Pharmacokinetics of clavulanic acid, given in combination with amoxycillin, in volunteers

To study the absorption and disposition of clavulanic acid, ten healthy men received one intravenous and one oral dose of 125 mg clavulanic acid in combination with amoxycillin. Serum and urine concentrations were measured with high-performance liquid chromatography. The mean terminal half-lives in serum were 0.97 and 0.94 h, respectively. Total serum clearance was 248 +/- 55 ml/min X 1.73 m2. Renal clearance was 108 +/- 20 and 115 +/- 18 ml/min X 1.73 m2 after intravenous and peroral administration. Urinary recovery over 12 h was 49.4 +/- 8.7% of the intravenous and 35.7 +/- 13.0% of the oral dose. The bioavailability of the oral dose averaged 60.0 +/- 23.1% but varied considerably (range 31.4-98.8%), indicating very variable absorption from the gastrointestinal tract.     

In vitro activity of amoxicillin in combination with clavulanic acid against Mycobacterium tuberculosis.

The comparative in vitro activity of amoxicillin alone and in combination with clavulanic acid against 15 isolates of Mycobacterium tuberculosis was evaluated by broth dilution susceptibility testing. Amoxicillin inhibited 4 of 15 isolates at 8 micrograms/ml or less but was not bactericidal against any of the isolates at that concentration. Amoxicillin in combination with clavulanic acid was bactericidal for 14 of 15 isolates tested at an amoxicillin concentration of 4 micrograms/ml or less and a clavulanic acid concentration of 2 micrograms/ml or less.     

Susceptibility of multidrug-resistant strains of Mycobacterium tuberculosis to amoxycillin in combination with clavulanic acid and ethambutol

Thirty clinical isolates of Mycobacterium tuberculosis, 20 of which were multidrug-resistant (MDR), were tested for susceptibility to different combinations of amoxycillin, clavulanic acid and subinhibitory concentrations of ethambutol. beta-Lactamase production was assessed semiquantitatively with the nitrocefin method and susceptibility testing was performed with the BACTEC method. All isolates were beta-lactamase positive and were resistant to 16 mg/L amoxycillin. The MIC of amoxycillin in combination with clavulanic acid was > or =2 mg/L for 27/30 (90%) isolates. Addition of subinhibitory concentrations of ethambutol significantly reduced the MIC of amoxycillin for all tested isolates. Twenty-nine (97%) isolates had an MIC of amoxycillin of < or =0.5 mg/L when subinhibitory concentrations of ethambutol were added; this is well below the concentrations achievable in serum and tissue.     

Severe toxic hepatitis associated with amoxycillin and clavulanic acid

Toxic hepatitis secondary to amoxycillin-clavulanic acid is an infrequent clinical picture. Most of the cases are reported to have a benign course. We report two cases of severe hepatic failure following amoxycillin-clavulanic acid use. One of the cases had cholestatic features primarily, and the other had hepatocellular injury prominently. The first case had also findings of trombotic trombositic purpura and had a fatal course.     

In vitro susceptibility of Mycobacterium fortuitum to amoxicillin or cephalothin in combination with clavulanic acid

The comparative in vitro activity of cefoxitin, cephalothin, amoxicillin, and clavulanic acid in combination with the latter two agents against 13 isolates of Mycobacterium fortuitum was evaluated by agar dilution susceptibility testing. Amoxicillin was more active than cephalothin but less active than cefoxitin against the strains tested. Clavulanic acid in combination with these beta-lactams usually improved the activity by one or two dilutions compared with the beta-lactams alone.     

Treatment of respiratory tract infections in children: a study of a combination of amoxycillin and clavulanic acid

In an open study, 70 in-patients and 23 out-patients aged between 1 and 14 years with sinusitis (n = 1), perforated otitis media (n = 4), pharyngotonsillitis (n = 25), tracheobronchitis (n = 30) or broncho-pneumonia (n = 33) were treated daily with a combination of 40 mg/kg amoxycillin and 10 mg/kg clavulanic acid in three equal doses for between 6 and 15 days. Purulent specimens were cultured when obtainable and pathogenic organisms identified were Staphylococcus aureus, beta-haemolytic streptococcal group A, Pseudomonas aeruginosa, Pseudococcus species and Klebsiella pneumoniae infections, of which 45.7% were beta-lactamase-producing and 54.3% were ampicillin-susceptible. After treatment, only one beta-lactamase-producing Streptococcus and one Staphylococcus infection persisted. Side-effects (vomiting, nausea, diarrhoea, maculopapular exanthema, rash) occurred in 16 patients and treatment was withdrawn in eight. It is concluded that the amoxycillin--clavulanic acid combination is a suitable first choice for the treatment of respiratory tract infections in children in whom the pathogenic organism may not have been established.     

The beta-lactamase stability of amoxycillin with the beta-lactamase inhibitor, clavulanic acid

The stability of low concentrations of amoxycillin in the presence of clavulanic acid (potassium salt) was determined for a wide range of clinically important beta-lactamases including the staphylococcal and TEM plasmid mediated enzymes. Even with enzyme preparations which completely hydrolysed the amoxycillin within a minute, clavulanic acid provided significant protection. The time course of the protection of amoxycillin reflected the time dependent action of clavulanic acid.     

In-vitro susceptibility of Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium kansasii to amoxycillin and ticarcillin in combination with clavulanic acid

The in-vitro susceptibility of Mycobacterium tuberculosis, M. bovis, and M. kansasii to amoxycillin alone and in combination with 2 mg/l of clavulanic acid was evaluated by broth dilution. The MIC90 of amoxycillin plus clavulanic acid was 4 mg/l compared with greater than 32 mg/l for amoxycillin alone when tested against M. tuberculosis (n = 27). M. bovis (n = 8) was the most susceptible species with an MIC90 of amoxycillin 8 mg/l, compared with 0.5 mg/l for the combination. M. kansasii (n = 6), with an MIC90 of 16 mg/l for amoxycillin plus clavulanic acid was more resistant than either M. tuberculosis or M. bovis. Ticarcillin plus clavulanic acid with an MIC90 of 32 mg/l was less active against M. tuberculosis (n = 28) than amoxycillin plus clavulanic acid. The addition of clavulanic acid to amoxycillin greatly improves its in-vitro activity against M. tuberculosis and M. bovis.     

Penetration of amoxycillin and clavulanic acid into bone

The levels of amoxycillin and clavulanic acid have been measured in bone, serum and synovial fluid following the administration of 1.2 g Augmentin prior to hip replacement. Both antibiotics readily enter synovial fluid in levels similar to that found in serum. The levels found in bone are a minimum of ten times lower than those found in serum. Sequential administration of Augmentin with a six-hourly dose schedule does not increase the levels found in any of the tissues studied.     

Synergistic effects of dicloxacillin or clavulanic acid in combination with penicillin G or cephalothin against Yersinia enterocolitica.

Cultures of Yersinia enterocolitica grown at 22 degrees C produced beta-lactamases, whereas cultures grown at 37 degrees C produced these enzymes much less effectively. Both dicloxacillin and clavulanic acid inhibited the beta-lactamase activity of bacterial crude extracts and potentiated the activity of penicillin G or cephalothin against 14 Y. enterocolitica strains. It appeared that the beta-lactamase activity present in Y. enterocolitica cells grown at 37 degrees C was great enough to play a role in bacterial resistance to beta-lactam antibiotics, since combining penicillin G or cephalothin with clavulanic acid or dicloxacillin resulted in synergistic activity against cultures grown at 37 degrees C that was equal to or greater than the activity against cultures grown at 22 degrees C.     

In vitro activity of clavulanic acid, amoxicillin, and ticarcillin against Chlamydia trachomatis.

In vitro, growth of Chlamydia trachomatis was not entirely eliminated by 960 micrograms of ticarcillin per ml, 64 micrograms of amoxicillin per ml, 32 micrograms of clavulanic acid per ml, a combination of ticarcillin (480 micrograms/ml) and clavulanic acid (32 micrograms/ml), and a combination of amoxicillin (32 micrograms/ml) and clavulanic acid (8 micrograms/ml). However, a greater than or equal to 99% decrease in the number of inclusions was obtained at concentrations readily attainable in serum.     

In vitro activity of carbenicillin, ticarcillin, sisomicin and netilmicin alone and in combination against Pseudomonas aeruginosa.

The in vitro activity of carbenicillin, ticarcillin, sisomicin and netilmicin alone and in combination against 35 strains of Pseudomonas aeruginosa was investigated. Ticarcillin was more active than carbenicillin and sisomicin was more active than netilmicin. There was enhanced killing of many strains of P. aeruginosa by the combination of carbenicillin or ticarcillin with sisomicin or netilmicin.     

Activity of penicillin or ticarcillin in combination with clavulanic acid in the treatment of experimental intra-abdominal abscess

The combination of clavulanic acid (CA) with penicillin or ticarcillin was evaluated in a rat intra-abdominal abscess model. Gelatin capsules filled with a mixture of Bacteroides fragilis and Escherichia coli were implanted intraperitoneally in male Wistar rats. Four different groups of animals with appropriate controls were treated with penicillin or ticarcillin alone or in combination with CA. The treatment was started either immediately or delayed for 48 h after peritoneal inoculation. The therapeutic regimen was given for ten days at 8-hourly intervals. The mortality rate decreased to almost one-half when antibiotic therapy was started within 6 h. Seventy-nine to 89% of animals were cured when treated with ticarcillin in combination with CA showing that ticarcillin + CA was the most effective regimen of those tested in the treatment of experimental intra-abdominal abscess of rats caused by Bact. fragilis and E. coli.     

The pharmacokinetics of orally absorbed cefuroxime compared with amoxycillin/clavulanic acid

The pharmacokinetics of a new orally absorbed pro-drug of cefuroxime were compared with those of co-administered amoxycillin and clavulanic acid in six healthy male volunteers. Doses of 600 mg of acetoxyethyl cefuroxime and 500 mg amoxycillin plus 250 mg clavulanic acid were each administered for ten doses 8 hourly. Tissue penetration after the first dose of the antibiotic was estimated by a cantharides blister method. The faecal flora of the volunteers was studied throughout the study. The pharmacokinetics of cefuroxime and amoxycillin were very similar, peak levels of about 6.4 mg/l being found between 2 and 2.5 h after administration. The peak serum level of clavulanic acid was 4.3 mg/l at 1.25 h after administration. The serum half-lives were about 1.1 h for all three agents. No drug accumulation occurred over the four days of the study. The 0-8 h urinary recovery of cefuroxime was 30%. All three agents penetrated the blister fluid rapidly, the main peak levels being 64% of the peak serum level for cefuroxime, 72% for amoxycillin and 55% for clavulanic acid. The incidence of side effects was similar for each regimen. Three volunteers having diarrhoea after cefuroxime showed significant alterations in their bowel flora.     

In vitro combination of mecillinam with cephradine or amoxycillin for organisms resistant to single agents.

Of 36 multi-resistant Gram-negative bacilli isolated from different cases of urinary tract infection, 18 strains of Escherichia coli, klebsiella, enterobacter, proteus, providencia and serratia with the exception of Acinetobacter species showed synergy when mecillinam was combined with cephradine or amoxycillin in the ratio of 1:1. Combination with cephradine was synergistic on sixteen occasions and amoxycillin on six. Synergy, which might have clinical relevance, was demonstrated only when the test organism was either fully or moderately sensitive to one of the two antibiotics combined but not when resistant to both.     

Bactericidal effects of amoxycillin/clavulanic acid against Legionella pneumophila

The antibacterial activities of amoxycillin, clavulanic acid and the combination of both agents against Legionella spp. were compared in serial-dilution tests, time-kill curve studies and in turbidimetric studies in a continuous recording biophotometer. Both beta-lactam compounds showed high levels of activity against L. pneumophila in serial dilution tests, clavulanic acid (MIC 0.1-0.25 mg/l) being two-fold more active than amoxycillin. The combination of amoxycillin and clavulanic acid was more effective than either of the constituents and was two to four times more active than erythromycin. Clavulanic acid was shown to reduce the extent of inactivation of amoxycillin by L. pneumophila and amoxycillin/clavulanic acid was rapidly bactericidal against the organism in tests in which amoxycillin was ineffective. Microscopical examination showed distinctive morphological effects produced by amoxycillin and by clavulanic acid and synergy between the compounds could be attributed to beta-lactamase inhibition, or by binding to different penicillin binding proteins, or both. These results warrant further studies in vitro and in vivo to elaborate the bactericidal effects demonstrated by amoxycillin and clavulanic acid against Legionella spp.     

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.     

In vitro activity of moxalactam alone and in combination with penicillin against common meningeal pathogens.

Moxalactam demonstrated marked activity against beta-lactamase-positive and -negative Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis by both standard minimal inhibitory concentration testing and growth curve studies. Moxalactam was ineffective against S. pneumoniae partially susceptible to penicillin G. Moxalactam (5 micrograms/ml) and penicillin (1 microgram/ml) in combination were indifferent to each other's antibacterial activity, exerting neither synergism nor antagonism against these organisms.