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PubMed1985

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

Fundamental and clinical studies on BRL 25000 granules were carried out in the pediatric field. BRL 25000 is a formulation comprising 1 part of clavulanic acid (CVA) and 2 parts of amoxicillin (AMPC). The MICs of BRL 25000 and AMPC were assessed against 24 clinically isolated strains of S. aureus (including 23 beta-lactamase producing strains), 22 S. pyogenes, 20 E. coli (8 beta-lactamase producing strains), 24 K. pneumoniae (24 beta-lactamase producing strains), 20 H. influenzae (6 beta-lactamase producing strains). BRL 25000 showed MIC80 (cumulatively 80% of strains were inhibited) at 6.25 micrograms/ml against S. aureus, less than or equal to 0.10 micrograms/ml against inst S. pyogenes, 12.5 micrograms/ml against E. coli, 6.25 micrograms/ml against K. pneumoniae and 0.39 micrograms/ml against H. influenzae. BRL 25000 showed no improvement in MIC terms against beta-lactamase nonproducing strains compared with AMPC. However, BRL 25000 was markedly more effective against beta-lactamase producing strains. Thus BRL 25000 was up to 8 fold more active against S. aureus, 2 to 64 fold against E. coli, 4 to 128 fold against K. pneumoniae, 4 to 16 fold against H. influenzae than AMPC. Following oral administration of BRL 25000 granules (at a dose level of 12.5 mg/kg) to 2 children aged 9 and 11 years, the mean peak serum concentrations of AMPC and CVA were 8.33 +/- 2.43 micrograms/ml and 4.44 +/- 1.65 micrograms/ml respectively 1 hour after dosing. The half-lives of AMPC and CVA were 1.35 +/- 0.42 hours and 0.91 +/- 0.05 hour, respectively. The urinary excretion was 48.21 +/- 3.83% for AMPC and 16.90 +/- 7.06% for CVA in the first 6 hours after administration. In clinical studies, 23 pediatric patients aged 2 months to 12 years with bacterial infections were treated with BRL 25000 granules and the clinical effectiveness, bacteriological response and side effects were evaluated. The clinical response was assessed in 23 cases, 3 with acute rhinitis, 6 with acute purulent tonsillitis, 5 with acute bronchitis, 4 with acute pneumonia, 3 with impetigo, 1 with furunculosis and 1 with periproctal abscess. Results were excellent in 13 cases, good in 7, fair in 3 and hence the efficacy rate (excellent and good cases) was 87.0% (20/23). In particular the clinical response in 9 cases with infections due to beta-lactamase producing organisms was excellent in 6, good in 2, fair in 1 and the efficacy rate was 88.9% (8/9).(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMedDate not supplied

Amoxicillin-potassium clavulanate, a beta-lactamase-resistant antibiotic combination.

The chemistry, microbiology, pharmacokinetics, therapeutic use, adverse effects, and dosage of amoxicillin-potassium clavulanate, a beta-lactamase-resistant antibiotic combination, are reviewed. Clavulanic acid is a "suicide" inhibitor of bacterial beta-lactamase enzymes and has been effective in preventing destruction of penicillins by these enzymes. Clavulanic acid alone has weak antibacterial activity against most organisms. After oral administration, clavulanic acid is rapidly absorbed; amoxicillin appears to increase its absorption. Absorption of amoxicillin-clavulanic acid is not affected by food. Amoxicillin-clavulanic acid is effective in treating both acute uncomplicated and complicated urinary-tract infections and exacerbations of chronic bronchitis caused by amoxicillin-resistant organisms in adults. It appears to be comparable in efficacy to cefaclor for treating uncomplicated urinary-tract infections in adults and children, acute bronchitis and bronchopneumonia, and acute sinusitis, otitis media, and skin and soft-tissue infections in children. Other infections for which the combination has been effective include cellulitis and intra-abdominal and pelvic sepsis caused by mixed aerobic/anaerobic organisms. Amoxicillin-clavulanic acid has also successfully cured urethritis in men caused by penicillinase-producing Neisseria gonorrhoeae and is superior to amoxicillin alone for beta-lactamase-positive Haemophilus ducreyi infections (chancroid). Diarrhea or loose stools is the most common side effect seen with amoxicillin-clavulanic acid; nausea, vomiting, and skin rash may also occur. Nausea, vomiting, and diarrhea may be lessened by taking the combination with food.(ABSTRACT TRUNCATED AT 250 WORDS)

Amoxicillin↗
PubMed1996

Pharmacokinetics of amoxicillin/clavulanic acid combination and of both drugs alone after intravenous administration to goats.

The pharmacokinetic behaviour of an amoxicillin/clavulanic acid combination (25 mg kg-1), and both drugs alone (amoxicillin 20 mg kg-1), clavulanic acid 5 mg kg-1), was studied after intravenous (i.v.) administration of single doses of 10 goats. The objective was to determine whether there were differences in the plasma kinetics of these drugs when administered in combination or alone. The plasma concentration-time data were analysed by compartmental pharmacokinetics and non-compartmental methods. The disposition curves for both drugs alone and in combination were best described by a biexponential equation (two-compartment open model). The elimination half-lives of amoxicillin were 1.05 +/- 0.09 h alone and 1.13 +/- 0.19 h in combination, and those of clavulanic acid were 0.87 +/- 0.07 h and 0.85 +/- 0.09 h, respectively. The apparent volumes of distribution of amoxicillin and clavulanic acid were similar in the two treatments. Body clearances of amoxicillin were 0.12 +/- 0.01 l h-1.kg alone and 0.11 +/- 0.01 l h-1.kg in combination, and of clavulanic acid were 0.12 +/- 0.02 l h-1.kg alone and 0.12 +/- 0.01 l h-1.kg in combination with amoxicillin. The half-lives and body clearances of amoxicillin and clavulanic acid did not differ significantly when administered alone and in combination. It was concluded that the i.v. administration of amoxicillin and clavulanic acid as a combination product did not alter the disposition kinetics of either drug.

Amoxicillin↗
PubMed1986

[In vitro susceptibilities of BRL 25000 (clavulanic acid-amoxicillin) against causative organisms in the field of obstetrics and gynecology].

The in vitro susceptibilities of various causative organisms recently isolated from patients with genital infections to BRL 25000 (a formulation with 2 parts of amoxicillin and 1 part of potassium clavulanate), amoxicillin (AMPC), cefaclor (CCL), cephalexin (CEX), cefadroxil (CDX) and cefroxadine (CXD) were determined. beta-Lactamase-producing strains were detected by the nitrocefin disc method. Frequencies of isolation of beta-lactamase producing strains of E. coli, K. pneumoniae and B. fragilis were 36%, 96% and 100%, respectively. The activity of BRL 25000 against S. agalactiae and anaerobic GPC (anaerobic Streptococci, Peptostreptococcus spp.) was slightly less than that of AMPC but was 2- to 4-fold higher than CCL and 8- to 16-fold higher than CEX, CDX and CXD. Against E. coli and K. pneumoniae, the activity of BRL 25000 was superior to that of AMPC and approximately equal to CEX, CDX and CXD but 2-fold less than CCL. Against the B. fragilis group, BRL 25000 was much more active than AMPC or any of the cephalosporins tested, clearly demonstrating the beta-lactamase inhibitory properties of the clavulanic acid in BRL 25000. At inocula of 10(6) CFU/ml, MIC values of BRL 25000 were 12.5-50 micrograms/ml against some strains of E. coli, K. pneumoniae and B. fragilis. A mechanism of resistance other than beta-lactamase production is obviously prevalent in these strains. It is speculated that the resistance may be due to a low affinity of the drug to target proteins. Mixed infections of B. fragilis and E. coli or K. pneumoniae are commonly found in the obstetric and gynecological patients. BRL 25000 shows activity against these strains and also against both aerobic and anaerobic GPC. Therefore, BRL 25000 is considered useful for the treatment of genital infections.

Amoxicillin↗
PubMed1981

Amoxycillin/clavulanic acid: a review of its antibacterial activity, pharmacokinetics and therapeutic use.

Clavulanic acid is a beta-lactamase inhibitor produced from Streptomyces clavuligerus, which when combined with certain beta-lactam antibiotics extends their activity against bacteria which owe their resistance to the production of beta-lacatamases. In combination with amoxycillin it extends the antibacterial activity of amoxycillin to include beta-lactamase-producing strains, which are otherwise resistant, as well as amoxycillin-resistant species such as Bacteroides fragilis. The addition of clavulanic acid to amoxycillin occasionally extends (but does not decrease) the susceptibility of amoxycillin-sensitive bacteria. Clavulanic acid is adequately absorbed after oral administration and its basic pharmacokinetic characteristics are similar to those of amoxycillin. Preliminary therapeutic trials suggest that amoxycillin plus clavulanic acid is effective in urinary tract infections caused by amoxycillin-resistant organisms and in lower respiratory tract infections unresponsive to previous routine antibiotic therapy, in hospitalised patients. It is generally well tolerated; nausea, vomiting, diarrhoea and skin rash being the most frequently reported adverse effects.

Amoxicillin↗
PubMed1986

Suppressive effects of B-lactam-antibiotics on in vitro generation of cytotoxic T-cells.

The in vitro effect of several compounds containing the B-lactam structure (including 6-aminopenicillanic acid, piperacillin, 7-aminocephalosporanic acid, ceftazidime and clavulanic acid) on the generation of cytotoxic lymphocytes was investigated in two different in vitro systems: (1) generation of virus specific cytotoxic T-cells and (2) proliferation of lymphocytes were assessed in secondary in vitro anti-viral immune responses. Both activities were suppressed by B-lactams in a dose-dependent manner. In these experiments, as found previously with human in vitro granulopoesis and proliferation of the human erythroleukaemic cell line K-562, cephalosporins and clavulanic acid were five to twenty times more suppressive than penicillins. Since concentrations that were effective in vitro are being achieved, particularly with cephalosporins, in the serum of patients, the possible clinical consequences of our findings may have to be taken into consideration.

Animals↗
PubMed2005

In vitro evaluation of faropenem activity against anaerobic bacteria.

Faropenem, a new oral penem with broad spectrum activity, could be used as empirical treatment in infections due to unidentified anaerobes, but only a few investigations have been carried out on these bacteria. The aim of this study was to compare faropenem in vitro activity with that of positive antimicrobial controls (metronidazole, imipenem, meropenem, amoxicillin, amoxicillin-clavulanic acid, ticarcillin-clavulanic acid, cefotetan, cefoxitin and clindamycin) against 462 anaerobic bacterial strains. The reference agar dilution method was used according to the NCCLS standard. Faropenem demonstrated high antimicrobial activity, similar to that of both imipenem and meropenem (faropenem Minimal Inhibitory Concentrations 50% and 90% were 0.12 and 1 mg/L for all Gram-negative anaerobes, 0.25 and 1 mg/L for all Gram-positive anaerobes). Only 5 strains of the Bacteroides fragilis group (1.1% of all anaerobes) were resistant to faropenem, which compared favorably with that of other reference antianaerobic drugs. The results obtained confirm those previously reported.

Anti-Bacterial Agents↗
PubMed1988

[Determination of antibiotype by a computer program. Epidemiological significance and antibiogram-identification correlates].

By means of a computer program disk diffusion diameter were analysed and an antibiotic susceptibility code (antibiotype) was determined for enterobacteriaceae. This code was a 6 figure-number. Each figure summarised susceptibility (susceptible or resistant) to 3 antibiotics. Thus a 18 serial antibiotics was necessary to calculate the 6 figure-code. At least following antibiotics were chosen for their characteristic behavior: amoxycillin, ticarcillin, amoxycillin + clavulanic acid, cephalothin, ticarcillin + clavulanic acid, cefotaxime, gentamycin, tobramycin, amikacin, nalidixic acid, pefloxacin, ciprofloxacin, fosfomycin and colistin. This code allowed three kind of utilisation: epidemiology by comparing biochemical and susceptibility patterns of same isolated species; laboratory control: a data base with main antibiotic susceptibility patterns for each species allowed a rapid compatibility control of biochemical identification with antibiogram. An inconsistent result lead to a checking of biochemical and susceptibility tests or to record a new code in a file to a further enrichment of the data base. Impression of a message depending of the code for a therapeutic purpose.

Drug Resistance, Microbial↗
PubMed1995

Pharmacokinetics of amoxicillin/clavulanic acid combination after intravenous and oral administration in goats.

The intravenous and oral pharmacokinetics of an amoxicillin and clavulanic acid combination (20 mg/kg of sodium amoxicillin and 5 mg/kg of potassium clavulanate) were studied in six goats. After intravenous administration the pharmacokinetics of both drugs could be described by an open two-compartment model. Amoxicillin had a greater distribution volume (0.19 +/- 0.01 l/kg) than clavulanic acid (0.15 +/- 0.01 l/kg), whereas the distribution and elimination constants were higher for the latter, which was eliminated more quickly than amoxicillin. After oral administration of both drugs their pharmacokinetic behaviour was best described by an open one-compartment model with first-order absorption. Elimination half-lives were twice as long after oral (2.15 +/- 0.20 h and 1.94 +/- 0.16 h for amoxicillin and clavulanic acid respectively) than after intravenous administration (1.20 +/- 0.16 h and 0.86 +/- 0.09, respectively). An apparent 'flip-flop' situation was evident in this study. Bioavailability was 27% for amoxicillin and 50% for clavulanic acid.

Absorption↗
PubMed2005

BEL-1, a novel clavulanic acid-inhibited extended-spectrum beta-lactamase, and the class 1 integron In120 in Pseudomonas aeruginosa.

Screening by a double-disk synergy test identified a Pseudomonas aeruginosa isolate that produced a clavulanic acid-inhibited expanded-spectrum beta-lactamase (ESBL). Cloning and sequencing identified a novel ESBL, BEL-1, weakly related to other Ambler class A ESBLs. beta-Lactamase BEL-1 hydrolyzed significantly most expanded-spectrum cephalosporins and aztreonam, and its activity was inhibited by clavulanic acid, tazobactam, cefoxitin, moxalactam, and imipenem. This chromosome-encoded ESBL gene was embedded in a class 1 integron containing three other gene cassettes. In addition, this integron was bracketed by Tn1404 transposon sequences at its right end and by P. aeruginosa-specific sequences at its left end.

Amino Acid Sequence↗
PubMed1988

Role of beta-lactamase and different testing conditions in oxacillin-borderline-susceptible staphylococci.

A group of staphylococcal isolates for which oxacillin MICs were intermediate (1 to 4 micrograms/ml) were studied to establish the role of beta-lactamase in this phenomenon. MICs and MBCs of oxacillin and penicillin with and without clavulanic acid or sulbactam (4 or 16 micrograms/ml, respectively) were determined for 11 Staphylococcus aureus and 2 coagulase-negative Staphylococcus isolates for which oxacillin MICs were 1 to 4 micrograms/ml. The susceptibility studies were done with incubation at 35 and 30 degrees C, and the MICs were read at 24 and 48 h. Of the 13 isolates, 4 became resistant when longer incubation or 30 degrees C incubation was used, and the MICs for 9 remained in the intermediate range. Only three of these strains were susceptible to penicillin, and beta-lactamase was not detected. For 6 of 10 beta-lactamase-positive strains, there was a greater-than-twofold-dilution reduction in oxacillin MICs with the addition of clavulanic acid or sulbactam. Of the four strains that became resistant with incubation at the lower temperature, a clavulanic acid effect was observed in three but only at 35 degrees C. The oxacillin MIC for one of the beta-lactamase-negative strains was also reduced with clavulanic acid; however, this strain was inhibited by 1 microgram of clavulanic acid per ml alone. Bactericidal activity was observed with two or four times the oxacillin MIC in eight strains tested at both temperatures, and the combination with clavulanic acid was bactericidal at higher than four times the MIC in five of the strains at 30 degrees C. Our results suggest that oxacillin intermediate MICs for staphylococcal isolates are due not only to beta-lactamase hyperproduction but also some other unidentified factor. The reduction in oxacillin MIC observed when clavulanic acid was added to one strain was probably due to the intrinsic inhibitory activity of clavulanic acid.

Clavulanic Acids↗
PubMed1994

Penetration of amoxycillin/clavulanic acid into bronchial mucosa with different dosing regimens.

BACKGROUND: The efficacy of an antibiotic is related to its concentration at the site of infection. Previous studies of the concentrations of amoxycillin and clavulanic acid (co-amoxiclav) in respiratory secretions or whole lung tissue have suffered from methodological problems. The concentration of amoxycillin and clavulanic acid was determined in bronchial mucosal biopsy samples obtained at bronchoscopy following five different dosing regimens. METHODS: Bronchial biopsy and serum samples were obtained from 50 patients undergoing diagnostic bronchoscopy. Ten patients each received 375 mg, 625 mg, 750 mg, and 3.25 g oral, and 1.2 g intravenous co-amoxiclav 1-3 hours before bronchoscopy. The concentrations of clavulanic acid and amoxycillin were determined by high performance liquid chromatography using a microbore column, solid phase extraction, and preconcentration to improve sensitivity tenfold over previous methods. RESULTS: Concentrations of both clavulanic acid and amoxycillin in bronchial mucosa were dose related and were well above the MIC90 of co-amoxiclav for the common bacterial respiratory pathogens including Haemophilus influenzae, Micrococcus catarrhalis and Streptococcus pneumoniae for all dosing regimens. Mean mucosal levels were 200% and 118% of the corresponding serum levels for amoxycillin and clavulanic acid respectively. CONCLUSIONS: Amoxycillin and clavulanic acid are concentrated in bronchial mucosa and, even at the lowest dose of 375 mg orally, are likely to produce tissue levels in the lung sufficient to inhibit all the common community acquired respiratory pathogens.

Amoxicillin↗
PubMed1989

Pharmacokinetics of amoxycillin/clavulanic acid in serum and ascitic fluid in cirrhotic patients.

A combination of amoxycillin and clavulanic acid (Augmentin) might be useful for first-line treatment of spontaneous bacterial peritonitis in patients with cirrhosis. We have studied the pharmacokinetics of amoxycillin/clavulanic acid in serum and ascitic fluid of six cirrhotic patients. A total of 66 simultaneous serum and ascitic samples were analysed. Following iv injection of 1 g amoxycillin plus 0.2 g clavulanic acid, the ascites to serum AUC ratio was 1.38 for amoxycillin and 1.01 for clavulanic acid, indicating a good distribution of these drugs into the ascitic fluid. In this study, experimental data were fitted to a three compartment body model which revealed that the prolonged serum half-lives of amoxycillin (274 min) and clavulanic acid (200 min) were probably due to the slow return from the ascitic compartment.

Adult↗
PubMed1994

Effect of hyperproduction of TEM-1 beta-lactamase on in vitro susceptibility of Escherichia coli to beta-lactam antibiotics.

The susceptibility of 173 TEM-1-producing isolates of Escherichia coli was assessed by determination of MICs by the agar dilution method. MICs of amoxicillin, mezlocillin, cephaloridine, and, to a smaller extent, amoxicillin-clavulanic acid (but not cephalexin, cefuroxime, cefotaxime, ceftazidime, or imipenem) were higher for isolates that produced large amounts of beta-lactamase than for isolates that produced smaller amounts. The effect of fixed concentrations of clavulanic acid on resistance to amoxicillin was assessed for 34 selected TEM-1-producing isolates. Low concentrations of the inhibitor (0.5 to 1 microgram/ml) reduced the amoxicillin MICs substantially for almost all the isolates, although the reductions were not sufficient to render any of the isolates amoxicillin susceptible. Higher concentrations of clavulanic acid had progressively greater effects on amoxicillin MICs, but even at 8 micrograms/ml some of the isolates with high beta-lactamase activities remained resistant or only moderately susceptible to amoxicillin. All the isolates were inhibited by clavulanic acid (in the absence of amoxicillin) at concentrations of 16 to 32 micrograms/ml. TEM-1 beta-lactamase activity was inhibited in vitro by clavulanic acid, but not totally, with approximately 2% of the initial activity remaining at 2 micrograms/ml and 0.4% remaining at 8 micrograms/ml. These findings suggest that the amount of beta-lactamase activity is a major determinant of the degree of resistance to several beta-lactam antibiotics and can make the difference between susceptibility and resistance to some compounds, notably the combination of amoxicillin with clavulanic acid.

Amoxicillin↗
PubMedDate not supplied

Pharmacokinetics of amoxicillin/clavulanic acid combination after intravenous and intramuscular administration to pigeons.

The pharmacokinetics of amoxicillin/clavulanic acid (4:1) combination were studied after intravenous and intramuscular administration of single doses (25 mg kg(-1) bodyweight) to 50 pigeons. The plasma concentrations-time data were analysed by compartmental pharmacokinetics and non-compartmental methods. The disposition curves for both drugs after intravenous administration were best described by a two-compartment open model. The apparent volumes of distribution of amoxicillin and clavulanic acid were 1.77 litres kg(-1) and 1.30 litres kg(-1) respectively. The body clearances of amoxicillin and clavulanic acid were not significantly different. The elimination half-lives of amoxicillin after intravenous and intramuscular administration were 1.22 (0.09) hour and 1.52 (0.09) hour respectively, and those of clavulanic acid were 1.15 (0.08) hour and 1.49 (0.08) hour. After intramuscular administration both drugs had a significantly longer half-life (P<0.05) than that after the intravenous treatment. The bioavailability after the intramuscular injection was high and similar for both drugs (75.98 per cent for amoxicillin and 74.61 per cent for clavulanic acid). The mean peak plasma concentration of clavulanic acid (0.29 hour) was reached earlier than amoxicillin (0.38 hour) and peak concentrations were proportional to the dose of both products administered (5.81 mg litre(-1) of amoxicillin and 1.89 mg litre(-1) of clavulanic acid). From a single administration it is proposed that an intramuscular dosage regimen of 105 mg kg(-1) of the combination (84 mg kg(-1) of amoxicillin and 21 mg kg(-1) of clavulanic acid) every 12 hours will achieve minimum concentrations > or =0.5 mg litre(-1) (minimum inhibitory concentration of most susceptible pathogens).

Amoxicillin↗
PubMed2003

Antibiotic resistance among anaerobic Gram-negative bacilli: lessons from a French multicentric survey.

Temporal changes of antibiotic susceptibilities among anaerobes in France are followed in our laboratory since 1992. For Bacteroides strains, resistance increased from 1992 to 1998 for amoxicillin-clavulanic acid, cefotetan and clindamycin. The present study evaluates the situation in 2000 for 434 Gram-negative anaerobic clinical isolates (obtained from 9 large university hospitals) by testing amoxicillin and ticarcillin alone or combined with clavulanic acid, cefoxitin, cefotetan, imipenem, clindamycin and metronidazole (using the NCCLS-approved method for MIC determination. The main genera tested included Bacteroides (359 strains of the fragilis group), Prevotella (40 strains), Fusobacterium (23 strains) and miscellaneous species (8 strains). Resistance rates within the B. fragilis group were: amoxicillin-clavulanic acid 5.6%, ticarcillin 33%, ticarcillin-clavulanic acid 2%, cefoxitin 13%, cefotetan 44%, clindamycin 33%, imipenem 1% and metronidazole <1%, respectively. Only one strain of B. fragilis was resistant to metronidazole (MIC=64 mg/L); due to the presence of the nimA gene on the chromosome. Resistance to imipenem or metronidazole was only found among the B. fragilis species. These two former drugs excepted, B. fragilis was less resistant to antibiotics than the other species. beta-lactamase production was detected for 357/359 strains of the fragilis group, 26/40 stains of Prevotella and 3/23 strains of Fusobacterium. Dynamic changes of antibacterial resistance are occurring within the B. fragilis group: decreased resistance to amoxicillin-clavulanic acid, ticarcillin-clavulanic acid, imipenem while resistance for cefoxitin, cefotetan, clindamycin continues to increase. Regular antibiotic surveys are needed as a source of information to guide the empirical therapy of anaerobic infections.

Journal Article↗