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Michael S Benninger – One of the best experts on this subject based on the ideXlab platform.

  • Amoxicillin clavulanate potassium extended release tablets a new antimicrobial for the treatment of acute bacterial sinusitis and community acquired pneumonia
    Expert Opinion on Pharmacotherapy, 2003
    Co-Authors: Michael S Benninger

    Abstract:

    Community-acquired bacterial respiratory tract infections are among the most common health disorders requiring medical care and are associated with substantial morbidity, mortality, and direct and indirect costs. Recent increases in the prevalence of antimicrobial resistance have resulted in reduced susceptibility of the most common respiratory tract bacterial pathogens to a number of antimicrobials. Amoxicillin/clavulanate potassium extended release (ER) tablets (Augmentin XR, GlaxoSmithKline) is a new formulation of Amoxicillin/clavulanate that retains activity against betalactamase-producing organisms whilst increasing the activity against Streptococcus pneumoniae through elevated and sustained plasma Amoxicillin concentrations. The bilayer tablet provides immediate release of clavulanate and both immediate and sustained release of Amoxicillin to maintain therapeutic concentrations of Amoxicillin over longer periods of the dosing interval. In clinical trials of acute bacterial sinusitis (ABS) and community-acquired pneumonia (CAP), Amoxicillin/clavulanate ER was shown to have excellent bacteriological and clinical success rates, even in patients infected with antimicrobial-resistant pathogens, and was found to be generally well tolerated. Amoxicillin/clavulanate ER is approved in the US for the treatment of patients with ABS or CAP caused by beta-lactamase-producing pathogens (ie, Haemophilus influenzae, Moraxella catarrhalis, Haemophilus parainfluenzae, Klebsiella pneumoniae, or methicillin-susceptible Staphylococcus aureus) and S. pneumoniae with reduced susceptibility to penicillin (penicillin minimum inhibitory concentration = 2.0 microg/ml).

  • Amoxicillin/clavulanate potassium extended release tablets: a new antimicrobial for the treatment of acute bacterial sinusitis and community-acquired pneumonia.
    Expert Opinion on Pharmacotherapy, 2003
    Co-Authors: Michael S Benninger

    Abstract:

    Community-acquired bacterial respiratory tract infections are among the most common health disorders requiring medical care and are associated with substantial morbidity, mortality, and direct and indirect costs. Recent increases in the prevalence of antimicrobial resistance have resulted in reduced susceptibility of the most common respiratory tract bacterial pathogens to a number of antimicrobials. Amoxicillin/clavulanate potassium extended release (ER) tablets (Augmentin XR, GlaxoSmithKline) is a new formulation of Amoxicillin/clavulanate that retains activity against betalactamase-producing organisms whilst increasing the activity against Streptococcus pneumoniae through elevated and sustained plasma Amoxicillin concentrations. The bilayer tablet provides immediate release of clavulanate and both immediate and sustained release of Amoxicillin to maintain therapeutic concentrations of Amoxicillin over longer periods of the dosing interval. In clinical trials of acute bacterial sinusitis (ABS) and community-acquired pneumonia (CAP), Amoxicillin/clavulanate ER was shown to have excellent bacteriological and clinical success rates, even in patients infected with antimicrobial-resistant pathogens, and was found to be generally well tolerated. Amoxicillin/clavulanate ER is approved in the US for the treatment of patients with ABS or CAP caused by beta-lactamase-producing pathogens (ie, Haemophilus influenzae, Moraxella catarrhalis, Haemophilus parainfluenzae, Klebsiella pneumoniae, or methicillin-susceptible Staphylococcus aureus) and S. pneumoniae with reduced susceptibility to penicillin (penicillin minimum inhibitory concentration = 2.0 microg/ml).

Paul Benfield – One of the best experts on this subject based on the ideXlab platform.

  • Amoxicillin/Clavulanic Acid
    Drugs, 1990
    Co-Authors: Peter A. Todd, Paul Benfield

    Abstract:

    Synopsis Clavulanic acid enhances the antibacterial spectrum of Amoxicillin by rendering most β-lactamase-producing isolates susceptible to the drug. In clinical trials Amoxicillin/clavulanic acid is clinically and bacteriologically superior to Amoxicillin alone and at least as effective as numerous other comparative agents, such as orally administered cephalosporins, cotrimoxazole, doxycycline and bacampicillin, in the treatment of adults and children with the most common forms of infection encountered in general practice, i.e. urinary tract infections, upper and lower respiratory tract infections, otorhinolaryngological infections, and skin and soft tissue infections. It may also provide effective treatment for uncomplicated gonorrhoea, chancroid and gynaecological infections as well as acting as a prophylactic agent against surgical infection. Thus, in general practice environments where β-lactamase production has restricted the effectiveness of Amoxicillin, the combination of clavulanic acid with Amoxicillin has clearly extended the usefulness of a tried and proven first-line antibacterial agent. Antibacterial Activity Clavulanic acid is an irreversible ‘suicide’ inhibitor of intracellular and extracellular β-lactamases, effective against a wide variety of these enzymes including those of Richmond and Sykes classes II to V (but not class I cephalosporinases), staphylococcal β- lactamase, and β-lactamase produced by Bacteroides fragilis. Clavulanic acid, therefore, protects Amoxicillin from inactivation by many β-lactamases. As a consequence the antibacterial activity of Amoxicillin has been restored at a time when the spread of resistance due to β-lactamase production severely threatened its usefulness. Clavulanic acid alone possesses only weak antibacterial activity, except against Legionella spp., and certain strains of Branhamella catarrhalis, B. fragilis and Neisseria gonorrhoeae. However, the addition of clavulanic acid to Amoxicillin increases the susceptibility to Amoxicillin of Amoxicillin-resistant strains of Gram-negative and Gram-positive aerobic and anaerobic bacteria where resistance is caused by β-lactamase production. These include Staphylococcus aureus (but not methicillin-resistant strains), Haemophilus spp., Branhamella catarrhalis, Neisseria gonorrhoeae, Escherichia coli, Proteus spp., Klebsiella pneumoniae, Citrobacter diversus, Salmonella and Shigella spp., Campylobacter jejuni, Bacteroides spp., and Mycobacterium spp. The susceptibility of Amoxicillin-sensitive strains is not generally affected by the addition of clavulanic acid. Amoxicillin/clavulanic acid is bactericidal in vitro , usually at concentrations no more than one dilution higher than in vitro inhibitory concentrations. The in vitro synergy of clavulanic acid combined with Amoxicillin has been confirmed in vivo in numerous experimental infections in animals. The combination of Amoxicillin with clavulanic acid appears to suppress the development of resistance under experimental conditions. Pharmacokinetic Properties Combining clavulanic acid with Amoxicillin causes no appreciable alteration of the pharmacokinetics of either drug compared with their separate administration. After oral administration, both components achieve maximum plasma concentrations in about 1 hour and these concentrations show a direct relationship to the dose administered. The absolute bioavailability of clavulanic acid is about 60%. Absorption is unaffected by concomitant administration of food, milk, ranitidine or pirenzepine and little affected by antacid administration, but cimetidine may increase the rate of absorption of both components. Probenecid increases the plasma concentration of Amoxicillin but not clavulanic acid. Clavulanic acid has a volume of distribution of about 25% of bodyweight and is about 22% protein bound in vitro. The tissue and body fluid distribution of both components is generally adequate to achieve antibacterial levels, although concentrations may be somewhat low in bronchial secretions and cerebrospinal fluid. Both components transfer across the placenta but only very small quantities transfer into breast milk. Both clavulanic acid and Amoxicillin possess a mean elimination half-life of about 1 hour and a mean total clearance of about 25 L/h in healthy subjects. The main route of elimination is via the urine, and 6-hour urinary recovery of intact drug after oral administration is about 60 to 80% for Amoxicillin and 30 to 50% for clavulanic acid. Clavulanic acid is excreted mainly by glomerular filtration and Amoxicillin by tubular secretion; thus, probenecid delays the excretion of Amoxicillin but not clavulanic acid. While Amoxicillin is mainly excreted unchanged, clavulanic acid is subject to hydrolysis and subsequent decarboxylation. Gastrointestinal disease may slow the rate of absorption of Amoxicillin and clavulanic acid. The pharmacokinetic profile in children administered bodyweight adjusted dosages paralleled that in adults. Renal impairment decreases the clearance of Amoxicillin and less markedly clavulanic acid: dosage reductions or increasing the dose interval are thus required. Both components are removed by haemodialysis and appropriate dose supplementation is therefore necessary at the end of a haemodialysis session. Therapeutic Trials Amoxicillin/clavulanic acid has usually been administered empirically to patients with symptoms suggestive of bacterial infection without selection of patients according to the resistance or susceptibility of the pathogen. Dosages of Amoxicillin/clavulanic acid wereusually in the range 250/125 to 875/125mg 2 or 3 times daily in adults and bodyweight adjusted dosages were administered to children. In adult patients with complicated or uncomplicated urinary tract infection, Amoxicillin/clavulanic acid was clinically and bacteriologically superior at a statistically significant level compared with Amoxicillin alone and cefatrizine propylene glycol, and bacteriologically superior compared with cotrimoxazole. In addition, it was at least as effective as cefaclor, cefalexin and pivmecillinam/pivampicillin. In adult patients with upper or lower respiratory tract infections, Amoxicillin/clavulanic acid was clinically more effective than Amoxicillin alone or josamycin at a statistically significant level. Clinically and bacteriologically it was at least as effective as bacampicillin, pivmecillinam/pivampicillin, doxycycline, erythromycin, cefuroxime axetil, cefixime and cefaclor. Amoxicillin/clavulanic acid has been shown to be clinically more effective at a statistically significant level than Amoxicillin alone in the treatment of acute otitis media in adults, but statistically significant differences were not identified in comparisons with Amoxicillin in children with otitis media or maxillary sinusitis. Some studies have shown statistically significant superiority of Amoxicillin/clavulanic acid over cefaclor or myringotomy both clinically and bacteriologically in children with acute otitis media. In skin and soft tissue infection Amoxicillin/clavulanic acid produced a statistically significant higher bacteriological response rate and a tendency towards a higher clinical response rate compared with Amoxicillin in adults with wound infection and children with nonbullous impetigo. In addition, in adults with wound infection Amoxicillin/clavulanic acid was equivalent to cefuroxime axetil. In adults and children with skin and soft tissue infection, Amoxicillin/clavulanic acid and cefaclor achieved similar clinical and bacteriological responses. In uncomplicated gonorrhoea, administration of 2 doses of amoxieillin/clavulanic acid 3000/125 or 3000/250mg 4 to 6 hours apart or a single dose concomitantly with probenecid 1g proved the most satisfactory and convenient regimens, with antibacterial activity extended to cover penicillinase-producing Neisseria gonorrhoeae. Amoxicillin/ clavulanic acid 500/250mg 3 times daily for 3 days appears to provide an excellent treatment for chancroid. Amoxieillin/clavulanic acid may provide an effective and more manageable regimenthan the standard triple combination of a β-lactam/an aminoglycoside/an imidazole in the treatment of obstetric and gynaecological infections but more study is required in this area before any definitive conclusions may be drawn. Amoxieillin/clavulanic acid has shown excellent results compared with other prophylactic regimens such as cephalosporins or aminoglycosides, and was superior to metronidazole at a statistically significant level, in the prevention of postoperative infectious complications following gynaecological, abdominal and vascular surgery. Adverse Effects About 13% of patients report adverse effects with amoxieillin/clavulanic acid, requiring withdrawal of treatment in less than 3% of patients. The adverse effects are primarily mild gastrointestinal disturbances, including diarrhoea, nausea, vomiting and indigestion. Rash, and Candida vaginitis or stomatitis each occur in about 1 % of patients. There have been isolated reports of urticaria, anaphylaxis, behavioural changes, and laboratory test abnormalities. Gastrointestinal adverse effects may be reduced by taking the drug with food. Their frequency may be related to the dose of clavulanic acid and they may also occur considerably more frequently in children. Compared with other antibacterial agents, amoxieillin/clavulanic acid has usually been at least as well tolerated, although some orally administered cephalosporins (e.g. cefaclor) caused fewer gastrointestinal effects. Dosage and Administration The usual dosage for routine oral use in adult infections is 250/125mg or 500/125mg 3 times daily, although in Italy the usual dose is 875/125mg twice or 3 times daily, depending on the severity of infection. A number of parenteral preparations are available which may be administered intravenously in cases of severe infection or as a prophylactic in patients undergoing surgery. The recommended daily dose in children is 20 to 40mg/ kg, based on the Amoxicillin component. Doses towards the lower end of this range should be adequate in mild to moderate infections while higher doses may be used against more severe infections. Dosage reductions are necessary in patients with renal failure. Amoxieillin/clavulanic acid should be administered with food and is contraindicated in patients with a known history of β-lactam hypersensitivity.

Takahisa Furuta – One of the best experts on this subject based on the ideXlab platform.

  • Effect of dosing schemes of Amoxicillin on eradication rates of Helicobacter pylori with Amoxicillin-based triple therapy.
    The Journal of Clinical Pharmacology, 2013
    Co-Authors: Takahisa Furuta, Mitsushige Sugimoto, Mihoko Yamade, Takahiro Uotani, Shu Sahara, Hitomi Ichikawa, Takanori Yamada, Satoshi Osawa, Ken Sugimoto, Hiroshi Watanabe

    Abstract:

    Objectives

    In standard regimens for Helicobacter pylori infection, Amoxicillin is dosed twice daily, although the bactericidal effect of Amoxicillin depends on the %time-above-MIC. We aimed to examine whether dosing schemes of Amoxicillin influenced eradication rates of Amoxicillin-based regimens.

    Methods

    One hundred eighty-seven patients infected with clarithromycin-sensitive strains of H. pylori were treated with PPI, clarithromycin 200 mg bid and Amoxicillin 750 mg bid, 500 mg tid or 500 mg qid for 1 week and 125 infected with clarithromycin-resistant strains were treated with PPI, metronidazole 250 mg bid and Amoxicillin 750 mg bid, 500 mg tid or 500 mg qid for 1 week.

    Results

    Eradication rates (ITT) of the triple PPI/Amoxicillin/clarithromycin therapy with bid, tid and qid dosings of Amoxicillin were 77.8% (49/63), 93.5% (58/62), and 91.9% (57/62), respectively. Those of the triple PPI/Amoxicillin/metronidazole therapy were 80.5% (33/41), 90.5% (38/42), and 95.2% (40/42), respectively. Eradication rates in regimens with tid and qid dosing of Amoxicillin were higher than those of regimens with the bid dosing of Amoxicillin.

    Conclusions

    The dosing scheme of Amoxicillin significantly influenced eradication rates of triple therapies. Although Amoxicillin is empirically dosed twice daily, Amoxicillin should be dosed at least three times daily in Amoxicillin-based triple therapies.

  • effect of genotypic differences in cyp2c19 on cure rates for helicobacter pylori infection by triple therapy with a proton pump inhibitor Amoxicillin and clarithromycin
    Clinical Pharmacology & Therapeutics, 2001
    Co-Authors: Takahisa Furuta, Hiroyuki Hanai, Naohito Shirai, Misako Takashima, Fang Xiao

    Abstract:

    Background

    Proton pump inhibitors such as omeprazole and lansoprazole are mainly metabolized by CYP2C19 in the liver. The therapeutic effects of proton pump inhibitors are assumed to depend on CYP2C19 genotype status.

    Objective

    We investigated whether CYP2C19 genotype status was related to eradication rates of H pylori by triple proton pump inhibitor–clarithromycin–Amoxicillin (INN, Amoxicilline) therapy and attempted to establish a strategy for treatment after failure to eradicate H pylori.

    Methods

    A total of 261 patients infected with H pylori completed initial treatment with 20 mg of omeprazole or 30 mg of lansoprazole twice a day, 200 mg of clarithromycin three times a day, and 500 mg of Amoxicillin three times a day for 1 week. CYP2C19 genotypes of patients were determined with polymerase chain reaction–restriction fragment length polymorphism analysis. Patients without eradication after initial treatment were retreated with 30 mg of lansoprazole four times daily and 500 mg of Amoxicillin four times daily for 2 weeks.

    Results

    Eradication rates for H pylori were 72.7% (95% confidence interval, 64.4%-81.8%), 92.1% (confidence interval, 86.4%-97.3%), and 97.8% (confidence interval, 88.5%-99.9%) in the homozygous extensive, heterozygous extensive, and poor metabolizer groups, respectively. Thirty-four of 35 patients without eradication had an extensive metabolizer genotype of CYP2C19. Nineteen of those patients were infected with clarithromycin-resistant strains of H pylori. However, there were no Amoxicillin-resistant strains of H pylori. Re-treatment of H pylori infection with dual high-dose lansoprazole-Amoxicillin therapy succeeded in 30 of 31 patients with extensive metabolizer genotype of CYP2C19.

    Conclusion

    The majority of patients without initial eradication of H pylori had an extensive metabolizer CYP2C19 genotype but were successfully re-treated with high doses of lansoprazole and an antibiotic to which H pylori was sensitive, such as Amoxicillin, even when the patients were infected with clarithromycin-resistant strains of H pylori.

    Clinical Pharmacology & Therapeutics (2001) 69, 158–168; doi: 10.1067/mcp.2001.113959