CLAVAM (Amoxicillin and Clavulanate Potassium)

CLAVAM (Amoxicillin and Clavulanate Potassium)

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CLAVAM (Amoxicillin and Clavulanate Potassium)

Amoxicillin is a semi-synthetic antibiotic with a broad spectrum of antibacterial activity against many gram-positive and gram-negative micro-organisms. Amoxicillin is however, susceptible to degradation by beta-lactamases and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes.

Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of beta-lactamase enzymes commonly found in micro-organisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid mediated beta-lactamases frequently responsible for transferred drug resistance. It is generally less effective against chromosomally-mediated type 1 beta-lactamases.

The presence of Clavulanic acid in Amoxicillin-Clavulanic acid formulations protects amoxicillin from degradation by beta-lactamase enzymes and effectively extends the antibacterial spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other penicillins and cephalosporins. Thus Amoxicillin-Clavulanic acid possesses the distinctive properties of a broad spectrum antibiotic and a beta-lactamase inhibitor.

Pharmacokinetics

Absorption: The two components of Amoxicillin-Clavulanic acid, are fully dissociated in aqueous solution at physiologically pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of Amoxicillin-Clavulanic acid is optimised when taken at the start of a meal.

Amoxicillin serum concentrations achieved with Amoxicillin-Clavulanic acid are similar to those produced by the oral administration of equivalent doses of amoxicillin alone.

Distribution: Following I.v. Administration, therapeutic concentrations of both amoxicillin and Clavulanic acid may be detected in the tissues and interstitial fluid. Therapeutic concentrations of both drugs have been found in gall bladder, abdominal tissue, skin, fat and muscle tissues; fluids found to have therapeutic levels include synovial and peritoneal fluids, bile and pus.

Neither amoxicillin nor Clavulanic acid is highly protein bound, studies show that about 25% for Clavulanic acid and 18% for amoxicillin of total plasma drug content is bound to protein.

Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of Clavulanic acid can also be detected in breast milk. With the exception of the risk of sensitisation associated with this excretion, there are no known detrimental effects for the breast-fed infant.

Reproduction studies in animals have shown that both amoxicillin and Clavulanic acid penetrate the placental barrier. However, no evidence of impaired fertility or harm to the foetus was detected.

Metabolism: Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man to 2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid and 1-amino-4-hydroxy-butan-2-one and eliminated in urine and faeces as carbon dioxide in expired air.

Elimination: As with other penicillins, the major route of elimination for amoxicillin is vial the kidney, whereas for Clavulanic acid it is by both renal and non-renal mechanisms. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the Clavulanic acid are excreted unchanged in urine during the first 6 hr after administration of a single 250/125 mg or a single 500/125 mg tablet.

Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of Clavulanic acid.

Indications

Amoxicillin-Clavulanic acid should be used in accordance with local official antibiotic-prescribing guidelines and local susceptibility data.

Amoxicillin-Clavulanic acid is indicated in adults and children for short term treatment of bacterial infections at the following sites when caused by Amoxicillin-Clavulanic acid susceptible organisms

  • upper respiratory tract infections (including ENT) e.g. recurrent tonsillitis, sinusitis, otitis media
  • lower respiratory tract infections e.g. acute exacerbation of chronic bronchitis, lobar and bronchopneumonia
  • genito-urinary tract infections e.g. cystitis, urethritis, pyelonephritis
  • skin and soft tissue infections e.g. boils, abscess, cellulitis, wound infections
  • bone and joint infections e.g. osteomyelitis
  • other infections e.g. septic abortion, puerperal sepsis, intra-abdominal sepsis.

Susceptibility to Amoxicillin-Clavulanic acid will vary with geography and time. Local susceptibility data should be consulted where available and microbiological sampling and susceptibility testing performed where necessary.

Infections caused by amoxicillin-susceptible organisms are amenable to Amoxicillin-Clavulanic acid treatment due to its amoxicillin content. Mixed infections caused by amoxicillin susceptible organisms in conjunction with Amoxicillin-Clavulanic acid susceptible beta-lactamase producing organisms may therefore be treated by Amoxicillin-Clavulanic acid

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Dosage and administration

Dosage depends on the age, weight and renal function of the patient and the severity of the infection.

Dosage are expressed throughout in terms of Amoxicillin-Clavulanic acid content except when doses are stated in terms of an individual component.

To minimise potential gastrointestinal intolerance, administer at the start of meal.

The absorption of Amoxicillin-Clavulanic acid is optimised when taken at the start of a meal.

Treatment should not be extended beyond 14 days without review.

Adults

Mild to moderate infections250/125 mg given 3 times daily OR 500/125 mg given 2 rimes daily, OR 875/125 mg given twice daily
Severe infections (including chronic and recurrent urinary tract infections and those of the lower respiratory tract)2 times 250/125mg given 3 times daily, OR 1 to 2 times 500/125 mg given 3 times daily, OR 875/125 mg given 2 or 3 times daily

Children

Dosage should be expressed in terms of the child and either in mg/kg/day (given in 2 or 3 divided doses) or ml of suspension per dose or equivalent for other presentations.

Children weighing 40kg and over should be dosed according to adult recommendations


Three times daily (4:1) formulationsTwice daily (7:1) formulations)
Lower dose (mg/kg/day)20/5 to 40/1025/3.6 to 45/6.4
Higher dose (mg/kg/day)40/10 to 60/1545/6.4 to 70/10

Contraindications

Amoxicillin-Clavulanic acid is contraindicated

  • in patients with a history of hypersensitivity to beta-lactams, e.g. penicillins and cephalosporins
  • in patients with a previous history of Amoxicillin-Clavulanic acid associated jaundice/hepatic dysfunction.

Warnings and precautions

Before initiating therapy with Amoxicillin-Clavulanic acid, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens.

Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity. If an allergic reaction occurs, Amoxicillin-Clavulanic acid therapy should be discontinued and appropriate alternative therapy instituted. Serious anaphylactoid reactions require immediate emergency treatment with adrenaline. Oxygen, I.v. Steroids and airway management including intubation may also be required

Amoxicillin-Clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin.

Prolonged use may also occasionally result in overgrowth of non-susceptible organisms.

In general Amoxicillin-Clavulanic acid is well tolerated and possesses the characteristic low toxicity of the penicillin group of antibiotics. Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy.

Drug interactions

Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use with Amoxicillin-Clavulanic acid may result in increased and prolonged blood levels of amoxicillin, but not of Clavulanic acid.

Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. There are no data on the concomitant use of Amoxicillin-Clavulanic acid and allopurinol.

In common with other antibiotics, Amoxicillin-Clavulanic acid may affect the gut flora, leading to lower oestrogen re-absorption and reduce efficacy of combined oral contraceptives.

In literature there are rare cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin.

Pregnancy and lactation

Pregnancy: Reproduction studies in animals (mice and rats at doses up to 10 times the human dose) with orally and parenterally administered Amoxicillin-Clavulanic acid have shown no teratogenic effects. In a single study in women with preterm, premature rupture of the foetal membrane (pPROM), it was reported that prophylactic treatment with Amoxicillin-Clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. As with all medicines, use should be avoided in pregnancy, unless considered essential by the physician.

Lactation: Amoxicillin-Clavulanic acid may be administered during the period of lactation. With the exception of the risk of sensitization, associated with the excretion of trace quantities in breast milk, there are no known detrimental effects for the breast-fed infant.

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