As the results of bacteriological studies of amikacin (BB-K8) made under the same conditions in comparison with kanamycin (KM), gentamicin (GM), and 3', 4'?dideoxykanamycin B (DKB), being known as aminoglycoside antibiotics;
(1) The antimicrobial spectrum and activity of amikacin were similar to those of 3', 4'-dideoxykanamycin B (DKB).
(2) The sensitivity distribution of clinical isolates of Staphylococcus aureus was different from kanamycin.
None of amikacin-resistant strains was observed and there was no correlation with kanamycin-resistant strains.
(3) The influences of pH of medium, human serum and inoculum size on the in vitro antimicrobial activity of amikacin showed the same pattern as those in kanamycin.
(4) From the growth curve of Staphylococcus aureus with biophotometer, amikacin at the minimal inhibitory concentration was found to have a growth-inhibiting effect against Staphylococcus aureus.
(5) The in vitro combination between amikacin and synthetic penicillin type antibiotics for Pseudomonas was found to be effective.
(6) Amikacin was effective in experimental infections in vivo with kanamycin-resistant Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa as well as in vitro.

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The results of some studies on amikacin were summarized as follows;
1. The minimum inhibitory concentration (MIC) of 23strains of Pseudomonas aeruginosa which were clinically isolated distributed in the range from 0.73 μg/ml to 25 μg/ml and the peak of MIC was 3.13.μ9/ml.
2. Tissue concentration of amikacin in rats after intramuscular injection (20 mg/kg) was measured by means of cup plate method using Bacillus subtilis PCI-219 as test organism and the value was the highest in serum, lowering in order in kidney, lung and liver, among which the latter's concentration was especially poor. The peak was obtained after 30 minutes of the administration.
3. The blood concentration following an intramuscular injection of 100 mg of amikacin was determined in 4 normal adults. The blood concentration reached the peak after 1/2-1 hour, exhibiting a considerable individual difference. The peak of serum levels of amikacin given intramuscularly at adose of 200 mg in a cross over experiment was 14.7 μg/ml after 30 minutes and was about twice of that of given 100 mg of amikacin.
4. As to amikacin sputum concentration after its intramuscular injection, the value was the highest in the sputa which were reserved from injection time to 3 hours after administration and its value was 1.8 μg/ml. The peak concentration in sputum was 26% of the peak concentration in serum. Incomparison with the ratio of penicillin groups which were 1 × 5%, the transition of amikacin in sputum is better than that of penicillin groups.
5. Amikacin was applied at a dose of 100-300 mg daily for 3-44 days to 10 cases of the internal infections. Seven cases of respiratory infections (bronchiectasis 1, chronic bronchiolitis 1, pneumonia 3, bronchopneumonia 1, chronic obstructive lung disease 1) and two cases of suspected hepatic abscess and one case of peritonitis were treated with amikacin and the results obtained were effective in 3 cases, slightly effective in 1 case, ineffective in 2 cases and undecided in 4 cases. Though amikacin was administered intramuscularly to 4 cases over 25 days, no particular side effects were observed. The reason of low percentage of effective case may probably be attributed to the associated severe underlying diseases in most of our cases.

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Antibacterial activities of amikacin (BB-K8) were examined. Minimum inhibitory concentration (MIC) of amikacin against human tubercle bacilli, strain H37Rv, was 0.39 μg/ml. Six patient strains were inhibited by the drug at the concentrations of 0.09 to 0.39 μg/ml, but none out of 9 patient strains, which were highly resistant to kanamycin, was inhibited by amikacin. Though 8 out of 11 patient strains of Staphylococcus aureus were equally susceptible to amikacin and kanamycin, the remaining 3 strains, highly resistant to kanamycin, were inhibited at the concentrations of 6.25 to 12.5 μg/ml of amikacin. No marked difference in antibacterial activities against E. coli and Klebsiella pneumoniae strains was observed between amikacin and kanamycin. Amikacin inhibited all of 19 patient strains of Pseudomonas aeruginosa at 1.56 to 12.5 μg/ml, but MIC of kanamycin against these strains was 100 μg/ml or more.
Clinical evaluation of amikacin was made in 13 patients with respiratory tract infection and 1 with urinary tract infection. In 2 patients, with primary lung abscess and pyelocystitis respectively, an excellent therapeutic response was obtained. A good response was seen in 5 patients. Six patients with secondary respiratory infectious diseases exhibited no significant therapeutic effect. The response of 1 case was unidentified because of simultaneous administration of sulfobenzyl penicillin.
None of 14 patients treated with amikacin showed any signs of auditory disturbance. Results of kidney and liver function tests revealed values in normal range before and after administration of amikacin.

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Experimental and clinical studies were made on amikacin, a new aminoglycoside antibiotic derived from kanamycin A on the basis of the mechanism of kanamycin resistance. The results obtained were as follows.
1. Antibacterial activity
The antibacterial activity of amikacin was determined against 50 clinical isolates each of Staphylococcus aureus, Escherichia coli, Klebsiella and Pseudomonas aeruginosa.
Out of them, 39 isolates of Staphylococcus aureus (78%), 43 isolates each of Escherichia coli and Klebsiella (86% each) and 40 isolates of Pseudomonas aeruginosa (80%) were inhibited by amikacin at a concentration of 6.25 μg/ml or less. By means of the standard 2-fold dilution technique, however, amikacin was approximately 2^-1-2^-4 times as active as gentamicin and dideoxykanamycin B.
2. Absorption, excretion and tissue concentration
The peak serum concentration of amikacin in healthy adults occurred after one hour of intramuscular injection in either case of 50 mg/kg dose and 100 mg/kg dose, the values being 2.75-3.50μg/ml and 5.05μg/ml, respectively. The serum concentrations then decreased, showing the serum half-life of 1.4-1.7 hours. The urinary recovery of amikacin within 6 hours of intramuscular injection ranged from 50-60 %.
The peak serum concentrations of amikacin in patients with renal insufficiency were higher than those of healthy adults, and marked prolongation of their serum concentration was observed.
The highest tissue concentration of amikacin by a single intramuscular injection to rats at a dose of 10 mg/kg was found in the kidney, following by the serum and lungs. Little distribution to the liver was observed.
3. Clinical results
Four cases with urinary tract infection and one case with pyothorax, totalling 5 cases, were treated with amikacin. Response was excellent or good in 3 cases with urinary tract infection, but its application was stopped due to exanthema in the case with pyothorax. No other side-effects were observed.

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On a new aminoglycoside antibiotic, amikacin, which has been developed in Japan, the basic and clinical studies were performed, and the following results were obtained.
1. The susceptibilities of a majority of clinical isolates against amikacin were inferior to DKB and gentamicin in a degree of two-fold dilution in general.
2. The peak organ level of amikacin following intramuscular injection to mice ranked in order of kidneys and lungs. The liver level was not detectedat any time of measurements.
3. The comparison of two lots of amikacin, the one is in powder form and dissolved in lidocain hydrochloride just prior to injection and the other is the solution prepared already, was performed in cross over test. In the results of blood levels and urinary recovery, there were no significant differences bet-ween both preparations.
4. Amikacin was administered intramuscularly to one case with pyelonephritis due to Pseudomonas aeruginosa, and the result was described.

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Amikacin was applied clinically to 10 cases of various infections in the field of internal medicine.
The results obtained were effective in 5 (including markedly effective cases), moderately effective in 3 and ineffective in 2.
No side effects were observed in any of all the cases.
In comparison between the antibacterial activities of amikacin and KM against the clinical isolates of Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus, amikacin was more active than KM but slightly less active than GM and DKB.

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1) Amikacin (BB-K8) was administered to 21 patients of various infections, and showed the excellent or good response in 14 cases.
2) In the patients with normal renal function, amikacin should be used above 400 mg daily to obtain a good clinical response.
3) No remarkable side effect was observed in kidney, liver, and bone marrow functions, but in auditory function, 3 patients seemed to be slightly damaged among the 5 investigated patients. Two of them were old, and 1 was uremic.

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The experimental and clinical studies on amikacin, a new derivative of kanamycin, were made. The results obtained were as follows.
1) The antibacterial activity of amikacin against the clinical isolates of Staphylococcus aureus, E. coli, Klebsiella, Proteus and Pseudomonas aeruginosa was compared with those of DKB and GM. Thirty-two out of 36 strains of Staphylococcus aureus were inhibited by 1.56 to 25 μg/ml, with a peak distribution at 3.12 μg/ml.
This antibacterial activity was considerably inferior to that of DKB and GM each. Forty out of 42 strains of E. coli were inhibited by 1.56 to 12.5 μg/ml. This antibacterial activity was slightly inferior to that of DKB and considerably inferior to that ofGM. Eighteen strains of Klebsiella were inhibited by 1.56 to 12.5 μg/ml. In this case, the antibacterial activities of amikacin and DKB were almost the same, while GM was more active than amikacin.
Nine out of 10 strains of Proteus were inhibited by 3.12 to 12.5 μg/ml. In this case, the antibacterial activities of amikacin, DKB and GM were almost the same. Twelve strains of Pseudomonas aeruginosa were inhibited by 3.12 to 50 μg/ml. In this case, the antibacterial activities of amikacin and DKB were almost the same, while amikacin was considerably less active than GM.
2) The peak serum concentration of amikacin administered intramuscularly to healthy adults was observed after one hour of dosing. The mean concentration level of two volunteers administered amikacin at a dose of 200 mg was 9.9 μg/ml and that of three volunteers administered amikacin at a dose of 100 mg was 5.6 μg/ml. Then, these concentration levels decreased gradually. The former reached to 1.9 μg/ml 6 hours after dosing and the latter to 1.2 μg/ml. The urinary recovery of amikacin within 6 hours of dosing was 60% or so.
3) Amikacin at a daily dose of 200-400 mg was administered to 9 patients, 7 with respiratory tract infections, 1 with urinary tract infections and 1 with intestinal tract infections. The effects and side-effects of amikacin were as follows. Bacteriologically, response was effective in 3, ineffective in 5 and unknown in 1. Clinically, response was effective in 4, and slightly effective in 3. No side-effects were observed.

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Amikacin is a new antibiotic which belongs to aminoglycosides. Present study clarified the followings.
1) Antimicrobiological activity : Minimum inhibitory concentrations (MIC) of amikacin were investigated comparing with MICs of gentamicin. Sixhundred and twenty one strains isolated from the clinical materials (91 pyogenic Staphylococci, 51β-Streptococci, 57 Enterococci, 14 Shigella, 102 E. coli, 111 Klebsiella aerogenes, 12 Enterobacter aerogenes, 30 Enterobacter cloacae, 22 Proteus vulgaris, 29 Proteus mirabilis, 27 Morganella, 58 Pseudomonas aeruginosa) and 17 standard strains stocked in our laboratory were used in this test.
Antimicrobiological activity of amikacin was inferior to GM and the MIC of amikacin was 2 to 4 fold higher than that of GM. Antimicrobiological activity of aminoglycosides to Pseudomonas aeruginosa was assessed as the following order; TOB-DKB-GM-Amikacin-LVM.
2) Absorption and excretion : In 4 healthy adult volunteers who were intramuscularly given 100 mg of amikacin, the peak level in blood was 7.2 to 9.8 μg/ml at half to one hour after injection. When 200 mg were given, it became 11.5 to 12.5 μg/ml. The concentration at 6 hours after injection was 1.1 μg/ml and 3.25 μg/ml respectively on average. Urinary recovery rate for 6 hours was 67.8% on average.
3) Distribution in the organs : The highest concentration was seen in the kidney. The order of concentration in the organs was clarified as kidney-serum-lung-liver in the experimental animal (rats).
4) Concentration in the sputum; To a case expectorated the purulent sputa of 50-80 ml every day, 200 mg of amikacin was given intramuscularly, b.i.d. The maximum concentration in sputum to blood was 0.2.
5) Clinical evaluation : Two hundreds mg of amikacin were given intramuscularly, b.i.d., to 12 pa-tients with respiratory infectious diseases (bacterial pneumonia, lung abscess and bronchiectasis with infection, 6, 5, 1 case respectively) for 6 to 13 days. It was beneficial in 50% of the cases. Advanced reaction was not seen in the viewpoints of signs and symptoms, blood-chemistry and urine-analysis.

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Amikacin was used to 10 cases of respiratory diseases : 4 pulmonary abscess, 2 bronchiectasis, 2 bronchopneumonia, and 2 bronchitis. Clinical effects of amikacin were as follows : Two of four pulmonary abscess were effective, one slightly effective and one unchanged. Two bronchiectasis were effective. One of two bronchopneumonia was effective and one slightly effective. One of bronchitis was markedly effective and one effective. As the results, clinical effective rate was 90 percent. Side effects of amikacin were not experienced.

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With amikacin solution (100 mg/ml), a series of experimental and clinical studies were made in our clinic. The results obtained were as follows.
(1) The intramuscular administration of amikacin solution at a dose of 4.0 mg/kg yielded a peak serum concentration of 9.18 μg/ml at 1 hour, 3.11 μg/ml at 3 hours and 0.45 μg/ml at 6 hours, respectively. In comparison between this solution and an aqueous solution prepared from amikacin powder for injection by cross over method, both serum concentrations resembled eath other. The urinary excretion rate of the former within 6 hours was 59.2% of the given dose. This was similar to that of the latter, being 48.9%.
(2) Thirty hospitalized children with acute infections as mentioned below were treated mainly with amikacin. The overall clinical effectiveness was shown to be about 90%. The relation between diseases and daily doses in the clinical course was as follows.
Acute tonsillitis and acute lacunar tonsillitis ……4.0-5.0 mg/kg/day
Acute bronchitis ……5.0 mg/kg/day
Acute bronchopneumonia ……7.0-10.0 mg/kg/day
Acute colicystitis ……4.0 mg/kg/day
Whooping cough ……6.0-8.0 mg/kg/day
(3) In these children with bronchopneumonia, hemolytic infections or whooping cough, the liver and renal function tests (S-GOT, S-GPT and BUN) were made before intramuscular administration and 10 days after the onset of consecutive intramuscular administration. No abnormal elevations were observed in any of the function tests.
(4) The consecutive intramuscular administration of amikacin solution was done throughout 10 days. No local changes caused by the intramuscular administration, particularly such as induration, were observed in any of the cases.

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The authors carried out the laboratory and clinical studies of amikacin.
The results were as follows :
The sensitivity was determined by the plate dilution method with 31 strains of Staph. aureus, 31 strains of P. aeruginosa, 26 strains of Proteus and 20 strains of E. coli isolated from patients. The growth of 93.5% of Staphylococci was inhibited at a concentraiton of less than 0.78μg/ml. The growth of 58% of P. aeruginosa was inhibited at concentration of less than 1.56μg/ml.
The growth of 92.3% of Proteus and 85% of E. coli was inhibited at a concentration of less than 6.25 μg/ml.
Amikacin was given a single intramuscular dose of 2 mg per kg. b. w. to 3 children.
The maximum blood level was reached at 30 minutes respectively after injection.
And the blood level at 6 hours after injection was 0.9 μg/ml.
The excretion rate of amikacin in the urine after a single intramuscular dosing was 42.2-61.6% up to 6 hours of period.
Amikacin was effective in 7 of 9 cases of bacterial infections.
No significant side effects were seen at all.

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Laboratory and clinical investigations were performed with amikacin and the following conclusions were obtained.
The sensitivity distribution was examined among 54 strains of Staphylococcus aureus isolated from surgical lesions. The peak of sensitivity of amikacin was observed at 12.5 μg/ml in 24 strains, followed by 6.25μg/ml in 13 strains. The sensitivity distribution among 54 strains of E. coli, the peak of sensitivity was observed at 12.5 μg/ml in 20 strains, followed by 6.25 μg/ml in 10 strains. About 49 strains of Pseudomonas aeruginosa, the peak was observed at 6.25 μg/ml in 19 strains. Thirty-nine strains among 49 of Pseudomonas aeruginosa were inhibited the growth by 3.13-12.5 μg/ml of amikacin.
By means of cup method using Moni-trol as standard, serum level was measured after intramuscular injections of 100 mg, a peak level of 6.7 μg/ml was attained at 30 minutes after injection. The peak concentration of 347, μg/ml in the urine obtained at 1 hour after injection. The urinary recovery rate within 6 hours after injection was 56.9% on the average.
In a group of 3 rats of SD strain, the tissue concentration was high in kidney and lung, followed by muscle, heart and spleen in order. In the liver it was not detectable biologically. Amikacin was used in the treatment of 20 cases of surgical infections. Results obtained were effective in 13 cases and ineffective in 7 cases. No noteworthy side effect was encountered except one case of local pain.

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Amikacin is a new semisynthetic aminoglycoside antibiotic.
The minimal inhibitory concentrations (MIC) of amikacin, gentamicin, DKB, and kanamycin were determined in 30 Pseudomonas aeruginosa strains clinically isolated. The susceptibility to amikacin was as almost same as that of gentamicin but was significantly better than its parent compound, kanamycin. The antibacterial potency of DKB was slightly higher than that of amikacin and gentamicin.
Intramuscular administration of 50 mg amikacin produces a serum concentration of 3.9 μg/ml after 30 minutes, and its half life was 1 hour 15 minutes.
Patients with complicated urinary tract infections were treated with this drug (daily doses 100-400 mg). The clinical responses were excellent in 3 cases, good in 5 cases, and fair in 1 case. We can evaluate this amikacin as one of effective therapeutic drugs for complicated urinary tract infection. In our clinical experiences, any significant change of laboratory findings could not be revealed except increasing eosinophils in 1 case.

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1) Amikacin (BB-K8) was administered intramuscularly to 104 cases of urinary tract infections consisting of outpatients and inpatients from the Department of Urology of the University of Kyushu and their related hospitals.
Dropout was seen in two, so that 102 cases were subjected to the treatment.
2) Out of 36 cases of acute simple urinary tract infections (cystitis in 23, and pyelonephritis in 13), in 25 amikacin was administered intramuscularly at a dose of 200 mg once a day for 5 days, in 4 at a dose of 200 mg once a day for 3 days, in 4 at a dose of 100 mg twice a day for 5 days and in 3 at a dose of 400 mg once a day for 5 days.
Out of 63 cases of complicated urinary tract infections (complicated cystitis in 33, postoperative cystitis in 16, complicated pyelonephritis in 14 and postoperative pyelonephritis in 3), in 51 amikacin was administered intramuscularly at a dose of 100 mg twice a day for 5 days and in 12 at a dose of 200 mg twice a day for 5 days.
Out of 3 cases of prostatitis, in 2 amikacin was administered intramuscularly at a dose of 100 mg twice a day for 5 days and in 1 at a dose of 200 mg twice a day for 5 days.
3) The global clinical results were seen to be excellent in 46, good in 21 and poor in 35, its effectiveness rate being 66%.
4) In 36 cases of acute simple urinary tract infections, the results were seen to be excellent in 24, good in 6 and poor in 6, its effectiveness rate being 83%. In 63 cases of complicated urinary tract infections, the results were seen to be excellent in 21, good in 14 and poor in 28, its effectiveness rate being 56%. In 3 cases of prostatitis, the results were seen to be excellent in 1, good in 1 and poor in 1, respectively.
5) It was impossible to compare between the clinical results on the basis of doses because the number of cases in the 400 mg/day dosing group was small, being 16 cases, but in complicated urinary tract infections the clinical results of amikacin at a dose of 400 mg were not so good.
6) Pain at the injected area was seen in 2. In 56 cases recorded their hematological findings (hemoglobin, RBC, WBC, BUN, creatinine, GOT and GPT) transiently, no abnormal changes due to the administration of the drug were observed. No other significant side-effects were observed.
7) Amikacin (BB-K8) proved to be useful for not only acute simple urinary tract infections but also complicated urinary tract infections. Concerning the dose and duration of amikacin, however, the need of further careful examinations is keen felt.

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1) The intramuscular administration of amikacin to mature rabbits at a dose of 40 mg/kg resulted in a peak serum concentration of 38.0 μg/ml at 30 minutes after dosing and in a peak aqueous humor concentration of 4.2 μg/ml at 1 hour after dosing.
2) The subconjunctival administration of amikacin to mature rabbits at a dose of 10 mg (0.2 ml) resulted in a peak aqueous humor concentration of 5.7 μg/ml at 1 hour after dosing, but relatively high concentrations were kept for hours in the posterior chamber where an aqueous humor concentration of 11.0 μg/ml was observed 4 hours after dosing.
3) In healthy adults, the intramuscular administration of amikacin at a dose of 100 mg resulted in a peak serum concentration of 11.0 μg/ml at 30 minutes after dosing.
4) Amikacin was administered intramuscularly to preoperative patients with cataract at a dose of 100 mg, in order to determine their aqueous humor concentrations. Most of them were less than 0.3μg/ml, but an aqueous humor concentration of 6.0 μg/ml was observed in a patient with past historyof iritus.
5) Clinically, amikacin was administered to 13 patients consisting of external hordeolum, acute dacriocystitis and endophthalmitis. Clinical response was excellent in 2, good in 10 and unknown in 2, its effectiveness rate being 92%.
No particular side-effects were observed.

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The fundamental and clinical investigations with a new aminoglycoside derivative, amikacin were performed with the results which may lead to the following conclusion.
1) In vitro antibacterial activity : The minimal inhibitory concentration of amikacin was measured. by an agar plate dilution method. The MIC of amikacin against 80 strains of coagulase positive Staphylococcus isolatedfrom otorrhoea was distributed over a range of 0.39 to 50 μg/ml, with a peak being observed particularly at 3.13 μg/ml. Further, the MIC against 60 strains of Pseudomonas aeruginosa was at 0.78 to 25 μg/ml of amikacin, showing its peak at 3.13 μg/ml. Clinical isolated Proteus mirabilis, Klebsiella pneumoniae and Escherichia coli strains were also examined on their sensitivity to amikacin as well as other antibiotics.
2) Concentration in blood : The blood level of amikacin in healthy adults who were given 100 mg intramuscular injection reached maximum of 9.3 μg/ml 30 minutes after administration. Even at 6 hours after intramuscular injection, clinically effective serum amikacin concentration 0.9 μg/ml was still demonstrable.
3) Concentration in tissues : Amikacin activity was demonstrable at the concentration of 3 to 6.2 μg/g at human palatine tonsilla and mucous membrane of maxillary specimen one hour after the intramuscular injection of 200 mg. Further, the serum concentration of amikacin was then 16.5 to 19μg/ml.
4) Results of clinical treatment : When amikacin was injected intramuscularly in 35 cases of representative infection in the otorhinolaryngologic field, it was excellent in 13 cases, good in 16 cases, fairin 4 cases and poor in 2 cases. When the cases in which it was excellent and good were considered together, good results were obtained in 20 cases, that is an effectiveness ratio of 83 per cent.
5) Side effect : No side effect was shown with the intramuscular injection of amikacin. The comparative examination of hepatic function, electrocyte and auditory acuity before and after injection showed no significant disturbance.

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Antibacterial activities of amikacin, gentamicin, dideoxykanamycin B and kanamycin against clinically isolated gram-negative bacteria, 168 strains of Escherichia coli, 27 strains of Klebsiella pneumoniae, 22 strains of Citrobacter, 25 strains of Enterobacter, 20 strains of Proteus and 84 strains of Pseudomonas aeruginosa were examined by the twofold agar-dilution method and compared. The experiments revealed the poor sus ceptibility of the bacteria to kanamycin, moderate to dideoxykanamycin B and gentamicin, and excellent to amikacin. For example, all of the kanamycin-resistant strains of Klebsiella and Citrobacter were susceptible to amikacin, and 82.3% of Pseudomonas aeruginosa which were completely resistant to kanamycin were susceptible to amikacin. A number of susceptible profiles were obtained when the kanamycin resistant strains of the examined bacteria were tested against gentamicin, dideoxykanamycin B, tobramycin, amikacin, lividomycin and neomycin. From the profiles, distribution of the possible resistance mechanisms to the aminoglycosides among the gram-negative bacteria were proposed.

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