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At least 343 records · Page 19Linked to original sources
PubMed1992

Two isozymes of clavaminate synthase central to clavulanic acid formation: cloning and sequencing of both genes from Streptomyces clavuligerus.

Clavaminate synthase (CS) is an alpha-ketoglutarate-dependent oxygenase central to the biosynthesis of clavulanic acid, a potent inhibitor of beta-lactamases. CS catalyzes the oxidative cyclization/desaturation of proclavaminic acid to clavaminic acid in a two-step process involving the intermediacy of dihydroclavaminic acid [Salowe, S. P., Krol, W. J., Iwata-Reuyl, D., & Townsend, C. A. (1991) Biochemistry 30, 2281-2292]. During the purification of CS to homogeneity from Streptomyces clavuligerus [Salowe, S. P., Marsh, E. N., & Townsend, C. A. (1990) Biochemistry 29, 6499-6508], two forms of the enzyme capable of carrying out the complete reaction having very similar molecular weights and kinetic properties were isolated by Mono-Q chromatography. The gene for each has been cloned, sequenced, and found to be significantly homologous (87% identity). The two genes so isolated, cs1 and cs2, have open reading frames of 975 and 978 nucleotides, respectively, encoding proteins of M(r) 35,347 and 35,774. These genes are located in different loci of the genome separated by > 20 kbp. This separation is large for a natural product biosynthetic pathway in bacteria where gene duplication and limited divergence are typically observed to occur within narrower confines of a gene cluster. Sequence comparisons made between cs1/cs2 and other genes encoding iron-dependent proteins involved in penicillin and cephalosporin biosynthesis in the same organism show minimal homology. Further sequence alignments made to other non-heme iron oxygenases reveal unexpected dissimilarity within the alpha-ketoglutarate-dependent class itself. The limited data available suggests evolutionary convergence among these proteins.

Amino Acid Sequence↗
PubMed1983

Amoxicillin combined with clavulanic acid for the treatment of soft tissue infections in children.

We compared responses to amoxicillin combined with clavulanic acid (ACA) with a cefaclor regimen in children with skin and soft tissue infections (impetigo and cellulitis) due to Staphylococcus aureus, Streptococcus pyogenes, and Haemophilus species. All isolates from the 41 patients we were able to evaluate were susceptible to ACA by disk susceptibility testing at the onset of treatment. The 21 children receiving ACA and 18 (90%) of 20 taking cefaclor responded to therapy. Clinical cure was achieved in 18 (86%) of 21 and 18 (90%) of 20 in the two groups, respectively. Bacteriological failure occurred in 2 (10%) patients in the cefaclor group and none in the group receiving ACA; however, there were 2 (9%) relapses and 1 (5%) reinfection among the 21 children taking ACA. Adverse effects, although mild, occurred more commonly (9 of 21 versus 1 of 20; P = 0.005) with ACA than with cefaclor.

Amoxicillin↗
PubMed1984

Absorption, metabolism and excretion studies on clavulanic acid in the rat and dog.

At least one third of an oral dose of sodium [G-14C]clavulanate was absorbed by rat and dog. Excretion of radioactivity was rapid in both species. In addition to urinary and faecal excretion of radioactivity, appreciable elimination of 14CO2 occurred, particularly in the rat. This was produced in part by the action of the gut microflora. In the rat, only a small proportion of the radioactive dose was secreted in the bile. The major metabolite in urine was identified as 1-amino-4-hydroxybutan-2-one. Clavulanic acid was also a major component in urine.

Animals↗
PubMed2005

Expression of ccaR, encoding the positive activator of cephamycin C and clavulanic acid production in Streptomyces clavuligerus, is dependent on bldG.

In Streptomyces coelicolor, bldG encodes a putative anti-anti-sigma factor that regulates both aerial hypha formation and antibiotic production, and a downstream transcriptionally linked open reading frame (orf3) encodes a putative anti-sigma factor protein. A cloned DNA fragment from Streptomyces clavuligerus contained an open reading frame that encoded a protein showing 92% identity to the S. coelicolor BldG protein and 91% identity to the BldG ortholog in Streptomyces avermitilis. Sequencing of the region downstream of bldG in S. clavuligerus revealed the presence of an open reading frame encoding a protein showing 72 and 69% identity to the ORF3 proteins in S. coelicolor and S. avermitilis, respectively. Northern analysis indicated that, as in S. coelicolor, the S. clavuligerus bldG gene is expressed as both a monocistronic and a polycistronic transcript, the latter including the downstream orf3 gene. High-resolution S1 nuclease mapping of S. clavuligerus bldG transcripts revealed the presence of three bldG-specific promoters, and analysis of expression of a bldGp-egfp reporter indicated that the bldG promoter is active at various stages of development and in both substrate and aerial hyphae. A bldG null mutant was defective in both morphological differentiation and in the production of secondary metabolites, such as cephamycin C, clavulanic acid, and the 5S clavams. This inability to produce cephamycin C and clavulanic acid was due to the absence of the CcaR transcriptional regulator, which controls the expression of biosynthetic genes for both secondary metabolites as well as the expression of a second regulator of clavulanic acid biosynthesis, ClaR. This makes bldG the first regulatory protein identified in S. clavuligerus that functions upstream of CcaR and ClaR in a regulatory cascade to control secondary metabolite production.

Anti-Bacterial Agents↗
PubMed1994

Hepatocellular-cholestatic liver injury due to amoxycillin-clavulanic acid combination.

Two cases (first cases from Poland and Eastern Europe) with liver injury due to amoxycillin-clavulanic acid (augmentin) are reported. Pruritus and jaundice were the main symptoms. Liver biopsy revealed mixed hepatocellular-cholestatic liver injury in both cases. In addition, in one case the microgranulomalike aggregate of inflammatory cells was found. Clinical and laboratory abnormalities returned to normal within 13 weeks.

Amoxicillin↗
PubMed1996

[Clarithromycin versus amoxicillin-clavulanic acid in the treatment of acute maxillary sinusitis in adults].

The efficacy and safety of clarithromycin and amoxicillin-clavulanate in the treatment of acute maxillary sinusitis was compared in an open multicenter outpatient study. Two hundred and eighty patients were randomly assigned to receive either clarithromycin 500 mg 12-hourly or amoxicillin-clavulanate 500 mg 8-hourly orally for 8 days. Clinical and radiologic signs and symptoms, and sinus culture were not significantly different in the two treatment groups. A clinical and radiological success or improvement was achieved after the end of treatment in 115/134 (85.8%) patients treated with clarithromycin and in 110/129 (85.3%) patients treated with amoxicillin-clavulanate. Adverse events were reported for 14.8% and 12.2% of patients for clarithromycin and amoxicillin-clavulanate, respectively. In this study clarithromycin was as effective and well tolerated as amoxicillin-clavulanate acid in the treatment of acute maxillary sinusitis.

Acute Disease↗
PubMed1993

Activity of 13 beta-lactam agents combined with BRL 42715 against beta-lactamase producing gram-negative bacteria compared to combinations with clavulanic acid, tazobactam and sulbactam.

The activity of six cephalosporins, six penicillins and one monobactam combined with BRL 42715, clavulanic acid, sulbactam or tazobactam at 0.1, 0.5, 1, 2, 5 and 10 mg/L was determined for 45 beta-lactamase producing Gram-negative bacteria. The combination of BRL 42715 with any of the agents was more active than any of the other inhibitor and beta-lactam combinations. Unlike the other beta-lactamase inhibitors, BRL 42715 enhanced the activity of the beta-lactams for strains that constitutively expressed Richmond & Sykes Class I beta-lactamase and against strains expressing extended-spectrum plasmid-mediated beta-lactamases.

Anti-Bacterial Agents↗
PubMed1987

Serum levels and pharmacokinetics of ticarcillin and clavulanic acid in dog following parenteral administration of Timentin.

The serum concentration-time data for ticarcillin (TICAR) and clavulanic acid (CLA) following intravenous and intramuscular administration of Timentin (TICAR, 50 mg/kg with CLA, 1.7 mg/kg) indicated that absorption of CLA following intramuscular injection and its overall elimination from the body was faster than that of TICAR. This is supported by comparison of certain pharmacokinetic parameters for TICAR and CLA. These include the shorter value of Tmax for CLA (11.45 +/- 1.60 min) than that for TICAR (29.93 +/- 1.94 min) and significant variation in the elimination rate constants (0.183 +/- 0.0018 min -1 for CLA vs. 0.0097 +/- 0.0006 min -1 for TICAR) for the intravenous group of animals. The biological half-life of CLA (approximately 39 min) was significantly shorter (P less than 0.01) than that of TICAR (approximately 73 min). In spite of initial faster absorption, the intramuscular bioavailability of CLA (65.02%) was less than that of TICAR (91.37%). Though the pharmacokinetic behaviour of TICAR and CLA is not similar, yet based on the therapeutically optimal concentrations of CLA and TICAR reached in serum, Timentin at the dose used in the present study should be effective in treating most TICAR-resistant Enterobacteriaceae infections in dogs. Timentin is not likely to be effective in the treatment of infections caused by TICAR-resistant pseudomonads, at the dose used in the present study.

Animals↗
PubMed1995

[Resistance to amoxicillin and amoxicillin-clavulanic acid combination of 231 clinical strains of Escherichia coli, isolated in 1992 at the Cochin Hospital].

Among 231 clinical strains of Escherichia coli tested during may 1992, 89 isolates (38.5%) were resistant to beta-lactams. The resistant strains were principally recovered from urinary and genital specimen from medicine and surgical departments. MICs of beta-lactams were determined alone or combined with clavulanic acid, and beta-lactamases were identified by isoelectric point characterization and by enzymatic inhibition tests. Among the resistant strains, 92.1% were secreting a penicillinase and 6.7% a cephalosporinase. No extended-spectrum beta-lactamase was observed. 85.5% of penicillinases were TEM-1 enzymes, 4.9% SHV-1 beta-lactamase, 1.1% OXA-1 beta-lactamase and 8.5%, 7 strains, were IRT beta-lactamases (formerly called TRI). For 24 clinical E. coli strains, the MICs values were > or = 32 mg/l for amoxicillin plus clavulanic acid. The 7 IRT beta-lactamases showed the highest MICs, 256 to 4096 mg/l. Four of them exhibited a beta-lactamase of pI 5.4 and 3 a beta-lactamase of pI 5.2. The IRT beta-lactamases represent 3% of all the Escherichia coli strains. This frequency is comparable or lower than the values reported by other studies conducted between 1992 and 1994.

Amoxicillin↗
PubMed1995

[Identification of a cephalosporinase susceptible to clavulanic acid in a clinical strain of Serratia fonticola].

We analyzed the beta-lactamase production of a Serratia fonticola isolated for its resistance to cefuroxime (Minimum Inhibitory Concentration > 256 mg/l) in December 1993 from a patient hospitalized in Meaux. The wild strain was resistant to amoxycillin but sensitive to augmentin, that suggested the production of a beta-lactamase susceptible to clavulanic acid. For the wild strain, beta-lactamase production was inducible and only one enzyme with an isoelectric point of 8.12 was detected. beta-lactamase production was 16 mU/mg for non-induced extracts and ranged from 100 to 230 mU/mg in the presence of inducing beta-lactams (enzyme activity was measured with penicillin G as substrate). On a Szybalski gradient a constitutive strain was obtained. Its enzyme production was 13,000 mU/mg. The kinetics and isoelectric points of the enzymes produced by the two strains were identical. This beta-lactamase hydrolyzes penicillins (amoxycillin: Vm = 60 relative to penicillin G = 100, ticarcillin: 15), first generation cephalosporins (cephalothin Vm = 930). However, this enzyme hydrolyzes efficiently oxyimino-cephalosporins: cefuroxime (Vm = 70) and cefotaxime (Vm = 120), but cephamycins are not substrates. Clavulanic acid has a very good affinity for this beta-lactamase (Ki = 0.09 microM) which is inactivated progressively (I50 = 0.045 microgram/ml). These properties shows some similarities with those of the class A beta-lactamases of P. vulgaris RO104 (pI = 8.3), P. penneri 14HBC (pI = 6.65) and the plasmid-mediated extended-spectrum MEN-1 (pI = 8.4).

Aged↗
PubMed2005

High resolution crystal structures of the trans-enamine intermediates formed by sulbactam and clavulanic acid and E166A SHV-1 {beta}-lactamase.

Antibiotic resistance mediated by constantly evolving beta-lactamases is a serious threat to human health. The mechanism of inhibition of these enzymes by therapeutic beta-lactamase inhibitors is probed using a novel approach involving Raman microscopy and x-ray crystallography. We have presented here the high resolution crystal structures of the beta-lactamase inhibitors sulbactam and clavulanic acid bound to the deacylation-deficient E166A variant of SHV-1 beta-lactamase. Our previous Raman measurements have identified the trans-enamine species for both inhibitors and were used to guide the soaking time and concentration to achieve full occupancy of the active sites. The two inhibitor-bound x-ray structures revealed a linear trans-enamine intermediate covalently attached to the active site Ser-70 residue. This intermediate was thought to play a key role in the transient inhibition of class A beta-lactamases. Both the Raman and x-ray data indicated that the clavulanic acid intermediate is decarboxylated. When compared with our previously determined tazobactam-bound inhibitor structure, our new inhibitor-bound structures revealed an increased disorder in the tail region of the inhibitors as well as in the enamine skeleton. The x-ray crystallographic observations correlated with the broadening of the O-C=C-N (enamine) symmetric stretch Raman band near 1595 cm(-1). Band broadening in the sulbactam and clavulanic acid inter-mediates reflected a heterogeneous conformational population that results from variations of torsional angles in the O-(C=O)-C=C=NH-C skeleton. These observations led us to conclude that the conformational stability of the trans-enamine form is critical for their transient inhibitory efficacy.

Anti-Bacterial Agents↗
PubMed1989

[Long-term therapy with amoxicillin and clavulanic acid in recurrent urinary tract infections in childhood].

Experiments have been carried out with an association of amoxicillin and clavulanic acid for the long-term treatment of recurrent urinary tract infections. 20 children whose antibiogram showed that the microbe in question was insensitive to amoxicillin alone were selected for treatment; five suffered from urinary tract malformations. Urine sterilisation was obtained by administering a dose of 40 mg/kg/die for five days. Treatment continued with a single evening dose of 20 mg/kg for six months. A positive result was obtained in 18 subjects (90%). One case of E. coli proved resistant to the antibiotic. In another case, treatment had to be suspended for vomiting. At the end of treatment, haematological controls proved normal.

Amoxicillin↗
PubMedDate not supplied

[Amoxicillin-clavulanic acid combination in bacterial infections of the upper respiratory tract in childhood. Controlled clinical study].

A comparative clinical trial of amoxycillin - clavulanic acid combination versus erythromycin was carried out in a case series of 20 pediatric patients, suffering from upper respiratory tract infections with a proven bacterial etiology and different localization (tonsils, nasal and paranasal sinuses and ear). The results have confirmed the highly innovative efficacy of amoxycillin - clavulanic acid combination: the clinical judgement was in fact favourable, with eradication of the pathogenic agent in 90% of cases. The tolerability of the combination was globally good from both the general and local point of view.

Acute Disease↗
PubMed1991

Susceptibilities of Mycobacterium fortuitum biovar. fortuitum and the two subgroups of Mycobacterium chelonae to imipenem, cefmetazole, cefoxitin, and amoxicillin-clavulanic acid.

MICs of imipenem, cefoxitin, cefmetazole, and amoxicillin-clavulanic acid were determined against 100 strains of Mycobacterium fortuitum and 200 strains of Mycobacterium chelonae. Imipenem and cefmetazole were more active against M. fortuitum than cefoxitin was, and imipenem (which inhibited 39% of strains at 8 micrograms/ml) was the only beta-lactam active against M. chelonae subsp. chelonae.

Amoxicillin↗
PubMed1984

In vitro activity of ticarcillin plus clavulanic acid against bacteria isolated in three centers.

Over 10,000 bacterial isolates were tested against ticarcillin alone or combined with clavulanic acid (2.0 micrograms/ml). Of 5,295 Enterobacteriaceae, 72% were susceptible to ticarcillin alone, whereas 91% were susceptible to the combination. Bacteroides fragilis and Bacteroides melaninogenicus isolates were more susceptible to the combination. The activity of ticarcillin against other microorganisms was not profoundly influenced.

Anti-Bacterial Agents↗
PubMed2003

Continuous clavulanic acid adsorption process.

Adsorption kinetics and equilibrium data of clavulanic acid, a beta-lactam antibiotic, on ion-exchange resin Amberlite IRA 400 were utilized to carry out the modeling and simulation of a continuous adsorption process. These simulations allowed the estimation of yield, concentration, and purification factors of the process utilizing the product final concentration. Experimental runs of this process were carried out using the conditions pointed out by simulation studies. Comparison of the experimental results and those calculated by the proposed model showed that the model could describe very well the main features of the continuous process.

Adsorption↗