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PubMed1987

In vitro activity of ampicillin alone and in combination with different concentrations of 6 beta-bromopenicillanic acid, clavulanic acid and mecillinam.

The antibacterial activity of ampicillin against Enterobacteriaceae strongly increased when combined with 6 beta-bromopenicillanic acid (BPA) or clavulanic acid (CA). In vitro, the combination ampicillin: BPA in the ratio 1:1 proved to be the most effective one. The antibacterial activity of mecillinam against Enterobacteriaceae was strongly potentiated by the addition of ampicillin. The combination mecillinam:ampicillin in the ratio 4:5 showed an antibacterial activity comparable to that of new beta-lactam compounds such as cefotaxime and ceftazidime.

Amdinocillin↗

PubMed1979

The inhibition of staphylococcal beta-lactamase by clavulanic acid.

Clavulanic acid inhibited both the extracellular and cell-extract beta-lactamases of the four Staphylococcus aureus strains tested. The inhibition of S. aureus Russell cell-extract enzyme appeared to be active-site-directed and proceeded in a first-order fashion consistent with the formation of a covalent intermediate. Inhibited enzyme free of excess clavulanic acid was shown to regenerate enzyme activity slowly at pH 7.0, but the rate of reactivation increased at acid pH. When the enzyme was incubated with excess clavulanic acid complete inhibition was rapidly obtained, during further incubation clavulanic acid was shown to disappear slowly and complete loss of clavulanic acid from the reaction mixture coincided with the onset of the return of enzyme activity. A reactive enamine resulting from enzymic hydrolysis of the beta-lactam ring of clavulanic acid has been proposed as a possible intermediate in the inhibitory mechanism.

Anti-Bacterial Agents↗

PubMed1985

Positive direct antiglobulin tests due to clavulanic acid.

Clavulanic acid, a beta-lactamase inhibitor, was found to be associated with the development of a positive direct antiglobulin test. Of 23 antibiotic courses in patients treated with ticarcillin, clavulanic acid, and tobramycin, 10 (43.5%) developed positive direct antiglobulin tests versus 2 of 26 (7.7%) patients treated with piperacillin and tobramycin (P = 0.0044). In vitro immunohematological studies showed that clavulanic acid caused a nonimmunologic adsorption of plasma proteins onto the erythrocyte surface. Hemolysis was not associated with such nonimmunologic adsorption. However, the resulting positive antiglobulin test might delay cross matching of blood products for transfusions or interfere with the evaluation of true immune-mediated hemolytic anemia.

Clavulanic Acid↗

PubMed2002

In vitro susceptibility of Staphylococcus aureus towards amoxycillin-clavulanic acid, penicillin-clavulanic acid, dicloxacillin and cefuroxime.

Sixty-three Staphylococcus aureus isolates with a wide distribution in quantitative beta-lactamase production were tested in vitro against amoxycillin and penicillin in combination with clavulanic acid to establish the influence of total amount of beta-lactamase present on the ability of clavulanic acid to protect against beta-lactamase degradation. The beta-lactamase stability of cefuroxime and dicloxacillin was also evaluated. MIC was determined by agar dilution using Mueller-Hinton agar with both a conventional as well as a 100 times higher inoculum. The strains were tested both with and without induction of the beta-lactamase production. Clavulanic acid was highly effective in protecting against beta-lactamase degradation of both penicillin and amoxycillin. Even when using a high inoculum of strains with induced beta-lactamase production, all strains had MICs below the NCCLS breakpoint of 4/2 mg/l for amoxycillin-clavulanic acid. Both cefuroxime and dicloxacillin were highly stable against staphylococcal beta-lactamase degradation. This study encourages further in vivo evaluation of amoxycillin-clavulanic acid for severe staphylococcal infections.

Amoxicillin-Potassium Clavulanate Combination↗

PubMed1987

[Measure by turbidimetry and bactericidal effect of the speed of action of clavulanic acid, amoxicillin and their combinations on a Haemophilus influenzae producer of beta-lactamase].

The amoxicillin-acid clavulanic acid combination is known to be active on H. influenzae beta-lactamase producer. Clavulanic acid possesses its own antibacterial activity at high concentrations. As the combination of two beta-lactams is sometimes antagonist, we studied the action of amoxicillin, clavulanic acid alone and in combination on H. influenzae beta-lactamase producer by kinetic turbidimetry and time-kill curve. Clavulanic acid alone has slowed down the growth at 8 micrograms/ml, has inhibited at 32 micrograms/ml and was bactericidal at 128 micrograms/ml. The amoxicillin-clavulanic acid combination (proportion 4/1) was bactericidal at 2-0.5 micrograms/ml. The speed of bactericidal activity was only slightly dependent on concentrations. The increase in biomass measured by turbidimetry has been important. As for all beta-lactams it was due to the formation of spheroplasts, non viable after 24 h.

Amoxicillin↗

PubMed1989

In vitro activity of amoxycillin plus clavulanic acid and ticarcillin plus clavulanic acid compared with that of other antibiotics against anaerobic bacteria.

The activity of amoxycillin/clavulanic acid (Augmentin) and ticarcillin/clavulanic acid (Timentin) was tested against 303 unselected clinical anaerobic isolates recently collected in seven Belgian university hospitals and compared with that of 11 other antimicrobial agents. Bacteroides spp. accounted for 52.1% of the isolates, Clostridium spp. for 23.4%, anaerobic cocci for 15.5%, nonsporeforming gram-positive bacilli for 4.6% and Fusobacterium spp. for 3.3%. Ticarcillin/clavulanic acid (fixed clavulanic acid concentration of 2 mg/l) was the most active drug with an overall susceptibility rate of 99.7%. Amoxycillin/clavulanic acid (fixed ratio of 2:1) and chloramphenicol inhibited 97.4% of the isolates, metronidazole 95.4%, piperacillin 92.4%, ticarcillin 91.4%, clindamycin 87.8%, cefotetan 81.2%, cefazolin 63.0%, cefuroxime 60.4%, erythromycin 57.8%, penicillin 57.1% and doxycycline 52.1%. beta-lactamases were detected exclusively in Bacteroides spp. isolates (79.1% positive).

Amoxicillin↗

PubMed1979

Studies on the biosynthesis of clavulanic acid. II. Chemical degradations of 14C-labelled clavulanic acid.

Two chemical degradations of clavulanic acid are described which are useful for locating label in 14C-clavulanate. In the first, the beta-hydroxyethylidene side chain of p-bromobenzyl clavulanate is removed by ozonolysis to give p-bromobenzyl (2R, 5R)-3,7-dioxo-4-oxa-1-azabicyclo [3.2.0] heptane-2-carboxylate. The second involves the reaction of p-bromobenzyl clavulanate with dibenzylamine in methanol, to isolate the three beta-lactam carbons as methyl trans-3-(N-N-dibenzyl)amino acrylate. These techniques were used to degrade clavulanic acid derived from fermentations fed with 2-14C-acetate or universally 14C-labelled glycerol. The amount of label retained in the degradation products was in agreement with the distribution of 13C in clavulanic acid derived from 2-13C-acetate, or 1,3-13C2-glycerol, as observed by 13C-NMR.

Anti-Bacterial Agents↗

PubMed1988

[Comparative study of a combination of amoxicillin and clavulanic acid and a combination of ticarcillin and clavulanic acid on 249 enterobacteria].

A comparison between the MIC of amoxicillin (AMX) and ticarcillin (TIC) in the presence of clavulanic acid (Augmentin: AUG and Claventin: CLV) was made on 168 strains of Escherichia coli resistant to amoxicillin (MIC greater than 16 mg/l) and yet sensitive to ceftriaxone (MIC less than or equal to 4 mg/l) and 81 strains of Klebsiella pneumoniae sensitive to Ceftriaxone. All those strains have been isolated between 1986-87 in Bellevue Hospital in Saint-Etienne. On 168 Escherichia coli, 142 have a MIC greater than 128 mg/l of TIC. Those 142 Escherichia coli are sensitive or of an intermediary sensitivity to Cephalothin (MIC less than or equal to 32 mg/l) in 57% cases. Those 142 strains are sensitive to AUG (MIC less than or equal to 4 mg/l) in 13.4% cases, intermediary sensitive to AUG (4 less than MIC less than or equal to 16) in 30.3% cases, sensitive to CLV (CMI less than or equal to 16 mg/l) in 23.3% cases and intermediary sensitive to Claventin (16 less than MIC less than or equal to 64) in 47.2% cases. The 26 Escherichia coli of MIC less than or equal to 64 mg/l of TIC and resistant to Cephalothin (MIC greater than 32 mg/l) have MIC less than or equal to 4 mg/l of AUG In 3.8% cases and MIC less than or equal to 16 mg/l of Claventin in 79.6% cases. The 81 Klebsiella pneumoniae

Amoxicillin↗

PubMed1995

[Comparative study of ofloxacin+amoxicillin-clavulanic acid versus doxycycline+amoxicillin-clavulanic acid combination in the treatment of pelvic Chlamydia trachomatis infections].

OBJECTIVE: To evaluate the efficacy and safety of ofloxacin+coamoxiclav versus doxycycline-coamoxiclav in the treatment of chlamydial pelvic infections. DESIGN: An open, comparative, randomised, monocentric study. SUBJECTS: A hundred and eighteen patients (85 endometritis and 33 salpingitis) were included. Clinical, laparoscopic and bacteriological assessments were performed before treatment. 30.4% of salpingitis were considered as severe (COGIT score > 6). 25.4% of acute pelvic infections were only caused by Chlamydia trachomatis. TREATMENT: A hundred and eighteen patients were treated orally with 3 week combination ofloxacin (200 mg b.i.d.) + coamoxiclav (1 g b.i.d.) (n = 60) or with a 6 week coamoxiclav (1 g b.i.d.) + doxycycline (100 mg b.i.d.) (n = 58). RESULTS: Oral combination ofloxacin-coamoxiclav is as effective as oral combination doxycycline+coamoxyclav with respectively 96.7% versus 96.6% and 100% versus 98.4% satisfactory clinical et bacteriological results.

Adolescent↗

PubMed2000

Expansion of the clavulanic acid gene cluster: identification and in vivo functional analysis of three new genes required for biosynthesis of clavulanic acid by Streptomyces clavuligerus.

Clavulanic acid is a potent inhibitor of beta-lactamase enzymes and is of demonstrated value in the treatment of infections by beta-lactam-resistant bacteria. Previously, it was thought that eight contiguous genes within the genome of the producing strain Streptomyces clavuligerus were sufficient for clavulanic acid biosynthesis, because they allowed production of the antibiotic in a heterologous host (K. A. Aidoo, A. S. Paradkar, D. C. Alexander, and S. E. Jensen, p. 219-236, In V. P. Gullo et al., ed., Development in industrial microbiology series, 1993). In contrast, we report the identification of three new genes, orf10 (cyp), orf11 (fd), and orf12, that are required for clavulanic acid biosynthesis as indicated by gene replacement and trans-complementation analysis in S. clavuligerus. These genes are contained within a 3.4-kb DNA fragment located directly downstream of orf9 (cad) in the clavulanic acid cluster. While the orf10 (cyp) and orf11 (fd) proteins show homologies to other known CYP-150 cytochrome P-450 and [3Fe-4S] ferredoxin enzymes and may be responsible for an oxidative reaction late in the pathway, the protein encoded by orf12 shows no significant similarity to any known protein. The results of this study extend the biosynthetic gene cluster for clavulanic acid and attest to the importance of analyzing biosynthetic genes in the context of their natural host. Potential functional roles for these proteins are proposed.

Amino Acid Sequence↗

PubMed1991

Acquired resistance of Nocardia brasiliensis to clavulanic acid related to a change in beta-lactamase following therapy with amoxicillin-clavulanic acid.

Previous studies have demonstrated that Nocardia brasiliensis is susceptible to amoxicillin-clavulanic acid and that its beta-lactamases are inhibited in vitro by clavulanic acid. A cardiac transplant patient with disseminated infection caused by N. brasiliensis was treated with this drug combination with good response, but relapsed while still on therapy. The relapse isolate was found to be identical to the initial isolate by using genomic DNA restriction fragment patterns obtained by pulsed field gel electrophoresis, but it was resistant to amoxicillin-clavulanic acid. On isoelectric focusing, the beta-lactamase from the relapse isolate exhibited a shift in the isoelectric point (pI) of its major band from 5.10 to 5.04 compared with the enzyme from the pretreatment isolate. As determined by using values of the amount of beta-lactamase inhibitor necessary to give 50 +/- 5% inhibition of beta-lactamase-mediated hydrolysis of 50 microM nitrocefin, the beta-lactamase of the relapse isolate was also 200-fold more resistant than the enzyme from the pretreatment isolate to clavulanic acid and was more resistant to sulbactam, tazobactam, cloxacillin, and imipenem. The beta-lactamase of the relapse isolate exhibited a 10-fold decrease in hydrolytic activity for cephaloridine and other hydrolyzable cephalosporins compared with that for nitrocefin. Acquired resistance to amoxicillin-clavulanic acid in this isolate of N. brasiliensis appears to have resulted from a mutational change affecting the inhibitor and active site(s) in the beta-lactamase.

Amoxicillin↗

PubMed2002

New reactions in clavulanic acid biosynthesis.

Clavulanic acid is only a modestly effective antibiotic against bacterial infections in humans, but a potent inhibitor/inactivator of beta-lactamase enzymes that confer bacterial resistance. The biosynthetic pathway to clavulanic acid is considerably more complex than that to the structurally related penicillins and cephalosporins and has revealed several interesting reactions.

Amidohydrolases↗

PubMed1983

Synthesis and beta-lactamase inhibitory activities of some clavulanic acid analogues.

Clavulanic acid analogs lacking the C-3 carboxyl group are potent inhibitors of both plasmid and chromosomally mediated beta-lactamases. They exhibit only low intrinsic anti-bacterial activity, but potentiate the activity of ampicillin and cephaloridine against beta-lactamase producing Escherichia coli and Enterobacter cloacae in vitro. No synergism was observed in beta-lactamase negative strains. The E. coli TEM 1 and the E. cloacae P99 enzymes are inhibited in a progressive and irreversible manner by these compounds.

Anti-Bacterial Agents↗

PubMed2005

ORF17 from the clavulanic acid biosynthesis gene cluster catalyzes the ATP-dependent formation of N-glycyl-clavaminic acid.

(3R,5R)-Clavulanic acid, a clinically used inhibitor of serine beta-lactamases, is produced by fermentation of Streptomyces clavuligerus. The early steps in clavulanic acid biosynthesis leading to the bicyclic beta-lactam intermediate (3S,5S)-clavaminic acid have been defined. However, the mechanism by which (3S,5S)-clavaminic acid is converted to the penultimate intermediate (3R,5R)-clavaldehyde is unclear. Disruption of orf15 or orf16, of the clavulanic acid biosynthesis gene cluster, blocks clavulanic acid production and leads to the accumulation of N-acetyl-glycyl-clavaminic acid and N-glycyl-clavaminic acid, suggesting that these compounds are intermediates in the pathway. Two alternative start codons have been proposed for orf17 to encode for two possible polypeptides, one of which has 92 N-terminal residues less then the other. The shorter version of orf17 was successfully expressed in Escherichia coli and purified as a monomeric protein. Sequence analyses predicting the ORF17 protein to be a member of the ATP-grasp fold superfamily were supported by soft ionization mass spectrometric analyses that demonstrated binding of ATP to the ORF17 protein. Semisynthetic clavaminic acid, prepared by in vitro reconstitution of the biosynthetic pathway from the synthetically accessible intermediate proclavaminic acid, was shown by mass spectrometric analyses to be converted to N-glycyl-clavaminic acid in the presence of ORF17, ATP, and glycine. Under the same conditions N-acetyl-glycine and clavaminic acid were not converted to N-acetyl-glycyl-clavaminic acid. The specificity of ORF17 as an N-glycyl-clavaminic acid synthetase, together with the reported accumulation of N-glycyl-clavaminic acid in orf15 and orf16 disruption mutants, suggested that N-glycyl-clavaminic acid is an intermediate in clavulanic acid biosynthesis.

Adenosine Triphosphate↗

PubMed1998

The claR gene of Streptomyces clavuligerus, encoding a LysR-type regulatory protein controlling clavulanic acid biosynthesis, is linked to the clavulanate-9-aldehyde reductase (car) gene.

Two genes, claR and car, encoding proteins involved in clavulanic acid biosynthesis, have been found in a 2.8-kb BglII-EcoRI DNA fragment of Streptomyces clavuligerus adjacent to the region containing the cephamycin and clavulanic acid biosynthesis gene cluster. claR encoded a protein of 431 amino acids (deduced Mr 47080), that showed a significant degree of homology with several transcriptional activators of the LysR family. The ClaR protein contained two helix-turn-helix (HTH) motifs in the amino and carboxyl terminal regions. The second gene, car, encoded a protein of 247 amino acids (Mr 26629) that showed a strong similarity to oxydoreductases of the SDR family. Twelve amino acids of the amino-terminal region were identical to those previously obtained by Edman degradation of the purified clavulanic-9-aldehyde reductase of S. clavuligerus. Amplification of the claR gene in multicopy plasmids resulted in a threefold increase in clavulanic acid production and in a five- to sixfold increase of alanylclavam biosynthesis, whereas cephamycin production was significantly reduced both in defined and in complex media. By contrast, amplification of the car gene had no significant effect on clavulanic acid and alanylclavam or cephamycin production. Both claR and car are expressed as monocistronic transcripts; the level of transcript declined rapidly after 48h in complex media, but low sustained levels of both transcripts were observed in defined GSPG medium until 96h. claR and car were not significantly expressed in mutants disrupted in the ccaR gene, a regulatory gene that controls positively clavulanic acid and cephamycin biosynthesis. These results indicate that clavulanic acid and cephamycin biosynthesis in S. clavuligerus is controlled by a cascade of regulatory proteins that include CcaR and ClaR.

Alcohol Oxidoreductases↗

PubMed1996

Risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid.

BACKGROUND: Amoxicillin-clavulanic acid combination-associated hepatitis and jaundice was first identified in 1988. Numerous case reports and case series have been published since then, but there is no precise estimate of this risk. METHODS: A retrospective cohort study in the United Kingdom to estimate the risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid and compare it with the one of amoxicillin alone. Data were derived from a cohort of 93,433 users of the combination drug amoxicillin-clavulanic acid and 360,333 users of amoxicillin alone who were aged between 10 and 79 years and who were followed up from 1991 through 1992. After reviewing the information on subjects with suspected liver injury that was recorded on computer files, the clinical records of 177 patients from the attending general practitioners were requested. RESULTS: They were 35 cases of idiopathic acute liver injury. None was fatal. There were 14 cases of acute liver injury among users of amoxicillin alone. The type of liver injury was hepatocellular in half the cases. There were 21 cases of acute liver injury among users of amoxicillin and clavulanic acid together. The type of liver injury was cholestatic in three quarters of the cases. The incidence rates and 95% confidence intervals (CIs) of developing acute liver injury associated with the combination of amoxicillin and clavulanic acid and amoxicillin alone were 1.7 (1.1-2.7) and 0.3 (.02-0.5) per 10 000 prescriptions, respectively. The rate ratios and 95% CIs of acute liver injury for amoxicillin and clavulanic acid together compared with amoxicillin alone were 6.3 (3.2-12.7) for all patients and 8.4 (3.6-20.8) for patients presenting with jaundice. Among users of amoxicillin and clavulanic acid together, the risk of developing acute liver injury was more than 3 times greater after a course of 2 or more consecutive prescriptions than after a single course of therapy. The risk also increased with age among users of amoxicillin and clavulanic acid together. The combination of advancing age and repeated prescriptions resulted in a risk of developing acute liver injury greater than 1 per 1000 users of amoxicillin and clavulanic acid together.

Acute Disease↗

PubMed1978

Chemical studies on the inactivation of Escherichia coli RTEM beta-lactamase by clavulanic acid.

Incubation of clavulanic acid with the beta-lactamase from Escherichia coli RTEM leads to enzyme-catalyzed depletion of clavulanic acid, to transient inhibition, and to irreversible inactivation of the enzyme. Both the transiently inhibited and the irreversibly inactivated species show a marked increase in the absorbance at 281 nm that is proportional to the decrease in enzyme activity. Hydroxylamine treatment of irreversibly inactivated enzyme restores about one-third of the catalytic activity, with a concomitant decrease in absorbance at 281 nm. Polyacrylamide isoelectric focusing of the irreversibly inactivated enzyme shows three bands of approximately equal intensity, different from native enzyme. Upon hydroxylamine treatment, one of the three bands disappears and now focuses identically with native enzyme. It is evident that the irreversible inactivation of enzyme by an excess of clavulanic acid generates three products, one of which can be reactivated by hydroxylamine.

Escherichia coli↗

PubMedDate not supplied

Biosynthesis and molecular genetics of clavulanic acid.

The biosynthesis of clavulanic acid and related clavam metabolites is only now being elucidated. Understanding of this pathway has resulted from a combination of both biochemical studies of purified biosynthetic enzymes, and molecular genetic studies of the genes encoding these enzymes. Clavulanic acid biosynthesis has been most thoroughly investigated in Streptomyces clavuligerus where the biosynthetic gene cluster resides immediately adjacent to the cluster of cephamycin biosynthetic genes. A minimum of eight structural genes have been implicated in clavulanic acid biosynthesis, although more are probably involved. While details of the early and late steps of the pathway remain unclear, synthesis proceeds from arginine and pyruvate, as the most likely primary metabolic precursors, through the monocyclic beta-lactam intermediate, proclavaminic acid, to the bicyclic intermediate, clavaminic acid, which is a branch point leading either to clavulanic acid or the other clavams. Conversion of clavaminic acid to clavulanic acid requires side chain modification as well as inversion of ring stereochemistry. This stereochemical change occurs coincident with acquisition of the beta-lactamase inhibitory activity which gives clavulanic acid its therapeutic and commercial importance. In contrast, the other clavam metabolites all arise from clavaminic acid with retention of configuration and lack beta-lactamase inhibitory activity.

Anti-Bacterial Agents↗