Amoxicillin/Clavulanic Acid

Abstract

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. 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. 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. 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. 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. 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.