Incidence of cephalosporin-resistant staphylococcal infections is increasing recently. We tried to find out the possible first choice antibiotic for these infections. We estimated minimal inhibitory concentrations (MIC) of each one of the broad spectrum antibiotics with different mode of actions as well as representative drugs of penicillins and cephalosporins against strains of Staphylococcus epidermidis and Staphylococcus aureus.
Trend of antibiotic susceptibility of S. epidermidis was found to be as same as that of S. aureus. MIC of minocycline was found to be the lowest in the drugs tested, and there found no resistant strains. MIC of erythromycin was next low but more than a half strains were found to be resistant to this drug. Some of the strains were thought to be treated with amikacin or sulfonamides by the MIC against them, but there also found many resistant strains. Therefore, use of these drugs should be decided after sensitivity test of the causative bacteria. Most of the strains were found not to be treated with β-lactam antibiotics.
In conclusion, minocycline could be the only one first choice drug for staphylococcal infections before antibiotic susceptibility test of the causative strains in the present moment.

View full abstract

Ototoxic effect of micronomicin (MCR) in intravenous drip administration was investigated in guinea pigs (300-400g) receiving MCR for 30 days at dose of 50 and 100 mg/kg, respectively. MCR was dissolved in physiologic saline and 1.5ml of the solution was infused through polyethylene tube into the left external jugular vein with Perista mini-pump for 60 minutes every day after measurement of body weight. Auditory impairment was monitored by pinna reflex audiometry.
1. Pinna reflex loss was not detected in any animal in frequency range (0.5 to 20kHz).
2. Cochlear hair cell damage generally was of mild degree. Two out of 6 animals treated with MCR 50 mg/kg (Table 1) showed outer hair cell loss confined to unilateral basal end and posterior 3/4 of the first turn, respectively. Outer hair cell loss was noticed in 4 of 9 animals receiving MCR 100 mg/kg (Table 2); much less extensive in 3 animals, unsymmetric slightly extensive in remaining 1. Unilateral circumscribed loss of inner hair cells was noticed at lower part of the hook in the latter one.
3. Vestibular hair cell loss was scattered and less extensive and occurred in 4 of the 6 50 mg/kg given animals and in 7 of the 9 100mg/kg ones.
04. Comparison in incidence and extension of the outer hair cell loss of the cochlea (Tables 3, 4) in the present study and previous ones on the ototoxic effect of MCR in intramuscular and intravenous administration suggests that there was no distinct difference in enhancement of the ototoxic effect in the intravenous drip administration.

View full abstract

Clinical studies were done on cefoxitin (CFX), the first cephamycin antibiotic, in the field of obstetrics and gynecology and following results were obtained.
CFX was administrated by intravenous drip infusion for average 6.9 days at a daily dose of 2-6g to 58 patients; 15 with intrauterine infections, 5 with intrapelvic infections, 11 with adnexitis, 3 with mastitis, 5 with urinary tract infections, 2 with other infections and 17 for prophylaxis of postoperative infections.
The clinical results were excellent in 8 cases, good in 39 cases, fair in 4 cases, poor in 6 cases and unknown in 1 case, with the efficacy of 82.5%. Total bacteriological effective rate was 88.9%.
As to side effects, eruption was observed only in 1 case.
From the results of the present study, the usefulness of CFX was demonstrated in the field of obstetrics and gynecology.

View full abstract

A combined agent of sulbactam, a β-lactamase inhibitor, plus cefoperazone (SBT/CPZ: 1/1) was studied on the passage into the maternal milk as well on the clinical application and the results were followings:
1. One or 2 grams of SBT/CPZ was given by one shot intravenous injection to puerperal mothers to determine the passage into the milk up to 6 hours after the administration. A trace of passage was detected for both SBT and CPZ as in the case of other antibiotics.
2. Good clinical efficacy was observed in all 5 patients with female genital organ infections, to whom a daily dose of 2.0g of SBT/CPZ was administered by drip infusion for 4 to 6 days.
3. No side effects were noticed.

View full abstract

A comparative study to determine the transfer of cefroxadine (CXD), an oral cephem antibiotic, to the human tears was undertaken using cephalexin (CEX) as the control drug.
The mean tear levels of 250mg each of CXD and CEX after oral administration in 6 volunteers were equally peaked at 0.26 μg/ml with CXD after 1 to 2 hours and with CEX after 2 hours. The changes of tear levels were also equal for both drugs. The ratios between the tear and the blood levels at 2 hours after oral administration were almost equal with 4.1% for CXD and 3.7% for CEX. From the above evidence it has been confirmed that the both drugs were equivalent with regard to the concentration profiles in human tears after oral medication.

View full abstract

Susceptibilities in various types of clinical isolates to cefmetazole (CMZ) were determined by the disk method and the serial agar dilution method for MIC measurement. CMZ showed high antibacterial activity for all Grampositive cocci except E. faecalis, and for H. influenzae, E. colt, Klebsiella sp. and Proteus sp.
CMZ was administered on 33 patients with infections, mainly biliary tract infections, in the field of internal medicine. The clinical efficacy of the drug was 86.7% for infections of the biliary tract, 80.0% for respiratory tract infections, 100% for urinary tract infections and 76.7% for all cases. There were no adverse reaction or changes in laboratory findings caused by CMZ in any of the patients.

View full abstract

DNA-degradation reaction by bleomycin was conducted with form I of SV40 DNA as the substrate under “iron-limited conditions” and “iron-sufficient conditions”. For “iron-limited conditions”, the iron ions in reaction mixtures were derived from contaminant iron in the bleomycin preparation, the molar ratio of bleomycin/iron being 1/0.05. For “iron-sufficient conditions”, Fe(II) was added to reaction mixtures to attain the molar ratio of bleomycin/iron at 1/1 to 1/29. DNA-degradation reaction by Fe(II) without bleomycin, or “Fe(II) alone”, was also run for comparison. In any case, the reaction was allowed to proceed at such low rates that other products than form II and form III, due to further fragmentation, were negligible. The mass of DNA in each form was quantitatively determined by spectrofluorometry after agarose gel electrophoresis and staining with ethidium bromide. “Iron-limited conditions” and “iron-sufficient conditions” showed similar reaction characteristics as follows. As form I decreased with incubation time, form II increased faster than form III, hit a plateau (ca. 65% of total DNA) and decreased gradually thereafter. Form III kept increasing throughout the incubation. The reaction was dependent on incubation time and on doses of both bleomycin and Fe(II) but rather independent of temperature. The reaction was inhibited by acidic pH, Tiron (a specific chelator of iron) and Cu(II) but not EDTA. Octanucleotides with specific base sequence inhibited the reaction.
DNA-degradation reaction by “Fe(II) alone” showed different characteristics as follows. The reaction proceeded rapidly at first, but ceased within 2 minutes. The extent of reaction was dependent on dose of Fe(II). The reaction product was form II accompanied by little amount of form III. The reaction was highly dependent on temperature, inhibited by EDTA, and not inhibited by Cu(II) and acidic pH. Octanucleotides, irrespective of their base sequences, inhibited the reaction.

View full abstract

Laboratory and clinical studies on BRL 25000 granules (containing clavulanic acid (CVA) 1 part plus amoxicillin (AMPC) 2 parts) were performed in infections in the pediatric field.
Following oral administration of BRL 25000 granules at a dose of 15 mg/kg body weight, the maximum serum levels of AMPC and CVA achieved approximately 1 hour after dosing were 8.68 μg/ml and 4.09 μg/ml and declined thereafter with half-lives of 1.39 and 0.80 hours, respectively. The 6-hour urinary recovery rates for AMPC and CVA were 55.81% and 26.08%, respectively.
Following oral administration of BRL 25000 granules at a dose of 22.5 and 24.3 mg/kg body weight, the serum levels of AMPC and CVA peaked at 7.37 μg/ml and 2.98 μg/ml after 1 hour and declined with half-lives of 2.52 and 0.99 hours, respectively. The 6-hour urinary recovery rates for AMPC and CVA were 40.02% and 13.95%, respectively.
The clinical efficacy of BRL 25000 granules was evaluated in 23 patients with upper respiratory tract infections, skin infections, etc. Overall the clinical efficacy was good to excellent in 21/23 (91.3%). The bacteriological and clinical efficacy rates for β-lactamase producing bacteria and non-producing bacteria were 50% (1/2) and 100% (12/12), respectively. Side effects were observed in 1 patient, who experienced mild diarrhea and abdominal pain but not of a severe nature.

View full abstract

BRL 25000 granules containing amoxicillin 2 parts and clavulanic acid 1 part, were administered to 14 patients with pediatric infections. The overall efficacy rate was 71.4% (10/14). An adverse reaction was observed in 1 case with diarrhea, but there were no other side effects or abnormal laboratory findings noted.

View full abstract

BRL 25000 granules containing 2 parts amoxicillin and 1 part potassium clavulanate were administered to children suffering from acute infections at a daily dose of 50mg/kg in 3 or 4 divided doses for at least 3 days. Infections included acute airway infections (81), scarlet fever and suspected scarlet fever (4), urinary tract infections (4), impetigo contagiosa (1) and acute colitis (1).
Bacteria were eradicated in 91.3% (63/69) of cases treated with the BRL 25000 granules, with only 2 strains of Staphylococcus aureus, 2 of Escherichia colt, 1 of Haemophilus influenzae and 1 of Steptococcus pneumoniae remaining.
Eight β-lactamase producing strains were detected amongst the 49 clinical isolates studied and of these, 6 were eradicated after administration of the BRL 25000 granules.
Good clinical efficacy was obtained in 97.8% of cases (89/91), with 1 case of acute tonsillitis and 1 of acute colitis showing no improvement.
Adverse reactions were limited to 1 case of vomiting and 3 of diarrhea, and no abnormal laboratory findings were detected.

View full abstract

BRL 25000 granules, a formulation of amoxicillin (AMPC) and the β-lactamase inhibitor clavulanic acid (CVA) in a ratio of 2 to 1, was studied clinically and bacteriologically in pediatric infections.
The in vitro antibacterial activity of BRL 25000 was superior to AMPC against β-lactamase producing strains.
The pharmacokinetics of the BRL 25000 granule were studied following oral administration to a 6 years old female and 9 years old male in the fasting state at dose levels of 10mg/kg and 16.1mg/kg, respectively.
In the case of the female dosed at 10mg/kg, the peak serum concentrations were found to be 6.38 μg/ml for AMPC and 1.83 μg/ml for CVA at 1 hour following administration. The elimination half-life of AMPC was 0.86 hour and that of CVA was 0.67 hour. The 4-hour urinary recovery was 61.89% for AMPC and 17.92% for CVA. In the male receiving 16.1mg/kg, the peak concentrations were 2.55 μg/ml for AMPC at 3 hours following administration and 1.46 μg/ml for CVA at 1.5 hours following administration. The elimination half-life of AMPC was 1.59 hours and that of CVA was 1.19 hours. The 6-hour urinary recovery was 44.19% for AMPC and 30.05% for CVA.
In clinical studies, the BRL 25000 granule was administered to 36 infants with upper respiratory tract infections, mainly tonsillitis, urinary tract infections etc. Good clinical efficacy was obtained in 33/36 cases (91.7%).
Diarrhea and rash were occasionally noted side effects but were not severe.
From the above results, it can be concluded that the BRL 25000 granule is a suitable and effective drug for use in the treatment of pediatric infections.

View full abstract

Fundamental and clinical studies have been performed on the BRL 25000 granules (combination of amoxicillin (AMPC) and potassium clavulanate (CVA) in 2: 1 ratio) in the pediatric field.
In bacteriological studies a potentiated antibacterial activity of BRL 25000 was recognized against AMPC-resistant and β-lactamase producing clinical isolates.
The pharmacokinetics of the BRL 25000 granules were studied at dose levels from 10 to 20mg/kg. The peak serum concentrations of AMPC and CVA achieved approximately 1 hour after dosing were 4.29-9.55 μg/ml and 3.87-4.78 μg/ml, respectively. The serum half-life was found to be 0.90-1.31 hours for AMPC and 1.01-1.22 hours for CVA. Six-hour urinary excretion rates were 29.5-62.6% for AMPC and 12.6-37.9% for CVA.
In the clinical studies, the BRL 25000 granules were administered to 36 pediatric patients (15 with upper and lower respiratory tract infections, 10 with urinary tract infections and 11 with skin or soft tissue infections, etc.) at dose levels of 30-50mg/kg/day. Clinical results in all cases were excellent or good. In particular, good bacterial and clinical effects were obtained against infections caused by β-lactamase producing AMPC-resistant strains except E. cloacae 1 strain.
No adverse reactions or abnormal laboratory findings were recognized in any patient.

View full abstract

BRL 25000, granules preparation containing 2 parts of amoxicillin (AMPC) and 1 part of clavulanic acid (CVA, β-lactamase inhibitor) as its potassium salt, has been investigated fundamentally and clinically.
An in vitro study of the antibacterial activity of BRL 25000 against clinically isolated S. aureus (34 strains) showed higher activity than for AMPC alone and demonstrated that CVA potentiated the activity of AMPC, showing a synergistic effect against β-lactamase producing organisms.
A total of 27 pediatric patients aged between 6 months and 13 years 8 months (23 with respiratory infections and 4 with urinary tract infections) were treated with a daily dose ranging from 31.7 to 54.5mg/kg, divided into 3 or 4 doses a day for periods of 4-18 days.
The clinical effect was evaluated as excellent in 26 cases, poor in 1 case and the efficacy ratio was therefore 96.3% (26/27). The bacteriological effect against 12 organisms isolated from 9 patients was studied and all were eradicated (12/12).
A drug-related side effect was observed in only 1 patient who developed diarrhea on the 4th day of treatment which continued during the treatment for 10 days. However, no severe side effect and no abnormality related to the drug in laboratory findings were observed.
From these results it is concluded that BRL 25000 will be a clinically effective drug in the treatment of mild and moderate infections in the pediatric field.

View full abstract

BRL 25000 is a preparation comprising 2 parts of amoxicillin (AMPC) to 1 part of clavulanic acid (CVA). Basic and clinical studies have been performed on BRL 25000 granules in the pediatric field.
The antibacterial activities of BRL 25000 and AMPC against 48 strains of E. coli isolated from patients with urinary tract infections were studied. The MICs of BRL 25000 were all below 100 μg/ml, except for 1 strain with MIC≥800 μg/ml. However, 19 strains (40%) were resistant to AMPC, with MICs more than 800 μglml.
BRL 25000 granules were administered to 23 children with bacterial infections and the clinical response was assessed as excellent in 10, good in 9, fair in 3, poor in 1, giving an overall efficacy rate of 83% (19/23).
Isolated organisms were eradicated in 12 out of the 16 strains which were evaluated bacteriologically.
Changes in intestinal bacterial flora following administration of BRL 25000 granules were studied in several children and decreases in flora were observed in some cases.
No severe side effects were observed although there seemed to be a slightly higher incidence of diarrhea than with other drugs.

View full abstract

Fundamental and clinical studies have been performed on BRL 25000 (clavulanic acid 1 part-amoxicillin 2 parts) granules in the pediatric field.
The antibacterial activities of BRL 25000 and amoxicillin (AMPC) were investigated against clinically isolated and laboratory stocked strains. BRL 25000 was superior to AMPC against strains of E. coli, Salmonella sp. and Klebsiella sp., and similar against Gram-positive cocci.
Serum concentrations of AMPC and clavulanic acid (CVA) were measured 0.25, 0.5, 1, 2, 4 and 6 hours after administration of BRL 25000 granules at dose levels of 7.5, 10, 15 and 20mg/kg. At 7.5mg/kg peak level of AMPC of 2.69 μg/ml was achieved about 2 hours after dosing with a biological half-life of 1.64 hours; corresponding value for CVA was 0.53 μg/ml at 1 hour with a T 1/2 of 1.46 hours. At 10mg/kg, AMPC also peaked after 2 hours (3.82 μg/ml) and the T 1/2 was 1.63 hours, whilst for CVA the value was 0.56 μg/ml with a T 1/2 of 1.24 hours. Value for AMPC at 15mg/kg was 5.18 μg/ml at 1 hour post dose with a T 1/2 of 1.48 hours, and for CVA 4.01 μg/ml at 1 hour with a T 1/2 of 0.89 hour. At the highest dose of 20mg/kg, AMPC level reached 4.21 μg/ml after 2 hours with a T 1/2 of 2.39 hours, and the CVA peak was 1.64 μg/ml at 1 hour with a T 1/2 of 1.01 hours.
The 6 hours urinary recovery of AMPC and CVA following administration of the BRL 25000 granules ranged from 38-64% and 2-33%, respectively.
In the clinical studies, the BRL 25000 granules are administered to 15 cases with pediatric infections and the clinical response was excellent or good in all cases treated (100%).
Bacteriological investigation was performed on 13 strains from 12 cases and all strains were eradicated (100%).
Regarding side effects, elevation of eosinophil was observed in 1 case and vomiting in 3 cases.

View full abstract

Fundamental and clinical studies on BRL 25000 granules were carried out in the pediatric field. BRL 25000 is a formulation comprising 1 part of clavulanic acid (CVA) and 2 parts of amoxicillin (AMPC).
The MICs of BRL 25000 and AMPC were assessed against 24 clinically isolated strains of S. aureus (including 23 β-lactamase producing strains), 22 S. pyogenes, 20 E. coli (8 β-lactamase producing strains), 24 K. pneumoniae (24 β-lactamase producing strains), 20 H. influenzae (6 β-lactamase producing strains). BRL 25000 showed MIC₈₀ (cumulatively 80% of strains were inhibited) at 6.25 μg/ml against S. aureus, ≤0.10 μg/ml against S. pyogenes, 12.5 μg/ml against E. coli, 6.25 μg/ml against K. pneumoniae and 0.39 μg/ml against H. influenzae.
BRL 25000 showed no improvement in MIC terms against β-lactamase nonproducing strains compared with AMPC. However, BRL 25000 was markedly more effective against β-lactamase producing strains. Thus BRL 25000 was up to 8 fold more active against S. aureus, 2 to 64 fold against E. coli, 4 to 128 fold against K. pneumoniae, 4 to 16 fold against H. influenzae than AMPC.
Following oral administration of BRL 25000 granules (at a dose level of 12.5mg/kg) to 2 children aged 9 and 11 years, the mean peak serum concentrations of AMPC and CVA were 8.33±2.43 μg/ml and 4.44±1.65 μg/ml respectively 1 hour after dosing. The half-lives of AMPC and CVA were 1.35±0.42 hours and 0.91±0.05 hour, respectively.
The urinary excretion was 48.21±3.83% for AMPC and 16.90±7.06% for CVA in the first 6 hours after administration.
In clinical studies, 23 pediatric patients aged 2 months to 12 years with bacterial infections were treated with BRL 25000 granules and the clinical effectiveness, bacteriological response and side effects were evaluated.
The clinical response was assessed in 23 cases, 3 with acute rhinitis, 6 with acute purulent tonsillitis, 5 with acute bronchitis, 4 with acute pneumonia, 3 with impetigo, 1 with furunculosis and 1 with periproctal abscess. Results were excellent in 13 cases, good in 7, fair in 3 and hence the efficacy rate (excellent and good cases) was 87.0% (20/23). In paticular the clinical response in 9 cases with infections due to β-lactamase producing organisms was excellent in 6, good in 2, fair in 1 and the efficacy rate was 88.9% (8/9).
The bacteriological response was assessed against 4 strains of S. aureus (including 3 β-lactamase producing strains), 1 S. pyogenes, 7 H. influenzae (5 β-lactamase producing strains) and 1 K. pneumoniae (β-lactamase producing) which appeared to be causative organisms. Twelve strains were eradicated and 1 decreased (a β-lactamase producing H. influenzae) and hence the eradication ratio was 92.3% (12/13).
No side effects or abnormalities in laboratory findings were observed during the study.

View full abstract

Bacteriological and clinical evaluations of BRL 25000 (1 part clavulanic acid plus 2 parts amoxicillin) granules in the pediatric field have been performed.
The MICs of BRL 25000 against 25 clinically isolated strains of S. aureus, 40 E. coli, and 14 K. pneumoniae were compared with those of AMPC. Against β-lactamase non-producing strains of S. aureus and E. coli, the MICs of both drugs were nearly equal, however, against β-lactamase producing strains of these species and K. pneumoniae, BRL 25000 was superior to AMPC.
The blood levels of AMPC and CVA after single oral administration of approximately 15mg/kg of BRL 25000 granules to fasted children were studied in 3 subjects. The mean levels of AMPC and CVA peaked about 1 hour after administration at values of 11.40 and 5.49 μg/ml, respectively, with half-lives of 0.91 and 1.02 hours, and AUCs of 23.52 and 12.66 hr · μg/ml, respectively.
The 6-hour urinary recovery of AMPC ranged from 30.59% to 52.03% and for CVA from 16.31% to 45.18%.
There was no significant difference between the blood level of AMPC following single oral administration of approximately 10mg/kg AMPC granules and that of AMPC following single oral administration of approximately 15mg/kg BRL 25000 granules to the same children.
Clinical evaluation of BRL 25000 granules administered orally 3-4 times a day at total daily doses of between 42.9-52.9mg/kg resulted in improvement, judged excellent or good, in all 7 cases of tonsillitis and 2 cases of pyelonephritis. In particular, the clinical effect was excellent in the case of tonsillitis where a β-lactamase producing H. influenzae was isolated.
In the total 11 cases treated, including 2 cases of mycoplasmal pneumonia excluded from the clinical evaluation, 1 case of rash and eosinophilia was observed. No other adverse reactions or abnormal laboratory findings were observed.
The taste and flavor of the drug were well accepted by the children.
It was concluded that BRL 25000 granules are promising new drug which should be markedly useful in the treatment of infections in pediatric outpatients.

View full abstract

BRL 25000 granules (containing 2 parts amoxicillin and 1 part clavulanic acid) have been studied fundamentally and clinically.
The MICs of BRL 25000 against strains of S. aureus, E. coli, K. pneumoniae which were resistant to CEZ and β-lactamase producing strains of H. influenzae were determined. The MICs of BRL 25000 at an inoculum of 10⁶ cells/ml were 1/4 to 1/128 of those of AMPC and, in particular, the MICs of BRL 25000 were especially reduced against the organisms for which those of AMPC were more than 100μg/ml.
The pharmacokinetics of BRL 25000 were studied in 46 children at dose levels of 7.5mg (8 fasting children, 7 non-fasting children), 10mg/kg (4 fasting, 4 non-fasting), 15mg/kg (4 fasting, 4 non-fasting), 20mg/kg (8 fasting, 7 non-fasting). The peak serum concentrations in fasting children were marginally higher than those in non-fasting subjects. Values for AMPC and CVA from BRL 25000, dosed at 7.5, 10, 15 and 20mg/kg to fasting children, 0.5-1 hour after dosing were 4.86 and 2.36μg/ml, 5.20 and 1.69μg/ml, 7.50 and 3.27μg/ml, 9.38 and 6.30μg/ml, respectively. In non-fasting subjects, corresponding values were 2.84 and 1.01μg/ml, 4.53 and 2.10μg/ml, 7.29 and 4.08 μg/ml, 6.83 and 2.96μg/ml, respectively.
The biological half-lives of AMPC and CVA, following the administration of BRL 25000, show no significant difference between the fasting and non-fasting states. Values for AMPC and CVA in fasting children were 0.85-1.15 hours and 0.64-1.03 hours, and in non-fasting children, 1.18-1.79 hours and 0.78-4.02 hours, respectively. The time to reach the peak serum concentration and half-lives were similar for AMPC and CVA when dosed as BRL 25000. Peak urinary concentrations for BRL 25000 (AMPC and CVA) at dose levels of 7.5, 10, 15, 20mg/kg to fasting children were 681.8 and 148.2μg/ml, 247.1 and 66.3μg/ml, 484.2 and 149.1μg/ml, 1,796.5 and 372.0μg/ml, whilst in the non-fasting state the values were 496.3 and 83.2μg/ml, 991.1 and 156.7μg/ml, 2,397.5 and 460.7μg/ml, 1,896.3 and 323.4μg/ml, respectively.
The peak urinary concentration in the fasting state was observed at 0-2 hours after dosing, and in non-fasting individuals it occurred at 2-4 hours after dosing. The urinary recovery rates of AMPC and CVA for 6 hours were 44.3-118.58% and 14.2-49.72% in non-fasting, and 33.73-53.0% and 13.97-24.7% in fasting children.
In clinical studies BRL 25000 was administered at doses of 26.9-64.3mg/kg, 3-4 times a day to 39 children with bacterial infections, consisting of 15 with tonsillitis, 11 bronchitis, 5 urinary tract infection, 2 scarlet fever, 3 otitis media, 1 lymphadenitis, 1 pyoderma and 1 pneumonia. The clinical efficacy rate was 89.7%(35/39) and bacteriologically 35 out of 39 isolated strains were eradicated including 5 β-lactamase producing organisms.
Side effects were limited to 1 case of transient diarrhea and no abnormal laboratory findings were found in this study.

View full abstract

BRL 25000 granules, a formulation consisting of amoxicillin (AMPC) and clavulanic acid (CVA), was evaluated in the field of pediatrics.
In a pharmacokinetic study, serum concentrations were determined in a patient after oral administration of BRL 25000 granules in the non-fasting state at a dose of 11.76mg/kg. The serum levels of amoxicillin (AMPC) and clavulanic acid (CVA) 1 hour after administration were 7.76μg/ml and 6.64μg/ml, with biological half-lives of 0.86 hour and 0.88 hour respectively. The serum concentration profile at a dose of 31.58mg/kg showed almost the same tendency as at 11.76mg/kg, although the peak level and biological half-life of the serum concentrations were not obtained. These serum levels and their peak levels were considered reasonable compared with those obtained in adults at similar dose levels.
In clinical studies, 34 patients were evaluated including 8 patients with acute pharyngitis or acute tonsillitis, 1 patient with acute bronchitis, 1 patient with bronchopneumonia, 23 patients with scarlet fever and 1 patient with pertussis.
BRL 25000 granules were administered orally 3-4 times per day for 4-8 days to 2 patients at doses of 20-30mg/kg/day, to 18 patients at doses of 30-40mg/kg/day, to 11 patients at doses of 40-50mg/kg/day, and to 3 patients at doses of 50-60mg/kg/day. The clinical response was assessed excellent in 13 cases and good in 21 cases giving an overall clinical efficacy rate of 100% (34/34).
The causative organisms were isolated in 17 cases and included 12 strains of Streptococcus group A, 2 S. pneumoniae, 3 H. influenzae and 1 H. parainfluenzae. The clinical response in these 17 patients was excellent in 10 and good in 7. Twelve strains of Streptococcus group A and 2 strains of S. pneumoniae were eradicated after the treatment.
No side effects were observed, although in laboratory findings there was 1 case of slightly elevated GOT and GPT.

View full abstract

Fundamental and clinical studies on BRL 25000 granules, containing 2 parts amoxicillin (AMPC) and 1 part clavulanic acid (CVA)(a β-lactamase inhibitor) were carried out in the pediatric field.
Serum concentrations and urinary excretion rates were determined after oral administration of BRL 25000 granules at a dose of 20mg/kg to 2 children. The mean peak serum concentrations of AMPC and CVA were 4.89 and 2.85μg/ml at 1 hour after administration, with serum half-lives (T 1/2) of 1.15 and 0.89 hours, respectively. Mean cumulative urinary excretion rates of AMPC and CVA in the 6 hours after administration were 24.91% and 10.19%, respectively.
BRL 25000 granules were also administered at daily doses of 25.1-60.4mg/kg in 3 divided doses, to 20 pediatric patients with bacterial infections (4 acute tonsillitis, 2 acute pharyngitis, 3 suspected scarlet fever, 3 acute bronchitis, 8 urinary tract infection). The efficacy rate was 100% clinically and 70% bacteriologically.
No adverse reactions were observed, however, abnormal laboratory findings were observed in 4 cases (slight elevation of GOT in 2, GPT in 1, eosinophilia in 1).

View full abstract

The authors have carried out laboratory and clinical studies on the BRL 25000 granule (containing 2 parts amoxicillin and 1 part clavulanic acid).
The antibacterial activity of BRL 25000 against 29 clinically isolated strains of S. aureus, 30 E. coli and 30 K. pneumoniae were measured by the agar dilution method using an inoculum size of 10⁶ cells/ml. β-Lactamase production was detected by the Nitrocefin method.
The MICs of BRL 25000 against S. aureus ranged from 0.2-12.5μg/ml, with the majority of strains being inhibited by 1.56μg/ml or less. Seven β-lactamase producing strains of S. aureus were all inhibited by less than 12.5μg/ml. The range against E. coli was 1.56-100μg/ml, with the majority inhibited by 6.25μg/ml or less. Fifteen β-lactamase producing strains of E. coli were inhibited by 6.25-100μg/ml and the majority by 25μg/ml or less. All strains of K. peumoniae were β-lactamase producers and the MIC distribution against K. pneumoniae was 1.56-50μg/ml, with a majority inhibited by 3.13μg/ml or less, 96% of strains, were inhibited by less than 6.25μg/ml. Against K. pneumoniae, BRL 25000 showed a 8 to 16-fold superiority when compared with AMPC.
In a pharmacokinetic study, BRL 25000 granules were orally administered to children in the fasting state at single doses of 7.5mg/kg and 20mg/kg. The peak serum levels of AMPC were 6.13 and 6.94μg/ml approximately 1 hour after administration and decreased with half-lives of 1.08 and 0.97 hours, respectively. The corresponding serum levels of CVA were 1.16 and 1.90μg/ml at 1 hour after administration, with half-lives of 0.99 and 0.87 hour, respectively.
In clinical studies, the BRL 25000 granule was effective in 39 cases of bacterial infection out of a total of 41 treated.
Side effects were limited to 2 cases of diarrhea and minor changes in laboratory findings were elevation of serum GOT (1 case), elevation of serum GPT (1 case), and eosinophilia (2 cases).

View full abstract

BRL 25000 (187.5 and 375mg tablets), a formulation of CVA-K and AMPC in the ratio of 1: 2, and AMPC (as control drug) were administered to healthy volunteers, aged 20-28 years and weighing 60-85kg (68.8kg, on average). Each drug was administered 3 times a day (after meals) for 5 days and the volunteers were separated into 3 groups of 4 subjects each. The effect on the fecal flora was studied before dosage, during administration (day 3 and 5) and day 3 and 5 after the administration course was completed. Studies were undertaken to isolate C. difficile on the last day of administration and 3 and 5 days after administration had ceased. Fecal concentrations and the susceptibility of the isolates to AMPC, CVA-K and BRL 25000 were measured. Side effects and laboratory findings were studied. The results obtained were as follows:
1. In BRL 25000 (187.5mg × 3/day) group, the population of E. coli was on average, 1 × 106-9 × 10⁶ cells/g feces before initiation of administration and it increased by 2 logarithms 3 and 5 days after initiation of administration. By 3 and 5 days after end of administration, the E. coli population was similar to the initial population. The population of Klebsiella sp. was 1 × 10⁶-9 × 108 cells/g feces on average before commencement of dosage and it increased by 2 logarithms 3 days after initiation of administration but there was no consistent change in the Klebsiella sp. population thereafter. The Enterobacter sp., population was not consistent neither was the population of other Enterobacteriaceae. In total, the mean Enterobacteriaceae population was 1 × 107-9 × 107 cells/g feces before initiation of administration and increased by 2 logarithms 3 days after initiation of administration, and then returned to the initial level 5 days after end of administration. No consistent changes in population were noted for the other Gram-negative bacilli. The Staphylococcus sp. population was 1×10⁶-9×10⁶ cells/g feces on average before initiation of administration. This organism was detected in only 1 case 3 days after initiation of administration and in another 5 days after initiation of administration, thereafter, the population was similar to the initial population. The population of Enterococcus sp. was 1×10⁶-9×10⁶ cells/g feces on average before initiation of administration and there was no remarkable change in population 3 and 5 days after initiation of administration, but it increased by 2 logarithms 3 and 5 days after administration had ceased. No consistent changes were found for other Gram-positive organisms. Throughout the study the population of Bacteroides sp., and the total population of anaerobic organisms, was 1×10⁹-9×10⁹ cells/g feces and 1×10⁹-9×10¹⁰ cells/g feces (average results) respectively, and no effect on these organisms was found. C. difficile was not found in any of the volunteers.
2. In BRL 25000 (375mg×3/day) group, the population of E. coli was 1×10⁶-9×10⁶ cells/g feces on average before initiation of administration, similar to the BRL 25000 (187.5mg×3/day) group, and it also increased by 2 logarithms 3 and 5 days after initiation of administration. Three and 5 days after the end of administration, the population was similar to the initial population. The number of cases from which Klebsiella sp. were detected gradually increased with time; i. e. 1 case before initiation of administration, 2 cases 3 days after initiation of administration and 4 cases 5 days after initiation administration.

View full abstract

MICs of BRL 25000, a combination of a newly developed β-lactamase inhibitor CVA and AMPC in the ratio of 1 to 2, were determined against a number of bacterial strains and compared with those of AMPC, CVA, CEX and CCL. The 98 bacterial strains tested included 2-S. aureus, 23-H. influenzae, 25-E. coli, 22-K. pneumoniae and 26-P. mirabilis.
In pharmacokinetic studies, BRL 25000 medium granules were administered to groups of 3 male subjects, aged between 7 years 8 months and 9 years 5 months, at doses of 10, 15 and 20mg/kg, 2 hours after a meal. The resultant serum and urine concentrations and drug recoveries were measured.
Furthermore, BRL 25000 was administered to a total 43 patients 2-pharyngitis, 8-tonsillitis, 3-bronchitis, 2-pneumonia and 28-urinary tract infection) whom clinically evaluable. An average daily dosage of 45.3mg/kg was given, in 3 or 4 divided doses, for a period of 8 days on average. Clinical and bacteriological effects as well as side effects were studied.
In the microbiological studies on 98 clinical strains, including β-lactamase negative bacteria, BRL 25000 showed MICs against the Gram-positive cocci (2-S. aureus) superior to the other 4 drugs at inoculum sizes of 10⁸ and 10⁶ cells/ml. For the Gram-negative bacilli, against H. influenzae at inoculum sizes of 10⁸ and 10⁶ cells/ml, BRL 25000 was inferior in the small MIC range but superior in the large MIC range to AMPC, and was superior to the other 3 drugs. Against E. coli at an inoculum of 10⁸ cells/ml, BRL 25000 showed antibacterial activity next to AMPC and CCL whilst at an inoculum of 10⁶ cells/ml, it was inferior in the small MIC range but superior in the large MIC range to AMPC and CEX and was inferior to CCL but superior to CVA. Against K. pneumoniae at an inoculum of 10⁸ cells/ml, BRL 25000 was equal to AMPC, CVA and CEX but inferior to CCL, whilst at an inoculum of 10⁸ cells/ml, it was inferior to CCL but superior to the other 3 drugs. Against P. mirabilis at inoculum sizes of 10⁸ and 10⁶ cells/ml, BRL 25000 was inferior in the small MIC range but equal or superior in the large MIC range to AMPC, and was superior to CVA and CEX. It was equal or inferior in the small MIC range but equal in the large MIC range to CCL.
With regard to the susceptibilities of β-lactamase producing bacteria, out of the 98 strains tested, the 2 S. aureus strains were both positive and susceptible as already mentioned. Against 1 H. influenzae strain at inoculum sizes of 10⁸ and 10⁸ cells/ml, BRL 25000 was superior to the other 4 drugs. Against 24 E. coli and 19 K. pneumoniae strains, at inoculum sizes of 10⁸ and 10⁶ cells/ml, BRL 25000 showed about the same antibacterial activities as it did against all strains, including β-lactamase negative strains. Against 1 P. mirabilis strain at an inoculum of 10⁸ cells/ml, BRL 25000 was equal to AMPC, superior to CVA and CEX but inferior to CCL. At an inoculum of 10⁶ cells/ml, it was equal to CCL and superior to the other 3 drugs.
In the pharmacokinetic studies, serum concentrations of AMPC and CVA in the 10, 15 and 20mg/kg groups all reached peaks 1 hour after administration. At that time, the mean AMPC levels by groups were 4.38, 7.08 and 7.52mcg/ml and the corresponding mean CVA levels were 2.19, 4.10 and 4.37mcg/ml, respectively. The former showed 1.7-to 2-fold higher values than the latter and a close dose response being observed between the 10mg/kg and the 15, 20mg/kg groups, though not between the latter 2 groups. This trend was also seen in the AUC's. The mean half-lives of AMPC by groups were 1.10, 1.31 and 1.91 hours, and those of CVA 0.94, 0.86 and 0.91 hours, AMPC tending to remain longer.

View full abstract

BRL 25000 is a combination of a newly-developed β-lactamase inhibitor clavulanic acid (CVA) and amoxicillin (AMPC) in the ratio of 1 to 2. The drug, as medium granules, was administered to a total of 92 pediatric patients, ranging in age from 1 month to 13 years and 2 months, with cutaneous/soft tissue infections (70 impetigo, 6 furuncle, 7 phlegmon, 6 abscess and 3 cases of lymphadenitis). It was found subsequently that 2 of the 70 impetigo cases had received topical antibiotic medication and these were excluded from clinical evaluation to give a total of 90 evaluable cases. The daily dosage of BRL 25000 ranged from 23.7 to 75.0mg/kg, given in 3 or 4 divided doses (average 48.5mg/kg) and the duration of treatment was for 3 to 13 days (average 6 days).
Clinical isolates of S. aureus from the above cases were examined for β-lactamase production and their susceptibility determined to the 5 antibiotics BRL 25000, AMPC, CVA, cephalexin (CEX) and cefaclor (CCL). The drugs' clinical effects on the various diseases, bacteriological effects and side effects were also studied.
At an inoculum of 10⁸ cells/ml, major MICs of BRL 25000, AMPC, CVA, CEX and CCL against 71 strains of S. aureus, including β-lactamase negative ones, were 3.13mcg/ml, 12.5mcg/ml, 50mcg/ml, 12.5mcg/ml and 12.5mcg/ml, accounting for 60.6, 38.0, 49.3, 38.0 and 43.7% of the strains respectively, whilst at an inoculum of 10⁶ cells/ml, major MICs were 1.56mcg/ml, 3.13mcg/ml, 25mcg/ml, 6.25mcg/ml and 3.13mcg/ml, accounting for 57.7, 33.8, 83.1, 50.7 and 54.9%, respectively. It was noted that all drugs tended to show smaller MIC values as the inoculum size was reduced to 10⁶ cells/ml and that BRL 25000 showed the most potent antibacterial activity of all 5 drugs.
At an inoculum of 10⁸ cells/ml, major MICs of BRL 25000, AMPC, CVA, CEX and CCL against 65 β-lactamase producing strains were 3.13mcg/ml, 12.5mcg/ml, 50mcg/ml, 12.5mcg/ml and 12.5mcg/ml, and practically the same values as against all strains inclusive of β-lactamase negative ones, accounting for 64.6, 41.5, 52.3, 38.5 and 43.1% of strains respectively whilst at an inoculum size of 10⁶ cells/ml, major MICs of BRL 25000, AMPC, CVA, CEX and CCL were 1.56mcg/ml, 3.13mcg/ml, 25mcg/ml, 6.25mcg/ml and 3.13mcg/ml, respectively, all tending to be smaller than those at the higher inoculum size of 10⁸ cells/ml and being not much different from those against all strains, inclusive of β-lactamase negative ones. Again, BRL 25000 proved itself to be the most potent of all 5 drugs.
Clinical efficacy as assessed by the chief physicians for impetigo was 94.1%. The drug was assessed as good or excellent in 5 out of 6 furuncle cases, in all 7 phlegmon and all 6 abscess cases and in 2 out of 3 lymphadenitis cases. The efficacy rate for all cases was therefore, 93.3% and for the 58 β-lactamase positive cases 94.8%, both being similarly high.
The impetigo cases were divided according to daily dosage into 3 groups of 31.0-40.0, 41.0-50.0 and 51.0-60.0mg/kg, which were compared for clinical effects as assessed by the chief physicians. The efficacy rates were 89.5, 100 and 90.9%, respectively. If only the cases of β-lactamase positive strains were considered, the efficacy rates were 88.2, 100 and 92.3%, respectively. There were no significant intergroup differences nor were there any significant differences in efficacy between β-lactamase negative and positive cases. In order to obtain an efficacy rate of over 90%, it was considered necessary to use this drug at a daily dosage of 41.0-50.0mg/kg. Classified by the frequency of daily administrations, the group given the drug in 3 divided doses showed no difference in effectiveness from the group receiving 4 divided doses, though the number of cases considered were not high.
Clinical effects were also assessed by the score method.

View full abstract