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PubMed1985

Ticarcillin plus clavulanic acid versus moxalactam therapy of osteomyelitis, septic arthritis, and skin and soft tissue infections.

A controlled, randomized study to compare the efficacy and safety of ticarcillin plus clavulanic acid with moxalactam was carried out in 25 evaluable patients with bone, joint, and skin or skin structure infections. Of the 13 patients in the ticarcillin plus clavulanic acid-treated group, nine had osteomyelitis, two had septic arthritis, one had cellulitis, and one had a wound infection. Four of the 12 moxalactam-treated patients had osteomyelitis, one had septic arthritis, and the other seven had cellulitis and/or infected ulcers. A total of 21 causative organisms were isolated in the group treated with ticarcillin plus clavulanic acid: Enterobacteriaceae (10), Pseudomonas aeruginosa (five), obligate anaerobes (three), Staphylococcus aureus (two), and Acinetobacter species (one). Cultures in the moxalactam-treated group yielded 23 pathogens: Enterobacteriaceae (seven), S. aureus (six), group B streptococci (four), P. aeruginosa (two), obligate anaerobes (two), Streptococcus pyogenes (one), and Aeromonas species (one). A cure or satisfactory response was achieved in 12 of the 13 (92 percent) patients who received ticarcillin plus clavulanic acid and in 10 of the 12 (83 percent) patients who received moxalactam. One patient with septic arthritis who received ticarcillin plus clavulanic acid had a relapse during therapy, as did one moxalactam-treated patient with a post-surgical wound infection. The other patient in whom moxalactam treatment failed had a wound infection that became reinfected. Some abnormalities in laboratory parameters occurred in each group, but none was severe enough to warrant discontinuation of treatment.

Adult↗
PubMed1987

The effects of three beta-lactamase inhibitors: YTR830H, sulbactam and clavulanic acid on the growth of human cells in culture.

Three beta-lactamase inhibitors: YTR83OH (YTR), sulbactam and clavulanic acid were studied for their effects on the growth of human amnion FL line cells. The numbers of viable cells after the 3-day culture were almost unaffected by YTR at concentrations up to 250 mg/l. The effects of sulbactam on FL cells were similar to those of YTR. The growth inhibitory effects of clavulanic acid were significantly different and were effective down to a concentration of 50 mg/l. The morphological effects were also observed microscopically.

Cell Division↗
PubMed2004

Mechanisms of reduced susceptibility to amoxycillin-clavulanic acid in Escherichia coli strains from the health region of Tortosa (Catalonia, Spain).

This study investigated the mechanisms involved in reduced susceptibility to amoxycillin-clavulanic acid and the prevalence of enzymes compatible with inhibitor-resistant TEM (IRT) beta-lactamases produced by Escherichia coli isolates from patients in north-eastern Spain. The resistance mechanisms of 158 strains showing resistance or intermediate resistance to amoxycillin-clavulanic acid among 1122 ampicillin-resistant clinical isolates of E. coli were assessed on the basis of their beta-lactam resistance phenotypes. beta-Lactamases produced by strains showing resistant phenotypes suggestive of inhibitor-resistant penicillinase production were characterised by their isoelectric point. Specific activity and the concentration of clavulanic acid required to inhibit beta-lactamase activity by 50% (IC50) were determined in strains harbouring enzymes that focused at pI 5.2 or 5.4 in order to achieve presumptive identification of IRT beta-lactamases. Resistance phenotypes were consistent with overproduction of TEM-1, TEM-2 or SHV-1 beta-lactamases in 56 strains, with AmpC cephalosporinase hyperproduction in 46 strains, and with production of inhibitor-resistant penicillinases in 49 strains. Of the latter isolates, 17 produced moderately high or high levels of enzymes co-focusing with TEM-1, 17 produced enzymes co-focusing with OXA-1 (n = 12) or with PSE-1 (n = 5), either alone or in association with TEM-1, while only 15 produced enzymes with a phenotype characteristic of IRT beta-lactamases. It was concluded that resistance to amoxycillin-clavulanic acid in E. coli isolates from this area was mainly associated with presumptive overproduction of TEM-1, TEM-2 or SHV-1 beta-lactamases (46%) or of AmpC cephalosporinase (29%), while the occurrence of enzymes categorised as IRT beta-lactamases was unusual (9.5%).

Amoxicillin-Potassium Clavulanate Combination↗
PubMed1997

In vitro assessment of the effect of clavulanic acid at concentrations achieved in human serum on the bactericidal activity of amoxicillin at physiological concentrations against Staphylococcus aureus: implications for dosage regimens.

The effects on Staphylococcus aureus viability and beta-lactamase activity of concentrations that simulated those in human serum after a combined dose of 875 mg of amoxicillin and 125 mg of clavulanic acid were studied in an in vitro pharmacodynamic model. Six hours of preexposure to concentrations of the amoxicillin-clavulanic acid combination that were higher than the amoxicillin-clavulanic acid MIC led to a reduction of the initial inoculum of >90% and to a significant decrease of beta-lactamase activity versus those of the control even from 6 h, when concentrations were subinhibitory. The postantibiotic effect and post-beta-lactamase inhibitor effect contributed to these results.

Amoxicillin↗
PubMed1992

Comparative clinical and microbiological study of amoxycillin-clavulanic acid and ciprofloxacin in acute purulent exacerbations of chronic bronchitis.

In a retrospective study, the clinical and microbiological efficacy of amoxycillin-clavulanic acid and ciprofloxacin were evaluated in outpatients observed within the previous year who were affected by acute purulent exacerbations of chronic bronchitis. Of the 95 patients included in the trial, 50 received amoxycillin 875 mg-clavulanic acid 125 mg 8-hourly for 10 days and 45 received ciprofloxacin 500 mg 12-hourly before meals for 10 days. Of the amoxycillin-clavulanic acid-treated patients, 90% showed clear clinical improvement and in 10% treatment failed. In the ciprofloxacin group, 75.5% of patients showed improvement and in 24.5% treatment failed. All pathogens isolated prior to therapy were susceptible to the antibiotic used for therapy. At the end of treatment, in the amoxycillin-clavulanic acid-treated group, 84% of strains were eradicated and 8% persisted; others were superinfections. In the ciprofloxacin group, 57.7% of strains were eradicated, 26.6% persisted and 15.5% were superinfections. No clinically significant side effects were observed in either group. Overall, amoxycillin-clavulanic acid demonstrated superior clinical and microbiological efficacy to ciprofloxacin, although this might be attributable to the higher proportion of aerobic Gram-negative pathogens in the ciprofloxacin group.

Adult↗
PubMed1985

Ticarcillin-clavulanic acid therapy in severe infections.

Twenty patients with severe infections were treated with a fixed combination of ticarcillin + clavulanic acid. Nineteen of them had severe underlying diseases. Fifteen were bacteraemic; four of these were in shock. Eleven were infected with microorganisms resistant in vitro to ticarcillin. Eleven were clinically cured, 6 improved and 3 failed to respond, the latter being infected with ticarcillin-resistant microorganisms (2 E. coli, 1 P. mirabilis). Six patients experienced side-effects, which were usually mild and reversible, consisting mainly of moderate elevation of serum transaminases. In one patient ticarcillin-clavulanic acid was stopped due to worsening of a pre-existing drug hepatitis.

Adult↗
PubMed2002

Simultaneous determination of amoxicillin and clavulanic acid in human plasma by HPLC with UV detection.

A simple and accurate high-performance liquid chromatographic method with ultraviolet detection at 220 nm has been validated for the simultaneous determination of amoxicillin and clavulanic acid in human plasma. Plasma samples were pretreated by direct deproteinization with methanol. A good chromatographic separation between both compounds was achieved using a reversed phase C8 column and a mobile phase, consisting of acetonitrile-phosphate solution-tetramethyl ammonium chloride solution. The calibration curves were linear over the concentration range of 0.625-20 mg l(-1) for amoxicillin and 0.3125-10 mg l(-1) for clavulanic acid with determination coefficients > 0.998. The method is accurate (bias < 7%) and reproducible (intra- and inter-day R.S.D. < 15%), with a quantitation limit of 0.625 and 0.3125 mg l(-1) for amoxicillin and clavulanic acid, respectively. Analytical recoveries from human plasma ranged from 91 to 102% for both components. This fully validated method, which allows the simultaneous measurement of amoxicillin and clavulanic acid in biological samples, is rapid (total run time < 10 min) and requires only a 100 microl sample. This assay is suitable for biomedical applications and was successfully applied to a pilot pharmacokinetics study in healthy volunteers after a single-oral administration of amoxicillin/clavulanic acid combination (500/125 mg).

Amoxicillin↗
PubMed1982

Effects of azlocillin in combination with clavulanic acid, sulbactam, and N-formimidoyl thienamycin against beta-lactamase-producing, carbenicillin-resistant Pseudomonas aeruginosa.

We investigated the effects of the combination of azlocillin with the beta-lactamase inhibitors clavulanic acid and sulbactam and with N-formimidoyl thienamycin against strains of Pseudomonas aeruginosa with R-factor-mediated carbenicillin resistance. The 10 strains tested (1 R-, 9 R+) were isogenic, except for the presence of individual plasmids determining each of nine plasmid-mediated beta-lactamases found in P. aeruginosa. We utilized a checkerboard technique for testing antibiotic combinations. Low concentrations of clavulanic acid produced synergy with azlocillin against the strains producing the TEM-1, TEM-2, PSE-1, PSE-3, and PSE-4 beta-lactamases; for the strains producing the OXA-1, OXA-2, OXA-3, and PSE-2 beta-lactamases, such synergy was not found. With sulbactam, synergy was demonstrated in all strains except that producing PSE-2 beta-lactamase; for several strains, however, the concentration of sulbactam required to produce synergy was substantially higher than that for clavulanic acid. N-Formimidoyl thienamycin was highly active as a single agent against all of the strains, regardless of beta-lactamase production. The combination of N-formimidoyl thienamycin and azlocillin produced synergy against only two of the strains tested.

Azlocillin↗
PubMed2002

Mutants of Streptomyces clavuligerus with disruptions in different genes for clavulanic acid biosynthesis produce large amounts of holomycin: possible cross-regulation of two unrelated secondary metabolic pathways.

A Streptomyces clavuligerus ccaR::aph strain, which has a disruption in the regulatory gene ccaR, does not produce cephamycin C or clavulanic acid, but does produce a bioactive compound that was identified as holomycin by high-performance liquid chromatography (HPLC) and infrared and mass spectrometry. S. clavuligerus strains with disruptions in different genes of the clavulanic acid pathway fall into three groups with respect to holomycin biosynthesis. (i) Mutants with mutations in the early steps of the pathway blocked in the gene ceaS (pyc) (encoding carboxyethylarginine synthase), bls (encoding a beta-lactam synthetase), or open reading frame 6 (ORF6; coding for an acetyltransferase of unknown function) are holomycin nonproducers. (ii) Mutants blocked in the regulatory gene ccaR or claR or blocked in the last gene of the pathway encoding clavulanic acid reductase (car) produce holomycin at higher levels than the wild-type strain. (iii) Mutants with disruption in cyp (coding for cytochrome P450), ORF12, and ORF15, genes that appear to be involved in the conversion of clavaminic acid into clavaldehyde or in secretion steps, produce up to 250-fold as much holomycin as the wild-type strain. An assay for holomycin synthetase was developed. This enzyme forms holomycin from holothin by using acetyl coenzyme A as an acetyl group donor. The holomycin synthase activities in the different clavulanic acid mutants correlate well with their production of holomycin.

Anti-Bacterial Agents↗
PubMed1998

Enhanced biosynthesis of clavulanic acid in Streptomyces clavuligerus due to oxidative challenge by redox-cycling agents.

Streptomyces clavuligerus produces a clinically important beta-lactamase inhibitor, clavulanic acid. When several of the selected redox-cycling agents were treated, an increase in clavulanate production was observed. The stimulatory effect was seen when the reaction was fed with menadione, plumbagin and phenazine methosulfate (PMS), whereas feeding with methyl viologen had a negative effect. PMS exerted the strongest effect, enhancing the accumulation of clavulanic acid by 150%. Induction of superoxide dismutase upon the addition of PMS suggested an involvement of superoxide in the enhancing process. The stimulatory effect of PMS was offset by the addition of butylated hydroxyanisole, further supporting the involvement of the active oxygen. The enhanced production of clavulanic acid correlated well with the increased total activity of clavaminic acid synthase, a key enzyme in its biosynthesis, and the transcription of cas2, its coding gene. The results suggested that active oxygen species could enhance the biosynthesis of secondary metabolites through the transcriptional activation of the biosynthetic gene.

Anti-Bacterial Agents↗
PubMed1988

Evaluation of in vitro methods for testing susceptibility of anaerobes to ampicillin-sulbactam and amoxicillin-clavulanic acid.

A total of 97 anaerobic bacteria were tested for susceptibility to ampicillin, ampicillin-sulbactam, and amoxicillin-clavulanic acid by broth microdilution and disk elution methods, the results of which were compared with those of the reference agar dilution method. With the broth microdilution method, approximately 95% of MICs were within 1 dilution of those of the reference agar method, with a definite (0.6 to 0.7 dilution) trend toward lower MICs. The disk elution test performed satisfactorily, but additional anaerobic isolates resistant to ampicillin-sulbactam and/or amoxicillin-clavulanic acid (currently rare) are needed to assure the predictability of resistance by the disk elution test.

Amoxicillin↗
PubMed2006

Sequential injection analysis for the simultaneous determination of clavulanic acid and amoxicillin in pharmaceuticals using second-order calibration.

In this paper, we report on a method for quantifying clavulanic acid and amoxicillin simultaneously in pharmaceuticals using sequential injection analysis (SIA) with a diode-array spectrophotometric detector and multivariate curve resolution with alternating least squares (MCR-ALS). We optimized the experimental parameters so that the analytical sequence could distinguish the concentrations and spectrum profiles of the species of interest with optimum resolution quality. After establishing the optimum conditions, we quantified clavulanic acid and amoxicillin in four pharmaceuticals. In most cases our results were slightly higher than those in the prospectus of the pharmaceutical. The relative standard deviations were below 5% for amoxicillin and below 7% for clavulanic acid. These results are acceptable because, to prevent degradation due to bacteriostatic activity, the concentration of the main reactant is usually higher.

Amoxicillin↗
PubMedDate not supplied

[Treatment of urinary infections with ticarcillin and clavulanic acid (Clavucar) by the intramuscular route].

20 patients suffering from hospital-acquired UTI received intramuscularly ticarcillin 1 g and clavulanic acid 200 mg for 8 days. At the end of antimicrobial therapy 84.2% of the pts presented sterile urine. After 2 weeks 68.4% of the pts continued to have sterile urine. No significant side effects were registered. The results demonstrate that the association of ticarcillin with clavulanic acid can be considered a useful option in hospital acquired UTI.

Adult↗
PubMed2001

Applications of gene replacement technology to Streptomyces clavuligerus strain development for clavulanic acid production.

Cephamycin C production was blocked in wild-type cultures of the clavulanic acid-producing organism Streptomyces clavuligerus by targeted disruption of the gene (lat) encoding lysine epsilon-aminotransferase. Specific production of clavulanic acid increased in the lat mutants derived from the wild-type strain by 2- to 2.5-fold. Similar beneficial effects on clavulanic acid production were noted in previous studies when gene disruption was used to block the production of the non-clavulanic acid clavams produced by S. clavuligerus. Therefore, mutations in lat and in cvm1, a gene involved in clavam production, were introduced into a high-titer industrial strain of S. clavuligerus to create a double mutant with defects in production of both cephamycin C and clavams. Production of both cephamycin C and non-clavulanic acid clavams was eliminated in the double mutant, and clavulanic acid titers increased about 10% relative to those of the parental strain. This represents the first report of the successful use of genetic engineering to eliminate undesirable metabolic pathways in an industrial strain used for the production of an antibiotic important in human medicine.

Cephamycins↗
PubMed1978

[Kinetics of beta-lactamase inhibition by clavulanic acid].

The mechanisms of action of 3 R-factors on beta-lactamases (penicillin amido-beta-lactamhydrolase, EC 3.5.2.6) (TEM-1 pI = 5.4, TEM-2 pI = 5.6 and Pitton's type 2 pI = 7.7) have been kinetically analyzed for clavulanic acid inactivation. Clavulanic acid appears as a competitive and irreversible inhibitor (Kcat inhibitor) reacting in two steps: a, formation of a reversible enzyme . inhibitor complex (characterized by a Ki); b, evolution of the reversible complex into a new derivative (covalent, stable and inactive) by monomolecular kinetics characterized by a k6 (or Kcat) related to half-life. The kinetic constants are: TEM-1: Ki = 0.8 micrometer, k6 = 0.027 s-1; TEM-2: Ki = 0.7 micrometer, k6 = 0.03 s-1; type 2: Ki = 0.6 micrometer, k6 = 0.046 s-1. These results justify the 'progressive irreversible' character of the inhibition generally described.

Anti-Bacterial Agents↗
PubMed1983

Pharmacokinetics and tissue penetration of ticarcillin combined with clavulanic acid.

A combination of 3 g of ticarcillin and 200 mg of clavulanic acid was administered intravenously to six healthy male volunteers, after which the concentrations of these agents in serum and blister fluid were measured. The ratio of the two drugs in serum varied from 15:1 (ticarcillin-clavulanic acid) at the time of administration to 28:1 at 30 min and 62:1 at 5 h after injection. Both agents penetrated blister fluid rapidly, the ratio being 33:1 at 1 h and 66:1 at 3 h. The elimination rates of these agents were different, but for each compound they were similar in serum and blister fluid.

Adult↗
PubMed1987

[Activity of ticarcillin combined with different concentrations of clavulanic acid on 137 Gram-negative bacilli resistant to ticarcillin].

The MIC of ticarcillin exclusively or joined with 3 concentrations of clavulanic acid: (2, 4 and 8 mg/l) was determined by agar dilution in relation to 137 bacilli resistant to ticarcillin (MIC greater than or equal to 256 mg/l) detected between 1985 and 1986 in the Bellevue Hospital in Saint-Etienne. We could study 26 Escherichia coli, 30 Klebsiella, 28 Enterobacter, 36 Serratia and 17 Pseudomonas aeruginosa. The concentration of 2 mg/l of clavulanic acid allows to lower the MIC of ticarcillin over the very large majority of strains of Escherichia coli and Klebsiella resistant to ticarcillin. In those conditions, ticarcillin becomes more active than piperacillin over those species. The concentration of 4 and 8 mg/l of clavulanic acid doesn't bring any real advantage to those bacilli. Moreover the concentrations of 2, 4 and 8 mg/l slightly change the MIC of ticarcillin on the strains of Serratia, Enterobacter and Pseudomonas aeruginosa.

Clavulanic Acids↗