sensitivity to KW-1062 which was almost equal to that to GM.
2. When 40 mg of KW-1062 was intramuscularly infused, its blood levels reached a peak of about 3.67μg/ml after one hour. KW-1062 excreted into urine was about 64 to 90%of the dose in 4 hours and about 75 to 97%in 8 hours. Thus KW-1062 was excreted well.
3. The therapeutic effect of KW-1062 was excellent in 3 cases, good in 2, fair in 1 and poor in 2. In view of the fact that KW-1062 was used in cases of severe infections, the effectiveness of 62.5% seemed to represent excellent clinical results.
4. No changes attributable to KW-1062 were noted in hematologic data, liver function or renal function.

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