HAPA-B is a new aminoglycoside antibiotic synthesized from gentamicin B. The antibacterial activities of HAPA-B were compared with those of amikacin (AMK) and gentamicin (GM). The results are summarized as follows.
1) HAPA-B showed a broad spectrum of antibacterial activity against gram-positive and gram-negative bacteria.
2) The MIC levels of HAPA-B against S. aureus, S. epidermidis and S. pyogenes were almost the same as those of AMK.
3) The MIC levels of HAPA-B against Enterobacteriaceae were almost the same as those of GM.
4) HAPA-B had greater activity against GM-resistant S. aureus, E. coli, S. marcescens and P. aeruginosa than AMK.
5) Bactericidal activity of HAPA-B against S. aureus, E. coil and S. marcescens was confirmed by determining the minimum bactericidal concentration.
6) The combination of HAPA-B with β-lactams acted synergistically against A.calcoaceticus and P. aeruginosa.
7) HAPA-B was very stable against aminoglycoside inactivating enzymes except for aminoglycoside 6'-acetyltransferase-4.

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MIC₉₀ of HAPA-B to 44 clinical isolates of M. tuberculosis was 1.6μg/ml. The antibiotic manifested also the MIC from 0.2 to 50μg/ml against various typical mycobacteria including M. avium-intracellulare complex. HAPA-B inhibited the intracellular growth of M. tuberculosis in human macrophages with 2-fold concentration of in vitro MIC.
Synergy of bactericidal effect between HAPA-B and the serum complement against E. coli, S. aureus and P. aeruginosa was moderate, and inferior than that of gentamicin (GM). The antibiotic, however, showed good synergy of phagocytosis and bactericidal activity with mouse cultured macrophages against E. coli, P. aeruginosa and S. aureus, suggesting that HAPA-B might possess a good in vivo effect on various bacterial infections.
HAPA-B may be a useful antibiotic for infections in compromized hosts where sometimes super-infections by mycobacteria will occur.

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The in vitro and in vivo antibacterial activities of HAPA-B, a new aminoglycoside, were investigated in comparison with those of amikacin, gentamicin, dibekacin and tobramycin. The follwing results were obtained.
HAPA-B showed a broad antibacterial spectrum against both gram-positive and gram-negative bacteria. Among them, S. marcescens, C. freundii and E. cloacae were extremely susceptible.
HAPA-B was active against most of aminoglycoside-resistant bacterial strains. It acted bactericidally and the activity war stronger than that of amikacin.
On the protective effects in experimental infections with various bacteria, HAPA-B showed excellent therapeutic effects as obtained in in vitro. Furthermore, HAPA-B was effective in experimental infections caused by various aminoglycoside-resistant bacteria including amikacinresistant strains.
The peak value of the serum level of HAPA-B in mice gave almost same features as that of amikacin.

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Renal toxicity in male rats of HAPA-B, a new aminoglycoside antibiotic, was examined in comparison with Amikacin (AMK) and Gentamicin (GM). These drugs were given intramuscularly daily for 7, 14, 21 days to the rat at 50, 150 and 300 mg/kg of HAPA-B and AMK or 25, 50 and 100mg/kg of GM. A recovery test was performed for 28 days after the last injectioin following 21 days treatment. There were no deaths in rats which received HAPA-B but the high dose group with AMK and GM showed a high incidence of mortality. Water consumption increased in rats which received 300mg/kg of HAPA-B, 150mg/kg and 300mg/kg of AMK and 50mg/kg of GM. Urine volume increased in rats which received 150 mg/kg and 300 mg/kg of HAPA-B but it was less than those with AMK. Osmolality showed a dose-related decrease, in contrast to urine volume with all drugs. Urine NAG activity indicated a significant increase after the first day of treatment at the lowest dose group with all drugs. The peak of NAG activity was observed early during treatment and sharply in a dose-dependent manner. It's peak of 300 mg/kg of HAPA-B was similar to 150mg/kg of AMK.
Urine LDH activity also showed similar changes with NAG during treatment but sensitivity was less than NAG. Urine ALP and LAP activity also showed a dose-ralated increase, but unlike NAG and LDH, enzyme activities of treatment groups turned less than those of the control group during treatment. Serum urea-nitrogen and creatinine levels increased markedly at day 14 than day 21 of treatment with 300mg/kg of HAPA-B and AMK.
With the dependence on the duration and the dose of treatment with all drugs, discoloration, swelling and increase of organ weight in kidney were noted. Moreover, in histopathological findings, dilatation, eosinophilic granular degeneration and necrosis of the epithelial cells of the proximal convoluted tubuli were observed. These changes were dose-related and dependent on the duration of treatment with all drugs. Changes with HAPA-B were slight and were the least of all drugs tested. Electron microscopic findings indicated an increase in the number of large lysosomes containing myeloid bodies in the epithelial cells of the proximal convoluted tubuli with all drugs. Itwas concluded from these results that the order of severity of nephrotoxicity was GM<AMK<HAPA-B.

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The present experimental study was performed in 70 guinea pigs (male 35, female 35) to evaluate the ototoxicity of a new aminoglycoside antibiotic, HAPA-B, and to compare it with that of Amikacin (AMK). HAPA-B was given at dose of 25, 50, 100 and 200mg/kg respectively and AMK at dose of 100 and 200mg/kg respectively for 4 weeks intramuscularly.
The following results were obtained; 1) HAPA-B was least or less ototoxic at dose of 25, 50 and 100mg/kg, but became more ototoxic at dose of 200mg/kg. 2) The toxic effect of HAPA-B on the cochlear hair cells was milder than that of AMK at dose of 100 and 200mg/kg, whereas the effect of HAPA-B on the vestibular hair cells was slightly milder at dose of 100mg/kg but a little more intensive at dose of 200 mg/kg than that of AMK.

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Clinical studies of HAPA-B, a new aminoglycoside, in the field of respiratory tract infection were carried out and the following results were obtained.
1) HAPA-B was administered to nine patients with bacterial pneumonia and one patient of respiratory tract infection associated with old tuberculosis. The efficacy was excellent in four Patients, good in four Patients, fair and poor in one each patient, respectively. The efficacy rate was 80%.
2) As a side effect, anorexia was observed in one case. Transient increase in number of eosinophil and proteinuria were noted in one case.
3) HAPA-B was considered as a useful drug in treatment of respiratory tract infection.

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Strains resistant to many antibiotics have appeared despite recent development of new effective antibiotics.
A new aminoglycoside HAPA-B, the 1-N-S-3-amino-2-hydroxypropionyl derivative of gentamicin B, was chosen for clinical evaluation among a large number of derivatives which had been prepared on the basis of the results of studies on aminoglycoside resistance mechanism.
The clinical efficacy and tolerability of HAPA-B were evaluated by intramuscular injection in 17 patients of respiratory tract infection (12 patients with acute pneumonia, 3 with chronic bronchitis,
2 with infections.associated with bronchiectasis and lung cancer, respectively).
1. Clinical effects of HAPA-B in a total of 12 patients with acute pneumonia were excellent in 2, good in 8, poor in 2 patients and the efficacy rate was 83.3%.
2. Clinical effects of HAPA-B in all 17 patients with respiratory tract infections were excellent in 2, good in 12, fair in 1 and poor in 2 patients and the efficacy rate was 82.4%.
3. Seven strains out of 10 isolated pathogens were GNR and were eradicated except for one of the 2 strains of H. influenzae. In a mixed infection with K. oxytoca and E. cloacae, both pathogens were eradicated and the clinical effect was good.
4. No side effect and abnormal laboratory findings were observed except for a slight elevation of S-GOT and S-GPT in one patient.

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The antibacterial activity of HAPA-B, a new aminoglycoside, was tested against each 27 clinical isolates of 7 species, using plate dilution method with inoculum size of 106 cells/ml. The MIC values of HAPA-B were obtained at 0.2-6.25μg/ml for S. aureus, 0.2-0.78 for E. coli, 0.2-6.25 for K. pneumoniae, 0.78-50 for P. mirabilis, 3.13-50 for M. morganii, 1.56-100 for S. marcescens and 1.56-100 for P. aeruginosa. No strains whose MICs of HAPA-B were higher than 100μg/ml were observed.
The pharmacokinetic study of HAPA-B was conducted in 5 healthy male volunteers after single intramuscular 200mg and 300mg administration. Cmaxs were 10.62μg at 200mg dose and 16.69μg/ml at 300mg dose, respectively and AUCs were 39.05 and 62.58μg·hr/ml, respectively. It was found to be dose response between two injected doses. Tmax was around one hour and T_1/2 was 1.7 hour. The urinary recovery rates were 72.0% of 200mg dose and 79.4% of 300mg dose during 8 hours, respectively. The tolerance following administration of HAPA-B was good.
Sixteen cases with bacterial infections were treated with HAPA-B of 200mg b. i. d. for 3-8 days. Ten cases were excellent response and six were good. Bacteriological responses were also favorable that all pathogens were eradicated.
No side effects, no laboratory abnormalities including no abnormal audiogram were observed.

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HAPA-B was studied about its clinical efficacy, side effects and laboratory values with 19 cases of respiratory tract infection; 15 cases with bacterial pneumonia, 2 cases with mycoplasma pneumonia, 1 case with bronchiectasis and 1 case with lung infection in lung cancer. All patients received intramuscularly HAPA-B. As the pathogen, K. pneumoniae was identified in 5 cases of pneumonia and P. aeruginosa was identified in 1 case of bronchiectasis. These pathogens were eradicated in all cases following the administration of HAPA-B.
The cases studied showed the following clinical efficacy: 15 cases of pneumonia; 3 excellent, 10 good, 1 fair and 1 poor. 2 cases of mycoplasma pneumonia; 2 good. 1 bronchiectasis; 1 good. 1 lung cancer with infection; 1 poor. The whole efficacy rate was 84.2%.
As to side effects, skin eruption appeared 5 days after the administration in one case.
The abnomal laboratory finding recognized a slight elevation of serum creatinine, and serum GOT and GPT in each one case.

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HAPA-B, a new aminoglycoside antibiotic, was administered to 6 cases of respiratory infections, including 5 cases of pneumonia and one case of mixed infection complicated with mycoplasma pneumonia, at a daily dose of 400mg intramuscularly for 5 to 15 days.
Clinical efficacy was good in 4 cases, poor in one case and unknown in one case.
No side effect was observed.

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The clinical efficacy of HAPA-B, a new aminoglycoside antibiotic, was investigated in 7 patients suffered from respiratory tract infections. HAPA-B was given in a daily dose of 200mg and/or 400mg in 2 divided doses for parenteral administration (intramuscular injections). HAPA-B was given for 3 to 15 days and the total doses given to each patient ranged from 600mg to 6, 000mg. Among the 7 patients treated with HAPA-B, the clinical response was excellent in 1, good in 4 and poor in 2 patients respectively. Neither adverse reaction nor abnormal findings of laboratory examinations associated with HAPA-B were observed during and after the treatment.
It was suggested from these studies that HAPA-B is a useful antibiotic against bacterial respiratory tract infections especially to the bacterial pneumonia.

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Clinical and bacteriological studies were carried on HAPA-B and the following results were obtained;
1. Antipseudomonas effect was most excellent in HAPA-B, following by AMK, GM and SISO by the standard broth method. Ninety percent inhibition-concentration of HAPA-B was 3.13μg/ml against 80 strains of P. aeruginosa.
2. Maximum serum level of HAPA-B (9.17μg/ml) and maximum sputum level (1.85μg/g) were obtained by the intramuscular administration of HAPA-B 200 mg for a patient with chronic bronchobronchiolitis.
3. The clinical effects for four cases of chronic bronchobronchiolitis showed excellent in one case with A. calcoaceticus, poor in two cases with P. aeruginosa and one case with P. maltophilia.

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In vitro antimicrobial activity of HAPA-B, a new derivative of aminoglycoside, was examined by a broth dilution method with Dynatech MIC 2000 system. The minimum inhibitory concentrations of HAPA-B were compared with those of gentamicin (GM) and amikacin (AMK) dgainst the following 120 strains (each 20 strains) of clinical isolates of S. aureus, E. coli, K. pneumoniae, S. marcescens, Enterobacter spieces and P. aeruginosa. Against S. aureus, E. coli, K. pneumoniae and S. marcescens, HAPA-B was shown to be less active than GM, but more active than AMK. HAPA-B was as active as AMK, although less active than GM, against Enterobacter spieces and P. aeruginosa.

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I. Susceptibility of multi-drug resistant Serratia marcescens to HAPA-B.
Resistant strains of Serratia marcescens tested were all clinical isolates at Iwaki Kyoritsu General Hospital.
The activity of HAPA-B was distinctly superior to those of other aminoglycosides such as GM, TOB, DKB and AMK. The MIC of it distributed between 3.13 and 6.25μg/ml.
The strain of Serratia marcescens sensitive to HAPA-B and GM and insensitive to AMK, TOB, DKB, produced the aminoglycoside acetyl transferase which inactivates the aminoglycosides.
II. Clinical results
Clinical evaluation of HAPA-B was performed in three patients with RTI. They were consisted of one male and two females.
HAPA-B was given intramusculary in daily dose of 400mg in two divided portions.
The duration of administration were 14 days.
A total of three strains comprising P. aeruginosa two strains and S. pneumoniae one strain were identified from the sputum before administration.
One strain of Pseudomonas was decreased from 5×10⁶ cfu/ml to 5×10³ cfu/ml and the other Pseudomonas was decreased from 7×10⁷ cfu/ml to 6×10² cfu/ml but S. pneumoniae was not changed.
The clinical efficiency rate was 100%(3/3): Good in three cases.
There were no side effects and abnormal findings in laboratory test values in any of the patients.
From the above results, it is concluded that HAPA-B is effective, safety and useful aminoglycoside.

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HAPA-B, a new aminoglycoside antimicrobial agent (AGs) was evaluated on its efficacy and safety in this study.
MICs of HAPA-B for the strains resistant to GM or DKB (MIC>12.5μg/ml), and the concentrations in serum and sputum after the intramuscular administration were studied.
HAPA-B was administered intramuscularly to 29 cases with RTI & UTI at a daily dose of 200mg×2 for 5 to 29 days.
The resistant strains tested were more susceptible to HAPA-B than to AMK, NTL and ASTM. The peak serum concentrations were 10.6-15.6μg/ml 1 hour after the administration and the sputum peaks concentration were 1.6-4.4μg/ml. Efficacy rate was 50% on RTI, 87.5% on UTI and 61.5% on total cases. No side effect and abnormal laboratory findings were observed and the audiogram before and after the administration in 10 cases reveals no change.
Above results suggest that HAPA-B is active against resistant atrains to GM or DKB and a useful antimicrobial agent in the field of internal infections.

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Bacteriological and clinical studies on HAPA-B, a new aminoglycoside, were performed and following results were obtained.
MICs of HAPA-B against P. aeruginosa were almost the same as those of AMK and superior to those of ASTM by 4-to 8-fold. Antibacterial activity of HAPA-B against GM-or NTL-sensitive P. aeruginosa was inferior to those of the two drugs by 2-to 4-fold, however, against GM-or NTLresistant strains, MICs of HAPA-B were between 1.56-6.25μg/ml. Against S. marcescens HAPA-B was similar to GM and superior to AMK and NTL by 2-to 4-fold and 8-to 16-fold respectively. Against AMK-or NTL-resistant strains whose MICs were higher than 100mg/ml, MICs of HAPAB were less than 25mg/ml.
100mg and 200mg of HAPA-B were intramuscularly administered to healthy adult male volunteers. The mean peak serum levels showed 7μg/ml and 12μg/ml respectively at 1 hour after administration. In both cases serum half life was 1.6-1.7hour and about 88% of HAPA-B was recovered in urine within 8 hours.
HAPA-B was administered to 5 patients, one with diffuse panbronchiolitis and 4 with urinary tract infections. The clinical result was excellent in 1, good in 3 and poor in 1.
No side effects and no abnormal laboratory findings were observed.

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HAPA-B, a new aminoglycoside antibiotic, was administered to six patients, comprizing one case with obstructive pneumonia, two with urinary tract infection with catheter and three with sepsis. In all cases HAPA-B was intramuscularly injected twice a day at a daily dose of 400mg for 5-15 days.
In a case of obstructive pneumonia clinical effect was good, considering disappearance of fever and improvement of blood picture, though chest X-P was aggravated due to aggressive underlying disease. In two cases of urinary tract infection with catheter there was no clinical response nor bacterial response. In three cases of sepsis clinical effect was fair in two, including the case combined with PIPC, and poor in one.
Neither side effect nor abnormal clinical laboratory finding was observed.

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Clinical investigations were carried out on HAPA-B, a new aminoglycoside antibiotic, in the treatments of three patients (one with respiratory tract infection, two with urinary tract infection). HAPA-B was intramuscularly injected twice a day at a daily dose of 400mg.
There was no response in a case of respiratory tract infection. In two cases of urinary tract infection clinical results were excellent.
No side effect was observed.

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HAPA-B, a newly developed aminoglycoside antibiotic, was given in 11 aged (59 y.o.-93 y.o.) patients with various infections. HAPA-B was administered intramuscularly at the dosage of 200mg-400mg for 5-14 days. Clinical response was evaluable in 10 patients (one with bronchiectasis, six with pyelitis, two with chronic cystitis and one with prostatitis).
Seven patients responded satisfactorily.
Proteinuria was appeared in one case during the treatment.

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Clinical studies on HAPA-B were performed and following results were obtained.
Serum levels of HAPA-B were studied in 2 cases. Elevation of serum levels and prolongation of serum half-life of HAPA-B correlated with the degree of renal disfunction.
HAPA-B was intramuscularly administered 400mg per day, and was clinically evaluated in 2 cases of acute bronchitis, one case of chronic bronchitis, one case of bronchiectasis, 5 cases of pneumonia and one case of urinary tract infection.
The clinical responses were good in 6, fair in 3 and poor in one (pneumonia). The effective ratio was 60% in total. Transient elevation of GOT, GPT, ALP and LDH values in one case was observed, but there was no serious adverse reaction.
From the results, it was considered that HAPA-B would be expected to be useful for the treatment of patient without fundamentally serious chronic respiratory tract infection.

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HAPA-B, a new aminoglycoside antibiotic, was intramuscularly injected (200 mg, twice daily) to three patients (each one case of pyelonephritis, pyelonephritis complicated with bacteremia and pneumonia). HAPA-B was effective in two cases of pyelonephritis and ineffective in a case of pneumonia.
No side effect was observed except transient elevations of S-GOT and S-GPT.

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We studied the clinical efficacy of HAPA-B, a new derivative of gentamicin B, in ten patients with chronic lower respiratory tract infection. HAPA-B was administered intramuscularly or intravenously.
The results obtained were as follows:
1. HAPA-B showed effectiveness in 10% of 10 cases.
2. However P. aeruginosa was isolated from sputum in 9 cases, it decreased in only one case and persisted in remaining 8 cases after the treatment with HAPA-B.
3. As a side effect, diarrhea was found in one case.

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Laboratory and clinical studies were carried out on HAPA-B, a newly developed aminoglycoside antibiotic which is a dervative of Gentamicin B. HAPA-B was injected intramuscularly to 2 patients with diffuse panbronchiolitis accompanied by Pseudomonas aeruginosa infection. The peak serum concentrations were 9.23-11.55μg/ml after administration of 200mg, respectively. The peak sputum levels were 1.00-1.18μg/g.
Of 3 cases with diffuse panbronchiolitis all accompanied by P. aeruginosa infection clinical results were fair in one and not determined in 2 (one was short duration and another one was combined with other antibiotics) and the bacteriological results were unchanged in all cases. No side effects were observed.

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HAPA-B is a new aminoglycoside derivative with broad antibacterial spectrum (Gram positive bacteria, Gram negative bacteria).
HAPA-B was administered intramuscularly to 10 patients (pneumonia 4 cases, acute bronchitis 1 case, tonsillitis 1 case, acute pyelonephritis 4 cases) at daily dose of 400mg and good response were obtained in all cases (100%). HAPA-B was effective in 2 cases with Staphylococcal infection.
Eosinophilia was noted in 1 case. One case demonstrated a transient elevation of serum transaminase levels.

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Laboratory and clinical investigations on HAPA-B, a newly developed aminoglycoside antibiotic, were performed for 7 patients with respiratory tract infection.
1) The subjects were mostly middle-aged and senile patients with chronic respiratory tract infection, consisted of 3 patients of chronic bronchitis, 2 patients of acute exacerbation of bronchiectasia and 2 patients of diffuse panbronchiolitis. Among them, 3 patients had urinary tract infection simultaneously.
2) Among the 7 patients, the clinical response was good in 4, fair in 2 and poor in 1.
The clinical response of urinary tract infection were excellent or good.
3) Neither adverse reaction nor abnormal laboratory findings associated with HAPA-B were observed during the course of treatment.

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HAPA-B, a new aminoglycoside, was evaluated clinically in 9 patients aged 34-70 years with respiratory tract infection (5 cases) and with urinary tract infection (4 cases).A daily dose of HAPA-B was 200mg by intramuscular injection twice a day and duration of HAPA-B therapy was for 14 days.
The results were as follows,
1. Clinical response to HAPA-B therapy of respiratory tract infection was good in 3 cases, fair in one case and poor in one case and that of urinary tract infection was good in 3 cases and poor in one case.
Efficacy rate was 67%.
2. As a side effect, worsening of proteinuria (±→++) was shown in one case.

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An aminoglycoside HAPA-B was used for the treatment of respiratory tract infections: 4 cases of pneumonia, 2 cases of chronic bronchitis and 6 cases of bronchiectasis.
HAPA-B was administered by intramuscular injection at a daily dose of 400 mg twice a day for the periods of 5.5 to 14 days.
The clinical efficacy was good in 6 cases, poor in 5 cases and unevaluable in one case. The efficacy rate was 54.5%. Two strains of H. influenzae, one strain of E. coli and 3 strains of P.aeruginosa were isolated in 6 out of 12 cases as causative bacteria.
Neither side effects nor abnormal laboratory findings attributable to HAPA-B were observed.

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HAPA-B, a new aminoglycoside antibiotic, was by either intramuscular injection or intravenous drip infusion, administrated to 4 patients with respiratory tract infection, 6 with urinary tract infection and one with biliary tract infection.
The patient recieved the drug for 3 to 22 days in dose of 300-400mg/day.
Clinical effects were excellent in 2 cases, good in 6, fair in 2 and undetermined in one, showing 80% of efficacy rate.
Neither side effects nor abnormal laboratory findings possibly related to this drug were observed in any of these cases.

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The authors report on the results of their clinical investigation of HAPA-B, a new semisynthetic aminoglycoside antibiotic, and following results were obtained.
1. HAPA-B exhibited a wide-spectrum growth inhibitory action against gram-positive and gram-negative bacilli, and its antibacterial activity was somewhat stronger than that of NTL, AMK and GM against K. pneumoniae and S. marcescens.
2. HAPA-B was injected intramuscularly in doses of 400 mg per day for respiratory tract infection (RTI) and urinary tract infection (UTI). The responses were good in 9 (64.3%) out of 14 patients with RTI and excellent in 1 and good in 2 out of 3 patients with UTI.
3. As a side effect, transient elevation of eosinophile in 1, BUN in 1, LDH in 2 and GOT, GPT, Al-p in 1 case.

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The clinical efficacy of HAPA-B was investigated. The results obtained were as follows.
HAPA-B was administered to 15 patients; 10 patients with pneumonia, 2 with acute respiratory tract infection and 3 with chronic respiratory tract infection. One patient who was treated with other antibiotics as combined drugs and 1 with mycoplasmal pneumonia were excluded from efficacy evaluation. The clinical responses were excellent in 4 cases, good in 5 cases and fair in 4 cases. The efficacy rate was 69%. No side effects were observed except transient increase of eosinophile in 1 case.
In case of respiratory tract infections, HAPA-B proved a useful drug.

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The antibacterial activity and clinical efficacy of HAPA-B were investigated. The results obtained were as follows.
1) Antibacterial activity
The antibacterial activity of HAPA-B was compared to those of Gentamicin (GM), Amikacin (AMK), Tobramycin (TOB), and Dibekacin (DKB) in a total of 182 clinical isolates of S. aureus, E. coli, K. pneurnoniae, P. mirabilis, P. vulgaris, M. morganii, S. marcescens and P. aeruginosa. The MICs of HAPA-B was quite similar to that of AMK and the antibiotic showed the strongest activity against E. coli. Particularly almost all of GM, DKB and TOB-resistant strains of S. aureus and S. marcescens were susceptible to HAPA-B. Against P. aeruginosa it exhibited a little higher MICs than those of TOB and DKB.
2) Clinical results
HAPA-B was administered to 10 patients, 5 with pneumonia (included 1 with mycoplasmal pneumonia), 1 with atelectasis, 2 with acute exacerbation of chronic respiratory tract infection, 1 with acute cystitis and 1 with adnexitis. The clinical response was excellent in 3 cases, good in 5 cases, fair in 1 case and unknown in 1 case. The efficacy rate was 88.9%. As the bacteriological effects, Haemophilus sp. isolated from Case 4 and P. aeruginosa isolated from Case 9 were eradicated, but P. aeruginosa isolated from Case 8 was persisted. Neither side effects nor abnormal laboratory findings were found.

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Clinical effectiveness of a new antibacterial drug. HAPA-B was evaluated in respiratory tract, urinary tract and other infections. The drug was administered for 8-31 days at daily doses of 400mg to 1 case with chronic bronchitis, 3 cases with pneumonitis, 1 case with pulmonary suppuration, 4 cases with chronic cystitis and 1 case with suppurative arthritis of hip. It was effective in 1 case with respiratory tract infection, 1 case with cystitis and 1 case with suppurative arthritis of hip, including the cases combined with other antibiotics. The monotherapeutic effectiveness with HAPA-B was seen in 1 case with cystitis out of 5 cases (4 cases with cystitis and 1 case with pneumonia). No serious side effect was observed in any case.

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HAPA-B, a new aminoglycoside antibiotics, was administered to 7 cases with respiratory tract infections, and its merit was evaluated. HAPA-B was administered to a total of 7 cases consisting of 5 bronchopneumonia, 1 of obstructive pneumonia plus lower airway infection and 1 of diffuse panbronchiolitis. Organisms from transtracheal aspiration (6 cases) and endotrachea tube (1 case) were H.influenzae plus P. aeruginosa, S. pneumoniae, H. influenzae plus α-Streptococcus, P. matlophilia, S. aureus plus E. coli plus S. dysagalactiae, H. parainfluenzae and H. haemoglobinophilus.
1) Clinical responses were good in 6 cases and fair in 1 case.
2) Organisms were able to eradicate in 6 cases except 1 case (H. influenzae plus α-Streptococcus).
3) Side effect was observed in 1 case consisting of fever and elevation of GOT and GPT.

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HAPA-B, a new derivative of gentamicin B, was examined on its antibacterial activity in vitro, as well as on its clinical availability. The results obtained were as follows:
1) Antibacterial activity in vitro: MIC of HAPA-B against bacterial strains isolated from clinical infection foci were estimated and compared with those of gentamicin (GM), amikacin (AMK), and ofloxacin (OFLX). S.aureus strains were generally most sensitive to GM, and their sensitivity to HAPA-B was similar to AMK and OFLX. HAPA-B showed similar activity to AMK also against E. cloacae, P. mirabilis, and P. morganii strains, while its activity against strains of K. pneumoniae, E. coli, C. freundii, and S. marcescens was higher than that of AMK. P. aeruginosastrains were most sensitive to GM and similarly sensitive to HAPA-B, OFLX, and AMK. Generally speaking, however, OFLX showed lowest MIC against GNB, followed by GM, HAPA-B, and AMK. It should be an advantage for HAPA-B over other drugs, that several S. aureus and GNB strains resistant to other drugs were found to be considerably sensitive to HAPA-B.
2) Clinical trials: Eleven patients with various infections (RTI 4, septicemia 2, and UTI 5) were treated with HAPA-B 200mg × 2/day i. m. for 4-9 days. Two of the RTI cases, i. e. one with infected bulla (the causative bacteria: unknown), and another with lung abscess caused by P. aeruginosa, could not respond to the therapy. Among the two septicemia cases, the availability of the drug could not be evaluated in one of them, as C.albicans was detected from her blood, while the other case, i. e. K. aerogenes septicemia originated from BTI caused by cholangioma, was markedly improved by the therapy of eight days, resulting eradication of the bacteria in the blood. All of the five UTI cases well responded to the therapy.
As to the untoward reaction to the drug, neither clinical side effects nor abnormal hematological and chemical findings attributable to the drug therapy were found in the administered patients, excepting one of them who showed a temporary elevation of BUN.
These results obtained seem to suggest the satisfactory availability of HAPA-B in the clinic.

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HAPA-B was administered by intramuscular injection of 200 mg, twice daily for 5 to 22 days to a total of 7 patients, 2 cases of pneumonia, 1 case of infected lung cancer, 3 cases of chronic cystitis and 1 case of pyelonephritis.
The clinical responses were good in 2 and fair in 1 in respiratory tract infection and good in 2 and poor in 2 in urinary tract infection.
No side effects were observed except eosinophilia in 1 case and the elevation of serum transaminase in 1 case.

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Fundamental and clinical studies on HAPA-B, a new aminoglycoside antibacterial agent, were performed and the following results were obtained.
1) Antibacterial activity of HAPA-B was similar to that of AMK against S. aureus, Klebsiella spp., Proteus spp., P. aeruginosa and A. calcoaceticus and inferior to those of GM and TOB by 2-8-fold. Against S. marcescens the antibiotic was as active as GM.
2) Pleural effusion levels of 3.02-7.88mg/ml were observed at 2 hours after the intramuscular administration of HAPA-B 200mg.
3) HAPA-B 75-200mg was administered to 15 patients with respiratory tract infections twice day for 5-10 days and the efficacy was evaluated in 14 patients. Clinical effect was “good” in 8, “fair” in 4 and “poor” in 2 and the efficacy rate was 57.1%.
No side effects were observed.
Slight abnormality in laboratory data on eosinophils, WBC, Hb and Ht was observed.

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Clinical investigations were carried out on HAPA-B, a newly developed aminoglycoside antibiotic which is a derivative of Gentamicin B. HAPA-B was given intramuscularly to a total of 5 patients with respiratory tract and urinary tract infections, at, a daily dose of 400 mg.
The clinical response were good in 2, fair in 2 and poor in one.
No side effects was observed in this studies, but in only one case elevations of serum transaminase levels were recognized.

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The antimicrobial activities of HAPA-B against 427 clinically isolated strains of 28 species were compared with those of Gentamicin (GM) and Amikacin (AMK). As to Gram positive cocci five species such as S. aureus, S. epidermidis, α-and β-Streptococcus and S. faecalis were studied. GM showed superior activity to the other two aminoglycosides. The activities of HAPA-B were almost the same as those of AMK.
As to Gram negative bacilli 23 species such as E. coli, Shigella spp., S. typhi, Salmonella spp., K. pneumoniae, K. oxytoca, Enterobacter spp., C. freundii, S. marcescens, P. vulgaris, P. mirabilis, P. rettgeri, P. morganii, P. inconstans, P. aeruginosa, P. cepacia, P. maltophilia, V. parahaemolyticus, V. alginolyticus, A. calcoaceticus, Flavobacterium spp., Aeromonas spp. and H. influenzae were studied. Three drugs showed almost the same antimicrobial potencies against Enterobacteriaceae. Against P. cepacia, P. maltophilia and Flavobacterium spp. the aminoglycosides showed poor results. Against V. parahaemolyticus the activities of GM were slightly superior to HAPA-B and AMK. Antimicrobial activities of HAPA-B against Gram negative bacilli were much the same as AMK in general.
HAPA-B was administered intramuscularly to four cases of respiratory tract infection in doses of 400mg per day. In two cases of acute pneumonia good results were obtained.
Of the adverse reaction a case of the elevation of Al-P and γ-GTP value was observed.

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The clinical effect of HAPA-B, a new aminoglycoside antibiotic, was studied in eight patients, two with chronic pyelonephritis, one with acute cholecystitis, three with acute bronchitis, one with bacterial pneumonia and one with mycoplasma pneumonia complicated with bacterial pneumonia.
Clinical response was excellent in one, good in four, poor in one and not evaluated in two patients.
Neither side effects nor laboratory abnormalities was observed.

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Laboratory and clinical studies were performed on HAPA-B, a new derivative of gentamicin B, and results were follows;
1) Antimicrobial activity
MICs of HAPA-B against clinical isolates were determined. With the inoculum size of 10⁶cells/ml, percentages of strains susceptible to 12.5μg/ml or less were 100% for S. aureus, E. coli, K. pneumoniae, K. oxytoca, E. aerogenes, P. mirabilis, P. morganii and Citrobacter sp., 96% for E. cloacae, 82% for S. marcescens, 92% for P. vulgaris, 89% for P. aeruginosa and 0% for S. faecalis. The most of these clinical isolates were sensitive to 0.78-3.13μg/ml. However, all strains of S. faecalis and some strains of S. marcescens and P. aeruginosa were high-resistant to HAPA-B. HAPA-B was more active than AMK and GM, especially in GM resistant strains.
2) Clinical effect and adverse reaction
A patient with pneumonia, one with bronchitis, one with sepsis and 2 with cystitis were treated with HAPA-B daily dose of 200-600mg for 7-22 days. Clinical responses were excellent in one case, good in 2 cases and fair in 2 cases. No side effect and no abnormal laboratory findings were observed.

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HAPA-B was applied to the treatment of 6 patients with acute or chronic respiratory tract infections.
Clinical response were good in 2 and fair in 4.
Neither side effects nor abnormal laboratory findings were observed in any of these patients.

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Laboratory and clinical studies were carried out on HAPA-B, a newly developed aminoglycoside antibiotic. The following results were obtained.
1) Antibacterial activity
The antibacterial activity of HAPA-B was examined by the serial microbroth dilution method using MIC 2000 system (Dynateck Co.). The minimum inhibitory concentrations (MICs) of HAKA-B against a total of 590 clinical isolates were compared with those of GM, AMK and SISO. The antimicrobial activity of HAPA-B against the examined strains was less potent than those of GM and SISO, but it was as active as that of AMK. The MIC₈₀ of HAPA-B against P. aeruginosa and A. anitratus were 25 μg/ml and 1.56μg/ml, respectively.
2) Serum and sputum levels in a patient with diffuse panbronchiolitis
Two hundred mg of HAPA-B was injected intramuscularly to a patient with diffuse panbronchiolitis. The peak serum concentration was obtained 30 minutes after administration and the value was 9.83 μg/ml. The maximum sputum concentration was obtained 3-4 hours after administration, with the value of 0.86μg/ml in the same patient.
3) Clinical evaluation and adverse reaction
A total of 17 patients with respiratory tract infections (chronic bronchitis 9, pneumonia 6, chronic respiratory tract infection 1, diffuse panbronchiolitis 1) were treated with 200 mg of HAPA-B daily for 3 to 15 days by intramuscular injection. Eleven out of 17 patients responded satisfactorily to the treatment and the overall efficacy rate was 64.7%. Subjective and objective symptoms, hematological and biochemical data and renal functions were checked up before and after administration of HAPA-B. There were no significant adverse reactions among the patients treated with the same drug.

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Laboratory and clinical studies on HAPA-B, a new semisythetic aminoglycoside, were performed.
HAPA-B was more active in vitro against respiratory pathogenic Haemophilus influenzae, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Enterobacter species than amikacin. All the other aminoglycosides-resistant strains of Staphylococcus aureus were not resistant to HAPA-B and amikacin. Synergy of HAPA-B with cefsulodin could be demonstrated against the respiratory isolates of Pseudomonas aeruginosa.
When a dose of 200mg was administrated intramuscularly to a patient with chronic bronchitis, the peak serum concentration was 9.37μg/ml, the serum half-life being 2.00 hours, respectively. The intrabronchial level of HAPA-B was ranged 0 to 1.94;μg/ml.
When a dose of 100mg was inhalated in a patient with chronic bronchiolitis, the serum concentration were not detected, but the expectorated sputum level was 245;μg/ml.
Twelve respiratory infections were subjected to the clinical evaluation by intramuscular injections of HAPA-B (200mg·2 times/days). 50% of all the cases were effective. The inhalations of HAPA-B (15-100mg · 2-3 times/days) were performed in 4 patients, and 50% of all the cases were effective. Furthermore, one patient with pseudomonal pyothorax was treated with combination of HAPA-B and cefsulodin successfully.
No adverse effect were observed in 16 cases in this series.
These date indicate that HAPA-B is one of the most effective and useful aminoglycoside antibiotics for the treatment of respiratory bacterial infections.

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A new aminoglycoside antibiotic, HAPA-B for parenteral use, was administered intramuscularly to 10 patients; 4 with acute or subacute cholecystitis with cholelithiasis, 3 with acute localized peritonitis due to phlegmonous appendicitis and 3 with acute diffuse peritonitis due to gangrenous perforative appendicitis. HAPA-B in a dose of 200mg was administered twice a day for 4 to 7 days preoperative patients with biliary tract infection and postoperative patients with acute peritonitis. Clinical response was excellent in 4 cases, good in 6 cases, fair and poor in none. No adverse effect was observed. The organisms were isolated in 8 cases (12 strains), 8 were E. coli, 2 were K. pneumoniae and 2 were S. faecalis. The MICs of HAPA-B against E. coli were 0.39 to 6.25μg/ml in 10⁶cells/ml. The MIC of HAPA-B against K. pneumoniae was 0.78μg/ml and those against S. faecalis were 6.25 and 12.5μg/ml.
Before the operation of above cases (4 with biliary tract infection and 6 with acute peritonitis), HAPA-B in a dose of 200mg was administered intramuscularly, the materials of common duct bile, gall bladder wall, the appendix, ascites and serum samples were taken durig the operation. HAPAB concentration was determined by agar well bioassay method with Bacillus subtilis ATCC 6633 as a test organism. HAPA-B concentrations in common duct bile were 0.67 to 2.27μg/ml (mean 1.55± 0.58μg/ml) at 92 to 102 minutes after intramuscular administration. HAPA-B concentrations in gall bladder bile were 0.29 to 1.22μg/ml (mean 0.59±0.43μg/ml), those in gall bladder wall were 3.45 to 6.05μg/g (mean 4.83± 1.07 μg/g). HAPA-B concentrations in purulent ascites ranged from 2.44 to 14.89μg/ml (mean 7.87±5.09 μg/ml) at 10 to 215 minutes after intramuscular administration. HAPA-B concentrations in mucous membrane of appendix were 1.12 to 5.52μg/g (mean 2.35± 1.75 μg/g), those in other part of appendix were 1.45 to 6.64μg/g (mean 2.85±1.92μg/g), and those in pus in the appendix were 0.71 to 3.96μg/ml (mean 1.63±1.56μg/ml). HAPA-B concentrations in infected tissues, purulent ascites and other body fluids were almost higher than MICs of HAPA-B against isolated organisms.
Therefore, it was supported that HAPA-B could be used safely and usefully by intramuscular administration to biliary tract infection and acute peritonitis.

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Fundamental and clinical studies were carried out on HAPA-B. This drug possessed broad antimicrobial spectra and was active against gram positive and negative bacteria.
Antimicrobial activities of 9 aminoglycosides against clinical isolates were tested. The activity of HAPA-B was the most excellent against E. coli, similar to AMK against S. aureus, two times superior to AMK & ASTM against S. epidermidis, superior to other drugs except GM & SISO against K. pneumoniae, similar to GM, TOB & AMK against E. cloacae, similar to GM and superior to other drugs against S. marcescens, similar to AMK & ASTM against P. mirabilis, similar to ASTM against indole positive Proteus and similar to GM & MCR against P. aeruginosa.
HAPA-B was administered intramuscularly at a single dose of 200 mg to three healthy male volunteers to determine serum and urine levels by bioassay, HPLC and EIA method. Mean peak serum level of HAPA-B assayed by HPLC was 9.07μg/ml at one hour after administration and 0.87μg/ml of serum level was obtained at 8 hours. Mean peak of urine level assayed by HPLC was 1141μg/ml at 1 hour and recovery rate of HAPA-B was 91.8% within 8 hours.
Pharmacokinetic parameters were 3.35 hour^-1 for Ka, 0.37 hour^-1 for Kel, 1.89 hour for T_1/2, 16.7l, for Vd, 0.74 hour for T_max, 9.12μg/ml for C_max and 32.7μg·hour/ml for AUC.
HAPA-B was administered to 8 cases with surgical infection and the clinical responses were effective in 7 cases and failure in a case, with the effective rate of 87.5%. No side effect and no abnormal laboratory findings were observed.

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Fundamental and clinical studies of HAPA-B, a new aminoglycoside, in the surgical field were performed and the following results were obtained.
1) Antibacterial activities
Against S. aureus, E. coli, Klebsiella and P. aeruginosa isolated from surgical purulent specimens, the antibacterial activities of HAPA-B, Gentamicin (GM) and Amikacin (AMK) were measured. Strains resistant to GM and AMK, which HAPA-B still showed strong activity were found.
2) Bile excretion
In three patients with biliary tract disorder, the bile concentrations of HAPA-B were measured. The bile levels of HAPA-B were about 1/3 of the serum levels.
3) Clinical results
HAPA-B was administered to 12 patients with surgical infections and the clinical results were excellent in 2 cases, good in 6, poor in 3 and unknown in 1. No adverse reaction due to HAPA-B could be found but the elevation of S-GOT and S-GPT after HAPA-B therapy could be found in 2 cases.

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HAPA-B, a new aminoglycoside antibiotics, was investigated on its antimicrobial activity against clinical isolates, clinical efficacy and side effects.
1) HAPA-B was more active than gentamicin against E. coli, and was as active as gentamicin against Kiebsiella, Enterobacter, Serratia, and P. aeruginosa.
2) HAPA-B was administered to 21 patients with various surgical infections, such as peritonitis, postoperative intraabdominal infection, wound infection, adscess, postoperative intrathoracic infection, postoperative cholangitis, sepsis and cellulitis.
The results obtained were excellent in 5, good in 11, fair in 1, poor in 3 and unknown in 1 patient (efficacy rate: 80.0 %). Particularly satisfactory results were seen in abscess, wound infection and cellulitis.
3) Side effects noted in one patient each were eruption, weakness and increasing of tinnitus, eosinophilia and hepatic disorder (GOT, GPT elevation).

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HAPA-B, a new semisynthetic aminoglycoside, was employed in the treatment of various infectious diseases encountered in the surgical field, and clinical efficacy of the drug was investigated. HAPA-B was administered to a total of 20 patients. Two hundred mg of HAPA-I3 was administered twice a day for 4-15 days by intramuscular injection. The patients who were subjects of evaluation of the efficacy of HAPA-B consisted of 8 cases of infection of soft tissue, 3 cases of postoperative wound infection, 7 cases of peritonitis or postoperative intraabdominal infection (including perineal dead space infection after Miles' op.) and 2 cases of cholangitis.
The clinical results were excellent in 2 patients, good in 12, fair in 2, poor in 4 and the efficacy rate was 70.0%.
As side effect drug eruption was found in only one case, but no adverse reactions on clinical laboratory findings attributable to the drug were observed.
Therefore, HAPA-B is thought to be a useful drug in the surgical field.

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Fundamental and clinical studies of HAPA-B, a new aminoglycoside, in the surgical field were performed and following results were obtained.
1. Antibacterial activity
Generally HAPA-B was slightly superior or equal to AMK, and inferior to GM. But HAPA-B exhibited a good activity against some of GM-resistants.
2. Clinical results
HAPA-B was administered to 8 patients with surgical infections intramuscularly at a daily dose of 400mg. The overall clinical efficacy was excellent in one case, good in 5 cases and poor in 2 cases, the overall effectiveness rate being 75%.
No side effect was recognized.

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HAPA-B, a Gentamicin B derivative, was investigated on its clinical and bacteriological effect.
HAPA-B was administered by intramuscular injection to six patients with surgical infectionsfour patients with postoperative wound infection and two patients with postoperative intraabdominal infection.
Bacteriological evaluation: coagulase negative Staphylococcus (1), α-Streptococcus (1), γ-Streptococcus (1), S. faecalis (1), K. pneumoniae (2), E. aerogenes (1), Enterobacter (1) and P. aeruginosa (1) were eradicated. Three strains of P. aeruginosa were decreased.
Clinical response was good in 5 and fair in 1 case. Clinical efficacy rate was 83.3%.
No side effect was observed and no marked adverse reaction was noted.

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