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PubMed2005

Clavulanic acid inactivation of SHV-1 and the inhibitor-resistant S130G SHV-1 beta-lactamase. Insights into the mechanism of inhibition.

Clavulanic acid is a potent mechanism-based inhibitor of TEM-1 and SHV-1beta-lactamases, enzymes that confer resistance to beta-lactams in many gram-negative pathogens. This compound has enjoyed widespread clinical use as part of beta-lactam beta-lactamase inhibitor therapy directed against penicillin-resistant pathogens. Unfortunately, the emergence of clavulanic acid-resistant variants of TEM-1 and SHV-1 beta-lactamase significantly compromise the efficacy of this combination. A single amino acid change at Ambler position Ser130 (Ser --> Gly) results in resistance to inactivation by clavulanate in the SHV-1 and TEM-1beta-lactamases. Herein, we investigated the inactivation of SHV-1 and the inhibitor-resistant S130G variant beta-lactamases by clavulanate. Using liquid chromatography electrospray ionization mass spectrometry, we detected multiple modified proteins when SHV-1 beta-lactamase is inactivated by clavulanate. Matrix-assisted laser desorption ionization-time of flight mass spectrometry was used to study tryptic digests of SHV-1 and S130Gbeta-lactamases (+/- inactivation with clavulanate) and identified peptides modified at the active site Ser70. Ultraviolet (UV) difference spectral studies comparing SHV-1 and S130Gbeta-lactamases inactivated by clavulanate showed that the formation of reaction intermediates with absorption maxima at 227 and 280 nm are diminished and delayed when S130Gbeta-lactamase is inactivated. We conclude that the clavulanic acid inhibition of the S130G beta-lactamase must follow a branch of the normal inactivation pathway. These findings highlight the importance of understanding the intermediates formed in the inactivation process of inhibitor-resistant beta-lactamases and suggest how strategic chemical design can lead to novel ways to inhibit beta-lactamases.

Anti-Bacterial Agents↗
PubMedDate not supplied

Clavulanic acid degradation in Streptomyces clavuligerus fed-batch cultivations.

Clavulanic acid (CA) is an important antibiotic that is produced by Streptomyces clavuligerus. CA is unstable and product degradation has turned out to have a major impact on product titers in fed-batch cultivations. Three different types of experiments have been used to elucidate CA degradation under fed-batch cultivation conditions. First, the influence of individual medium compounds was examined. Second, degradation was monitored during the exponential growth phase in batch cultivations. Third, CA degradation was studied in the supernatant of samples taken during a fed-batch. In addition, data from six fed-batch cultivations were studied to derive information about CA degradation during the production phase. These cultivations were based on a mineral medium, containing glycerol, glutamate, ammonium, and phosphate as the main nutrients. The ammonium concentration had a large influence on the degradation rate constant. In addition, either changes in the substrate availability or high concentrations of ammonium or glycerol cause a major increase in the degradation rate constant. Finally, a linear and a fuzzy logic model were made to predict CA degradation rates in these fed-batches.

Biodegradation, Environmental↗
PubMed1999

Clinical and microbiological effects of initial periodontal therapy in conjunction with amoxicillin and clavulanic acid in patients with adult periodontitis. A randomised double-blind, placebo-controlled study.

The aim of the present study was to investigate the clinical and microbiological effects of initial periodontal therapy in conjunction with systemic amoxicillin plus clavulanic acid in adult periodontitis patients using a double-blind, parallel-group, and placebo-controlled protocol. 21 patients with a clinical diagnosis of generalised adult periodontitis were recruited. Clinical measurements and microbiological assessments were carried out at baseline, 3, and 12 months post-treatment. Approximately 6 weeks after initial periodontal treatment (3-6 h), patients were randomly assigned to receive coded study medication of 500 mg amoxicillin plus 125 mg clavulanic acid (Augmentin) or placebo, every 8 h for 10 days. Patients returned for follow-up visits 3, 6, 9, and 12 months after completion of the medication. The mean plaque index (PI) at baseline was 1.1 for placebo group and 0.9 for the test group. At 3 months, the PI had dropped to 0.3 in both groups, and was maintained during the rest of the study. The changes in bleeding on probing (BOP) and gingival index (GI) in the course of the study were similar in both groups. The mean whole mouth probing pocket depth (PPD) in the placebo group was 3.8 mm at baseline and 3.9 mm in the test group. A mean reduction of 1.0 mm in the placebo group and 0.9 mm in the test group was observed during the first 3 months. No further reduction in PPD was noticed during the study period in either group. There was no statistically significant difference in the PPD reduction between the 2 groups. The change in clinical attachment level (CAL) from baseline to 3 months amounted to 0.5 mm in both groups. Between 3 and 12 months, the CAL changed in neither group. In both groups, treatment resulted in a decrease in the number of spirochetes and motile rods in positive patients, but no significant differences between either group were noted in any of the dark field microscopy observations. At baseline, 1 patient in the placebo group and 2 patients in the test group were culture positive for Actinobacillus actinomycetemcomitans (Aa). After therapy, Aa was not detectable in the placebo group and 1 patient remained positive in the test group. In the placebo group, the number of patients positive for Porphyromonas gingivalis (Pg) decreased from 7 to 2 after therapy. In the test group, the 4 patients positive for Pg at baseline remained positive after therapy. In both groups, all subjects were positive for Prevotella intermedia (Pi) and Fusobacterium nucleatum (Fn) at baseline. At 12 months, all subjects had detectable subgingival Fn. 9 out of the 11 placebo and 8 of the 10 test patients remained positive for Pi. There were no differences in detection frequency of Peptostreptococcus micros (Pm) and Bacteroides forsythus (Bf) in both groups between baseline, 3, and 12 months post-treatment. The findings demonstrated that, in comparison to placebo, systemic amoxicillin plus clavulanic acid provided no additional clinical and microbiological effects in the treatment of adult periodontitis patients.

Adult↗
PubMed1989

[Comparison of the in vitro activity of amoxycillin + clavulanic acid and ampicillin + sulbactam combinations against 50 Haemophilus influenzae strains producing beta lactamase].

We compared the ability of two beta lactamase inhibitors, clavulanic acid and sulbactam, to reduce the minimal inhibitory concentrations (MICs) respectively of amoxycillin and ampicillin against fifty strains of Haemophilus influenzae producing a beta lactamase. The reduction of MICs of aminopenicillins was studied using low concentrations of beta lactamase inhibitors (0.125 to 0.5 mg/l). Moreover, the synergic effect of each association was evaluated against a heavy bacterial inoculum (10(8) cfu/ml). The combination of amoxycillin + clavulanic acid was more synergic on these strains than the association of ampicillin + sulbactam.

Amoxicillin↗
PubMed1998

Antiinflammatory effects of enterically coated amoxicillin-clavulanic acid in active ulcerative colitis.

The inflammatory activity of colonic mucosal lesions may be stimulated by intraluminal bacteria. Our aim was to investigate whether administration of broad-spectrum antibiotics decreases inflammatory activity in ulcerative colitis. To this end, we performed a randomized, 5-day study with either oral enterically coated amoxicillin-clavulanic acid (1 g + 250 mg, t.i.d.); i.v. methylprednisolone (40 mg/day) and oral placebo (t.i.d.); or both i.v. methylprednisolone and oral amoxicillin-clavulanic acid as above, in 30 patients with clinically active ulcerative colitis. Before and after 5 days of treatment, intestinal inflammation was assessed by the quantification of mucosal release of eicosanoids and interleukin-8 by rectal dialysis in each patient. Breath H2 excretion after oral lactulose was determined as an index of metabolic activity of colonic flora. The total release of (IL-8) interleukin-8 and eicosanoids significantly decreased in patients treated with antibiotic or steroids and antibiotic. Antibiotic treatment, but not steroids, markedly inhibited breath H2 excretion. In conclusion, short-term treatment with enteric-coated amoxicillin-clavulanic acid decreases the intraluminal release of IL-8 and other inflammatory mediators.

Adolescent↗
PubMed1994

[Cholestatic jaundice caused by amoxicillin-clavulanic acid in 4 patients].

In four patients, two men and two women aged 73, 68, 84 and 72 years respectively, reversible cholestatic liver injury was seen 28-35 days after the start of treatment with amoxycillin-clavulanic acid (Augmentin). This rare complication of amoxycillin-clavulanic acid treatment is characterized by a relatively long latent period before the onset of symptoms or biochemical abnormalities, which makes early recognition difficult. The mechanism responsible for this idiosyncratic cholestasis is unknown.

Aged↗
PubMed1986

[Tolerance of amoxicillin-clavulanic acid combination in the child].

Forty children all aged over 2 years and eutrophic were treated with the combination amoxycillin and clavulanic acid for various infections (twenty-three with meningitis, eleven with bronchial pneumonia, three with typhoid fever, two with lower urinary tract infections and one with ear infection of moderate severity). Nine of these patients had sickness during treatment which was mild and transient in the majority of cases and caused treatment to be stopped in only one case (2.5%). This low level of gastric tolerance should not concern the paediatrician faced with an infection due to (or most likely to be) a beta-lactamase producing micro-organism.

Amoxicillin↗
PubMed1989

Cholestatic hepatitis due to antibacterial combination of amoxicillin and clavulanic acid (augmentin)

Five case histories are presented of patients developing cholestatic hepatitis associated with the intake of the antibiotic combination agent amoxicillin and clavulanic acid (Augmentin). In two of these cases, signs of hepatic injury recurred after readministration of this combination but not after the intake of amoxicillin alone. In none of the patients was another cause for cholestatic hepatitis found and extrahepatic causes were excluded by ultrasonography, CT scanning, or ERCP. Most viral causes of hepatic injury were excluded in these patients. With the exception of one patient, who developed a transient rash, no immunoallergic signs were present. Biopsy in two patients showed extensive cholestasis without significant necrosis. Clavulanic acid seems to be responsible for this adverse effect.

Aged↗
PubMed1988

Rate of bactericidal activity for Branhamella catarrhalis of a new macrolide, CP-62,993, compared with that of amoxicillin-clavulanic acid.

The rate of bactericidal activity of a new macrolide, CP-62,993, was compared with that of the combination of amoxicillin and clavulanic acid (in the proportion of 4 to 1) on strains of Branhamella catarrhalis beta-lactamase producers. The antibacterial activity of CP-62,993 was bacterostatic at 0.01 micrograms/ml. After a 6-hour period of bacteriostasis a bactericidal activity (3 log10 CFU/ml) was observed for all concentrations from 0.1 to 10 micrograms/ml after 24 h. The bactericidal rate of amoxicillin-clavulanic acid combination was more rapid during the first 6 h at 1 and 10 micrograms/ml. However, the concentration required to kill 99.9% of bacteria within 24 h was 1 microgram/ml. In conclusion, CP-62,993 was a bactericidal antibiotic for B. catarrhalis at a lower concentration. This in vitro study suggests that this macrolide may be of great interest in infections due to the B. catarrhalis beta-lactamase producer.

Amoxicillin↗
PubMed1991

[Treatment of acute otitis media: comparative study of efficacy of cefatrizine and amoxicillin-clavulanic acid].

Fourty hospitalized patients (15 children, 25 adults) suffering from acute otitis media have been treated with either cefatrizine or amoxycillin-clavulanic acid. Bacteriological samples were done during surgery by tympanocentesis (N = 33) or by sampling of middle ear fluid specimens (13). H. influenzae was the most common isolate, following by Enterobacteriaceae, S. aureus, P. aeruginosa, and S. pneumoniae. We conclude that these two antibiotics can be used for treatment of acute otitis media in our country even in adults where the order of frequency of bacteria is different from those reported in children.

Acute Disease↗
PubMed1997

Simultaneous determination of amoxycillin and clavulanic acid in pharmaceutical products by HPLC with beta-cyclodextrin stationary phase.

A simple, rapid and accurate method for simultaneous determination of amoxycillin and clavulanic acid using HPLC with beta-cyclodextrin stationary phase was developed. It involves the use of tetraethylammonium acetate (TEAA) as an additive reagent, methanol-buffer solution (pH 4.5) (35:65; v/v) as the mobile phase, detection at 225 mm and chromatogram within 12 min. Linearity and precision of the internal standard method have been obtained. Recoveries ranged from 99.25 to 105.63% for amoxycillin in the synthetic mixture. For clavulanic acid it was from 99.50 to 101.64%. This method is convenient and reproducible for analyses of these two components in different dosage forms.

Amoxicillin↗
PubMed1989

Reassessment of susceptibility test interpretive criteria for ticarcillin and ticarcillin-clavulanic acid.

There are at least four different existing or proposed interpretive criteria for the disk diffusion susceptibility testing of ticarcillin and ticarcillin plus clavulanic acid (T/C). To assess these criteria, 570 gram-negative bacillary isolates were tested for susceptibility to ticarcillin and T/C by both disk diffusion and broth microdilution methods. These included 53 strains of the family Enterobacteriaceae selected for ticarcillin resistance and high-level beta-lactamase production. The broth microdilution test results were more influenced by increased beta-lactamase production than were disk diffusion results. In the absence of published data indicating which of the two standardized test methods better predicts clinical response, we conclude that until such data are available the more conservative National Committee for Clinical Laboratory Standards tentative criteria for tests with members of the Enterobacteriaceae are appropriate. Our data do not support the use of separate T/C interpretive criteria for Pseudomonas spp. and members of the Enterobacteriaceae. The appropriateness of different interpretive criteria needs further evaluation.

Anti-Bacterial Agents↗
PubMed1992

[Spread in hospital units of a Pseudomonas aeruginosa phenotype producing a beta-lactamase highly inducible by clavulanic acid in vitro].

Pseudomonas aeruginosa strains belonging to the serogroup O:11 exhibiting susceptibility to ticarcillin (TIC) and resistance to the ticarcillin-clavulanic acid (CA) combination were found in 19 inpatients over a 14 month period. Mean inhibition diameters obtained using the agar diffusion method were 21.75 mm around the TIC disks (75 micrograms) and 15.96 mm around the TIC+CA disks (75 + 10 micrograms). With control PaO:11 strains, these diameters were 25.27 and 25 mm, respectively. MIC for ticarcillin determined using the checkerboard method rose to 64 mg with CA levels of 16 mg/l or more. CA exhibited dose-dependent antagonism on TIC killing curves when TIC levels approximated the MIC; this effect was no longer present with higher TIC levels. In the crude bacterial extract, a betalactamase of the cephalosporinase type was detected in the absence of induction and increased threefold after exposure to cefoxitin (100 mg/l) and fourfold after exposure to CA (5 mg/l). All these PaO:11 strains exhibited the same antimicrobial resistance phenotype with decreased susceptibility to ureidopenicillins and resistance to aminoglycosides and fluoroquinolones. The induction of a chromosome-encoded cephalosporinase by CA proved useful as an epidemiologic marker. Nosocomial spread of this phenotype was likely the result of selection due to use of antimicrobials.

Anti-Bacterial Agents↗
PubMed1983

Prospective comparison of amoxicillin-clavulanic acid and cefaclor in treatment of uncomplicated urinary tract infections.

Patients with acute, uncomplicated urinary tract infections were treated with either amoxicillin-clavulanic acid (A-C) in fixed combination or cefaclor for 10 days in a prospective randomized comparison. The A-C group included 29 women and 1 man (mean age, 25.5 years), and the cefaclor group included 35 women and 1 man (mean age, 24.9 years). The cure rates were 26 (87%) of 30 with A-C and 26 (72%) of 36 with cefaclor (P greater than 0.20). There was one failure in each group, each caused by an isolate resistant to ampicillin. There were one relapse and two reinfections in the A-C group, compared with seven relapses and two reinfections in the cefaclor group. Side effects, including patients started on antibiotics but whose cultures did not confirm urinary tract infections, were diarrhea in 7 (16%) and rash in 1 (2%) of 44 A-C patients, compared with diarrhea in 1 (2%) and yeast vaginitis in 3 (6%) of 48 cefaclor patients. Although the A-C group had a greater proportion of antibody-coated bacterium-positive infections (22 versus 18 with cefaclor), there was a lower recurrence rate with fewer relapses in patients treated with A-C.

Adult↗
PubMed1992

Granulomatous hepatitis due to combination of amoxicillin and clavulanic acid.

We report the case of a patient with amoxicillin-clavulanic acid-induced hepatitis with histologic multiple granulomas. This type of lesion broadens the spectrum of liver injury due to this drug combination, mainly represented by a benign cholestatic syndrome. The association of granulomas and eosinophilia favor an immunoallergic mechanism. As penicillin derivatives and amoxicillin alone are known to induce such types of lesions, the amoxicillin component, with or without a potentiating effect of clavulanic acid, might have a major role.

Aged↗
PubMed1996

[Hepatitis caused by the amoxicillin-clavulanic acid combination. An example of drug-induced biliary hepatotoxicity].

Clinical and pathological findings of five cases of acute hepatitis due to amoxicillin-clavulanic acid intake are reported. Liver biopsies revealed cholestasis in all cases, associated with varied degrees of interlobular bile duct injury in four patients. There was no ductopenia. These alterations may mimic lesions observed in intra- and/or extrahepatic biliary tract obstruction. Drug-induced intrahepatic bile duct injuries are not uncommon and can lead to diagnosis difficulties.

Amoxicillin↗
PubMed1998

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.

Amoxicillin↗
PubMed1994

In vitro extracellular and intracellular activities of clavulanic acid and those of piperacillin and ceftriaxone alone and in combination with tazobactam against clinical isolates of Legionella species.

The activities of ceftriaxone, piperacillin, tazobactam, clavulanic acid, and combinations of ceftriaxone or piperacillin with tazobactam against 22 clinical Legionella isolates were measured by broth microdilution and macrodilution methods and in macrophages. The broth microdilution MICs that inhibited 90% of strains tested were 2 and 1 microgram/ml for ceftriaxone and tazobactam, respectively. Broth macrodilution MICs were 8 and 1 microgram/ml, respectively, for the two Legionella pneumophila strains tested with piperacillin and were 0.25 and 0.5 microgram/ml, respectively, for clavulanate. No significant intracellular anti-L. pneumophila activity was observed for ceftriaxone (32 micrograms/ml), piperacillin (32 micrograms/ml), tazobactam alone (16 micrograms/ml), clavulanate alone (2 micrograms/ml), or tazobactam in combination with ceftriaxone (ceftriaxone/tazobactam at 32/4 and 16/16 micrograms/ml) or piperacillin (32/4 micrograms/ml). Erythromycin (1 microgram/ml) was active against intracellular L. pneumophila in the same macrophage model of infection. It is very unlikely that tazobactam or clavulanate, alone or in combination with beta-lactam antimicrobial agents, will be effective for the treatment of Legionnaires' disease in humans.

Animals↗