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PubMedDate not supplied

Fatal Legionella pneumophila pneumonia: treatment failure despite early sequential oral-parenteral amoxicillin-clavulanic acid therapy.

A 68-year-old male, having just returned from a two-week holiday on the Island of Ischia, developed unilateral pneumonia for which he was treated with oral amoxicillin-clavulanic acid and hospitalized within three days when the disease worsened and spread to both lungs. Despite parenteral amoxicillin-clavulanic acid (up to 2.2 g i.v. t.i.d.) the pneumonia spread rapidly over the next three days. Sputum cultures returned post mortem yielded Legionella pneumophila serogroup 1 and urine tests revealed the presence of Legionella antigen. Disk diffusion susceptibility testing on BCYE of the causative pathogen revealed zone diameters of inhibition of the clinical isolate exceeding 50 mm, indicating high susceptibility to this antibiotic combination. The therapeutic failure of amoxicillin-clavulanic acid should stimulate further reports and studies on the efficacy against legionellosis of this drug and similar beta-lactam inhibitor combinations as well as other beta-lactamase-stable beta-lactams.

Administration, Oral↗
PubMed2004

Simultaneous determination of amoxicillin and clavulanic acid in human plasma by HPLC-ESI mass spectrometry.

A simple, fast and sensitive high-performance liquid chromatography (HPLC)-mass spectrometric (MS) method has been developed for simultaneous determination of amoxicillin and clavulanic acid in human plasma using terbutaline as internal standard. After precipitation of the plasma proteins with acetonitrile, the analytes were separated on a C(8) reversed-phase column with formic acid-water-acetonirile (2:1000:100) and detected using electrospray ionization (ESI) mass spectrometry in negative selected ion monitoring (SIM) mode. The method was validated and successfully applied to analysis of amoxicillin and clavulanic acid in clinical studies. The limit of quantitation, 0.12 microg/ml for amoxicillin and 0.062 microg/ml for clavulanic acid, was five times lower than that of the published HPLC-UV method.

Amoxicillin↗
PubMed2001

Evidence for a true post-beta-lactamase-inhibitor effect of clavulanic acid against Klebsiella pneumoniae and Haemophilus influenzae.

OBJECTIVE: The purpose of this study was to investigate and characterize in vitro the post-beta-lactamase inhibitor effect (PLIE) of clavulanic acid against two beta-lactamase-producing species of bacteria. METHODS: The PLIE was investigated against one strain of Klebsiella pneumoniae and one strain of Haemophilus influenzae. A stationary-phase inoculum of about 107 colony-forming units per mL of each bacterium was pre-exposed for 2 h to clavulanic acid, either alone or in combination with amoxicillin at various concentrations. After pre-exposure, the dilution required to remove the beta-lactamase inhibitor was 1:100 or 1:1000 according to the bacterial species and their susceptibilities to clavulanic acid. Bacteria were counted hourly after drug removal, on solid agar medium. RESULTS: Control cultures exposed to amoxicillin alone after dilution, showed a delay in growth, which may be inherent to the time required to synthesize sufficient beta-lactamase after the dilution steps. Control experiments clearly distinguished the post-antibiotic effect and the growth delay from the PLIE. CONCLUSION: The PLIE could be one of several factors explaining why beta-lactam/beta-lactamase inhibitor combinations remain effective throughout the dosing interval, even if a few hours after in vivo administration, serum concentrations of beta-lactamase inhibitor fall below levels that are active in vitro.

Amoxicillin↗
PubMed1996

Inhibition of TEM-2 beta-lactamase from Escherichia coli by clavulanic acid: observation of intermediates by electrospray ionization mass spectrometry.

Clavulanic acid, the therapeutically important inhibitor of beta-lactamases containing a nucleophilic serine residue at their active sites, inhibits Escherichia coli TEM-2 beta-lactamase via a complex mechanism. Electrospray ionization mass spectrometry (ESIMS) studies revealed that a minimum of four different modified proteins are formed upon incubation of clavulanate with the TEM-2 enzyme. These exhibit mass increments relative to the unmodified TEM-2 beta-lactamase of 52, 70, 88, and 155 Da. Time course studies implied that no long-lived forms of clavulanate-inhibited TEM-2 beta-lactamase retain the carbons of the oxazolidine ring of clavulanate. The absence of a 199 Da increment to unmodified TEM-2 suggests rapid decarboxylation of clavulanate upon binding to the enzyme. Proteolytic digestions of purified forms of clavulanate inhibited TEM-2 beta-lactamase followed by analyses using high-performance liquid chromatography coupled to ESIMS (HPLC-ESIMS) and chemical sequencing were used to provide positional information on the modifications to the enzyme. Increments of 70 and 80 Da increments were shown to be located in a peptide containing Ser-70. A further 70 Da mass increment, assigned as a beta-linked acrylate, was localized to a peptide containing Ser-130. A mechanistic scheme for the reaction of clavulanate with TEM-2 beta-lactamase is proposed in which acylation at Ser-70 and subsequent decarboxylation is followed either by cross-linking with Ser-130 to form a vinyl ether or by reformation of unmodified enzyme via a Ser-70 linked (hydrated) aldehyde. Purified cross-linked vinyl ether was observed to slowly convert under acidic conditions to a Ser-70 linked (hydrated) aldehyde with concomitant conversion of Ser-130 to a dehydroalanyl residue.

Clavulanic Acid↗
PubMed1981

A combination of amoxicillin and clavulanic acid in the treatment of respiratory tract infections caused by amoxicillin-resistant haemophilus influenzae.

This study was undertaken to evaluate the efficacy of a fixed combination of amoxicillin and clavulanic acid in 33 patients with chronic or recurrent respiratory tract infections (R.T.I.), mainly bronchitis. In two patients bronchopneumonia was diagnosed, and in one cystic fibrosis. The patients were treated with 750 mg of the drug combination (500 mg amoxicillin/250 mg clavulanic acid) t. i. d. for seven or ten days. Good clinical success was obtained in 17 patients and a clear improvement in another eight. The most frequently isolated micro-organism was Haemophilus influenzae; of the 22 strains isolated, 20 were resistant to 2 mg/l amoxicillin but sensitive to the combination of 2 mg/l amoxicillin and 1 mg/l clavulanic acid. Side-effects were reported in nine patients; two patients discontinued treatment for this reason. Amoxicillin/clavulanic acid is a useful therapeutic addition to the existing forms of treatment for amoxicillin-resistant respiratory tract infections.

Aged↗
PubMed1982

Treatment of chancroid by clavulanic acid with amoxycillin in patients with beta-lactamase-positive Haemophilus ducreyi infection.

Multiresistant strains of Haemophilus ducreyi, the aetiological agent of chancroid, are prevalent in Nairobi, Kenya, where tetracyclines and sulphonamides are no longer very effective in the treatment of chancroid. The following regimens (given three times daily for seven days) were compared in a double-blind randomised trial--amoxycillin 500 mg, amoxycillin 500 mg and clavulanic acid 125 mg, and amoxycillin 500 mg and clavulanic acid 250 mg. 68 of 100 ulcers were culture-positive for H. ducreyi. All strains of H. ducreyi produced beta-lactamase. At day 7 none of the amoxycillin-treated patients had responded clinically or bacteriologically, whereas all but 2 of 56 patients treated with an amoxycillin/clavulanic-acid regimen had responded clinically and H. ducreyi had been eradicated from their ulcers. The combination of amoxycillin-clavulanic acid appears to be very effective for the treatment of chancroid. The results of this study accord with H. ducreyi as the primary pathogen of chancroid.

Amoxicillin↗
PubMed1981

Amoxicillin-clavulanic acid in treatment of urinary tract infection due to gram-negative bacteria resistant to penicillin.

Twenty-two adult patients with urinary tract infections caused by penicillin-resistant bacteria completed treatment with amoxicillin alone or amoxicillin plus clavulanic acid in a randomized double-blind clinical trial. Of the 13 patients treated with amoxicillin plus clavulanic acid, the absence of bacteriuria within 7 days of therapy was observed in 85%, as compared with only 25% of the 8 patients receiving amoxicillin only. There were no significant side effects nor any clinical, biochemical, or hematological abnormalities related to either treatment. It was concluded that the combination of clavulanic acid and amoxicillin could be useful in the treatment of uncomplicated urinary tract infection caused by penicillin-resistant bacteria.

Amoxicillin↗
PubMed1992

Ticarcillin and ticarcillin-clavulanic acid susceptibility tests: error rates for disk tests with consecutively isolated members of the family Enterobacteriaceae.

A five-laboratory coordinated study was undertaken to determine whether ticarcillin and ticarcillin-clavulanic acid disk susceptibility tests could accurately detect resistance among enteric bacilli. Each facility performed disk tests and broth microdilution susceptibility tests with reagents distributed from a common source, and appropriate controls were included in order to ensure methodologic uniformity. Each institution tested 500 consecutively isolated enteric bacilli against ticarcillin and ticarcillin-clavulanic acid. The prevalence of discrepancies between disk tests and dilution tests with 2,435 unselected enteric bacilli provided a valid estimate of the true error rate for tests with the two disks. The current interpretive criteria for susceptibility tests with ticarcillin and ticarcillin-clavulanic acid disks were found to be reliable; i.e., there were major or very major discrepancies between MIC categories and disk test results for less than 1% of all strains and minor discrepancies for only 5 to 10%. Even lower error rates would occur if the zone size-interpretive criteria were modified, but at this time it is difficult to determine whether the practical problems created by making such changes can be justified by the magnitude of the problem that is being resolved.

Clavulanic Acids↗
PubMed1985

[Effect of an amoxicillin-clavulanic acid combination on the aerobic fecal flora in children].

Counts of aerobic fecal pathogens were done using serial dilutions of stools cultured on selective media with or without amoxicillin + clavulanic acid in 15 hospitalized pediatric patients under oral treatment with the association and in 12 non-hospitalized, non-treated controls. Susceptibility was confirmed by disk antibiotic sensitivity testing. The following microorganisms were studied: Enterobacteriaceae, Pseudomonas, Streptococci D, Staphylococci and Candida. In 8 of the 15 treated patients, Enterobacteriaceae were lacking in one sample or more, but subsequent emergence of resistant Enterobacteriaceae during treatment occurred in 4 of these cases. The 7 other treated patients were immediately colonized by resistant Enterobacteriaceae. No resistant Pseudomonas strains emerged. Streptococci D decreased in some cases. No detectable effect on Staphylococci or Candida was found. Enterobacteriaceae resistant to amoxicillin + clavulanic acid were found in 5 of the 12 controls and in 2 cases accounted for the majority of Enterobacteriaceae.

Adolescent↗
PubMed1988

Effect of the combination of clavulanic acid and cephalothin on an experimental infection with Yersinia enterocolitica in iron-overloaded mice.

Iron-overloaded mice were infected with a virulent strain of Yersinia enterocolitica by the oral route to study the effect of antimicrobial treatments. The effects of therapy were assessed by enumeration of viable yersiniae in Peyer's patches and in ileal contents. Combinations of cephalothin and clavulanic acid showed therapeutic effects, which were interpreted as in-vivo synergism, since each component alone was ineffective. Ceftazidime, which is relatively beta-lactamase resistant, showed in-vivo activity similar to that of the combination of cephalothin and clavulanic acid. These results suggest that clavulanic acid is able to protect cephalothin against Y. enterocolitica beta-lactamases in vivo, as has been shown previously in vitro.

Animals↗
PubMed2002

ORF6 from the clavulanic acid gene cluster of Streptomyces clavuligerus has ornithine acetyltransferase activity.

The clinically used beta-lactamase inhibitor clavulanic acid is produced by fermentation of Streptomyces clavuligerus. The orf6 gene of the clavulanic acid biosynthetic gene cluster in S. clavuligerus encodes a protein that shows sequence homology to ornithine acetyltransferase (OAT), the fifth enzyme of the arginine biosynthetic pathway. Orf6 was overexpressed in Escherichia coli (at approximately 15% of total soluble protein by SDS/PAGE analysis) indicating it was not toxic to the host cells. The recombinant protein was purified (to > 95% purity) by a one-step technique. Like other OATs it was synthesized as a precursor protein which underwent autocatalytic internal cleavage in E. coli to generate alpha and beta subunits. Cleavage was shown to occur between the alanine and threonine residues in a KGXGMXXPX--(M/L)AT (M/L)L motif conserved within all identified OAT sequences. Gel filtration and native electrophoresis analyses implied that the ORF6 protein was an alpha2beta2 heterotetramer and direct evidence for this came from mass spectrometric analyses. Although anomalous migration of the beta subunit was observed by standard SDS/PAGE analysis, which indicated the presence of two bands (as previously observed for other OATs), mass spectrometric analyses did not reveal any evidence for post-translational modification of the beta subunit. Extended denaturation with SDS before PAGE resulted in observation of a single major beta subunit band. Purified ORF6 was able to catalyse the reversible transfer of an acetyl group from N-acetylornithine to glutamate, but not the formation of N-acetylglutamate from glutamate and acetyl-coenzyme A, nor (detectably) the hydrolysis of N-acetylornithine. Mass spectrometry also revealed the reaction proceeds via acetylation of the beta subunit.

Acetyltransferases↗
PubMed1984

Augmentation of the in vitro activity of azlocillin against Bacteroides fragilis by clavulanic acid.

Azlocillin was active against 90% of 154 strains of Bacteroides fragilis at a concentration of 64 micrograms/ml. Twenty-eight strains of B. fragilis with an azlocillin MIC of greater than or equal to 8 micrograms/ml were retested with a combination of azlocillin plus clavulanic acid. Of these strains, 71% showed a 4- to 32-fold decrease in the MIC of azlocillin plus clavulanic acid.

Azlocillin↗
PubMed1986

Effect of clavulanic acid on the activity of ticarcillin against Pseudomonas aeruginosa.

We studied the ability of clavulanic acid (CA) to induce beta-lactamase in Pseudomonas aeruginosa isolates and what effect this might have on the susceptibilities to beta-lactam agents. We first used a disk approximation method to test 4 laboratory and 16 clinical P. aeruginosa isolates against antipseudomonal beta-lactam agents for truncation by CA and found this to be very common. All antimicrobial compounds except imipenem demonstrated truncation in the vicinity of CA. We also evaluated the extent to which chromosomal beta-lactamase is induced by CA and found this to occur to some degree in most isolates and to be dependent on the concentration of CA. Finally, we performed time kill curves on these isolates to compare bacterial growth in ticarcillin alone with growth in ticarcillin-CA (the CA at 2 or 4 micrograms/ml). We found that CA at this concentration has neither an antagonistic nor a synergistic antibacterial effect in combination with ticarcillin.

Anti-Bacterial Agents↗
PubMed1991

[Bactericide activity of cefadroxil comparated with amoxicillin-clavulanic acid, cefaclor and josamycin].

Betalactamase-producing organisms are responsible for an increasing number of ENT and lower respiratory tract infections. Or cephalosporins and the combination of amoxicillin with the beta-lactamase inhibitor clavulanic acid are alternatives to ampicillin therapy. The killing activity of cefadroxil on the organisms most often responsible for ENT and respiratory infections was evaluated in vitro using a viable bacteria count method, comparatively with cefaclor, josamycin, and amoxicillin-clavulanic acid. Killing activity was found to be time-dependent for all the antimicrobial agents studied. Cefadroxil exhibited the same bactericidal effect on Streptococcus pyogenes and S. pneumoniae than the other agents. Haemophilus influenzae and an increasing number of Pneumococcus strains were resistant to josamycin which is therefore not appropriate for first-line therapy. As compared with amoxicillin and amoxicillin-clavulanic acid, cefadroxil was less active on H. influenzae and more active on Staphylococcus aureus. Production of beta-lactamase failed to influence the killing activity of cefadroxil. These bacteriologic data, together with results of pharmacologic studies (long half-life and good penetration within tissues) can explain the clinical successes obtained with cefadroxil in ENT and lower respiratory tract infections.

Amoxicillin↗
PubMed1984

In vitro activity of ticarcillin plus clavulanic acid against 632 clinical isolates.

A total of 632 clinical bacterial isolates were tested for susceptibility to twofold dilutions of ticarcillin alone and in combination with 1, 2, and 4 micrograms of clavulanic acid (CA) (Timentin) per ml by a reference microdilution method. With the addition of CA, ticarcillin MICs were reduced eightfold or greater with 54 of 59 (92%) strains of the family Enterobacteriaceae with ticarcillin MICs of greater than or equal to 64 micrograms/ml. The inhibitory effect of CA on pseudomonads was minimal. Ticarcillin MICs for beta-lactamase-producing Haemophilus influenzae, Neisseria gonorrhoeae, and most Staphylococcus aureus were reduced to less than or equal to 0.5 micrograms/ml when CA was added. For dilution susceptibility testing of ticarcillin-clavulanic acid, dilutions of ticarcillin combined with 2 micrograms of CA per ml is suggested.

Bacteria↗
PubMed2004

The paralogous pairs of genes involved in clavulanic acid and clavam metabolite biosynthesis are differently regulated in Streptomyces clavuligerus.

Carboxyethylarginine synthase, encoded by the paralogous ceaS1 and ceaS2 genes, catalyzes the first reaction in the shared biosynthetic pathway leading to clavulanic acid and the other clavam metabolites in Streptomyces clavuligerus. The nutritional regulation of ceaS1 and ceaS2 expression was analyzed by reverse transcriptase PCR and by the use of the enhanced green fluorescent protein-encoding gene (egfp) as a reporter. ceaS1 was transcribed in complex soy medium only, whereas ceaS2 was transcribed in both soy and defined starch-asparagine (SA) media. The transcriptional start points of the two genes were also mapped to a C residue 98 bp upstream of ceaS1 and a G residue 51 bp upstream of the ceaS2 start codon by S1 nuclease protection and primer extension analyses. Furthermore, transcriptional mapping of the genes encoding the beta-lactam synthetase (bls1) and proclavaminate amidinohydrolase (pah1) isoenzymes from the paralogue gene cluster indicated that a single polycistronic transcript of approximately 4.9 kb includes ceaS1, bls1, and pah1. The expression of ceaS1 and ceaS2 in a mutant strain defective in the regulatory protein CcaR was also examined. ceaS1 transcription was not affected in the ccaR mutant, whereas that of ceaS2 was greatly reduced compared to the wild-type strain. Overall, our results suggest that different mechanisms are involved in regulating the expression of ceaS1 and ceaS2, and presumably also of other paralogous genes that encode proteins involved in the early stages of clavulanic acid and clavam metabolite biosynthesis.

Artificial Gene Fusion↗
PubMed1986

Pharmacokinetics of parenteral ticarcillin formulated with clavulanic acid: Timentin.

The pharmacokinetics of a formulation of clavulanate potentiated ticarcillin (Timentin) have been investigated following a bolus intravenous injection of 1.2 g, infusions of 3.2 g over periods ranging from 30 minutes to three hours, and a bolus dose of 1.2 g followed by an infusion of 3.2 g. The effect of probenecid has also been investigated. The serum levels of clavulanic acid are discussed in relation to the microbiology and therapeutic implications.

Bacteria↗