In vitro susceptibility of Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis, Mycobacterium avium, Mycobacterium fortuitum, and Mycobacterium chelonae to ticarcillin in combination with clavulanic acid.

The in vitro susceptibility of Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium avium, Mycobacterium fortuitum, and Mycobacterium chelonae (M. chelonei) to ticarcillin in combination with calvulanic acid (CA) was studied by the agar dilution method. All the M. tuberculosis, M. bovis, and M. africanum strains were inhibited at a ticarcillin concentration of 32 micrograms/ml or lower in combination with 5 micrograms of CA. M. chelonae and M. avium strains proved resistant to more than 128 micrograms of ticarcillin plus 5 micrograms of CA per ml. M. fortuitum strains needed 128 micrograms of ticarcillin plus 5 micrograms of CA to inhibit approximately 30% of the isolates.     

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.     

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.     

In-vitro bacterial killing kinetics of ticarcillin/clavulanic acid

An in-vitro model was developed to study the rates of killing by ticarcillin/clavulanic acid combinations of various beta-lactamase producing, ticarcillin resistant, logarithmic phase clinical isolates. Killing, defined as a 3 log reduction, was dependent on the organism, the concentration of clavulanic acid and the duration of exposure. For most isolates studied an optimum period of exposure to and concentration of clavulanic acid could be defined. Certain test strains showed optimum response to readily attainable in-vivo concentrations of clavulanic acid while other strains, although sensitive by MIC data showed a poor response. The clinical implications of this are discussed.     

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 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.     

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.     

In vitro study of clavulanic acid in combination with penicillin, amoxycillin, and carbenicillin.

The activity of clavulanic acid alone and in combination with penicillin, amoxycillin, and carbenicillin was studied. Marked reductions in the minimum inhibitory concentrations (MICs) for a wide spectrum of beta-lactamase-producing clinical isolates were found. Of particular interest were the decreased MICs of penicillin for Bacteroides fragilis and beta-lactamase-producing strains of Neisseria gonorrhoea in the presence of the clavulanic acid. Beta-lactamase-producing strains of Escherichia coli, Klebsiella spp., and indole-negative Proteus also showed considerably increased susceptibility to amoxycillin in combination with clavulanic acid. Two beta-lactamase-producing strains of Pseudomonas aeruginosa remained resistant to carbenicillin in the presence of clavulanic acid.     

Penetration of amoxycillin, ticarcillin and clavulanic acid into lymph after intravenous infusion in rabbits to simulate human serum pharmacokinetics

The distribution of amoxycillin, ticarcillin and clavulanic acid into lymph collected from the right lymphatic duct of rabbits was examined after intravenous administration. The compounds were administered to simulate, in the plasma of rabbits, the concentrations of amoxycillin, ticarcillin and clavulanic acid measured in human serum after the administration of either an iv bolus dose of amoxycillin 1.0 g plus clavulanic acid 200 mg, ticarcillin 3.0 g plus clavulanic acid 200 mg, or an iv infusion of amoxycillin 2.0 g plus clavulanic acid 200 mg or ticarcillin 3.0 g plus clavulanic acid 200 mg given over 30 min. Lymph concentrations of the compounds reached a peak rapidly after the simulation of a bolus dose (0-1 h) and the concentration-versus-time profiles in plasma and lymph were generally similar after 45 min. Following simulation of an iv infusion, peak concentrations of amoxycillin and clavulanic acid in lymph were reached at approximately the same time as for the bolus simulation, but that of ticarcillin occurred slightly later. The elimination half-lives of the compounds were similar in plasma and lymph. The percentage penetration values were high (greater than 80%) irrespective of the concentration-versus-time curve simulated. The penetration of clavulanic acid was compatible with that of the coadministered penicillin agent and was similar when given with either amoxycillin or ticarcillin.     

Induction of chromosomal beta-lactamases by different concentrations of clavulanic acid in combination with ticarcillin

The effect of different concentrations of clavulanic acid (CA) in combination with ticarcillin on beta-lactamase production and ticarcillin MIC was studied in four clinical isolates of Pseudomonas aeruginosa, Enterobacter cloacae, Serratia marcescens, Citrobacter freundii and indole positive Proteus strains. Ticarcillin alone showed a low inducing effect for all species tested, Ser. marcescens excepted. The increase in beta-lactamase activity after addition of CA (2-10 mg/l) was strain and species dependent. No synergy or antagonism was observed on the ticarcillin MIC for the micro-organisms producing only a chromosomally mediated beta-lactamase, though the susceptibility to ticarcillin strongly increased if the strains also produced a plasmid-mediated beta-lactamase. Addition of 50 or 100 mg/l CA resulted in all strains. C. freundii excepted, in a strong increase in beta-lactamase activity and in a strong synergistic effect on the ticarcillin MIC. However, these concentrations are unlikely to be achieved at clinical doses. Thus, irrespective of the inducing effect of ticarcillin and CA (2-10 mg/l) combinations, induction of the chromosomal beta-lactamase did not result in a decrease in ticarcillin susceptibility.     

Penetration to peripheral human lymph of clavulanic acid and ticarcillin

An intravenous dose of 3.0 g ticarcillin and 0.2 g clavulanic acid was given to 11 healthy human volunteers in whom peripheral lymph, serum and urine were monitored for 8 h. The concentrations were assayed microbiologically. The mean levels in lymph collected during the period 0-1 h was 39.3 mg/l of ticarcillin and 2.93 mg/l of clavulanic acid. The mean peak concentration in lymph (appearing between 1.25 and 2.25 h) was 66.3 mg/l for ticarcillin and 4.1 mg/l for clavulanic acid. Elimination was slightly slower from lymph than from serum, the half-life being only 1.04 times longer from lymph than from serum for ticarcillin, but 1.22 times longer for clavulanic acid. The total areas under the concentration curves in lymph was 58% of the serum value of ticarcillin and 81.0% of clavulanic acid. This reflects the ability of the substances to penetrate to lymph. The mean 8-h urinary recovery was 63.7% of the dose of ticarcillin and 43.8% of clavulanic acid. The total body clearances were 14.61/h for ticarcillin and 7.91/h for clavulanic acid and the corresponding d beta distribution volumes 12.21 and 19.11. The ratio of the concentrations of ticarcillin to clavulanic acid in all body fluids increased with time. Pharmacokinetically, clavulanic acid is well suited to be given together with ticarcillin.     

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.     

Pharmacokinetics and tissue penetration of ticarcillin combined with clavulanic acid

A combination of 3 g of ticarcillin and 200 mg of clavulanic acid was administered intravenously to six healthy male volunteers, after which the concentrations of these agents in serum and blister fluid were measured. The ratio of the two drugs in serum varied from 15:1 (ticarcillin-clavulanic acid) at the time of administration to 28:1 at 30 min and 62:1 at 5 h after injection. Both agents penetrated blister fluid rapidly, the ratio being 33:1 at 1 h and 66:1 at 3 h. The elimination rates of these agents were different, but for each compound they were similar in serum and blister fluid.     

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.     

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.     

Effect of clavulanic acid on the susceptibility of clinical anaerobic bacteria to ticarcillin: a multicenter study

Over 2,000 recent clinical isolates of anaerobic bacteria were tested at five medical centers for susceptibility to ticarcillin, ticarcillin plus clavulanic acid, clindamycin, and metronidazole. At 64 micrograms/ml, ticarcillin inhibited 92% of all isolates, but 98% were inhibited at this concentration when 2 micrograms/ml of clavulanic acid was added. With different Bacteroides species, clavulanic acid reduced ticarcillin MICs 2- to 32-fold; other anaerobic species were not significantly affected.     

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.     

Divergent disk susceptibility of coagulase-negative staphylococci to penicillinase-resistant penicillins and augmentin (amoxycillin/clavulanic acid)

30 representative intrinsically penicillin-resistant coagulase-negative staphylococcal (CONS) isolates yielded discrepant agar disk diffusion test (Bauer-Kirby) results for augmentin. Clavulanic acid (2.5 micrograms/ml) enhanced the activity of amoxycillin from 8- to greater than or equal to 128-fold (mean = 26-fold); MICs of amoxycillin (combined with 2.5 micrograms/ml clavulanate) ranged from 1-16 (mean = 3) micrograms/ml. It is recommended that clinical microbiology laboratories withhold 'susceptible' augmentin disk tests results from their reports regarding intrinsically penicillin-resistant CONS isolates. No such discrepancies were encountered among clinical isolates of Staphylococcus aureus.     

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.