amoxicillin and clavulanate potassium
Augmentin, Augmentin ES-600, Clavulin ◆

Available forms
Available by prescription only
Oral suspension: 125 mg amoxicillin trihydrate and 31.25 mg clavulanic acid/5 ml (after reconstitution); 200 mg amoxicillin trihydrate and 28.5 mg clavulanic acid/5 ml (after reconstitution); 250 mg amoxicillin trihydrate and 62.5 mg clavulanic acid/5 ml (after reconstitution); 400 mg amoxicillin trihydrate and 57 mg clavulanic acid/ 5 ml (after reconstitution), 600 mg amoxicillin trihydrate and 42.9 mg clavulanic acid/5 ml (after reconstitution)
Tablets: 250 mg amoxicillin trihydrate, 125 mg clavulanic acid; 500 mg amoxicillin trihydrate, 125 mg clavulanic acid; 875 mg amoxicillin trihydrate, 125 mg clavulanic acid
Tablets (chewable): 125 mg amoxicillin trihydrate, 31.25 mg clavulanic acid; 200 mg amoxicillin trihydrate, 28.5 mg clavulanic acid; 250 mg amoxicillin trihydrate, 62.5 mg clavulanic acid; 400 mg amoxicillin trihydrate, 57 mg clavulanic acid

Indications and dosages
 Lower respiratory tract infections, otitis media, sinusitis, skin and skin structure infections, and urinary tract infections caused by susceptible organisms. Adults and children who weigh more than 40 kg (88 lb): 250 mg (based on amoxicillin component) P.O. q 8 hours or one 500-mg tablet q 12 hours. For more severe infections, 500 mg q 8 hours or 875 mg q 12 hours.
Children who weigh less than 40 kg: 25 to 45 mg/kg P.O. daily (based on amoxicillin component) given in divided doses q 8 to 12 hours.
Neonates and infants younger than 12 weeks: 30 mg/kg daily in divided doses q 12 hours.
≡ Dosage adjustment. For patients with creatinine clearance of 15 to 30 ml/minute, give usual dose q 12 to 18 hours. If clearance is 5 to 15 ml/ minute, give usual dose q 20 to 36 hours. If clearance is less than 5 ml/minute, give usual dose every 48 hours. Some clinicians recommend not using drug if creatinine clearance is less than 30 ml/minute. In hemodialysis patients, give 500 mg P.O. midway through treatment and then 500 mg P.O. at the end of treatment.
 Recurrent or persistent acute otitis media caused by Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis, in children with antibiotic exposure within the last 3 months who either attend daycare or are 2 years old or younger. Infants and children ages 3 months and older: 90 mg/ kg/day Augmentin ES-600 (based on amoxicillin component) P.O. q 12 hours for 10 days. Experience with this medication in patients weighing 40 kg or more is unavailable.

Pharmacodynamics
Antibiotic action: Amoxicillin is bactericidal; it adheres to bacterial penicillin-binding proteins, thus inhibiting bacterial cell wall synthesis.
 Clavulanate has only weak antibacterial activity and doesn’t affect mechanism of action of amoxicillin. However, clavulanic acid has a beta-lactam ring and is structurally similar to penicillin and cephalosporins; it binds irreversibly with certain beta-lactamases and prevents them from inactivating amoxicillin, enhancing its bactericidal activity.
 This combination acts against penicillinase- and non-penicillinase-producing gram-positive bacteria, Neisseria gonorrhoeae, Neisseria meningitidis, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Proteus mirabilis, Citrobacter diversus, Klebsiella pneumoniae, Proteus vulgaris, Salmonella, Shigella, Clostridium, Peptococcus, and Peptostreptococcus.

Pharmacokinetics
Absorption: Well absorbed after oral administration.
Distribution: Distributed into pleural fluid, lungs, and peritoneal fluid; high urine concentrations are attained. Amoxicillin also is distributed into synovial fluid, liver, prostate, muscle, and gallbladder and penetrates into middle ear effusions, maxillary sinus secretions, tonsils, sputum, and bronchial secretions. Amoxicillin and clavulanate cross the placental barrier, and low concentrations appear in breast milk. Amoxicillin and clavulanate potassium have minimal protein-binding of 17% to 20% and 22% to 30%, respectively.
Metabolism: Amoxicillin is metabolized only partially. The metabolic fate of clavulanate potassium isn’t completely identified, but it appears to undergo extensive metabolism.
Excretion: Amoxicillin is excreted principally in urine by renal tubular secretion and glomerular filtration; drug also appears in breast milk.
 Clavulanate potassium is excreted by glomerular filtration. Elimination half-life of amoxicillin in adults is 1 to 11/2 hours; it is prolonged to 71/2 hours in patients with severe renal impairment. Half-life of clavulanate in adults is about 1 to 11/2 hours, prolonged to 41/2 hours in patients with severe renal impairment.
 Both drugs are removed readily by hemodialysis and minimally removed by peritoneal dialysis.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug or other penicillins and in those with a previous history of amoxicillin-related cholestatic jaundice or hepatic dysfunction. An oral penicillin shouldn’t be used in patients with severe pneumonia, empyema, bacteremia, pericarditis, meningitis, and purulent or septic arthritis. Use with caution in patients with mononucleosis.

Interactions
Drug-drug. Allopurinol: Appears to increase likelihood of rash from both drugs. Avoid use together.
Hormonal contraceptives: May reduce effectiveness of hormonal contraceptives. Advise using alternative barrier method.
Methotrexate: Large doses of penicillins may interfere with renal tubular secretion of methotrexate, thus delaying elimination and prolonging elevated methotrexate serum level. Monitor patient for adverse effects.
Probenecid: Blocks tubular secretion of amoxicillin, raising its serum level; it has no effect on clavulanate. Avoid use together.

Adverse reactions
CNS: agitation, anxiety, insomnia, confusion, behavioral changes, dizziness.
GI: nausea, vomiting, diarrhea, indigestion, gastritis, stomatitis, glossitis, black "hairy" tongue, enterocolitis, pseudomembranous colitis.
GU: vaginitis.
Hematologic: anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, agranulocytosis.
Other: hypersensitivity reactions (erythematous maculopapular rash, urticaria, anaphylaxis), overgrowth of nonsusceptible organisms.

Effects on lab test results
• May increase AST, ALT, alkaline phosphatase, and bilirubin levels.
• May increase eosinophil count. May decrease hemoglobin and platelet, WBC, and granulocyte counts.

Overdose and treatment
Evidence of overdose includes neuromuscular sensitivity and seizures.
 After recent ingestion (4 hours or less), empty the stomach by induced emesis or gastric lavage; follow with activated charcoal to reduce absorption. Amoxicillin/clavulanate potassium can be removed by hemodialysis.

Special considerations
• Amoxicillin/potassium clavulanate alters results of urine glucose tests that use cupric sulfate (Benedict’s reagent or Clinitest). Make urine glucose determinations with glucose oxidase methods (Chemstrip uG or Diastix or glucose enzymatic test strip). Positive Coombs’ tests have been reported with other clavulanate combinations. Amoxicillin/potassium clavulanate may produce a positive direct antiglobulin test.
• Amoxicillin/clavulanate potassium has been used to treat infections caused by Eikenella corrodens or Pasteurella multocida and infections caused by anaerobic and mixed aerobic-anaerobic bacterial infections.
 ALERT Both 250-mg and 500-mg film-coated tablets contain the same amount of clavulanic acid (125 mg); therefore, two 250-mg tablets aren’t equivalent to one 500-mg tablet. Also, don’t interchange the oral suspensions because of clavulanic aid content.
• Augmentin ES-600 is intended for children only. There is no experience with this drug in adults or adults who have trouble swallowing.
• Recommend that patients take drug with a meal or snack to prevent stomach upset.
• Oral dosage is maximally absorbed from an empty stomach, but food doesn’t cause significant impairment of absorption.
• For reconstitution, add specified water in 2 parts and agitate well after each addition.
• Monitor renal, hepatic, and hematologic function periodically.
• Test for Clostridium difficile in patients with diarrhea.
• Suspension is stable for 10 days in refrigerator after reconstitution.
• Because amoxicillin/clavulanate potassium is dialyzable, patients undergoing hemodialysis may need dosage adjustments.
Pregnant patients
• There are no adequate and controlled studies of use of this drug in pregnant women. Use in pregnant women only if clearly needed.
Breast-feeding patients
• Both amoxicillin and potassium clavulanate appear in breast milk; use cautiously in breast-feeding women.
Pediatric patients
• Commercial products that contain aspartame shouldn’t be used in children with phenylketonuria.
Geriatric patients
• In geriatric patients, diminished renal tubular secretion may prolong half-life of amoxicillin.

Patient education
• Tell patient to chew chewable tablets thoroughly or crush before swallowing and wash down with liquid to ensure adequate absorption of drug; capsule may be emptied and contents swallowed with water.
• Instruct patient to report diarrhea promptly.
• Inform patient to complete full course of medication.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use