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PubMed1978

Studies on the biosynthesis of clavulanic acid. I. Incorporation of 13C-labelled precursors.

The biosynthesis of clavulanic acid was investigated by feeding 13C-labelled precursors to Streptomyces clavuligerus fermentations. The resulting samples of clavulanic acid were isolated as the benzyl ester and were examined by 13C NMR spectroscopy for 13C-enrichment. The results showed that the carbon skeleton of 1,3-13C2-glycerol was incorporated intact into the three beta-lactam carbons of clavulanic acid. Studies with 1-13C-acetate, 2-13C-acetate and 1,2-13C2-acetate indicated that the remaining five carbons of clavulanic acid were probably derived from alpha-ketoglutarate. 1-13C-Propionate and 3-13C-propionate were not metabolised via the same route as glycerol, but were probably converted to succinate, via methylmalonyl CoA, and hence via the tricarboxylic acid cycle to the clavulanic acid precursors.

Anti-Bacterial Agents↗
PubMed1987

Pharmacokinetics and bacteriological efficacy of ticarcillin-clavulanic acid (timentin) in experimental Escherichia coli K-1 and Haemophilus influenzae type b meningitis.

The pharmacokinetics and bacteriological efficacy of ticarcillin and clavulanic acid administered individually or in combination were assessed in rabbits with experimental Escherichia coli K-1 and Haemophilus influenzae type b meningitis. The mean penetrations into the cerebrospinal fluid (CSF) of infected animals after a single dose of ticarcillin-clavulanic acid were approximately 11 and 28% for ticarcillin and clavulanic acid, respectively. In continuous-infusion experiments, the mean penetrations into CSF were 14.6 and 35% for ticarcillin and clavulanic acid, respectively, in rabbits with E. coli meningitis and 6.1 and 24%, respectively, in rabbits with H. influenzae meningitis. In animals that received a continuous infusion of the two drugs alone or in combination, the median CSF bactericidal titers for E. coli were less than 1:2, less than 1:2, and 1:2 for ticarcillin, clavulanic acid, and ticarcillin-clavulanic acid, respectively, and for H. influenzae the titers were less than 1:2, less than 1:2, and 1:4, respectively. The addition of clavulanic acid potentiated significantly the bacteriological efficacy of ticarcillin in reducing the number of bacteria in CSF of infected rabbits. Additional studies in animals and humans are required before recommendations can be made regarding the use of ticarcillin-clavulanic acid for treatment of meningitis.

Animals↗
PubMed2002

Improvement for the production of clavulanic acid by mutant Streptomyces clavuligerus.

AIMS: To improve the production of clavulanic acid through the development of strains, the selection of a production medium and a pH shift strategy in a bioreactor. METHODS AND RESULTS: Streptomyces clavuligerus mutant 15 was selected by antibacterial activities. As a result of pH control in a 2.5 l bioreactor, the highest productivity (3.37 microg x ml(-1) x h(-1)) was obtained at a controlled pH of 7.0. CONCLUSIONS: The highest level of production obtained was an increase of about 36% compared with a non-controlled pH. When the production of clavulanic acid reached the maximum level, the pH was shifted from 7.0 to 6.0 for reduction in decomposition rate. The maximum concentration of clavulanic acid was maintained for 24 h as a result of the pH shift control, and a significant reduction in the decomposition of clavulanic acid was obtained. SIGNIFICANCE AND IMPACT OF THE STUDY: Clavulanic acid decomposition was considerably reduced as a result of the pH shift control. The results of this study can be applied for the efficient production of beta-lactamase inhibitory antibiotics.

Bioreactors↗
PubMed1987

Interaction of clavulanic acid, sulbactam and cephamycin antibiotics with beta-lactamases.

The inhibitory effects of clavulanic acid, sulbactam and cephamycin antibiotics on chromosomally-mediated or plasmid-mediated beta-lactamases were investigated. The inhibition constants were determined by a non-linear regression analysis. Clavulanic acid and sulbactam had high affinities for the purified plasmid-mediated beta-lactamases such as SHV-1, TEM-1 and PSE-4, and were potent inhibitors as shown by their low Ki values. Except for Bacteroides beta-lactamase, which is sensitive to inhibition by cephamycin antibiotics, clavulanic acid and sulbactam were found not to be as effective against chromosomally-mediated beta-lactamases. The cephamycin antibiotics were better inhibitors of chromosomally-mediated beta-lactamases than those that are plasmid mediated. Except for P99 beta-lactamase, against which sulbactam and clavulanic acid were inactive, the cephamycin antibiotics were less effective inhibitors than sulbactam and clavulanic acid.

Anti-Bacterial Agents↗
PubMed1978

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.

Amoxicillin↗
PubMed1991

Polarographic determination of clavulanic acid.

A method is proposed for the determination of clavulanic acid by differential pulse polarography. The electroactive product was obtained by hydrolysis in sulphuric medium. It shows a reduction peak, that can be used analytically, at -0.75 V (vs SCE). The optimum conditions for the polarographic signal were determined and a study was made of the different parameters affecting the electrochemical process. A polarographic procedure is proposed for the determination of clavulanic acid in a concentration range of 8.0 X 10(-6) -1.4 X 10(-4) M. The detection limit is about 2 x 10(-6) M and the relative standard deviation is 1.1%. The method was applied to the determination of clavulanic acid in the presence of amoxicillin.

Anti-Bacterial Agents↗
PubMedDate not supplied

On the absorption of clavulanic acid.

It was not possible to computer fit oral clavulanic acid data using exponential or model equations incorporating a single exponential defining the absorption phase. Using the Loo-Riegelman method three phases of the absorption process became apparent, an initial slow phase, a more rapid phase and a final slow phase, contributing approximately 20, 70, and 5%, respectively, to the overall absorption process. Statistical moment analysis of clavulanic acid data following intravenous and oral solution administration gave mean values for the mean residence time, mean absorption time, and volume of distribution steady-state of 56 min, 43 min, and 14.01, respectively. Weibull analysis of the oral solution data gave mean values for lag-time and mean absorption time of 8 min and 46.8 min, respectively. Administration of clavulanic acid in a capsule formulation increased the lag-time before absorption but had no significant effect on the mean absorption time.

Administration, Oral↗
PubMed2004

Five additional genes are involved in clavulanic acid biosynthesis in Streptomyces clavuligerus.

An approximately 12.5-kbp region of DNA sequence from beyond the end of the previously described clavulanic acid gene cluster was analyzed and found to encode nine possible open reading frames (ORFs). Involvement of these ORFs in clavulanic acid biosynthesis was assessed by creating mutants with defects in each of the ORFs. orf12 and orf14 had been previously reported to be involved in clavulanic acid biosynthesis. Now five additional ORFs are shown to play a role, since their mutation results in a significant decrease or total absence of clavulanic acid production. Most of these newly described ORFs encode proteins with little similarity to others in the databases, and so their roles in clavulanic acid biosynthesis are unclear. Mutation of two of the ORFs, orf15 and orf16, results in the accumulation of a new metabolite, N-acetylglycylclavaminic acid, in place of clavulanic acid. orf18 and orf19 encode apparent penicillin binding proteins, and while mutations in these genes have minimal effects on clavulanic acid production, their normal roles as cell wall biosynthetic enzymes and as targets for beta-lactam antibiotics, together with their clustered location, suggest that they are part of the clavulanic acid gene cluster.

Anti-Bacterial Agents↗
PubMed1998

A pathway-specific transcriptional activator regulates late steps of clavulanic acid biosynthesis in Streptomyces clavuligerus.

A Streptomyces clavuligerus gene (designated claR) located downstream from the gene encoding clavaminate synthase in the clavulanic acid biosynthetic gene cluster is involved in regulation of the late steps in clavulanic acid biosynthesis. Nucleotide sequence analysis and database searching of ClaR identified a significant similarity to the helix-turn-helix motif (HTH) region of LysR transcriptional regulators. A gene replacement mutant disrupted in claR was unable to produce clavulanic acid, suggesting that claR is essential for clavulanic acid biosynthesis. Furthermore, the accumulation of clavaminic acid in the claR mutant suggested that ClaR regulates the late steps in the clavulanic acid pathway, i.e. those involved in the conversion of clavaminic acid to clavulanic acid. Transcriptional analysis using RNA isolated from the wild type and the claR mutant showed that the expression of the putative late genes, but not the early genes, was regulated by ClaR. High-resolution S1 nuclease analysis of claR suggested that it is expressed as a monocistronic transcript and also as a bicistronic transcript along with the late gene orf-9. The transcription start site of the monocistronic claR transcript was identified as a C residue 155 nucleotides upstream from the claR start codon.

Amino Acid Sequence↗
PubMed1990

Differences between clavulanic acid and sulbactam in induction and inhibition of cephalosporinases in enterobacteria.

The ability of clavulanic acid and sulbactam to induce and inhibit cephalosporinases was evaluated in 16 clinical isolates of enterobacteria. Using the quantitative induction assay, the checkerboard method and the disc approximation test, clavulanic acid was shown to act as inducer for all species, whereas sulbactam only induced strains of Providencia stuartii. Antagonism was achieved using a combination of clavulanic acid and cefotaxime but a combination of sulbactam and cefotaxime was either synergistic or indifferent. This variation in effect was probably due to the fact that sulbactam, but not clavulanic acid could inhibit cephalosporinases. The data revealed a significant difference between sulbactam and clavulanic acid, which may have relevance to their relative usefulness in combination with beta-lactam antibiotics for the treatment of infections due to enterobacteria that produce inducible cephalosporinase.

Cephalosporinase↗
PubMed1984

The in-vitro susceptibility of the Bacteroides fragilis group to amoxycillin-clavulanic acid.

The susceptibility to amoxycillin-clavulanic acid of 150 strains belonging to the Bacteroides fragilis group was tested by both disc diffusion and agar dilution methods. On the basis of minimum inhibitory concentrations (MICs), at least 99% of the isolates were sensitive to this agent. However, problems encountered with the disc diffusion method suggest that at present it is unsatisfactory for assessing the in-vitro activity of amoxycillin-clavulanic acid against this group of organisms.

Amoxicillin↗
PubMed1986

Bactericidal effects of ticarcillin-clavulanic acid against beta-lactamase-producing bacteria in vivo.

The comparative efficacies of ticarcillin and ticarcillin plus clavulanic acid have been determined in the mouse against experimental infections caused by ticarcillin-resistant bacteria. The infections studied comprised an intraperitoneal infection, local tissue infections, pyelonephritis, and pneumonia. Both ticarcillin and clavulanic acid penetrated readily to the sites of infection studied and at the doses employed were present at concentrations of the same order as those obtained in humans after the administration of ticarcillin-clavulanic acid formulations (Timentin; Beecham). At these concentrations, the ticarcillin-clavulanic acid combination caused significant bactericidal effects at the sites of infection against the ticarcillin-resistant strains of Bacteroides fragilis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus investigated. The efficacy of ticarcillin plus clavulanic acid against the infections resistant to therapy with ticarcillin demonstrated the beta-lactamase-inhibitory activity of clavulanic acid in vivo.

Animals↗
PubMed2001

Kinetic studies of clavulanic acid recovery by ion exchange chromatography.

Clavulanic acid (CA) is a beta-lactamase inhibitor produced by strains of Streptomyces clavuligerus. Nowadays, the combination of CA with amoxycillin is the most successful example of the use of a beta-lactam antibiotic sensitive to beta-lactamases together with an inhibitor of these enzymes. Clavulanic acid is purified from fermentation broth by a series of steps consisting mainly of two-phase separation processes such as liquid-liquid extraction, adsorption or ion-exchange chromatography, among others. Amberlite IRA 400, a strong anion-exchange resin, has a very high adsorption capacity for CA (Mayer et al. 1997). This resin can be pre-treated with NaCl (chloride cycle), to remove selectively only those anions, which are able to displace chloride from the resin or with NaOH (hydroxyl cycle), to remove all species of anions. In order to decide the best operating conditions for CA recovery by ion-exchange resins and then to construct a model of this separation process, batch experiments were conducted using Amberlite IRA 400 in the chloride cycle. These runs were carried out in a 200 ml stirred tank, at two different initial solution pH, 6.2 and 4.0; the temperature was maintained at 10 degrees C and 20 degrees C during adsorption and 30 degrees C during the desorption step. It was possible, on the basis of these batch results, to model the separation process, including the adsorption kinetics, equilibrium data and mass transfer limitations.

Adsorption↗
PubMed1986

[In vitro activity of the combination ticarcillin-clavulanic acid on bacterial isolates in surgery].

The in vitro activity of ticarcillin in combination with clavulanic acid was tested, by disc diffusion, against 1,380 clinical bacterial isolates and was compared with that of ticarcillin alone. 83.8% of the isolates were susceptible to ticarcillin + clavulanic acid, whereas 56.6% were susceptible to ticarcillin alone. Minimal inhibitory concentrations (MIC) of ticarcillin in the presence of 4 micrograms/ml of clavulanic acid were determined against 157 ticarcillin resistant (MIC greater than 128 micrograms/ml) but ticarcillin + clavulanic acid susceptible strains of Gram negative bacilli and against 20 strains of beta-lactamase producing Staphylococcus aureus. With the addition of clavulanic acid, MICs of ticarcillin were respectively less than or equal to 16 micrograms/ml and less than or equal to 64 micrograms/ml for 50 and 90% of the Gram negative bacilli. All the Staphylococcus aureus were inhibited by concentrations of ticarcillin less than or equal to 1 microgram/ml.

Bacteria↗
PubMed1996

[Errors of the agar diffusion method to predict Escherichia coli's susceptibility to ampicillin-sulbactam and amoxicillin-clavulanic acid].

BACKGROUND: To evaluate the in vitro activity of the ampicillin-sulbactam and amoxicillin-clavulanic acid against Escherichia coli isolations resistant to ampicillin and amoxicillin and the efficacy of the disks of ampicillin sulbactam 10/10 microgram and amoxicillin-clavulanic acid 20/10 micrograms to differentiate the susceptible (S) and resistant (R) isolates. METHODS: We evaluated the in vitro susceptibility of 100 consecutive clinical isolates of ampicillin and amoxicillin resistant E. coli by the broth macrodilution method and disk diffusion test against ampicillin-sulbactam and amoxicillin-clavulanic acid. RESULTS: For amoxicillin-clavulanic acid the 64% of the isolates were susceptible, 34% were moderately susceptible and 2% were resistant. In contrast, the in vitro activity of ampicillin-sulbactam was inferior since 13% of the isolates were susceptible, 24% moderately susceptible and 63% were resistant. By using the disk of ampicillin-sulbactam 10/10 microgram we found a 13% of very major errors and a 44% of minor errors when we consider the actual rules of NCCLS (R < or = 11 mm and S > or = 15 mm). The best results were achieved when we took into account zone size < or = 15 mm as R and > or = 20 mm as S; however, the level of errors was high too (25% minor errors). For the disk of amoxicillin-clavulanic acid 20/10 micrograms we found a 31% of minor errors when using the advised break points (R < or = 13 mm and S > or = 18 mm). CONCLUSIONS: We consider that the disk diffusion tests are not applicable to these combinations when E. coli isolates resistant to aminopenicillin are evaluated. We advise not to extrapolate the results of sensibility or resistance from one combination to the other because it presents a different in vitro activity.

Amoxicillin↗
PubMed2001

Effects of preculture variability on clavulanic acid fermentation.

The production profile of clavulanic acid by Streptomyces clavuligerus was shown to be strongly dependent on inoculum activity. Two sets of fermentations (A and B) were investigated at industrial pilot-plant scale using complex media. Type A fermentations were inoculated using late exponential growth phase mycelia. Type B fermentations were inoculated using mycelia harvested at stationary phase. Productivities throughout type A fermentations were consistently higher than type B, reaching a maximum at about 70 h and then decaying to the same final productivities at 140 h of type B runs. Several scheduling alternatives, based on combinations of the two inocula types and different fermentation lengths, were compared in terms of the overall process economics (fermentation and downstream). An increase of ca. 22% on the overall process profit is predicted using late exponential growth phase inocula and a fermentation duration of only 96 h. A new operating strategy was thus proposed for inoculum production based on the control of preculture activity using off-gas analysis. This method ensures higher productivity and better batch-to-batch reproducibility of clavulanic acid fermentations than traditional methods based on constant age inocula.

Anti-Bacterial Agents↗
PubMed1984

[Combined antibacterial activity of clavulanic acid with amoxicillin and ampicillin against Gram-negative strains].

Clavulanic acid was tested for in vitro synergistic activity with Ampicillin and Amoxycillin against 41 Gram-negative strains beta-lactamase positive or negative. Clavulanic acid provides progressive inhibition of the beta-lactamases of many bacteria. The better protective effect of CA on AM or AMX is at concentration of 100 mcg. Some synergy was seen against E. coli, Klebsiella and Proteus. Enterobacter and Pseudomonas remained resistant to the combination of AMX and AM with clavulanic acid. We have seen no synergistic effect when non beta-lactamase producing organisms were tested. Although CA alone has a broad antibacterial spectrum, the degree of activity is generally rather poor.

Amoxicillin↗
PubMed2000

Clavulanic acid, a beta-lactamase inhibitor: biosynthesis and molecular genetics.

Clavulanic acid is a secondary metabolite produced by Streptomyces clavuligerus. It possesses a clavam structure and a characteristic 3R,5R stereochemistry essential for action as a beta-lactamase inhibitory molecule. It is produced from glyceraldehyde-3-phosphate and arginine in an eight step biosynthetic pathway. The pathway is carried out by unusual enzymes, such as (1) the enzyme condensing both precursors, N2-(2-carboxyethyl)-arginine (CEA) synthetase, (2) the beta-lactam synthetase cyclizing CEA and (3) the clavaminate synthetase, a well-characterized multifunctional enzyme. Genes for biosynthesis of clavulanic acid and other clavams have been cloned and characterized. They offer new possibilities for modification of the pathway and for obtaining new molecules with a clavam structure. The state of the regulatory proteins controlling clavulanic acid biosynthesis, as well as the relationship between the biosynthetic pathway of clavulanic acid and other clavams, is discussed.

Anti-Bacterial Agents↗