Disease relevance of CLAVULANIC ACID

• Randomised study of myringotomy, amoxycillin/clavulanate, or both for acute otitis media in infants [1].
• Amoxycillin/clavulanate resistant Escherichia coli [2].
• To understand the amino acid sequence requirements in class A beta-lactamases that confer resistance to clavulanate, we performed site-saturation mutagenesis of Arg-244 in SHV-1, a related class A beta-lactamase found in Klebsiella pneumoniae [3].
• Inhibitor-resistant class A beta-lactamases are an emerging threat to the use of beta-lactam/beta-lactamase inhibitor combinations (e.g. amoxicillin/clavulanate) in the treatment of serious bacterial infections [3].
• In addition, beta-lactamase-producing isolates of Hemophilus influenzae, Branhamella catarrhalis, Neisseria gonorrhoeae, and Staphylococcus aureus were susceptible to ticarcillin and clavulanate [4].

High impact information on CLAVULANIC ACID

• In the TEM family of Class A beta-lactamases, single amino acid substitutions at Arg-244 confer resistance to clavulanate inactivation [3].
• Twelve SHV enzymes with amino acid substitutions at Arg-244 resulted in significant increases in minimal inhibitory concentrations to ampicillin/clavulanate when expressed in Escherichia coli [3].
• 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 [5].
• We evaluated the effect of a combination product of amoxicillin-potassium clavulanate on adults with acute rhinosinusitis that was clinically diagnosed in a general practice setting [6].
• Clavulanate, an inhibitor for beta-lactamases, was the very first inhibitor for an antibiotic resistance enzyme that found clinical utility in 1985 [7].

Chemical compound and disease context of CLAVULANIC ACID

• CONCLUSIONS: Our results indicate that cefuroxime axetil twice a day is as effective as amoxicillin/clavulanate three times a day in the treatment of acute bacterial maxillary sinusitis but produces fewer adverse effects [8].
• Characterization of a new TEM-type beta-lactamase resistant to clavulanate, sulbactam, and tazobactam in a clinical isolate of Escherichia coli [9].
• 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 [10].
• Against Enterobacteriaceae producing Richmond and Sykes class III and V plasmid-mediated beta-lactamases, synergy was obtained against most strains with YTR 830- and clavulanate-beta-lactam combinations, with sulbactam being less effective [11].
• Thus, cefprozil with its convenient administration regimen appears to be a suitable alternative to cefaclor, cefixime, amoxicillin/clavulanate or erythromycin for the treatment of upper and lower respiratory tract infections, skin and skin-structure infections, and otitis media in children [12].

Biological context of CLAVULANIC ACID

• Amoxicillin/clavulanate or vancomycin were administered for 3 days via a computerized pump to mimic human drug kinetics in animals [13].
• All enzymes were inhibited by clavulanate (50% inhibitory concentration [IC50], 0.01 to 1.8 microM), sulbactam (IC50, 0.02 to 1.9 microM), tazobactam (IC50, 0.001 to 0.9 microM), cefoxitin (IC50, 0.002 to 0.35 microM), and moxalactam (IC50, 0.03 to 6.6 microM) [14].
• It also confers the same phenotype as the Ser-164 mutant enzyme, i.e., resistance to ceftazidime and ampicillin, with reversal of this resistance in the presence of clavulanate [15].
• The close similarity between 9-doexyclavulanate and clavulanate in kinetics, spectroscopic, and protein chemical terms show that the allyl alcohol group of clavulanate is irrelevant to its action as a beta-lactamase inactivator [16].
• The absence of a 199 Da increment to unmodified TEM-2 suggests rapid decarboxylation of clavulanate upon binding to the enzyme [17].

Anatomical context of CLAVULANIC ACID

• Clavulanate readily crosses the outer cell wall of most Enterobacteriaceae to interact with beta-lactamases in the periplasmic space [18].
• The median bronchial mucosal concentration of amoxycillin was 2.99 mg/l and of clavulanate was 1.65 mg/l; the median concentrations in ELF were 0.89 and 0.96 mg/l, and in macrophages 0 and 0.76 mg/l, respectively [19].
• The efficacy of amoxicillin/clavulanate and cefuroxime was determined in a gerbil model of otitis media with a mixed Streptococcus pneumoniae plus Haemophilus influenzae middle ear (ME) infection [20].
• Amoxycillin was assayed by inhibition of growth of Micrococcus lutea, and clavulanate (in serum, ELF, and bronchial mucosa) by inhibition of growth of Klebsiella pneumoniae; in macrophages clavulanate was measured by high performance liquid chromatography [19].
• Treatment of lower urinary tract infection caused by multidrug-resistant extended-spectrum-beta-lactamase-producing Escherichia coli with amoxicillin/clavulanate: case report and characterization of the isolate [21].

Associations of CLAVULANIC ACID with other chemical compounds

• Ciprofloxacin, enoxacin, ofloxacin, and temafloxacin have been evaluated in a number of clinical trials, compared to the reference agents ampicillin, amoxicillin (with and without clavulanate), cefaclor, doxycycline, and erythromycin [22].
• Nevertheless, since clinically relevant concentrations of clavulanate can antagonize the bactericidal activity of ticarcillin, the combination of ticarcillin-clavulanate should be avoided when selecting an antipseudomonal beta-lactam for the treatment of P. aeruginosa infections, particularly in immunocompromised patients [23].
• Inhibition of this enzyme by sulfones but not clavulanate varied grossly with pH, with 50% inhibitory concentrations of tazobactam and sulbactam up to 300-fold higher at pH 6.5 than at 8 [24].
• Resistance could be reversed with the beta-lactamase inhibitors clavulanate or sulbactam or could be circumvented by the use of a beta-lactamase-stable drug, imipenem, indicating that mycobacterial beta-lactamase, probably in conjunction with slow penetration, is a major determinant of M. tuberculosis resistance to beta-lactam antibiotics [25].
• A Ser-237-->Ala substitution, introduced by site-directed mutagenesis, caused minor alterations in the interaction of CTX-M-4 with beta-lactams, reducing slightly the relative hydrolytic activity against cefotaxime and the susceptibility to inhibition by clavulanate [26].

Gene context of CLAVULANIC ACID

• With the exception of the TEM-12 beta-lactamase, introduction of the Met69-->Leu substitution did not give rise to enzymes with increased resistance to clavulanate compared to that of the TEM-1 beta-lactamase [27].
• The clinical use of beta-lactam antibiotics combined with beta-lactamase inactivators, such as clavulanate, has resulted in selection of beta-lactamases that are insensitive to inactivation by these molecules [28].
• Replacement of Asn276 by Asp in SHV-5 beta-lactamase caused a ten-fold increase in the IC50 of clavulanate; the increases in the IC50s of tazobactam and sulbactam were 10- and 5.5-fold, respectively [29].
• Tazobactam and clavulanate combinations were studied, as previous observation showed that these inhibitors incompletely reversed the in-vitro amoxycillin and piperacillin resistance of beta-lactamase-positive staphylococci [30].
• To determine the potentiating effect of clavulanate on the antibacterial activity of penicillins, we studied MRSA in vitro by an agar-dilution method [31].

Analytical, diagnostic and therapeutic context of CLAVULANIC ACID

• Electrospray ionization mass spectrometry of clavulanate inhibited SHV-1 and R244S showed nearly identical mass adducts, arguing against a difference in the inactivation mechanism [3].
• This formulation has been shown to be safe and effective in the treatment of infections caused by penicillin-resistant S. pneumoniae (minimum inhibitory concentration 2 microg/mL); the clavulanate component provides adequate coverage of beta-lactamase-producing pathogens [32].
• High-performance liquid chromatography analysis of the peptidoglycan isolated from the clavulanate-grown cells showed major qualitative and quantitative changes in stem peptide composition, the most striking feature of which was the accumulation of peptide species carrying intact D-alanyl-D-alanine residues at the carboxy termini [33].
• The beta-lactamase PER-2 (formerly ceftibutenase-1; CTI-1) is highly susceptible to inhibition by clavulanate and is located at a pI of 5.4 after isoelectric focusing [34].
• A fixed ratio (2:1) and a fixed concentration (clavulanate, 2 and 4 micrograms/ml; sulbactam, 8 micrograms/ml) were used in the agar dilution technique [35].

References