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PubMed1982

Assay of amoxicillin and clavulanic acid, the components of Augmentin, in biological fluids with high-performance liquid chromatography.

Augmentin is a new antibacterial formulation comprised of amoxicillin and the beta-lactamase inhibitor clavulanic acid. In the present paper, the use of high-performance liquid chromatography (HPLC) to provide a rapid assay of the components of Augmentin in body fluids is described. Clavulanic acid was assayed by reacting the sample with imidazole, which readily produces a derivative absorbing at 311 nm. This derivative chromatographs on reverse-phase HPLC columns clear of interfering components in both human serum and urine. Concentrations of clavulanic acid as low as 0.1 microgram/ml were readily detectable in human serum with this procedure. There was no interference from amoxicillin, amoxicillin penicilloic acid, or the acid and alkali degradation products of clavulanic acid when this assay system was used. Amoxicillin in body fluids was assayed directly by HPLC without derivatization. The same chromatographic conditions were employed for the assay of amoxicillin and the clavulanic acid derivative, simplifying the methodology. Amoxicillin, however, was determined of the antibiotic per ml. An alkali blanking procedure for amoxicillin and clavulanic acid is also described which allows the detection of any underlying peaks which may cochromatograph. The use of ultrafiltration to remove protein from serum samples before HPLC was successfully applied to the assay of clavulanic acid and amoxicillin. Ultrafiltration is not an essential procedure for these assays, but it prolongs column life and reduces interference in the amoxicillin assay. Results obtained by HPLC were compared with those obtained by using microbiological assays.

Amoxicillin↗
PubMed1992

Phlegmonous and abscess-forming ENT infections: comparative efficacy of ceftriaxone versus amoxicillin-clavulanic acid.

In this randomized trial, 100 patients received ceftriaxone or amoxicillin-clavulanic acid in phlegmonous or abscess-forming ENT infections. Clinical and bacteriological results confirm that both antibiotics are equally effective, the advantage of ceftriaxone being one administration a day. Drainage surgery is necessary when an abscess has already formed. In 4 cases (ceftriaxone: 3; amoxicillin-clavulanic acid: 1), no positive response could be observed. Systemic and local tolerance was, as a general rule, excellent, and side effects were reported in 3 cases of the ceftriaxone group and in 3 cases of the amoxicillin-clavulanic acid group.

Adult↗
PubMed1987

[Sulbactam and clavulanic acid: studies of enzyme kinetics and synergism with ampicillin and mezlocillin].

Both inhibitors clavulanic acid and sulbactam exhibit high affinity (Ki-values less than 10(-6) mol/l) to the beta-lactamases of gram-negative bacteria with predominant penicillinase activity and lowered affinity to enzymes with cephalosporinase activity (above all clavulanic acid). As compared to sulbactam there was a stronger synergism of clavulanic acid with ampicillin or mezlocillin in those isolates producing either a plasmid-mediated or a chromosomally-mediated penicillinase. In beta-lactamase-overproducing Klebsiella ssp. variants both inhibitors could protect neither ampicillin nor mezlocillin from breakdown-independent of the synergy observed in the corresponding wild-type strains. Moreover, there was a marked synergism between mezlocillin (but not ampicillin) and sulbactam in beta-lactamase-overproducing Enterobacter cloacae variants. There was no strong relation between the amount of enzyme produced and the resulting synergy between inhibitor and antibiotic among clinical isolates. These observations agree with the results obtained for routinely performed susceptibility testing of amoxycillin/clavulanic acid and ampicillin/sulbactam.

Ampicillin↗
PubMed1987

Bactericidal activity against Haemophilus influenzae of cerebrospinal fluid of patients given amoxicillin-clavulanic acid.

Patients with purulent meningitis received amoxicillin-clavulanic acid (200/20 mg/kg [body weight] per day). Clavulanic acid levels in cerebrospinal fluid were less than or equal to 0.05 micrograms/ml in 5 of 18 samples and ranged from 0.1 to 0.8 micrograms/ml in the others. Of 12 cerebrospinal fluid samples tested, 10 lacked bactericidal activity in vitro against a beta-lactamase-producing strain of Haemophilus influenzae.

Adolescent↗
PubMed1990

Pharmacokinetics and tissue distribution of amoxicillin plus clavulanic acid after oral administration in man.

Augmentin (875 amoxicillin and 125 mg potassium clavulanate) was administered orally to patients with chronic bronchitis. Concentrations of amoxicillin and clavulanic acid were measured in serum, sputum and urine. Peak serum levels for amoxicillin of 11.23 +/- 2.61 micrograms/ml were observed at 2 hours and for clavulanic acid of 2.55 +/- 0.54 micrograms/ml at 1 hour. After 9 hours, 50% of the amoxicillin and 39% of the clavulanic acid had been renally excreted. The peak sputum concentration of amoxicillin was 1.31 +/- 0.42 micrograms/ml at 4 hours and of clavulanate was 0.79 +/- 0.23 micrograms/ml at 2 hours. Patients awaiting surgery received an oral dose of augmentin as above. Samples of lung, tonsil, middle ear mucosa and prostate were obtained and tissue concentrations of both compounds measured. Peak levels of amoxicillin ranged from 0.87 micrograms/g (tonsil) to 2.56 micrograms/g (lung) and of clavulanic acid from 0.20 micrograms/g (prostate) to 0.56 micrograms/g (lung) between 3 and 4 hours after dosing.

Administration, Oral↗
PubMed2001

Amoxicillin-clavulanic acid therapy may be associated with severe side effects -- review of the literature.

INTRODUCTION: There is a growing body of evidence that amoxicillin-clavulanic acid may induce severe adverse effects in patients. METHODS: A medline search of case reports and reviews on amoxicillin-clavulanic acid induced adverse effects was performed. The criteria of a consensus conference on the reporting of drug-induced liver disease were applied. RESULTS: Amoxicillin-clavulanic acid has been associated with drug-induced cholestatic hepatitis in 208 reported patients. In 153 evaluable patients there were 106 males and 47 females with a mean age of 60 years (1-90). Liver associated co-morbidity and co-medication does not play a major part in the development of disease. In most instances respiratory tract infection and sinusitis were treated by amoxicillin-clavulanic acid with a mean treatment duration of 13.9 days and a reaction time until first onset of jaundice of 25.2 days average. Infection and cholestasis from other reason were ruled out in most patients. Liver injury was classified according to laboratory parameters to be hepatocellular in 35 patients, cholestatic in 24 patients and mixed in 83 patients. Normalization of liver enzymes was observed 11.5 weeks after onset of drug administration (average); three of 153 patients did not survive the adverse event. CONCLUSION: Amoxicillin-clavulanic acid which is marketed for treatment of respiratory infections and sinusitis/otitis may in some cases induce severe adverse effects and death in patients of different age, especially if they are on multidrug regimens. In consideration of this fact many authors recommend to reflect carefully, whether amoxicillin-clavulanic acid is necessary in treatment of patients with localized or uncomplicated infections. If amoxicillin-clavulanic acid is prescribed, transaminase, alkaline phosphatase and bilirubin tests should be obtained within the first two weeks and after four to five weeks after beginning of treatment to recognize early enough undesired hepatic side effects.

Adolescent↗
PubMed2003

Identical pattern of highly variable absorption of clavulanic acid from four different oral formulations of co-amoxiclav in healthy subjects.

The aims of this investigation were to calculate the pharmacokinetic parameters of amoxicillin and clavulanic acid, and to identify parameters that may affect their observed differences in absorption. Data were obtained from plasma concentration-time curves from four different open, randomized, two-treatment, two-period, two-sequence, crossover Phase I bioequivalence studies, with the following co-amoxiclav formulations: tablets 250/125, 500/125 and 875/125 mg, or 10 mL of an oral suspension 250/62.5 mg per 5 mL. Data from 144 subjects and 288 drug administrations were available for evaluation. After a 125 mg clavulanic acid dose (administered as potassium clavulanate) for all four different formulations, the clavulanic acid AUC(t) data ranged from 1.5 to 8 mg.h/L, varying by a factor of 5. The absorption of clavulanic acid was not related to the absorption of amoxicillin, or demographic factors, and we were unable to identify the reasons for the large variability in the absorption of clavulanic acid. We conclude that the absorption of clavulanic acid, after oral administration, is highly variable and may vary over a five-fold range between patients.

Adult↗
PubMed2004

In vitro activities of the beta-lactamase inhibitors clavulanic acid, sulbactam, and tazobactam alone or in combination with beta-lactams against epidemiologically characterized multidrug-resistant Acinetobacter baumannii strains.

Acinetobacter baumannii is an important nosocomial pathogen usually in the context of serious underlying disease. Multidrug resistance in these organisms is frequent. The beta-lactamase inhibitors clavulanic acid, sulbactam, and tazobactam have intrinsic activity against Acinetobacter strains. To evaluate their potential therapeutic usefulness, we determined the in vitro activity of ampicillin, sulbactam, ampicillin-sulbactam, cefoperazone, cefoperazone-sulbactam, piperacillin, piperacillin-sulbactam, tazobactam, piperacillin-tazobactam, amoxicillin, clavulanic acid, amoxicillin-clavulanic acid, ticarcillin, and ticarcillin-clavulanic acid against multidrug-resistant A. baumannii. All isolates were epidemiologically characterized by RAPD [random(ly) amplified polymorphic DNA] analysis and/or pulsed-field gel electrophoresis and represented different strain types, including sporadic strains, as well as outbreak-related strains. The MICs were determined by agar dilution on Mueller-Hinton agar (using fixed concentrations, as well as fixed ratios for beta-lactamase inhibitors) and the E-test. The majority of E-test results were within two dilutions of those recorded by agar dilution, with the exception of piperacillin-tazobactam. Sulbactam was superior to clavulanic acid and tazobactam and may represent an alternative treatment option for infections due to multiresistant A. baumannii strains. beta-Lactamase inhibitors have intrinsic activity but do not enhance activity of beta-lactams against A. baumannii. Testing with the inhibitor added at a fixed concentration as recommended for piperacillin-tazobactam and ticarcillin-clavulanic acid by the National Committee for Clinical Laboratory Standards may falsely suggest high activity or gives uninterpretable results due to trailing. If combinations are used for testing, fixed ratios may give more useful results.

Acinetobacter Infections↗
PubMed1983

Single-dose pharmacokinetics of intravenous clavulanic acid with amoxicillin in pediatric patients.

Pharmacokinetics of a parenteral formulation comprised of 5 parts of amoxicillin and 1 part of clavulanic acid were determined in 12 pediatric patients, 2 to 14 years of age. A single dose amounting to 25 mg of amoxicillin and 5 mg of clavulanic acid per kg of body weight was infused intravenously over 2 min. Mean plasma concentrations 5 min after dosing were 89.4 micrograms of amoxicillin per ml and 19.5 micrograms of clavulanic acid per ml. Terminal phase plasma half-lives were 1.2 and 0.8 h, respectively. The data acquired in this study indicate that amoxicillin and clavulanic acid are pharmacokinetically compatible. Moreover, taken with assessment of microbiological activities by others, the present data suggest that intravenous administration of 25 mg of amoxicillin plus 5 mg of clavulanic acid per kg every 6 h is a reasonable starting regimen for assessing the activity of the combined drug formulation in noninvasive childhood diseases caused by Haemophilus influenzae, Staphylococcus aureus, Streptococci spp., Neisseria spp., Branhamella catarrhalis, and other susceptible organisms.

Adolescent↗
PubMed1986

In vitro activity of amoxicillin plus clavulanic acid against Haemophilus influenzae and Branhamella catarrhalis.

The in vitro activity of amoxicillin in the presence of clavulanic acid against clinical isolates of Haemophilus influenzae and Branhamella catarrhalis was assessed in comparison with ampicillin, amoxicillin, cefaclor and erythromycin. The isolates were selected so as to yield equal numbers of beta-lactamase producing and non-beta-lactamase producing strains of the two species. MICs obtained by agar dilution indicated that amoxicillin in the presence of clavulanic acid was the most active of the drugs tested. Clavulanic acid potentiated the activity of amoxicillin against beta-lactamase-producing strains of both Haemophilus influenzae and Branhamella catarrhalis. Further studies on a few strains of each species revealed that the beta-lactamase of Haemophilus influenzae (TEM-1) rapidly inactivated ampicillin and slowly inactivated cefaclor but not cefuroxime. The Branhamella catarrhalis enzyme rapidly inactivated cefaclor, ampicillin and to some extent cefuroxime. Clavulanic acid afforded protection against the beta-lactamase action of both species when beta-lactam antibiotics were added to bacterial cultures.

Amoxicillin↗
PubMed1988

Pharmacokinetics of amoxycillin and clavulanic acid in haemodialysis patients following intravenous administration of Augmentin.

1. Serum concentrations of amoxycillin and clavulanic acid were measured in patients with end-stage renal disease (ESRD) following intravenous administration of 1.2 g Augmentin. Augmentin was administered on a non-dialysis day and 2 h prior to a 4 h dialysis session. 2. The mean values of total serum clearance, mean residence time, volume of distribution at steady state, and terminal half-life for amoxycillin on the non-dialysis day were 14.4 ml min-1, 19.2 h, 14.9 l and 13.6 h, respectively. 3. The mean values of dialysis clearance, total serum clearance during dialysis, fractional drug removal during haemodialysis and half-life during dialysis for amoxycillin were 77.1 ml min-1, 91.5 ml min-1, 0.64 and 2.30 h, respectively. 4. The mean values of total serum clearance, mean residence time, volume of distribution at steady state, and terminal half-life for clavulanic acid on the non-dialysis day were 43.6 ml min-1, 4.4 h, 11.0 l and 3.05 h, respectively. 5. The mean values of dialysis clearance, total serum clearance during dialysis, fractional drug removal during haemodialysis and half-life during dialysis for clavulanic acid were 92.8 ml min-1, 136 ml min-1, 0.65 and 1.19 h, respectively. 6. The total serum clearance on the non-dialysis day, which represents non-renal clearance, was lower than that in normal subjects for both amoxycillin and clavulanic acid. These data would suggest some degree of hepatic impairment in patients with ESRD.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1988

Pharmacokinetics of ticarcillin and clavulanic acid given in combination to adult horses by intravenous and intramuscular routes.

The pharmacokinetics of ticarcillin and clavulanic acid following administration by the intravenous (i.v.) and intramuscular (i.m.) routes were investigated in six normal adult horses. Following i.v. administration, the ticarcillin disposition data conformed to a two-compartment model with an elimination half-life of 1.0 h. The disposition of clavulanic acid was described by a one-compartment model with an elimination half-life of 0.40 h. Following i.m. administration, the half-lives of both drugs were prolonged (ticarcillin 1.8 h, clavulanic acid 1.2 h). The bioavailability of ticarcillin was 84.4% and clavulanic acid 94.3%.

Animals↗
PubMed1986

In-vitro activity of amoxycillin and ticarcillin in combination with clavulanic acid compared with that of new beta-lactam agents against species of the Bacteroides fragilis group.

One hundred and one isolates representing five species of the Bacteroides fragilis group were examined for their susceptibility to amoxycillin and ticarcillin alone or in combination with clavulanic acid, as well as to cefoxitin, latamoxef (moxalactam), ceftizoxime, imipenem, chloramphenicol, clindamycin and metronidazole by the proposed NCCLS agar dilution method. Bactericidal activity of amoxycillin, ticarcillin, combinations of amoxycillin-clavulanic acid and ticarcillin-clavulanic acid, cefoxitin and latamoxef against 54 strains was further assessed by a dilution test in broth. The most active agents were imipenem and the combinations of amoxycillin-clavulanic acid and ticarcillin-clavulanic acid. MIC results indicated that Bacteroides fragilis and B. vulgatus were more susceptible to beta-lactams than were B. distasonis, B. ovatus and B. thetaiotaomicron. Clavulanic acid greatly potentiated the activity of amoxycillin and ticarcillin against the 94 beta-lactamase positive strains but had no effect on the seven B. distasonis isolates that were beta-lactamase negative. Synergistic bactericidal activities could be observed by the amoxycillin-clavulanic and ticarcillin-clavulanic combinations.

Amoxicillin↗
PubMed1986

Biliary pharmacokinetics of ticarcillin and clavulanic acid.

The biliary excretion of ticarcillin and clavulanic acid was studied in 26 patients who required elective biliary surgery. In patients with normal hepatic function or unconjugated hyperbilirubinaemia the mean concentrations of ticarcillin in bile from common bile ducts and functioning gall bladders exceeded the mean concentration in plasma and bile from gall bladders with poor or absent function. Concentrations of ticarcillin in the walls of gall bladders were comparable regardless of function. In patients with obstructive jaundice, concentrations of ticarcillin in bile and the wall of gall bladders were lower than the concentrations in plasma. In all patients the mean concentrations of clavulanic acid in the biliary samples were invariably lower than the mean concentration in plasma.

Bile↗
PubMed1987

Response of Streptococcus pyogenes to therapy with amoxicillin or amoxicillin-clavulanic acid in a mouse model of mixed infection caused by Staphylococcus aureus and Streptococcus pyogenes.

The response of Streptococcus pyogenes to amoxicillin or amoxicillin-clavulanic acid (Augmentin; Beecham Group) therapy of a mixed streptococcal-staphylococcal infection was studied in a surgical wound in mice. A superficial wound was produced on the backs of anesthetized mice, and a suture infected with S. pyogenes, Staphylococcus aureus, or a mixed inoculum of both organisms was inserted. Oral therapy was started 4 h after infection and continued for 3 days. Both amoxicillin and amoxicillin-clavulanic acid were effective in eliminating the streptococci from the pure wound infection. In contrast, amoxicillin failed to eliminate the streptococci from a mixed infection in which a beta-lactamase-producing strain of S. aureus was also present, wound counts reaching 10(7) streptococci per wound by 80 h, whereas amoxicillin-clavulanic acid reduced the count to less than 33 streptococci per wound by 24 h. Numbers of S. aureus were also reduced by amoxicillin-clavulanic acid therapy, controlling the infection, whereas amoxicillin was ineffective. Also of significance was the fact that successful therapy was achieved with blood and tissue concentrations of amoxicillin and clavulanic acid of the same order as those measured in humans. These results show that amoxicillin therapy failed to eliminate S. pyogenes from a wound infection in the presence of a beta-lactamase-producing strain of S. aureus and suggest the potential of amoxicillin-clavulanic acid in the treatment of mixed bacterial skin infections involving beta-lactamase-producing organisms.

Amoxicillin↗
PubMed1993

Ex vivo pharmacodynamic study of piperacillin alone and in combination with tazobactam, compared with ticarcillin plus clavulanic acid.

Ten volunteers received piperacillin (4 g), piperacillin (4 g) plus tazobactam (0.5 g) (Tazocin), and ticarcillin (3 g) plus clavulanic acid (0.2 g) (Timentin) intravenously over 30 min in a cross-over blinded scheme. Blood samples were obtained 0.5 and 3 h after the end of infusion to measure by (high-pressure liquid chromatography) the concentration and bactericidal titers against 70 gram-negative bacilli. Serum time-kill curves were done against 35 strains to measure killing rates and area under the time-kill curve. Using the measure of serum bactericidal activity, ticarcillin-clavulanic acid and piperacillin-tazobactam were equally effective against Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, Serratia marcescens, and Bacteroides fragilis. Piperacillin-tazobactam was superior to ticarcillin-clavulanic acid against piperacillin-resistant Klebsiella pneumoniae (4 to 16 times) and S. marcescens (2 to 4 times). By using the area under the time-kill curve, piperacillin-tazobactam was equivalent to ticarcillin-clavulanic acid against piperacillin-susceptible strains; piperacillin-tazobactam was significantly more active than piperacillin against piperacillin-resistant strains and was more active than ticarcillin-clavulanic acid when the sample obtained 3 h after the end of infusion to volunteers was considered. Serum piperacillin concentrations (mean +/- standard error of the mean; in mg/liter) were 115 +/- 13 at 0.5 h and 7.4 +/- 1.4 at 3 h after the administration of piperacillin alone and 105.5 +/- 12.6 (0.5 h) and 7.7 +/- 1.6 after the administration of piperacillin-tazobactam. Serum tazobactam concentrations (in milligram per liter) were 13.1 +/- 1.4 at 0.5 h and 1.2 +/- 0.2 at 3 h. The piperacillin-tazobactam ratio was 8 +/- 0.3 at 0.5 h and 6.2 +/- 0.5 at 3 h. Piperacillin-tazobactam appears promising against beta-lactamase-producing gram-negative bacilli.

Adult↗
PubMed1985

Single dose oral amoxycillin 3 g with either 125 mg or 250 mg clavulanic acid to treat uncomplicated anogenital gonorrhoea.

A single supervised oral dose of amoxycillin 3 g combined with clavulanic acid 125 mg as a suspension (Augmentin 3.125G) plus probenecid 1 g, cured 97 of 100 assessable patients who had uncomplicated anogenital gonorrhoea. Thirteen of the 100 patients were infected with penicillinase producing strains of Neisseria gonorrhoeae (PPNG) and 11 (85%) of these patients were cured, including one infected with a PPNG strain that was also resistant to spectinomycin. Another group of 93 assessable patients was treated with ampicillin 3 g plus probenecid 1 g, and only 85 (91%) patients were cured. Of the eight treatment failures in this group, five were found to be infected with PPNG strains. In a second study 144 assessable patients were treated with amoxycillin 3 g combined with clavulanic acid 250 mg, (Augmentin 3.250G) plus probenecid 1 g, and a 97% cure rate was again obtained. Five of seven (71%) patients infected with PPNG strains were cured. Although both Augmentin regimens were effective for treating gonorrhoea caused by PPNG and non-PPNG strains, side effects were noted in more patients treated with 250 mg clavulanic acid (24%) than with 125 mg clavulanic acid (5%). In addition, a similar cure rate was obtained in the three primary sites of infection, the urethra, cervix, and rectum.

Administration, Oral↗
PubMed1994

Ticarcillin-clavulanic acid pharmacokinetics in preterm neonates with presumed sepsis.

The objective of the reported study was to characterize the pharmacokinetics of ticarcillin and clavulanic acid in premature low-birth-weight (less than 2,200 g) neonates with presumed sepsis. Eleven infants received 12 courses of ticarcillin-clavulanic acid at 75 mg/kg of body weight intravenously every 12 h. Blood samples were collected at 0.5, 1.5, 4, and 8 h following the infusion of the initial dose. The concentrations of ticarcillin and clavulanic acid were determined by a microbiologic assay. Median (interpatient coefficients of variation) values for the volume of the central compartment, total steady-state volume, distributional clearance, total clearance, and terminal elimination half-life for ticarcillin were 0.030 liter/kg (21%), 0.26 liter/kg (48%), 0.41 liter/h/kg (47%), 0.047 liter/h/kg (47%), and 4.2 h (45%), respectively. For clavulanic acid the parameters were 0.28 liter/kg (32%), 0.36 liter/kg (34%), 11 liters/h/kg (36%), 0.12 liters/h/kg (72%), and 1.95 h (40%), respectively. Our results suggest that the current dosing recommendations of 75 mg/kg every 12 h risk subtherapeutic clavulanic acid concentrations and that 50 mg/kg every 6 h is a more rational dosing strategy.

Anti-Bacterial Agents↗