Clavulanic acid (CVA) was isolated from Streptomyces clavuligerus ATCC 27064 and it has a unique chemical structure. In the present study the in vitro and in vivo andtibacterial activity of amoxicillin (AMPC) plus CVA was compared with that of either AMPC or CVA against bacterial strains resistant to β-lactam antibiotics. The results can be summarized as follows.
1) CVA had week antibacterial activity but by the addition of small amount of CVA the antibacterial activity of AMPC against gram-positive and gram-negative bacteria was markedly increased.
2) The degree of resistance of the AMPC resistant strains was related to the β-lactamase producing activity.
3) CVA inhibited, at a low concentration, all types of penicillin β-lactamase (PCase) encoded by R plasmid and cefuroxime-hydrolysing β-lactamases (CXase) produced by P. vulgaris, B. fragilis, and P. cepacia.
4) The antibacterial activity of various ratios of AMPC to CVA was compared and the most effective ratio was shown to be between 5:1 and 1:5.
5) BRL 25000 (AMPC: CVA=2:1) showed potent antibacterial activity against clinical isolates of the followings bacterial species S. aureus, S. epidermidis, E. coli, K. pneumoniae, K. oxytoca, P. mirabilis, P. vulgaris and B. fragilis.
6) BRL 25000 was more effective than AMPC against experimental intraperitoneal infections with S. aureus, E. coli, K. pneumoniae, P. mirabilis and P. vulgaris in mice.

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Clavulanic acid (CVA) was compared with other β-lactamase inhibitors for the activities of transient inhibition and permanent inactivation against various types of β-lactamases, and synergistic antibacterial effect with β-lactamase susceptible antibiotics. Although CVA manifested a marked synergistic effect with ampicillin (ABPC) on gram-positive and gram-negative bacteria producing penicillinase (PCase)-type β-lactamases, that effect was hardly observed with cephaloridine (CER) on gram-negative bacteria producing cephalosporinase (CEPase).
It was confirmed that the permanent inactivation of β-lactamase was more critical for the manifestation of the synergistic effect of the drug with ABPC than the transient inhibition of the enzyme. CVA was found to be most potent β-lactamase inactivator among those ever tested against PCase-type enzymes. On the other hand, a weak antibacterial activity of CVA itself was elucidated by its weak binding activity to the PBP II of E. coli and PBPs of S. aureus.
Since CVA markedly potentiates the antibacterial effect of ABPC on PCase-producing bacteria, especially gram-negative bacteria carrying R (bla) plasmids, it can be considered as one of the powerful tools for chemotherapy of infectious diseases caused by β-lactam-resistant microbes.

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The inhibitory effect of clavulanic acid was investigated with amoxicillin against β-lactamase produced by ampicillin/amoxicillin resistant strains. The antibacterial activity of clavulanic acid was weak, but a potentiating effect was observed against resistant strains producing β-lactamase when combined with amoxicillin or ampicillin. Strong in vitro antibacterial activity of amoxicillin concomitant with clavulanic acid was shown against amoxicillin resistant strains of E. coli, K. pneumoniae and P. vulgaris, and the activity expected of the components was observed against resistant strains of P. mirabilis, P. morganii, P. rettgeri and P. inconstans.
The β-lactamase inhibitory effect of clavulanic acid was observed against type II, III, IV and V enzymes as classified by RICHMOND, but not against type Ia.
In vivo the formulation of clavulanic acid and amoxicillin was effective in the treatment of experimental intraperitoneal infections produced with resistant strains of E. coli and K. pneumoniae that did not respond to amoxicillin, clavulanic acid and cephalexin alone.

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The in vitro antibacterial activity of amoxicillin, ampicillin, carbenicillin, ticarcillin and cephalothirs was markedly potentiated by the addition of 1 and 5μg/ml of clavulanic acid against β-lactamase producing strains of Bacteroides sp. BRL 25000 which is a formulation comprising amoxicillin and clavulanic acid, showed potent antibacterial activity against Bacteroides sp., but had relatively poor activity against β-lactarnase producing strains of Clostridium ramosum and Clostridium clostriditforme.

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The in vivo antibacterial activity of BRL25000 was investigated against mouse experimental mixed infection coused by β-lactamase producing strain of B. fragilis and β-lactamase none producing strain of E. coli.
The influence of treatment on mouse cecal microflora was studied following treatment with either 2mg/kg of BRL25000 or amoxicillin for 7 days.
The following results were obtained.
1. BRL25000 produced a more potent therapeutic effect than amoxicillin and cefazolin in the mouse experimental infection study.
2. Following the administration of amoxicillin, strains of C. clifficile were detected in numbers in excess of 10⁵cfu/g of mouse cecal contents, whereas very small number were isolated following prophylactic treatment with BRL25000.

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The in vitro and in vivo antibacterial activity of amoxicillin (AMPC) plus clavulanic acid (CVA), a recently developed β-lactamase inhibitor, were investigated and the following results were obtained.
1. Antibacterial activity was studied against standard strains stocked in our laboratories. CVA showed a low level of antibacterial activity. The addition of CVA to AMPC at ratios of 1 to 2, 2 to 1 and 8 to 1 (AMPC plus CVA) markedly potentiated the antibacterial activity of AMPC against resistant strains of S. aureus, K. pneumoniae, and P. vulgaris, but had no effect on typically sensitive strains.
2. Similar results were obtained when these ratios were tested against a large number of clinical isolates and each of the ratios had antibactirial activity superior to that of cephalexin against AMPC resistant strains.
3. The potentiating effect of CVA on AMPC activity was further established in studies using the checkerboard dilution method.
4. The β-lactamase inhibitory activity of CVA was investigated in the presence of 12.5, 6.25 and 3.13μg/ml of AMPC against AMPC resistant clinical isolates. As a result, the enzyme inhibitory activity of CVA was shown to vary depending on both the bacterial species and strains within species studied. For example against K. pneumoniae species two distribution peaks were obtained.
5. Synergism was observed in bactericidal kill curve experiments using the established MIC concentrations for each of the ratios (1 to 2, 2 to 1 and 8 to 1).
6. The in vitro results were substantiated by in vivo mouse experimental infection studies with AMPC resistant strains of S. aureus, E. coli, K. pneumoniae, and P. vulgaris.
Analysis of ED₅₀ values showed that the 2 to 1 ratio was the most efficacious in these studies.

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The effect of a combination of clavulanic acid (CVA) and amoxicillin (AMPC) on transpeptidase activity of the peptidoglycan synthesis was studied on β-lactamase producing Escherichia coli CSH 2-RK 1 (RICHMOND type la) and CSH 2-RE 45 (RICHMOND type V), and their parent strain CSH 2-NAr.
Both β-lactamase producing strains were insusceptible to AMPC (MIC:≥6, 400μg/ml) and CVA (MIC: 100μg/ml). A combination of AMPC and CVA showed a marked synergistic effect. Transpeptidation of peptidoglycan synthesis in the ether treated cells was not inhibited by 100μg/ml of AMPC or CVA alone. However, the combination of both showed marked inhibition of the peptidoglycan synthesis. In contrast, transpeptidation of AMPC-sensitive parent strain was inhibited by 100 μg/ml of AMPC, moreover, no synergistic activity was shown by the combination of AMPC and CVA.β-lactamase activities from E. coli RK 1 and RE 45 were inhibited by CVA.
These results demonstrated that the mechanism of the synergistic action of the combination of AMPC and CVA was attributable to the fact that CVA inhibited the β-lactamase activity present in the periplasmic space, and AMPC could penetrate through the outer membrane and bind to its target sites, transpeptidase, on the cytoplasmic membrane (inner membrane).

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Basic studies on a new antibiotic BRL25000, a 2:1 ratio of amoxicillin (AMPC) and clavulanic acid (CVA) were performed and the following results were obtained.
The substrate profile of the β-lactamase produced by an ampicillin (ABPC) resistant H. influenzae (NNH 55161) was determined by a macro-idometric method, and the type was concluded to be a PCase type I (MITSUHASHI's grouping). Synergism was detected at a ratio of AMPC 256 to CVA 1 against four ABPC resistant β-lactamase producing strains of H. influenzae isolated from respiratory tract infections.
The antibacterial activity of BRL25000 was studied against clinically isolated ABPC resistant strains: 18 H. influenzae, 23 S. arueus, 25 K. pneumoniae, 3 B. catarrhalis, 10 S. faecalis, 32 P. aeruginosa, 9 E. coli and 10 E. cloacae.
Clavulanic acid potentiated the activity of amoxicillin against β-lactamase producing strains of H. influenzae, S. aureus, K. pneumoniae and B. catarrhalis. However, potentiation was not seen for the formulation (AMPC plus CVA) against strains of S. pneumoniae, S. faecalis, P. aeruginosa, E. coli and Enterobacter sp.
Serum and sputum concentrations were studied in 2 patients with chronic respiratory tract infections, the sputum concentrations of AMPC and CVA were 0.64 and 0.11μg/ml, respectively, following oral administration of 750mg of BRL25000.

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The in vivo dynamics of BRL25000 were investigated following a single oral administration of 375 mg [2 tablets of 187. 5 mg of BRL25000 containing 125 mg (pfa) amoxicillin trihydrate and 62.5mg (pfa) potassium clavulanate] to 9 patients with various degrees of renal function (creatinine clearance of less than 3 to 115 ml/min/1.48m²)(Table 1). In 2 of 9 patients, artificial kidney dialysis was performed during this study.
The results are shown in Table 2 and 3, and Fig. 1 and 2. Higher serum levels and prolonged serum half-lives of amoxicillin, and similar serum levels and half-lives of clavulanic acid were observed in patients with more severely impaired renal function. Urinary recovery of amoxicillin was prolonged, and that of clavulanic acid was prolonged and diminished in relation to the degree of renal failure. Artificial kidney dialysis reduced the serum levels of both amoxicillin and clavulanic acid.
The dosage modification required for BRL25000 in patients with various degrees of renal function could be similar to that of amoxicillin.

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Phase I study on BRL 25000, a 2 to 1 ratio of amoxicillin (AMPC) and clavulanic acid (CVA) was carried out in healthy male volunteers and the following results were obtained.
After oral administration of BRL 25000, the serum concentration of AMPC and CVA was distributed according to the dose volume and the half lives were almost 1 hr. Urinary recovery rate was about 60% in AMPC, about 30% in CVA. On consecutive administration of BRL 25000 375 mg tablets t. i. d. for 7 days, no accumulation was detected in serum and urine.
One volunteer after 2 tablets, 3 volunteers after 3 tablets of BRL 25000 oral administration complained of a slight nausea which disappeared immediately. In one volunteer the BUN was slightly elevated after consecutive administration for 7 days, but returned to a normal value at re-study 1 week later.

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BRL25000 is a 2 to 1 formulation of β-lactam compounds, namely the broad spectrum penicillin amoxicillin (AMPC), and the β-lactamase inhibitor clavulanic acid (CVA) respectively. Microbiological assay methods suitable for the measurement of amoxicillin and clavulanic acid in clinical specimens of serum and urine are described.
AMPC concentrations were measured by standard agar-diffusion microbiological assay using Micrococcus luteus ATCC9341 as assay organism. The CVA concentrations in body fluids were assayed using a β-lactamase producing strain of Klebsiella pneumoniae ATCC29665 in the presence of subinhibitory concentrations of penicillin G.
Fresh human serum and 0.1 M citrate buffer were used as body fluid diluents and studies showed that the AMPC and CVA content in serum and urine were stable for 2 weeks at temperatures below -55°C.

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A reversed phase ion pair HPLC method with UV detection has been developed for the determination of clavulanic acid (CVA) in human urine, taking solvent effects on detection wave length and on retention behavior on a hydrophobic stationary phase into account. The addition of tetrabutylammonium bromide (TBAB) to aqueous methanol containing phosphate buffer salts facilitated the detection of CVA at an accessible UV wave length, and also allowed the specific separation of CVA from endogenous urinary components.
The time courses of urinary excretion rate for intact CVA, amoxicillin (AMPC), and the latter's metabolites Denicilloic acid (AMPA) and penamaldic acid (AMPM) 3 following oral doses of BRL25000 or each of CVA and AMPC separately to healthy human subjects were determined by the established HPLC method. The statistical moment analysis of the time course curves indicated that when CVA was dosed in combination with AMPC, 27 to 45% of the dosed amount (125 mg) of CVA was excreted in the urine as the intact form with the mean residence time (MRT) ranging of 1.6 to 2. 1 hours after administration, while the corresponding values for AMPC were 56 to 73%(including metabolites) and 2.0 to 2.6 hours (for intact AMPC). These results indicate that CVA may undergo less absorption (and/or a greater degree of metabolism and extraurinary excretion) and faster urinary excretion than that of AMPC. From comparison of these results with those obtained after administration of individual doses of CVA and AMPC to the same subjects, it was found that there was no appreciable pharmacokinetic interaction between CVA and AMPC ascribable to the combination dose, although the analysis of variance indicated that the difference in the excreted amount of AMPM between individual and combined doses was significant at the 5% level.

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BRL 25000 is a formulation consisting of 2 parts of amoxicillin (AMPC) and 1 part of clavulanic acid (CVA). The antibacterial activity of BRL 25000 was investigated against clinical isolates of S. aureus, E. coli, K. pneumoniae, Proteus sp. and Bacteroides sp. using amoxicillin as a control drug, and the activity of BRL 25000 was superior to that of amoxicillin.
A cross over study with 187.5 and 375 mg BRL 25000 was carried out in 6 healthy volunteers and the serum concentrations and urinary excretion of AMPC and CVA were studied, respectively. The peak serum concentration of AMPC was 2.5 and 5.6μg/ml, and that of CVA was 1.4 and 3.1μg/ml.
The urinary excretion rate of AMPC was 64.6 and 67.0%, and that of CVA was 46.9 and 46.0% within 8 hours after administration. The serum and urine concentration ratio between AMPC and CVA was similar to that of the administration ratio.
Forty five patients with various infections were treated with 3 or 4 tablets daily of BRL 25000 (375 mg). The clinical response was excellent in 21 cases, good in 18 cases, fair in 3 cases and poor in 3 cases. Overall the efficacy rate was 87.0%.
Gastro intestinal side effects were observed in 3 cases. Two cases of elevated GPT and 1 eosinophilia were noted in the laboratory findings.

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Nine chronic bronchitic patients with either pneumoconiosis, hypothyroidism and diabetes mellitus, or syphylis and lung fibrosis and a previous long medical and therapeutic history (ages; 50-59 years 2 cases, 60-69 years 4 cases, 70-79 years 3 cases, sexes; male 8, female 1), and one patient with chronic panbronchiolitis (41 years, male) and another with moderate to severe acute bronchitis (31 years, female), were included in the study. In all 20 courses of therapy with BRL 25000 were studied in a total of 11 patients. The dosages (total in g.) and duration of therapy were as follows; one tablet, three times a day, after meals, 7 or 8 days (7.875-9.0g): 10 cases, 14 days (15.75g) 1 case, one tablet, four times a day, after meals and before sleep (10.5g): 2 cases, two tablets, three times a day, after meals, 7 days (15.75g): 1 case, 14 days (31.5g): 4 cases, 21 days (47.25g) and 28 days (63.0g) in each one case.
Clinically excellent results were obtained and the overall clinical effectiveness rate was 73.7%(14/19), the bacteriological eradication rate from sputum was 52.9%(9/17). No side effects and abnormal clinical findings were found.

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Minimum inhibitory concentrations (MICs) of BRL25000 against 51 strains of clinically isolated β-lactamase producing coagulase negative Staphylococcus were determined, as were MICs for amoxicillin (AMPC) against the same organisms. The MIC of BRL25000 was less than half that of AMPC for 47 of the 51 strains (92.2%). For 27 of the 51 strains (52.9%) the MIC of BRL25000 was less than 6.25μg/ml.
A single dose of 375 mg of BRL25000 was administered orally to 5 healthy male adults at times of fasting and non-fasting. At fasting, the peak plasma levels were 2.90μg/ml (1.5 hours) for AMPC and 1.91μg/ml (1.0 hour) for clavulanic acid (CVA). The peak urinary levels detected were 269.4μg/ml (2-4 hours) for AMPC and 94.8μg/ml (0-2 hours) for CVA. Urinary recovery rates during the first 6 hours averaged 66.0% and 32.8% for AMPC and CVA respectively. Non-fasting peak plasma levels were 3. 25μg/ml (1.5 hours) for AMPC and 1.89μg/ml (1.5 hours) for CVA and the peak urinary levels were 462.2μg/ml (0-2 hours) for AMPC and 131.6μg/ml (0-2 hours) for CVA. Urinary recovery rates during the first 6 hours averaged 49.5% for AMPC and 29.0% for CVA.
BRL25000 was administered to 44 patients with respiratory tract infections (RTI) and urinary tract infections (UTI). Individual doses of 375mg were administered either 3 or 4 times per day. The overall efficacy was evaluated as 84.1%, being 85.7% and 83.8% for RTI and UTI respectively. The clinical efficacy in UTI caused by AMPC-resistant bacteria was assessed by isolated bacterial, as follows; E. coli (92.9%, 14 cases), K. pneumoniae (50%, 4 cases) and K. oxytoca (100%, 1 case). The clinical efficacy in UTI caused by AMPC-resistant bacteria, assessed by individual disease was as follows; acute cystitis (100.0%, 7 cases), acute pyelonephritis (100.0%, 3 cases), chronic cystitis (75.0%, 4 cases), chronic pyelonephritis (100.0%, 2 cases) and complicated UTI (25.0%, 4 cases). The side effects were observed 3 cases of diarrhea, 1 of rash, 1 of nausea and 1 of dizziness. However, no laboratory abnormalities were found.

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1) One hundred and four strains of Haemophilus influenzae, including 12 β-lactamase positive strains, and 62 strains of Klebsiella pneumoniae were tested for susceptibility to BRL25000, amoxicillin, clavulanic acid and cefazolin by a twofold agar dilution method using an inocula replicator. All of these microorganisms were isolated from the sputum of chronic respiratory infectious diseases. The inoculum size used for this study was 10⁶cells/ml. The most striking aspect of the results was the marked susceptibility of the β-lactamase positive H. influenzae to BRL25000, although clavulanic acid and amoxicillin were not effective. Also Klebsiella pneumoniae exhibited susceptibility to the BRL25000, in spite of the lack of susceptibility to amoxicillin.
2) BRL25000 was administered orally at daily doses of 1.125-2.25 g for 7-34 days to 14 cases of chronic respiratory tract infectious disease caused by H. influenzae, three of which were infected with β-lactamase producing H. influenzae (case 1, 4, 7). The results obtained showed that BRL25000 was effective in 13 cases including the three cases from which β-lactamase positive H. influenzae were isolated. The drug was not effective in one case isolated with a β-lactamase negative amoxicillin resistant strain of H.influenzae.
3) Gastrointestinal adverse reaction was observed in three cases.

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The antimicrobial activity of BRL25000 which has a composition of 2:1 of amoxicillin and clavulanic acid, a potent inhibitor of many β-lactamases, was examined by a broth dilution method using the Dynatech MIC-2000 system. Also, the therapeutic efficacy of BRL25000 in the treatment of patients with respiratory tract infections was evaluated.
The minimum inhibitory concentrations (MICs) of BRL25000 were compared with those of amoxicillin (AMPC) and clavulanic acid (CVA) against 20 strains of each of the following clinical isolates: Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa. Reductions in the MICs of AMPC in the presence of CVA were marked for S. aureus, β-lactamase producing strains of E. coli and K. pneumoniae, but to a less extent for E. cloacae, S. marcescens and P. aeruginosa.
A daily dose of 1, 500 milli-grams of BRL25000 was given orally to a total of five patients with respiratory tract infections. The subjects examined consisted of one patient with acute pneumonia, one patient with infection associated with bronchiectasis and three patients with infection associated with lung cancer. Clinical response to the treatment with BRL25000 was excellent in two patients, good in two and poor in one. The following four potential pathogens were recovered from the sputum of these patients at the start of the treatment with BRL25000: three strains of Haemophilus infiuenzae and one strain of Klebsiella pneumoniae. Three of the strains were eradicated during the treatment with the drug. In one of these five patients, transient diarrhea was observed but disappeared after cessation of the drug.

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Five patients with respiratory tract infections and 12 with urinary tract infections were treated with BRL25000 (amoxicillin and clavulanic acid in the ratio 2:1). The effective rates were 75.0%(3/4) and 66.7%(8/12), respectively. The overall clinical effective rate was 68.8%(11/16).
Classifying the causative organisms by strain BRL25000 was effective in the treatment of 2 out of 5 cases of Klebsiella sp. 7 out of 7 cases of E. coli and 1 out of 2 cases of H. parainfluenzae. The Klebsiella sp. isolates from the two patients that responded to BRL25000 therapy were more susceptable to BRL25000 than AMPC in MIC tests.
Side effects were observed in 2 patients consisting of dizziness and nausea. Laboratory findings, transient elevation of BUN and S-creatinine were seen in one patient.

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BRL 25000, a formulation comprising the antibiotic amoxicillin and the β-lactamase inhibitor potassium clavulanate, was studied bacteriologically and therapeutically.
MIC's were measured to determine the sensitivities of 101 strains of gram-negative bacteria to BRL25000 and amoxicillin. The MIC's of amoxicillin for 12 of 49 strains of E. coli were 12.5μg/ml while MIC's for 28 strains were in excess of 200μg/ml. However, MIS's of BRL 25000 were 12.5-25μg/ml for 28 strains, 25-50μg/ml for 6 strains and in excess of 200μg/ml for only 2 strains.
Thus, most of the strains which were resistant to amoxicillin were susceptible to BRL25000. Similar results were obtained with 16 strains of Klebsiella, BRL 25000 showing MIC's of 12.5μg/ml or less for 10 of 14 strains which showed AMPC MIC's greater than 200μg/ml.
Similar results were obtained with P.vulgaris however, against P. aeruginosa the majority of both the AMPC and BRL 25000 MIC's were 200μg/ml or greater.
Using a BRL 25000 solution it was possible to determine AMPC and CVA by HPLC. AMPC and CVA were detected in urine and serum after administration of BRL 25000 but accurate measurement was not possible. A further study will therefore be required.
BRL 25000 was administered to 2 cases of acute pyelonephritis, 1 case of acute cystitis, 1 case of chronic cystitis and 1 case of bronchopneumonia.
The response to theraphy was assessed as exellent in 3 (60%), good in 1 (20%), and fair in 1 (20%). Overall the clinical efficacy was good to excellent in 80%(4/5) of the cases. In terms of bacteriological response, eradication was observed in 3 cases, a decrease in 1, and it was not possible to evaluate the response in the other. Laboratory abnormalities were observed in one patient consisting of temporary slightly elevated GOT and Al-P, but no severe side effects were found.

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BRL25000, a formulation of an antimicrobial agent amoxicillin and a β-lactamase inhibitor clavulanic acid, was evaluated to establish its antibacterial activity, absorption, excretion and clinical effect, and the following results were obtained.
The antibacterial activity of BRL25000 against clinically isolated strains of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and indole-positive Proteus sp. was 2 to 3 tubes superior to amoxicillin. This difference was particularly marked against amoxicillin-resistant strains of high MIC level (≥100μg/m l amoxicillin) where BRL25000 exhibited MIC value of (3.13-25μg/ml). On the other hand, the antibacterial activity of BRL25000 against Enterobacter sp., Serratia marcescens was equal to that of amoxicillin.
After oral administration of 375 mg of BRL25000 to healthy volunteers in the fasting state, the serum levels of amoxicillin and clavulanic acid peaked at 4.05±0.74 μg/ml and 2.79±0.66μg/ml after 1.5 hours, and declined with a half-life of 0.81±0.17 and 0.65±0.16 hours respectively. The urinary recovery rates for amoxicillin and clavulanic acid up to 6 hours after administration were 54.9±4.0 and 24.1±10.2% respectively. After administration of BRL25000, amoxicillin and clavulanic acid showed high serum concentration levels, and these urinary excretion were also good.
BRL25000 was administered 3 to 4 tablets per day for 2 to 19 days to a total 13 cases consisting of 1 case of acute tonsilitis and 12 cases of urinary tract infection. Among the 10 of 13 cases in which the clinical effect could be judged, the clinical effect of BRL25000 was excellent in 3, good in 4, fair in 1, and poor in 2 cases.
BRL25000 showed no noteworthy side effects save skin rash in 2 cases.

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BRL25000 was administered to a total of 18 patients at a dose of 4-6 tablets daily, 12 of which had a chronic bronchitic infection, and 6 pneumonia. Four of the patients with chronic bronchitis had not been previously treated, whilst the other 8 had responded poorly to treatment with other antibiotics (mainly AMPC). Four of the patients with pneumonia had not been previously treated, whilst the other 2 had responded poorly to treatment with other antibiotics (mainly AMPC). The clinical response was evaluated as good in 6 of the cases with chronic bronchitis and poor in 6, and good in 5 of the cases with pneumonia and poor in 1.
The overall effectiveness rate in the “initial treatment” group was 88%(7/8), whilst the rate in the group that had responded poorly to other treatment was 40%(4/10).
Side effects observed were 1 case of stomach discomfort and 1 of rash.
Thus, it is suggested that BRL25000 is a useful drug for the treatment of RTI, especially chronic complicated RTI, and further evaluation in this field would be worthwhile.

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BRL25000, a new antibiotic formulation consisting of 1 part clavulanic acid plus 2 parts amoxicillin, administered to 9 patients with various infectious diseases (pneumonia 1, acute bronchitis 3, acute pyelonephritis 1, chronic cystitis 4 cases). BRL 25000 was given orally 1, 125-2, 250 mg/day 3-11 days. Clinical efficacy was excellent in 3, good in 2, fair in 2 and poor in 2 cases. Side effect to BRL 25000, slight nausea, was observed in 1 case.

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The antibacterial activity of BRL25000 against amoxicillin resistant clinical isolates of E. coli and K. pneumoniae was studied and for the majority of strains the MIc's were lower for BRL25000 than for amoxicillin alone. It is suggested that this was due to the β-lactamase inhibitory properties of clavulanic acid.
Blood levels and urinary recoveries of BRL25000 and amoxicillin were determined in each of 12 healthy volunteers by the cross over method. There was no difference in the amoxicillin blood levels between BRL25000 administration and administration of amoxicillin alone, therefore the presence of clavulanic acid did not affect amoxicillin blood levels.
Clinical results showed BRL25000 administration to be ineffective in 2 cases of bronchiectasia effective in 14 cases of slight infection such as acute bronchitis, tonsillitis and cystitis, and effective in 3 cases of acute pneumonia. No side effects were observed, and it is concluded that BRL25000 is an effective antibiotic in the treatment of moderately infectious diseases.

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BRL25000 was administered to 3 cases of pyelonephritis and 8 cases of cystitis. Ampicillin resistant bacteria were found in the urine of 8 out of these 11 UTI cases, and 4 of the 8 responded satisfactorily to BRL25000. The bacteria detected in urine after cessation of BRL25000 treatment were Klebsiella sp.(1), Serratia marcescens (1), Proteus vulgaris (1), Proteus rettgeri (1), P. aeruginosa (1), Candida (1) and Proteus morganii (3).
The susceptibility of ampicillin resistant gram negative bacteria to BRL25000 was examined using sensitivity discs. Twenty six out of 30 strains of Klebsiella sp., 38 out of 53 E. coli strains, and 14 out of 18 strains of Proteus vulgaris were susceptible to BRL25000. Resistance to BRL25000 was found in all ampicillin resistant strains of Serratia marcescens (42), Enterobacter sp.(10) and Proteus morganii (24).

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BRL25000, a combination drug containing amoxicillin and clavulanic acid in a tablet, was given to total of 37 patients with infectious diseases. Twenty-eight out of 37 patients had respiratory infections and 9 out of 37 had urinary tract infections. The drug was orally administered in a dose of 1 tablet t. i. d. or q. i. d. for 4 to 7 days.
1) Clinical effectiveness: Good responses were observed in 3 out of 6 cases with acute tonsillitis, in 4 out of 7 cases with acute pharyngitis and 10 out of 15 cases with acute bronchitis. 1 case was undecided and the efficacy rate was 63.0%(17/27) in respiratory infections. Good responses were also observed in 3 out of 4 cases with acute cystitis (1 case was undecided) and in all of 5 cases with acute pyelonephritis, and the efficacy rate in urinary tract infections was 100%(8/8). The overall efficacy rate in the total 35 cases excluding 2 drop outs was 71.4%(25/35).
2) Bacteriological effectiveness: Each of one strain of H. parahaemolyticus, K. pneumoniae and H. influenzae isolated from respiratory infections was eliminated with this treatment. All of 5 strains of E. coli each of Proteus sp. and Enterobacter sp., both of 2 strains of gram-positive Micrococcus sp., and each of gram-positive Bacillus sp. and Enterococcus sp. isolated from urinary tract infections were eliminated with this treatment.
One strain of ampicillin-resistant E. coli (>800 μg/ml) isolated from a patient with acute pyelonephritis was MIC of 25 μg/ml to BRL25000 and was eliminated.
3) Side effects: Nausea, epigastric discomfort and diarrhea were noted in three different cases, though all of them were able to undergo treatment through out the study. Hematological and biochemical examinations were carried out on 24 patients before and after the treatment, no abnormal changes due to the drug being observed.

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BRL 25000 was administered to a total of 15 patients, 13 of which had respiratory tract infections, 1 urinary tract infection and 1 enteritis.
The clinical response was evaluated as excellent in 2 cases, good in 7 cases, fair in 2 cases poor in 3 cases, and unassesable in 1 case. The overall effectiveness rate was therefore 64.3%(9/14). Of the 13 cases with RTI, 8 were chronic airway infections. The effectiveness rate of BRL 25000 against these was 75%(6/8).
A clinical response of 90%(9/10) was obtained from cases excluding those from which P. aeruginosa was isolated.
Side effects were observed as 3 cases of nausea, anorexia and stomach pain. No laboratory abnomalities were observed.

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BRL 25000, a formulation drug of amoxicillin and clavulanic acid, was investigated for its antibacterial activity, absorption, excretion and clinical effects and the following results were obtained.
1. BRL 25000 had potent activity against strains of S. aureus, E. coli, K. pneumonia. and P.mirabilis, isolated from patients, and the MIC peaks of each strain were 0.39 μg/ml, 6.25 μg/ml, 3.13 μg/ml and 0.78 μg/ml, respectively.
2. Serum levels were determined after oral administration of 750mg of BRL 25000 with 150ml of water to four healthy adult volunteers, in the fasting and non-fasting states respectively. The serum levels reached a peak at 1.5 hr. after administration in the fasting and 2hrs. in the non-fasting state. The peak levels obtained were 4.37 μg/ml of amoxicillin and 4.19 μg/ml of clavulanic acid in the fasting and 3.15 μg/ml of amoxicillin and 1.93 μg/ml of clavulanic acid in the non-fasting state. The concentration ratio of each component in the serum was 1.0 to 2.0 and the ratio of non-fasting was larger than that of fasting. The peak urinary concentrations of the component of the drug were observed 2-4hr. after dosing, and were 1, 125 μg/ml for amoxicillin and 455 μg/ml for clavulanic acid when fasted and 2, 051 μg/ml for amoxicillin and 273 μg/ml for clavulanic acid at non-fasted. the urinary recovery rates 0-6hr. after administration were 59.0% for amoxicillin, and 43.4% for clavulanic acid when fasted and 72.5% for amoxicillin, and 24.3% for clavulanic acid when non-fasted.
3. Clinical results were obtained from 25 cases, consisting of 6 of acute tonsillitis, 4 of acute bronchitis, 1 of chronic bronchitis and 14 cases of acute cystitis. The therapeutic effects (dosage 4-8 tabs/day) were excellent in 3 of acute tonsillitis, 2 of acute bronchitis, 6 of acute cystitis, and good in 1 of chronic bronchitis and 8 of acute cystitis. BRL 25000 obtained good effectiveness in 5 cases in which pretreatment with amoxicillin or ampicillin was evaluatel as poor. No abnormal clinical and laboratory findings were observed.

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The relationship between antibacterial activity (MIC) and disc inhibition zone diameters and ampicillin inactivation by discs graded according zone size, was investigated on 20 isolates.
The results obtained: inactivating positive strains (penicillinase producing strains)/number of isolates can be summarized as follows, S. aureus 0/1, E. coli 4/10, K. pneumoniae 4/4 K. oxytoca 1/1, E. cloacae 1/1, P. vulgaris 1/1 P. morganii 0/1, P. aeruginosa 1/1
12 strains classified as inactivating positive, with the exception of P. aeruginosa, were shown to be insusceptible to AMPC by decreased MICs and enlarged disc inhibitory diameters to BRL25000.
Nine patients consisting of 5 with acute simple cystitis caused by E. coli, including 3 strains resistant to ABPC and AMPC, one cystitis with epididymitis caused by E. coli, one bronchopneumonia caused by S. pneumoniae, one angina acunaris caused by A type hemolytic Streptococci and one lymphangitis (unknown pathogen) were treated with BRL25000.
The clinical response in all of the cases was excellent or good. One side effect of rash was observed but no severe side effects were seen.

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BRL25000, one tablet of the drug containing 250 mg of AMPC and 125 mg of CVA, was administered to 13 patients with urinary or pulmonary infections.
Effective results were obtained in 9 out of 10 cases with urinary infections, and one out of 3 cases with pulmonary infections.
No side effects except 1 case with abdominal pain and diarrhea, were observed.
This drug shows very strong antibacterial activity against several strains which are resistant to AMPC. These include E. coli, K. pneumoniae, P. mirabilis and E. cloacae.
It is considered that BRL25000 may constitute an advance to the antibiotic treatment of β-lactamase proplucing bacterial infections.

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BRL25000, a Preparation containing two parts of amoxicillin with one part of clavulanic acid as its potassium salt, was examined as to its in vitro activity against clinically isolated bacteria, its serum levels and urinary excretion afer oral administration before and after meal, as well as to its clinical effectivness.
The results obtained were as follows:
1) Antibacterial activity in vitro:
BRL25000 was found to be active against most of the clinically isolated bacteria showing higher activity against most of E. coli and S. aureus strains than cephalexin.
2) Serum levels and urinary excretion in humans:
Cross-over studies were carried out administering BRL25000 (750mg) to five healthy volunteers either fasting or after meal. Concentrations of amoxicillin and those of clavulanic acid in the sera and urine.
No significant difference was detected in the serum levels of amoxicillin between those fasting and those after meal, peak levels being detected two hours after the dosage; serum concentrations of clavulanic acid after meal were lower than those during fasting.
The urinary excretion rates of amoxicillin six hours after administration was higher after a meal than fasting, whilst clavulanic acid showed the opposite result.
3) Clinical trials:
Thirty five cases with various infections were treated with BRL25000 (187.5-375mg×3/day). Seventy seven eight percent (14/18) of respiratory tract infection cases responded with good results.
All of 7 cases of urinary tract infection also responded well and BRL25000 was also effective in 77.8%(7/9) of patients with other diseases (colitis, lymphadenitis, cholangitis etc.).
As to side effects, in one of the patients the administration was discontinued due to nausea and vomiting, and another complained of nausea and anorexia. No abnormal results attributable to the drug administration were found from laboratory and biochemical examinations.
The results obtained should endorse the usefulness of the drug.

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BRL25000 is an antibiotic comprising amoxicillin and clavulanic acid (β-lactamase inhibitor). To evaluate its therapeutic efficacy, BRL25000 was orally administered to 8 patients with pulmonary infections at a daily dose of 1, 125mg or 3, 000mg administered as t. i. d. or q. i. d. respectively.
The clinical response was evaluated as excellent in 1 case, good in 4 cases, poor in 1 case and unassessable in 2 cases.
Side effects: gastrointectinal distress was observed in 5 of the 8 patients consisting of diarrhea, nausea and vomiting. Medication was discontinued in 3 cases.
Laboratory tests revealed nothing abnormal.

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BRL25000, a combination of clavulanic acid and amoxicillin, was administered to patients with respiratory tract infections, and its merit was evaluated. BRL25000 was administered to a total of 20 patients consisting of 17 cases of chronic lower airway infection, 1 of pneumonia, 1 of lung abscess and 1 of bronchitis. The clinical response was evaluated as excellent in 9 cases, good in 8 cases and poor in 2 cases. Evaluation was not possible in the other case due to discontinuation of treatment. The overall effectiveness rate was therefore 89%(17/19).
Organisms isolated by transtracheal aspiration from the 17 cases which responded favourably were H. influenzae (5), S. pneumoniae (4), H. parainfluenzae (2), B. catarrhalis plus S. marcescens (2), B. catarrhalis plus K. pneumoniae (1), S. pneumoniae plus H. influenzae (1), S. pneumoniae plus H. parainfiuenzae (1) and S. pneumoniae plus Propionibacterium (1). Organisms isolated from the 2 cases which responded poorly were H. influenzae and B. catarrhalis plus S. marcescens. 3 of the cases which responded favourably to the BRL25000 treatment had unsuccessfully been treated with other antibiotics. just prior to BRL25000.
Side effects were observed in 2 cases consisting of loss of appetite/nausea in one and diarrhea in the other (treatment discontinued) case.
From these results it appears that BRL25000 is a valuable drug in the treatment of respiratory tract infection.

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BRL25000, a preparation containing two parts of amoxicillin to one part of clavulanic acid (β-lacta mase inhibitor) as its potassium salt, was studied fundamentally and clinically.
A study of its MICs showed BRL25000 to be active against most of the clinically isolated bacteria, showing higher activity than amoxicillin (AMPC) against most strains of Staphylococcus aureus, E. coli, Klebsiella pneumoniae and Proteus vulgaris. The MICs of BRL25000 against most strains of Staphylococcus aureus were less than 6.25μg/ml. The MICs of BRL25000 and AMPC were similar against Haemophilus iniluenzae, Proteus mirabilis and Acinetobacter. However, against β-lactamase producing strains of Haemophilus BRL25000 was more active than AMPC. The MICs of BRL25000 were less than 0.78μg/ml against most of the above bacteria.
The MIC's of BRL25000 were in excess of 100μg/ml against Proteus morganii, Serratia marcescens, Pseudomonas aeruginosa and Pseudomonas cepacia.
Blood concentrations of AMPC and clavulanic acid (CVA), after oral administration of a 375 mg BRL25000 tablet following overnight fasting peaked 2 hours, mean concentrations of AMPC and CVA of 4.7μg/ml and 2.44μg/ml respectively. The concentrations of AMPC and CVA after 4 hours were 1.66μg/ml and 1.04μg/ml and after 6 hours were 0.54μg/ml and 0.28μg/ml respectively.
Urinary excretions rates were 47.4% for AMPC and 25.8% for CVA, monitored during the period of 0-6 hours.
A total of 23 patients (21 with respiratory infections and 2 with urinary tract infections) were treated with 3-4 375 mg BRL25000 tablets for 2-15 days. Clinical efficacy was evaluated as excellent in 2 cases, good in 11, fair in 3, poor in 6 and unassessable in 1. The overall effectiveness rate was therefore 59.1%(13/22).
Drug related side effects were observed in 2 patients, consisting of 1 case of nausea and loss of appetite, and 1 case of nausea and vomiting which led to discontinuation of treatment. However, no severe side effects and no laboratory abnormalities were observed.
From these results it is concluded that BRL25000 will be a clinically effective drug.

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The clinical effects of BRL 25000, a formulation of amoxicillin and clavulanic acid, were studied in patients with respiratory tract infection.
BRL 25000 was administered orally for 5 to 17 days at a daily dose of 750mg to 1, 500mg to 18 patients.
Excellent results were obtained in 8 cases, good in 6 cases, fair in 3 cases and poor in 1 case. Overall efficacy rate was 77.8%.
On the laboratory findings after treatment of the drug, slight elevation of S-GPT was observed in 1 case and that of Al-P and BUN in 1 case.

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Laboratory and clinical studies were performed on BRL25000, a formulation of 2 parts of amoxicillin (AMPC) and 1 part of clavulanic acid (CVA), and results were as follows.
1. Antimicrobial activities
MICs of BRL25000 against various clinical isolates were determined. With the inoculum size of 10⁶ cells/ml, percentages of strains susceptible to 12.5 μg/ml or less were S. aureus 84%, S. faecalis 100%, E. coli 67%, K. pneumoniae 82%, Enterobacter sp. 5%, S. marcescens 1%, Proteus sp. 60%, P. aeruginosa 0% and Non-fermentative GNB 43%. The potentiation of AMPC with CVA was seen against S. aureus, S. epidermidis, E. coli, K. pneumoniae, Proteus sp. and Acinetobacter sp.
2. Serum concentration and urinary recovery rate
Serum concentrations of BRL 25000 were measured in 6 healthy volunteers, given 375 mg of BRL 25000 (375×1 or 187.5×2) by oral administration. The peaks of mean serum concentrations of AMPC and CVA were about 3 μg/ml at 1.5 hours and 1.3 μg/ml at 1 hour respectively, and their biological half lives were 1.2 and 1.0 hours respectively. There was no significant difference between the two administration methods. Urinary recovery rates of AMPC and CVA were about 60% and 20% respectively.
3. Clinical efficacy
Eleven patients with pneumonia, 3 with acute bronchitis, 13 with chronic bronchitis, 4 with acute tonsillitis or pharyngitis, 2 with chronic pharyngitis, 3 with UTI, and 1 with cholecystitis were treated with BRL25000 daily dose of 0.75-2.25 g for 1-35 days. Clinical responses were excellent in 10, good in 17, fair in 7, poor in 3 patients. Side effects were observed in 8 patients and GOT, GPT elevation was seen in 1 patient.

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Laboratory and clinical studies on BRL25000, a new antibiotic (a formulation of amoxicillin and clavulanic acid in a 2:1 ratio) developed by Beecham, were performed.
The MIC of BRL25000 against the ma jority (59) of 97 clinically isolated strains of Haemophilus influenzae was 0.78μg/ml. The MIC of AMPC against the majority (50) of the strains was one dilution higher at 0.39μg/ml, but the MIC's of cefotetan and erythromycin were higher than BRL 25000. BRL25000 showed much greater activity than lincomycin and cephalexin against Bacteroides fragilis, the growth of all the strains being inhibited by concentrations under 6.25 μg/ml.
BRL25000 was administered to patients with chronic RTI. At a dose of 375 mg, peak serum concentrations of AMPC and CVA were 4.00μg/ml and 1.20 μg/ml, respectively. At a dose of 750 mg, peak serum concentrations of AMPC and CVA were 7.17μg/ml and 3.03μg/ml, respectively. Sputum levels of AMPC were very low after administration of the 375 mg dose of BRL25000, but higher (0.11μg/ml 3-4 hours after oral administration) for the 750 mg dose. CVA was hardly detected in the sputum after administration of either dose.
To evaluate the effect of CVA on beta-lactamase producing organisms, AMPC alone and AMPC combined with CVA were given to cases which had previously shown beta-lactamase in the sputum. The inhibition of ativity of beta-lactamase by CVA when using the AMPC/CVA combination was substantiated in uivo on the basis of higher concentration of AMPC being found in the sputum.
BRL25000 was given to a total of 13 cases with pulmonary infections, the efficacy rate being 84.6%.
Side effects were found in only 1 case consisting of slight elevations of BUN and creatinine.

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BRL25000 is an oral antibiotic, a formulation of amoxicillin (AMPC), derived from ampicillin (ABPC), and clavulanic acid (CVA) developed as aβ-lactamase inhibitor in 2 to 1 ratio. BRL25000 was orally administered 375mg×4 times/day or 750mg×3 times/day to 19 patients with respiratory tract infection (7 in bronchitis, 7 in bronchietasis, 4 in chronic bronchiolitis and 1 in lung abscess) and clinical evaluation was investigated. Causative organisms were eradicated in fifteen cases [infection caused by H. influenzae (1 strain producingβ-lactamase in 10), S. aureus (2 strains producing β-lactamase in 5), and S. pneumoniae in 1 strain producingβ-lactamase] after treatment with BRL25000. In contrast, 2 K. pneumoniae cases improved and 2 P. aeruginosa cases persisted after BRL25000 administration. These bacteriological responses were reflected in the clinical result. In the clinical effectiveness, 1 excellent, 15 good and 3 fair cases were obtained and overall clinical effectiveness was 84.2%(16/19). In 1 case, transient and slight nausea and anorexia were observed. In two cases, transient elevation of transaminase was found.
BRL25000 was evaluated to be a very effective and safe β-lactam antibiotic against respiratory tract infection, especially caused by β-lactamase producing strains.

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Fundamental and clinical studies on BRL25000 were investigated and the following results were obtained.
1) Antibacterial spectrum
BRL25000 showed excellent antimicrobial activity against both gram-positive and gram-negative bacteria except S. marcescens, Enterobacter sp., indole positive proteus group and P. aeruginosa.
2) Antimicrobial activity against clinically isolated strains
BRL25000 ixhibited excellent antimicrobial activity against clinical isolates of S. aureus, S. epidermidis, E. coli, P. mirabilis, K. pneumoniae and B. fragilis which produce penicillinase.
3) Serum and urinary concentrations
Serum concentrations were assayed by cup-plate method using a Moni-Trol I serum standard curve. Urinary concentrations were assayed by paper disc method using pH 6.5 0.1 M citrate buffer solution for the standard curve.
BRL25000 was administered orally at a dose of 375 mg (fasting) and serum concentrations of both amoxicillin and clavulanic acid attained a peak after 1 hour with the mean value of 3.00 μg/ml and 1.50 μg/ml, respectively. Urinary concentrations both amoxicillin and clavulanic acid attained a peak after 2 hours with the mean value of 992 μg/ml and 172 μg/ml respectively. Mean recovery rates in urine during 6 hours were 47.7% for amoxicillin and 16.2% for clavulanic acid, respectively.
4) Pharmacokinetic parameters
Pharmacokinetic parameters were calculated using computer by way of one compartment open model method and the following results, that is K_a (hr.^-1): 3.38, K_el (hr.^-1): 0.598, T_1/2 (hr.): 1.78, V_d (L): 48.3, T-max (hr.): 0. 623, C-max (μg/ml): 3.56 and AUC (μg/ml). hr.: 8.65 for amoxicillin and Ka (hr.-1): 3. 33, K_el (hr.^-1): 0.564, T_1/2 (hr.): 1.87, V_d (L): 49.5, T-max (hr.): 0.642, C-max (μg/ml): 1.76, and AUC (μg/ml) μhr.: 4.48 for clavulanic acid were obtained.
5) Metabolism
Metabolism of amoxicillin and clavulanic acid was examined in human urine after dosing 375 mg/of BRL25000. The results of bioautogram on samples obtained by thin-layer chromatography revealed that both amoxicillin and clavulanic acid were excreted in urine without being metabolized in vivo.
6) Tissue concentrations
Fifty mg/kg of BRL25000 was given orally to SD strains of male rats. This revealed that the tissue concentrations of both amoxicillin and clavulanic acid were the highest in kidneys, followed by liver, lungs, spleen, serum and heart.
7) Clinical results
BRL25000 was administered to 50 cases with surgical infections. Clinical response was excellent in 4 cases, effective in 40 cases, fair in 1 case, and failed in 5 cases with a clinical efficacy rate of 88.0%. Adverse reaction was observed in 1 case with eosinophilia, but no other marked adverse reaction was noted.

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Fundamental and clinical studies of BRL25000 were performed in the surgical field, and the following results obtained.
1) Antibacterial Activity
The antibacterial activity of BRL25000, AMPC and CEX against 47 strains of S. aureus, E. coli and Klebsiella isolated from surgical specimens was examined. BRL25000 showed superior activity against these strains, including those that were AMPC resistant.
2) BRL25000 Bile Levels
Bile and serum levels of BRL25000 were determined after oral administration of 750 mg BRL25000 (after meal) to a patient with obstructive jaundice. Absorption and bile excretion of AMPC was slower than CVA. Peak bile levels were 1. 44 μg/ml for AMPC and 0.63 μg/ml for CVA.
3) Clinical Results
BRL25000 was administered to 21 patients with soft tissue infections, and the clinical results were evaluated as excellent in 4 cases, good in 9, fair in 6, poor in 1 and unknown in 1. Side effects (nausea, vomiting, stomach discomfort and eruption) were found in 4 cases.

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Serum levels and urinary excretion and biliary levels of BRL25000 comprising amoxicillin (AMPC) and clavulanic acid (CVA) were investigated in a healthy adult volunteer and six patients with biliary drainage.
The peak serum concentrations were 6.30 μg/ml of AMPC and 2.50 pglml of CVA at one hour after 375 mg oral administration of BRL25000 in the healthy volunteer, however those of the six patients appeared 2-4 hours after administration and were lower than that of the healthy volunteer.
The biliary levels of BRL25000 were investigated in the six patients with biliary drainage after oral administration. In 4 cases given 375 mg of BRL25000, the range peak levels were 1.9-0.8μg/ml of AMPC and 0.3-0.1μg/ml of CVA, in 2 cases given 750 mg of BRL25000, the peak levels were 1.4, 1.3μg/ml of AMPC and 0.4, 0.3μg/ml of CVA.
BRL25000 was given to 33 patients with skin and soft tissue infections in the field of surgery.
The therapeutic results were excellent in 15, good in 16 and poor in 2 cases, showing an efficacy rate of 93.9%. The MICs of BRL25000 for 13 of 20 strains isolated from 33 cases were markedly reduced compared with those of AMPC.
As for side effects, upper abdominal pain in one and transient skin rash in one case were observed, laboratory finding were almost within normal limits after treatment.
BRL25000 seems to be a useful antibiotics for skin and soft tissue infection in the field of surgery, especially in cases of infections caused by β-lactamase producing organisms.

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BRL25000 (amoxicillin and clavulanic acid in the ratio 2:1) was administered 1, 125 mg-1, 500 mg per day for 3-16 days to 11 patients (6 abscess, 3 wound infections, 1 cholecystitis and 1 urinary tract infection).
The response to therapy was assessed as good in 8 (80%) fair and poor in 2 (20%) with abdominal abscess and perineal abscess, and unassessable in one due to diarrhea (third day). Overall the clinical efficacy was 80%(8/10).
The following bacterial species were eradicated after treatment: E. coli (5 strains), S. aureus, P. maltophilia, with the exception of P.mirabilis and S.epidermidis.
A side effect was observed in one patient with diarrhea but no severe side effect and no laboratory abnormality was found.
From these results, BRL25000 will be useful in this field.

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Basic and clinical studies were carried out on BRL25000, an antibacterial agent composed of a mixture of amoxicillin (AMPC) and clavulanic acid, a new β-lactamase inhibitor. The results of those studies were as follows.
(I) Antibacterial activity (MIC): The MICs of both BRL25000 and AMPC were determined for several species of bacteria, using clinical isolates. In the case of E. coli, the MIC distributions of both antibacterial agents showed a peak at 12.5 μg/ml, although the AMPC distribution showed a second peak as well. It was also found that strains which showed MICs of 200 μg/ml or more of AMPC were inhibited by lower BRL25000 concentrations, i. e., the MICs were 100 μg/ml or less with BRL25000. Thus, BRL25000 was shown to have superior antibacterial activity to AMPC against E. coli. The same patterns were found in the cases of P.mirabilis and indole Proteus sp. All of the tested K. pneumoniae strains were resistant to AMPC, whereas they all showed 100 μg/ml or less MICs of BRL25000. Both of these antibacterial agents were ineffective against all of the tested strains of Enterobacter sp. and P. aeruginosa. With regard to the S. marcescens strains, those which were resistant to AMPC showed lower MICs in relation to BRL25000, but there was no difference between these two antibacterial agents' MIC distributions against sensitive strains.
(II) Clinical results: A total of 17 patients diagnosed as having urinary tract infections were treated with BRL25000. In nine of these patients with acute uncomplicated cystitis, the results were excellent in eight cases and good in one case, for an efficacy rate of 100%. The remaining eight patients had complicated urinary tract infections, and the efficacy rate was 87.5%: four excellent cases, three good cases, and one poor case. The overall efficacy rate in these urinary tract infection cases was thus 94. 1%(16/17). The MICs of the clinical isolates obtained from these patients were also determined. In the effective cases, all of the isolates showed an MIC of 12.5μg/ml or less (using an inoculum level of 106 cells/ml). Therefore, a high degree of correlation was found between the clinical efficacy and the MICs of these causative organisms. The only side effects recorded were in one patient, who experienced a stomach discomfort and diarrhea.

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BRL 25000, a preparation comprising the antibiotic amoxicillin and β-lactamase inhibitor potassium clavulanate, was studied bacteriologically and clinically.
Bacteriological study:
MIC's of ABPC and BRL 25000 for 101 bacterial strains (including 68 in which β-lactamase production was detected) were determined. BRL25000 showed excellent antibacterial activity compared with ABPC BRL 25000 MICs were less than 3.13μg/ml for pathogens which showed ABPC MIC's in excess of 100 μg/ml.
Clinical study:
70 patients with gonorrheal urethritis were treated with BRL 25000. The response to therapy was assessed as excellent in 33 (47.2%), good in 36 (51.4%) and poor in 1 (1.4%). Thus clinical efficacy was good to excellent in 98. 6%(69/70) of cases. A good response was obtained by administration of double doses to the case (105 kg body weight) reported as showing a poor result to single dose therapy. Drug related side effects were observed in 3 patients consisting of 2 instances of diarrhea and one of facial hot flushes. However, no severe side effects were found.

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A total of 17 aged patients with complicated urinary tract infections were treated with BRL 25000 which is a formulation comprising the antibiotic amoxicillin and the β-lactamase inhibitor, potassium clavulanate.
The response to therapy was assessed as excellent in 3 (21.4%), good in 7 (50.0%), poor in 4 (28.6%) and unassessable in 3. Overall the clinical efficacy was good to excellent in 71.4%(10/14) of cases. On bacteriological response, the eradication rate was 85. 2% against 27 pathogens. Thus high effectiveness was obtained therapeutically and bacteriologically.
MICs for BRL 25000 were lower than for amoxicillin in 60% of isolates from this trial. For gramnegative isolates, MICs of BRL 25000 were lower than amoxicillin in 70% of the cases. This characterizes the high clinical efficacy of BRL 25000.
Drug related side effects were observed in 4 patients consisting of 3 cases of eosinophilia and 1 case of loss of appetite, but no severe side effects were found.

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The basic, clinical and safety evaluation of BRL 25000, a new oral antibiotic consisting of amoxicillin and clavulanic acid, was investigated in urinary tract infections.
The in vitro antibacterial activity of BRL 25000 was measured against the clinical isolates of E. coli and Klebsiella and amoxicillin was used as a control drug. The MICs of 42 strains of E. coli against BRL 25000 ranged from 6.25 to 12.5μg/ml and showed one peak, while that of amoxicillin ranged from 3.13 to ≥800μ/ml. The 20 strains of E. coli (β-lactamase producing) were shown to be highly resistant (≥800μg/ml) to amoxicillin, and almost all of them were inhibited by 12.5μg/ml of BRL 25000. The type of β-lactamase detected was almost all penicillinase of TEM type. BRL 25000 showed 4 to 5 tubes storonger MIC than amoxicillin.
The total number of the clinical cases was 67 including 48 cases of acute simple cystitis, 2 acute pyelonephritis, 8 chronic complicated cystitis and 5 ccmplicated pyelonephritis. The clinical effective rate was 96%(48/50) in acute simple cases, and 85%(11/13) in chronic cases. Ten cases, which had no response when pretreated by amoxicillin, showed a 90%(9/10) effective rate.
As for side effects, no abnormal clinical laboratory findings were observed after administration of BRL 25000 in the 22 cases studied. Four cases of abdominal discomfort and 2 cases of skin rash were found during treatment of BRL 25000, and administration were discontinued in the 2 cases of skin rash.
I concluded that BRL 25000 showed good tolerance and effectiveness in urinary tract infections caused by the β-lactam antibiotics resistant strains, for example E. coli and Klebsiella.

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Fundamental and clinical studies on BRL 25000, an antibiotic comprising amoxicillin and potassium clavulanate (β-lactamase inhibitor), were carried out and the following results were obtained.
(1) The in vitro activity of BRL 25000 against various strains of clinical isolates was compared with AMPC, CMZ, CCL, CFT, CED. BRL 25000 showed most potent activity against gram positive cocci. Antimicrobial activity of BRL 25000 against E.coli, Klebsiella sp. and Proteus sp. was inferior to that of CMZ, but was superior to that of AMPC, CCL, CFT and CED.
(2) BRL 25000 was administered to 57 patients with urinary tract infections (40 with acute uncomplicated cystitis, 10 with chronic complicated UTI and 5 with gonorrheal urethritis, etc.) at a daily dosage of 1.5g orally. According to the criteria proposed by UTI committee of Japan, the clinical results in acute uncomplicated cystitis were excellent in 25 cases and moderate in 7 cases, and in chronic complicated UTI were excellent in 5 cases and moderate in 2 cases. The overall clinical efficacy rate was 100% in both studies.
(3) Side effects were observed in 9 patients. These included gastro-intestinal disturbance (diarrhea, nausea, epigastralgia) in 7, uriticaria in 1 patient and fever in 1 patient.

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A new antibiotic BRL25000, comprising amoxicillin and clavulanic acid (β-lactamase inhibitor), was administered to 38 patients with urinary tract infection and the following results were obtained.
Clinical efficacy rate was 100% in acute simple urinary tract infections and 79% in chronic complicated urinary tract infections.
BRL25000 showed potent bacteriological response against amoxicillin-resistant organisms.
As for side effects, gastro-intestinal tract disturbances were observed in three patients, but they disappeared without discontinuance of administration. As to laboratory findings of the 11 cases investigated, no abnormal values were found.

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A new oral antibiotic agent BRL25000, containing 250 mg of amoxicillin and 125 mg of clavulanic acidβ-lactamase inhibitor), was studied both experimentally and clinically, and the following results were obtained;
1) The antibacterial activity of BRL25000 was excellent against gram positive cocci and gram negative bacilli (except for Pseudomonas aeruginosa) especially against penicillin resistant Escherichia coli and Klebsiella pneumoniae.
2) The effect of BRL25000 on a mixed culture of E.coli and Staphylococcus epidermidis (β-lactamase producing strain) in vitro was studied. The growth of E. coli was suppressed when BRL25000 was administered, but when amoxicillin alone was administered, E. coli growth continued unchanged.
3) An oral 375 mg dose of BRL25000 was administered to 3 healthy non fasting volunteers, and mean urinary excretions of amoxicillin and clavulanic acid were studied. The peak urinary concentrations of amoxicillin and clavulanic acid were 601.2μg/ml and 30.5μg/ml respectively in specimens 2-4 hours after administration of the drugs. The urinary concentrations of amoxicillin were about ten times to twenty times higher than those of clavulanic acid up to 6 hours after dosing.
4) Twenty eight patients wiht chronic complicated urinary tract infections were treated with BRL 25000 at a daily dose of 1, 125 mg for 5 days, and the therapeutic results were evaluated by the criteria proposed by the UTI committee, Japan. The overall clinical efficacies of treatment were excellent in 17 patients or 61%, moderate in 7 patients or 25% and poor in 4 patients or 14%. The overall effectiveness rate was thus 86%. A drug-related side effect, loss of appetite was observed in only one patient.

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Clavulanic acid is a new compound of very weak antibacterial activity, but which is a potent inhibitor of bacterial β-lactamases. BRL25000, a formulation comprising amoxicillin and clavulanic acid, might be expected to exhibit strong antimicrobial activities.
In the present study, the clinical efficacy and safety of BRL25000 was evaluated in patients with urinary tract infections. Forty-three patients with acute uncomplicated cystitis received 562. 5 mg or 1, 125mg of BRL25000 administered t. i. d. for 3 days and 38 patients with chronic complicated urinary tract infections received 1, 125mg of BRL25000 administered t. i. d. for 5 days.
The response to BRL25000 therapy in patients with acute uncomplicated cystitis was excellent in 74% and moderate in 26% with an overall effectiveness of 100%, whereas the response in cases with complicated urinary tract infections was excellent in 42%, moderate in 40% and poor in 18% with an overall effectiveness of 82%.
Drug related side effects were observed in 4 patients consisting of 2 cases of diarrhea and one each of epigastralgia and dizziness. Laboratory abnormalities were observed in 3 patients consisting of 3 cases of elevated GOT, 2 cases of elevated GPT, and 2 cases of elevated alkaline phosphatase.

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Fundamental and clinical studies on BRL25000, an antibiotic consisting of amoxicillin (AMPC) and potassium clavulanate (CVA, β-lactamase inhibitor), were performed and the following results were obtained.
1. Blood levels and urinary excretion
375 mg of BRL25000 was orally administered to one healthy adult volunteer to measure concentrations of AMPC and CVA in serum and urine by the cross over method, at times of fasting and nonfasting. The peak levels of CVA in the serum were 2.3 μg/ml (fasting) and 2.1 μg/ml (non-fasting) after 1. 5 hours respectively, those of AMPC were 6.3 μg/ml (fasting) after 1.5 hours and 4.5 μg/ml (non-fasting) after 2 hours. Over 6 hours, urinary excretion rates of CVA were 29.8%(fasting) and 32. 3%(non-fasting), those of AMPC were 59.2%(fasting) and 52.4%(non-fasting).
2. Antimicrobial activity
BRL25000 showed more potent antimicrobial activity against Klebsiella pneumoniae, Proteus mirabilis, indole-positive Proteus sp., Enterobacter sp., Serratia sp. and Citrobacter sp. than AMPC or cephalexin.
3. Clinical evaluation
BRL25000 was administered to 20 patients with chronic complicated UTI at a daily dose of 1, 500 mg. Clinical effects were evaluated as excellent in 9 cases, moderate in 3 cases and poor in 8 cases, and an overall clinical effectiveness rate was 60%. Especially, for 4 cases isolated with β-lactamaseproducing strains, the therapeutic effect was excellent, and MICs of BRL25000 were markedly lower than those of AMPC.
Side effects were observed in one case with dyspepsia, but discontinuance of the administration was not necessary.

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