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PubMed2005

New formulations of amoxicillin/clavulanic acid: a pharmacokinetic and pharmacodynamic review.

The pharmacokinetic properties of amoxicillin and clavulanic acid when used alone or in combination are extensively reviewed and discussed in this article. The reported data support a nonlinear absorption process for amoxicillin. Saturable transport mechanisms, limited solubility and the existence of an absorption window are possibly involved in the gastrointestinal absorption of this antibacterial, all leading to a decrease in the peak plasma concentration (Cmax)/dose ratio, a prolongation of the time to reach Cmax, and broad variability for high doses of amoxicillin. Data available in the literature also suggest a possible interaction between amoxicillin and clavulanic acid that might decrease the absolute bioavailability of clavulanic acid. In the present review the intrinsic pharmacodynamics of each drug, together with the synergism produced by the amoxicillin/clavulanic acid association, are also reviewed and analysed. Not only beta-lactamase-producing strains, but also Streptococcus pneumoniae strains, seem to be more efficiently eradicated by the association of amoxicillin and clavulanic acid, and a relevant post-antibacterial effect and post-beta-lactamase inhibitor effect are likely to operate when amoxicillin is administered together with clavulanic acid. The principles of pharmacokinetic/pharmacodynamic analysis applied to amoxicillin are reviewed, with special emphasis being placed on the results obtained from in vitro studies and animal models regarding the new pharmacokinetically enhanced formulation. Theoretical considerations concerning the efficacy of this formulation provided by the application of pharmacokinetic/pharmacodynamic analysis to the scarce pharmacokinetic data available are also included. The broad pharmacokinetic variability of both amoxicillin and clavulanic acid, particularly when administered together and at high doses of amoxicillin, is highlighted and the interest in considering this aspect to improve predictions based on pharmacokinetic/pharmacodynamic analyses for the new formulations is indicated. Methodological recommendations such as the Monte Carlo simulation are proposed in order to obtain more realistic predictions in clinical practice.

Amoxicillin↗
PubMed1998

Multiple-layer compression-coated tablets: formulation and humidity studies of novel chewable amoxicillin/clavulanate tablet formulations.

The purpose of this study was to produce novel multiple-layer, compression-coated, chewable tablet formulations containing amoxicillin trihydrate, and clavulanic acid as potassium clavulanate, and to test in vitro dissolution characteristics and the effect of humidity stability compared to Augmentin chewable tablets as a reference. Double- and triple-layer tablets were manufactured on a laboratory scale by multiple-layer dry compression, and dissolution profiles of both active ingredients were determined. Tablets were subjected to stability evaluation in laboratory-scale humidity tanks maintained at constant humidity. Assay of content was determined by HPLC or UV spectroscopy. Physical characteristics of the powder mixture, such as angle of repose, and of tablets for hardness and friability, were also determined. Chewable tablets showed similar dissolution profiles in vitro for both active ingredients, compared to the marketed reference, Augmentin. The stability of clavulanic acid, but not amoxicillin, was increased in the novel triple or bilayer formulation. The tablets showed suitable friability, hardness, and angle of repose for starting materials to suggest that industrial scale-up is feasible. This approach to formulation of drugs containing multiple or moisture-sensitive ingredients has been shown to increase the stability of the central core drug without changing the dissolution pattern of the active ingredients. This formulation is expected to be bioequivalent in vivo based on these in vitro results.

Amoxicillin↗
PubMed1985

[Experimental and clinical studies on BRL 25000 (clavulanic acid-amoxicillin) granules in the pediatric field].

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 beta-lactamase producing strains of H. influenzae were determined. The MICs of BRL 25000 at an inoculum of 10(6) 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 100 micrograms/ml. The pharmacokinetics of BRL 25000 were studied in 46 children at dose levels of 7.5 mg (8 fasting children, 7 non-fasting children), 10 mg/kg (4 fasting, 4 non-fasting), 15 mg/kg (4 fasting, 4 non-fasting), 20 mg/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 20 mg/kg to fasting children, 0.5-1 hour after dosing were 4.86 and 2.36 micrograms/ml, 5.20 and 1.69 micrograms/ml, 7.50 and 3.27 micrograms/ml, 9.38 and 6.30 micrograms/ml, respectively. In non-fasting subjects, corresponding values were 2.84 and 1.01 micrograms/ml, 4.53 and 2.10 micrograms/ml, 7.29 and 4.08 micrograms/ml, 6.83 and 2.96 micrograms/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 0.78-1.02 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, 20 mg/kg to fasting children were 681.8 and 148.2 micrograms/ml, 247.1 and 66.3 micrograms/ml, 484.2 and 149.1 micrograms/ml, 1,796.5 and 372.0 micrograms/ml, whilst in the non-fasting state the values were 496.3 and 83.2 micrograms/ml, 991.1 and 156.7 micrograms/ml, 2,397.5 and 460.7 micrograms/ml, 1, 896.3 and 323.4 micrograms/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.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1986

Antibacterial effects of ticarcillin/clavulanic acid in animal models of infection.

The therapeutic effects produced by ticarcillin plus clavulanic acid were compared with those of ticarcillin and clavulanic acid separately against infections in the mouse caused by beta-lactamase-producing bacteria. The infections studied included a pneumonia model, a local tissue infection and pyelonephritis. The distribution of ticarcillin and clavulanic acid in infected animals was evaluated by measurement of the concentrations of the substances present at sites of infection. The results showed that both ticarcillin and clavulanic acid were well-distributed in the mouse and at the doses employed were present at the sites of infection at concentrations of the same order as those obtained in man after administration of ticarcillin/clavulanic acid formulations (Timentin). The protection of ticarcillin by clavulanic acid from inactivation by the beta-lactamases produced in vivo by Bacteroides fragilis, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa was demonstrated by the pronounced bactericidal effects produced by the ticarcillin/clavulanic acid combination against the ticarcillin-refractory infections studied.

Animals↗
PubMed1983

[Experimental and clinical studies on BRL 25000 (clavulanic acid-amoxicillin) in the field of obstetrics and gynecology].

BRL 25000, consisting of 250 mg amoxicillin (AMPC) and 125 mg clavulanic acid (CVA), was studied in the field of obstetrics and gynecology. Tissue concentrations The concentrations in venous serum and arterial serum of uterus, different sites uterus, oviduct and ovarium were determined. Tissue concentrations of AMPC and CVA corresponded to 45--75% and 20--50%, respectively of serum concentrations. The good responses were obtained in cases with intrapelvic infection and the overall clinical effective responses were obtained in 100% of patients. Effectiveness was found microbiologically and clinically in infections due to AMPC resistant organisms. No side effects were found.

Adult↗
PubMed1991

Bactericidal effects of amoxycillin/clavulanic acid against a Legionella pneumophila pneumonia in the weanling rat.

Amoxycillin/clavulanic acid and clavulanic acid have been previously reported to demonstrate bactericidal activity in tissue culture studies against intracellular Legionella pneumophila. A rat model of legionellosis was therefore developed for the purpose of assessing the efficacy of these agents against L. pneumophila in vivo. Therapy by the subcutaneous route was started 12 h after infection when the majority of the bacteria observed in lavage fluid were residing in alveolar macrophages. Treatment with amoxycillin was ineffective in reducing the bacterial counts of L. pneumophila in lung homogenates whereas amoxycillin/clavulanic acid displayed bactericidal effects of the same order as the control antibiotic, erythromycin. Further in-vivo studies are planned to assess the clinical relevance of these findings.

Age Factors↗
PubMed1985

[Experimental and clinical studies on BRL 25000 (clavulanic acid-amoxicillin) granules in pediatric infections].

BRL 25000, granules preparation containing 2 parts of amoxicillin (AMPC) and 1 part of clavulanic acid (CVA, beta-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 beta-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 54.5 mg/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.

Administration, Oral↗
PubMed1985

[Clinical study of BRL 25000 (clavulanic acid-amoxicillin) granules in pediatric infections].

BRL 25000 granules, a formulation of amoxicillin (AMPC) and the beta-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 beta-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 10 mg/kg and 16.1 mg/kg, respectively. In the case of the female dosed at 10 mg/kg, the peak serum concentrations were found to be 6.38 micrograms/ml for AMPC and 1.83 micrograms/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 16.1 mg/kg, the peak concentrations were 2.55 micrograms/ml for AMPC at 3 hours following administration and 1.46 micrograms/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.

Administration, Oral↗
PubMed1985

[Experimental and clinical studies on BRL 25000 (clavulanic acid-amoxicillin) granules in the pediatric field].

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 micrograms/ml, except for 1 strain with MIC greater than or equal to 800 micrograms/ml. However, 19 strains (40%) were resistant to AMPC, with MICs more than 800 micrograms/ml. 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 three seemed to be a slightly higher incidence of diarrhea than with other drugs.

Administration, Oral↗
PubMed1998

Investigation of the Streptomyces clavuligerus cephamycin C gene cluster and its regulation by the CcaR protein.

As part of a search for transcriptional regulatory genes, sequence analysis of several previously unsequenced gaps in the cephamycin biosynthetic cluster has revealed the presence in Streptomyces clavuligerus of seven genes not previously described. These include genes encoding an apparent penicillin binding protein and a transport or efflux protein, as well as the CmcI and CmcJ proteins, which catalyze late reactions in the cephamycin biosynthetic pathway. In addition, we discovered a gene, designated pcd, which displays significant homology to genes encoding semialdehyde dehydrogenases and may represent the gene encoding the long-sought-after dehydrogenase involved in the conversion of lysine to alpha-aminoadipate. Finally, two genes, sclU and rhsA, with no obvious function in cephamycin biosynthesis may define the end of the cluster. The previously described CcaR protein displays homology to a number of Streptomyces pathway-specific transcriptional activators. The ccaR gene was shown to be essential for the biosynthesis of cephamycin, clavulanic acid, and non-clavulanic acid clavams. Complementation of a deletion mutant lacking ccaR and the adjacent orf11 and blp genes showed that only ccaR was essential for the biosynthesis of cephamycin, clavulanic acid, and clavams and that mutations in orf11 or blp had no discernible effects. The lack of cephamycin production in ccaR mutants was directly attributable to the absence of biosynthetic enzymes responsible for the early and middle steps of the cephamycin biosynthetic pathway. Complementation of the ccaR deletion mutant resulted in the return of these biosynthetic enzymes and the restoration of cephamycin production.

Actinomyces↗
PubMed1985

[Experimental and clinical studies on BRL 25000 (clavulanic acid-amoxicillin) granules in the pediatric field].

Fundamental and clinical studies on BRL 25000 granules, containing 2 parts amoxicillin (AMPC) and 1 part clavulanic acid (CVA) (a beta-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 20 mg/kg to 2 children. The mean peak serum concentrations of AMPC and CVA were 4.89 and 2.85 micrograms/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 25.1-60.4 mg/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).

Administration, Oral↗
PubMed1984

Resistance of Aeromonas hydrophila to beta-lactam antibiotics.

The activity of some beta-lactam antibiotics upon 20 strains of Aeromonas hydrophila and some properties of their beta-lactamases have been studied. High degree of resistance to benzylpenicillin and lower resistance to ampicillin and cephaloridine was observed. Clavulanic acid showed the highest activity. When clavulanic acid was assayed at subinhibitory concentrations in association with ampicillin. MICs of the latter decreased to two- to eight-fold. All strains produced inducible beta-lactamases with high activity upon ampicillin. A group of cephalosporinase-like enzymes was also found. Some beta-lactamases were inhibited by cloxacillin, and most of them were completely inhibited by 5 mg/l of clavulanic acid. Low impermeability of Aerom. hydrophila cells to beta-lactams was observed.

Aeromonas↗
PubMed1999

Effect of clavulanic acid-potentiated amoxycillin on semen quality in dogs.

Two different doses of clavulanic acid-potentiated amoxycillin were evaluated for their effect upon semen quality and libido in dogs. There was no significant difference in either parameter between control dogs and dogs treated with clavulanic acid-potentiated amoxycillin at either 12.5 mgkg-1 or 25 mgkg-1 orally twice daily for 28 d. Despite the marked effect of certain antibiotic agents upon spermatogenesis, it appears that clavulanic acid-potentiated amoxycillin can be used in dogs at up to twice the therapeutic dosage recommended by the manufacturer without a deleterious effect upon semen quality.

Amoxicillin↗
PubMed1982

Bacteriological investigations with beta-lactamase inhibitors.

MIC's of beta-lactamase producing strains of P. aeruginosa, E. coli, P. vulgaris, P. rettgeri, E. cloacae, K. pneumoniae, S. marcescens are determined against piperacillin and in the case of S. aureus against amoxycillin and penicillin G. All the strains studied were resistant to these antibiotics. Their MIC's were determined in the combination with different concentrations (2, 5, 10 mg/l) of clavulanic acid and penicillanic acid sulfone respectively. The combination of piperacillin and clavulanic acid acts synergisticly against Klebsiella sp., indolpositive Proteus sp., and E. coli. Penicillanic acid sulfone was less active than clavulanic acid apart from indolpositive Proteus sp. Against S. aureus however both inhibitors showed the same synergistic efficacy. In detail both inhibitors are very active against constitutive penicillinase, they also exhibited a good activity against Type OXA-2, OXA-3 and SHV-1 beta-lactamase; they were less active to Type TEM-1 and OXA-1 enzyme and did not work against Type Ib, TEM-2 and Type IV beta-lactamase. In investigations using the biophotometer it could be demonstrated that the beta-lactamase inhibitor and the penicillin should be given simultaneously in order to obtain an optimal synergistic effect.

Amoxicillin↗
PubMed1985

Antibacterial activity of ticarcillin in the presence of clavulanate potassium.

The antibacterial effects produced by ticarcillin disodium plus clavulanate potassium, a combination of the broad-spectrum penicillin ticarcillin, and the beta-lactamase inhibitor clavulanic acid as the potassium salt, have been measured in vitro and in experimental infection studies. The presence of clavulanic acid resulted in a significant enhancement of the activity of ticarcillin against a wide range of beta-lactamase-producing bacteria. These included ticarcillin-resistant strains of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, P. vulgaris, Yersinia enterocolitica, and the anaerobe Bacteroides fragilis. In addition, beta-lactamase-producing isolates of Hemophilus influenzae, Branhamella catarrhalis, Neisseria gonorrhoeae, and Staphylococcus aureus were susceptible to ticarcillin and clavulanate. Clavulanic acid did not influence the activity of ticarcillin against ticarcillin-susceptible bacteria. The bactericidal effects of the antibiotic combination were measured in an in vitro kinetic model in which the drug concentrations were varied to simulate those measured in humans after intravenous dosing with ticarcillin (3.0 g) and clavulanate potassium (100 mg clavulanic acid). In these tests, ticarcillin plus clavulanic acid had pronounced bactericidal activity against ticarcillin-resistant bacteria. The protection of ticarcillin by clavulanic acid from inactivation by bacterial beta-lactamases in vivo was demonstrated in experimental infection models in which the efficacy of the ticarcillin plus clavulanic acid combination against infections caused by beta-lactamase-producing bacteria was correlated with the presence of effective concentrations of both antibiotic and inhibitor at the site of infection.

Animals↗
PubMed1985

Ticarcillin/clavulanic acid pharmacokinetics in children and young adults with cystic fibrosis.

The single-dose pharmacokinetics of ticarcillin and clavulanic acid (Timentin) were evaluated in children and young adults with cystic fibrosis after a 0.5-hour intravenous infusion of both a 3.1 and a 3.2 gm formulation (representing 3.0 gm ticarcillin combined with 100 mg and 200 mg clavulanic acid, respectively) in a crossover design. A 75 mg/kg dose of the ticarcillin component was used. Model-dependent and noncompartmental pharmacokinetic parameters were congruous. The disposition of ticarcillin and clavulanic acid was characterized adequately by a one-compartment open model. The elimination half-life, apparent steady-state volume of distribution, and total body clearance of ticarcillin from serum were 1.19 hours, 0.231 L/kg, and 0.150 L/hr/kg, respectively, for the 3.1 gm formulation and 1.21 hours, 0.211 L/kg, and 0.123 L/hr/kg, respectively, for the 3.2 gm formulation. For ticarcillin, 86% and 93% of the dose of the 3.1 and 3.2 gm formulations, respectively, were excreted unchanged in urine during the first 6 hours after infusion. Concomitant renal clearance values were 0.120 and 0.112 L/hr/kg for the 3.1 and 3.2 gm formulations, respectively. Approximately 50% of a clavulanic acid dose was excreted unchanged in urine during the 6-hour postinfusion period for both formulations. For ticarcillin, no significant differences were observed between the 3.1 and 3.2 gm formulations. For clavulanic acid, a significant difference between the two formulations was observed in comparison of the area under the serum concentration vs time curve and dose size (P less than 0.01). Linear inverse relationships were identified between demographic factors (e.g., age, weight, height, body surface area) and both the apparent volume of distribution and total body clearance of ticarcillin and clavulanic acid for both formulations. The ticarcillin/clavulanic acid combination in either the 3.1 or 3.2 gm formulation is suitable for microbiologic and clinical evaluation in patients with cystic fibrosis.

Adolescent↗
PubMed1985

[Clinical trials of BRL 25000 (clavulanic acid-amoxicillin) granules on skin and soft tissue infections in the field of pediatrics].

BRL 25000 is a combination of a newly-developed beta-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 75.0 mg/kg, given in 3 or 4 divided doses (average 48.5 mg/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 beta-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 10(8) cells/ml, major MICs of BRL 25000, AMPC, CVA, CEX and CCL against 71 strains of S. aureus, including beta-lactamase negative ones, were 3.13 mcg/ml, 12.5 mcg/ml, 50 mcg/ml, 12.5 mcg/ml and 12.5 mcg/ml, accounting for 60.6, 38.0, 49.3, 38.0 and 43.7% of the strains respectively, whilst at an inoculum of 10(6) cells/ml, major MICs were 1.56 mcg/ml, 3.13 mcg/ml, 25 mcg/ml, 6.25 mcg/ml and 3.13 mcg/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 10(6) cells/ml and that BRL 25000 showed the most potent antibacterial activity of all 5 drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1985

[Laboratory and clinical studies of BRL 25000 (clavulanic acid-amoxicillin) granules in the pediatric field].

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 10(6) cells/ml. beta-Lactamase production was detected by the Nitrocefin method. The MICs of BRL 25000 against S. aureus ranged from 0.2 approximately 12.5 micrograms/ml, with the majority of strains being inhibited by 1.56 micrograms/ml or less. Seven beta-lactamase producing strains of S. aureus were all inhibited by less than 12.5 micrograms/ml. The range against E. coli was 1.56 approximately 100 micrograms/ml, with the majority inhibited by 6.25 micrograms/ml or less. Fifteen beta-lactamase producing strains of E. coli were inhibited by 6.25 approximately 100 micrograms/ml and the majority by 25 micrograms/ml or less. All strains of K. pneumoniae were beta-lactamase producers and the MIC distribution against K. pneumoniae was 1.56 approximately 50 micrograms/ml, with a majority inhibited by 3.13 micrograms/ml or less, 96% of strains, were inhibited by less than 6.25 micrograms/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 7.5 mg/kg and 20 mg/kg. The peak serum levels of AMPC were 6.13 and 6.94 micrograms/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 1.90 micrograms/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).

Administration, Oral↗