In vitro synergistic properties of clavulanic acid, with ampicillin, amoxycillin and ticarcillin

Two dosages of a liquid suspension formulation of amoxicillin and potassium clavulanate were tested in 34 infants and children. The smaller dosage resulted in suboptimal plasma concentrations. With the greater dosage (3.3 mg of clavulanate per kg and 13.3 mg of amoxicillin per kg), the mean peak plasma concentrations were 1.6 ,ug clavulanic acid per ml and 4.9 jxg amoxicillin per ml.Clavulanic acid is a beta-lactam compound with weak inherent antibacterial activity, but with the capability of binding irreversibly with a broad spectrum of beta-lactamases. When clavulanic acid is combined with beta-lactamasesusceptible antibiotics, such as ampicillin and amoxicillin, its binding properties permit activity of the antibiotic against beta-lactamase-producing bacteria (2). Many childhood infections are caused by Staphylococcus aureus and Haemophilus influenzae strains which elaborate beta-lactamase and thus are resistant to ampicillin and related drugs. The-combination of clavulanic acid with amoxicillin (Augmentin, Beecham Pharmaceuticals) provides a novel approach to increasing the clinical utility of amoxicillin.A liquid suspension of amoxicillin and potassium clavulanate in a 4:1 ratio by weight was tested in infants and children. The suspension contained 4 mg potassium clavulanate per ml and 16 mg amoxicillin per ml. Two dosages were tested; the smaller was approximately 1.7 mg of clavulanate per kg with 6.6 mg of amoxicillin per kg, and the larger was approximately 3.3 mg of clavulanate per kg and 13.3 mg of amoxicillin per kg. There were 17 children in each group. Each dose was substituted for one dose of the medication the child was receiving for treatment of otitis media or dermatological infections (12 h or more had elapsed since the previous dose of antibiotic).Blood samples were collected immediately before the dose and at 20, 40, 60, 120, 180, and 240 min thereafter. Plasma was separated and stored at -70°C for no longer than 72 h before the assay was performed.Clavulanic acid was assayed by a microdisk agar diffusion method by using an overnight seed culture of penicillinase-producing Klebsiella pneumoniae (ATCC 29665) grown in tryptose phosphate broth without dextrose. A sample of 1.5 ml of the seed culture was added per 100 ml of nutrient agar, and penicillin G-potassium was added at a concentration of 60 ,g/ml. The reference standard was clavulanic acid lithium (Beecham) in pooled normal human plasma.Twenty-Ru amounts of standards and samples were added to 6.35-mm disks in triplicate. Amoxicillin trihydrate was incorporated into the standards at a 1:4 ratio of clavulanic acid to amoxicillin. The concentrations of clavulanic acid were doubling dilutions from 1.6 to 0.1 ,g/ ml.Penicillinase in the seeded agar is inactivated by clavulanic acid diffusing from the disk, thereby causing a zone of inhibition due to penicillin activity against the assay organism.Amoxicillin was assayed by a standard disk diffusion microbioassay with Sarcina lutea (ATCC 9341).Mean plasma concentrations of clavulanic acid and a...

mentioning

confidence: 99%

Pharmacokinetics of potassium clavulanate in combination with amoxicillin in pediatric patients

Nelson

Kusmiesz

Shelton

1982

“…Two doses of ceftazidime given 8 h apart were more effective than the three doses of ticarcillin-clavulanic acid, in keeping with the in vitro activities of these compounds against the infecting organism. These results illustrate the ability of clavulanic acid to penetrate the blood-CSF barrier such that concentrations of the inhibitor in CSF potentiate the activity of ticarcillin against the ticarcillin-resistant, ,-lactamase-producing strain of K. pneumoniae.In the presence of clavulanic acid the antibacterial spectrum of ticarcillin is extended to include ticarcillin-resistant, P-lactamase-producing strains of members of the family Enterobacteriaceae, Pseudomonas aeruginosa, Bacteroides spp., Haemophilus influenzae, and staphylococci (6,8,20). For clavulanic acid to inhibit ,B-lactamases produced in vivo and allow ticarcillin to exert its bactericidal effect, both compounds should display similar distribution characteristics.…”

mentioning

confidence: 99%

Simulation of human serum pharmacokinetics of ticarcillin-clavulanic acid and ceftazidime in rabbits, and efficacy against experimental Klebsiella pneumoniae meningitis

Mizen

Woodnutt

Kernutt

et al. 1989

The penetration into cerebrospinal fluid (CSF) and efficacy of ticarcillin-clavulanic acid, ticarcillin alone, and ceftazidime were compared in rabbits with experimentally induced Klebsiella pneumoniae meningitis. The compounds were administered to simulate in rabbit plasma the concentration-versus-time curves observed in humans after 30-min infusions of Timentin (3 g of ticarcillin plus 100 mg of clavulanic acid), ticarcillin (3 g), and ceftazidime (2 g). Single-and multiple-dosing schedules were used. The penetrations of clavulanic acid into CSF (expressed as [area under the concentration-time curve for CSF/area under the curve for plasma] x 100) after the two dosing schedules were 28 and 24.5%, similar to that for ceftazidime (21%; multiple-dosing only) and greater than those for ticarcillin (8.4 and 9.3%). Ticarcillin was ineffective in reducing viable counts in CSF but, in the presence of clavulanic acid, reduced bacterial numbers by approximately 99% at 4 h after a single dose and by 99.99% at 12 h after three doses given at 4-h intervals. Two doses of ceftazidime given 8 h apart were more effective than the three doses of ticarcillin-clavulanic acid, in keeping with the in vitro activities of these compounds against the infecting organism. These results illustrate the ability of clavulanic acid to penetrate the blood-CSF barrier such that concentrations of the inhibitor in CSF potentiate the activity of ticarcillin against the ticarcillin-resistant, ,-lactamase-producing strain of K. pneumoniae.In the presence of clavulanic acid the antibacterial spectrum of ticarcillin is extended to include ticarcillin-resistant, P-lactamase-producing strains of members of the family Enterobacteriaceae, Pseudomonas aeruginosa, Bacteroides spp., Haemophilus influenzae, and staphylococci (6,8,20). For clavulanic acid to inhibit ,B-lactamases produced in vivo and allow ticarcillin to exert its bactericidal effect, both compounds should display similar distribution characteristics. This has been demonstrated both in animals (4, 5, 24) and in humans (1,3,22). In the study reported here, the penetration into cerebrospinal fluid (CSF) and the efficacy of ticarcillin-clavulanic acid were investigated in a rabbit model of meningitis (18) in which the infecting organism was a strain of Klebsiella pneumoniae.To compensate for the more rapid elimination of ticarcillin (elimination half-life, 0.4 to 0.6 h), clavulanic acid (0.3 to 0.6 h), and ceftazidime (0.75 to 0.88 h) from serum in the rabbit (16, 21, 23; unpublished data) than from serum in humans (half-life, 1.1 ± 0.5, 1.0 + 0.06, and 1.8 ± 0.21, respectively) (7, 9), the antibiotics were administered to infected rabbits by using a procedure designed to simulate in rabbit plasma the concentration-versus-time curves observed in human serum after therapeutic doses. The efficacy of ticarcillinclavulanic acid was compared with results for ticarcillin alone and with those for ceftazidime, a broad-spectrum cephalosporin considered useful for the treatment of gramnegative-bacilliary m...

“…Hence, penicillin therapy of such infections has been discouraged, and the use of P-lactamase-inhibitory compounds has been advocated (22). Clavulanic acid, a potent P-lactamase inhibitor which has been shown to protect penicillins and cephalosporins from inactivation by ,B-lactamases in vitro and in vivo (3,12,16,20,21), might be an effective agent in this situation.…”

mentioning

confidence: 99%

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

Boon¹,

Beale²

1987

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 ,-lactamase-producing strain of S. aureus was also present, wound counts reaching 107 streptococci per wound by 80 h, whereas amoxicillin-clavulanic acid reduced the count to <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 P-lactamase-producing strain of S. aureus and suggest the potential of amoxicillin-clavulanic acid in the treatment of mixed bacterial skin infections involving P3-lactamase-producing organisms.