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Amoxicillin and Clavulanate Potassium


Pronunciation

 (a moks i SIL in & klav yoo LAN ate poe TASS ee um)


U.S. Brand Names

 Augmentin®; Augmentin ES-600®; Augmentin XR™


Synonyms

 Amoxicillin and Clavulanic Acid


Generic Available

 Yes: Excludes extended release


Canadian Brand Names

 Alti-Amoxi-Clav; Apo-Amoxi-Clav®; Augmentin®; Clavulin®; ratio-AmoxiClav


Use

 Treatment of otitis media, sinusitis, and infections caused by susceptible organisms involving the lower respiratory tract, skin and skin structure, and urinary tract; spectrum same as amoxicillin with additional coverage of beta-lactamase producing B. catarrhalis , H. influenzae , N. gonorrhoeae , and S. aureus (not MRSA). The expanded coverage of this combination makes it a useful alternative when amoxicillin resistance is present and patients cannot tolerate alternative treatments.


Use - Dental

 Treatment of orofacial infections when beta-lactamase-producing staphylococci and beta-lactamase-producing Bacteroides are present


Pregnancy Risk Factor

 B


Pregnancy Implications

 Both amoxicillin and clavulanate potassium cross the human placenta. Teratogenic effects have not been reported. Use in women with premature rupture of fetal membranes may increase risk of necrotizing enterocolitis in neonates.


Lactation

 Enters breast milk/use caution (AAP rates "compatible")


Contraindications

 Hypersensitivity to amoxicillin, clavulanic acid, penicillin, or any component of the formulation; history of cholestatic jaundice or hepatic dysfunction with amoxicillin/clavulanate potassium therapy


Warnings/Precautions

 Prolonged use may result in superinfection; in patients with renal impairment, doses and/or frequency of administration should be modified in response to the degree of renal impairment; high percentage of patients with infectious mononucleosis have developed rash during therapy; a low incidence of cross-allergy with cephalosporins exists; incidence of diarrhea is higher than with amoxicillin alone. Use caution in patients with hepatic dysfunction. Hepatic dysfunction, although rare, is more common in elderly and/or males, and occurs more frequently with prolonged treatment, and may occur after therapy is complete. Due to differing content of clavulanic acid, not all formulations are interchangeable. Some products contain phenylalanine.


Adverse Reactions

>10%: Gastrointestinal: Diarrhea (3% to 34% incidence varies upon dose and regimen used)

1% to 10%:

Dermatologic: Diaper rash, skin rash, urticaria

Gastrointestinal: Abdominal discomfort, loose stools, nausea, vomiting

Genitourinary: Vaginitis

Miscellaneous: Moniliasis

<1%: Cholestatic jaundice, flatulence, headache, hepatic dysfunction, prothrombin time increased, thrombocytosis

Additional adverse reactions seen with ampicillin-class antibiotics: Agitation, agranulocytosis, ALT elevated, anaphylaxis, anemia, angioedema, anxiety, AST elevated, behavioral changes, black "hairy" tongue, confusion, convulsions, crystalluria, dizziness, enterocolitis, eosinophilia, erythema multiforme, exanthematous pustulosis, exfoliative dermatitis, gastritis, glossitis, hematuria, hemolytic anemia, hemorrhagic colitis, indigestion, insomnia, hyperactivity, interstitial nephritis, leukopenia, mucocutaneous candidiasis, pruritus, pseudomembranous colitis, serum sickness-like reaction, Stevens-Johnson syndrome, stomatitis, thrombocytopenia, thrombocytopenic purpura, tooth discoloration, toxic epidermal necrolysis


Overdosage/Toxicology

 Symptoms of overdose may include abdominal pain, diarrhea, drowsiness, rash, hyperactivity, stomach pain, and vomiting. Electrolyte imbalance may occur, especially in renal failure. Hemodialysis may be helpful to aid in removal of the drug from blood; otherwise, treatment is supportive or symptom-directed.


Drug Interactions

Allopurinol: Additive potential for amoxicillin rash

Aminoglycosides: May be synergistic against selected organisms

Methotrexate: Penicillins may increase the exposure to methotrexate during concurrent therapy; monitor.

Oral contraceptives: Anecdotal reports suggesting decreased contraceptive efficacy with penicillins have been refuted by more rigorous scientific and clinical data.

Probenecid: May increase levels of penicillins (amoxicillin)

Warfarin: Effects of warfarin may be increased


Stability

Powder for oral suspension: Store dry powder at room temperature of 25°C (77°F). Reconstitute powder for oral suspension with appropriate amount of water as specified on the bottle. Shake vigorously until suspended. Reconstituted oral suspension should be kept in refrigerator. Discard unused suspension after 10 days. Unit-dose antibiotic oral syringes are stable for 48 hours.

Tablet: Store at room temperature of 25°C (77°F).


Mechanism of Action

 Clavulanic acid binds and inhibits beta-lactamases that inactivate amoxicillin resulting in amoxicillin having an expanded spectrum of activity. Amoxicillin inhibits bacterial cell wall synthesis by binding to one or more of the penicillin binding proteins (PBPs); which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.


Pharmacodynamics/Kinetics

 Amoxicillin pharmacokinetics are not affected by clavulanic acid.

Amoxicillin: See Amoxicillin monograph.

Clavulanic acid:

Metabolism: Hepatic

Excretion: Urine (30% to 40% as unchanged drug)


Dosage

 Note: Dose is based on the amoxicillin component; see "Augmentin® Product-Specific Considerations" table.

Infants <3 months: 30 mg/kg/day divided every 12 hours using the 125 mg/5 mL suspension

Children 3 months and <40 kg:

Otitis media: 90 mg/kg/day divided every 12 hours for 10 days

Lower respiratory tract infections, severe infections, sinusitis: 45 mg/kg/day divided every 12 hours or 40 mg/kg/day divided every 8 hours

Less severe infections: 25 mg/kg/day divided every 12 hours or 20 mg/kg/day divided every 8 hours

Children >40 kg and Adults: 250-500 mg every 8 hours or 875 mg every 12 hours

Children 16 years and Adults:

Acute bacterial sinusitis: Extended release tablet: Two 1000 mg tablets every 12 hours for 10 days

Community-acquired pneumonia: Extended release tablet: Two 1000 mg tablets every 12 hours for 7-10 days

Dosing interval in renal impairment:

Clcr<30 mL/minute: Do not use 875 mg tablet or extended release tablets

Clcr 10-30 mL/minute: 250-500 mg every 12 hours

Clcr<10 mL/minute: 250-500 every 24 hours

Hemodialysis: Moderately dialyzable (20% to 50%)

250-500 mg every 24 hours; administer dose during and after dialysis. Do not use extended release tablets.

Peritoneal dialysis: Moderately dialyzable (20% to 50%)

Amoxicillin: Administer 250 mg every 12 hours

Clavulanic acid: Dose for Clcr<10 mL/minute

Continuous arteriovenous or venovenous hemofiltration effects:

Amoxicillin: ~50 mg of amoxicillin/L of filtrate is removed

Clavulanic acid: Dose for Clcr<10 mL/minute


Administration

Augmentin Product-Specific Considerations

Strength Form Consideration
125 mg CT, S q8h dosing
S For adults having difficulty swallowing tablets, 125 mg/5 mL suspension may be substituted for 500 mg tablet.
200 mg CT, S q12h dosing
CT Contains phenylalanine
S For adults having difficulty swallowing tablets, 200 mg/5 mL suspension may be substituted for 875 mg tablet.
250 mg CT, S, T q8h dosing
CT Contains phenylalanine
T Not for use in patients <40 kg
CT, T Tablet and chewable tablet are not interchangeable due to differences in clavulanic acid.
S For adults having difficulty swallowing tablets, 250 mg/5 mL suspension may be substituted for 500 mg tablet.
400 mg CT, S q12h dosing
CT Contains phenylalanine
S For adults having difficulty swallowing tablets, 400 mg/5 mL suspension may be substituted for 875 mg tablet.
500 mg T q8h or q12h dosing
600 mg S q12h dosing
Contains phenylalanine
Not for use in adults or children 40 kg
600 mg/5 mL suspension is not equivalent to or interchangeable with 200 mg/5 mL or 400 mg/5 mL due to differences in clavulanic acid.
875 mg T q12h dosing; not for use in Clcr <30 mL/minute
1000 mg XR q12h dosing
Not for use in children <16 years of age
Not interchangeable with two 500 mg tablets
Not for use in Clcr <30 mL/minute or hemodialysis
Legend: CT = chewable tablet, S = suspension, T = tablet, XR = extended release.

Administration

 Administer around-the-clock to promote less variation in peak and trough serum levels. Administer with food to decrease stomach upset; shake suspension well before use. Extended release tablets should be administered with food.


Monitoring Parameters

 Assess patient at beginning and throughout therapy for infection; with prolonged therapy, monitor renal, hepatic, and hematologic function periodically; monitor for signs of anaphylaxis during first dose


Test Interactions

 May interfere with urinary glucose tests using cupric sulfate (Benedict's solution, Clinitest®, Fehling's solution); may inactivate aminoglycosides in vitro


Dietary Considerations

 May be taken with meals or on an empty stomach; take with meals to increase absorption and decrease GI intolerance; may mix with milk, formula, or juice. Extended release tablets should be taken with food. Some products contain phenylalanine; avoid use in phenylketonurics. All dosage forms contain potassium.


Patient Education

 Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take as directed, for as long as directed, even if you are feeling better. (For small children, bottles may contain more suspension than needed, take for number of days prescribed.) Take at equal intervals around-the-clock; may be taken with milk, juice, or food. Extended release tablets should be taken with food. If you have diabetes, drug may cause false test results with Clinitest® urine glucose monitoring; use of another type of glucose monitoring is preferable. May cause nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). Report rash; unusual diarrhea; vaginal itching, burning, or pain; unresolved vomiting or constipation; fever or chills; abdominal pain; jaundice; unusual bruising or bleeding; or if condition being treated worsens or does not improve by the time prescription is completed. Some products contain phenylalanine. Avoid use in phenylketonurics. Breast-feeding precaution: Consult prescriber if breast-feeding.


Additional Information

 Two 250 mg tablets are not equivalent to a 500 mg tablet (both tablet sizes contain equivalent clavulanate). Two 500 mg tablets are not equivalent to a single 1000 mg extended release tablet.


Dental Health: Effects on Dental Treatment

 Prolonged use of penicillins may lead to development of oral candidiasis.


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Dental Comment

 In maxillary sinus, anterior nasal cavity, and deep neck infections, beta-lactamase-producing staphylococci and beta-lactamase-producing Bacteroides usually are present. In these situations, antibiotics that resist the beta-lactamase enzyme are indicated. Amoxicillin and clavulanic acid is administered orally for moderate infections. Ampicillin sodium and sulbactam sodium (Unasyn®) is administered parenterally for more severe infections.


Mental Health: Effects on Mental Status

 Penicillins have been reported to cause apprehension, illusions, agitation, insomnia, depersonalization, and encephalopathy


Mental Health: Effects on Psychiatric Treatment

 Disulfiram may increase amoxicillin levels


Dosage Forms

Powder for oral suspension: 200: Amoxicillin 200 mg and clavulanate potassium 28.5 mg per 5 mL (100 mL) [contains phenylalanine]; 400: Amoxicillin 400 mg and clavulanate potassium 57 mg per 5 mL (100 mL) [contains phenylalanine]

Augmentin®:

125: Amoxicillin 125 mg and clavulanate potassium 31.25 mg per 5 mL (75 mL, 100 mL, 150 mL) [banana flavor]

200: Amoxicillin 200 mg and clavulanate potassium 28.5 mg per 5 mL (50 mL, 75 mL, 100 mL) [contains phenylalanine 7 mg/5 mL; orange-raspberry flavor]

250: Amoxicillin 250 mg and clavulanate potassium 62.5 mg per 5 mL (75 mL, 100 mL, 150 mL) [orange flavor]

400: Amoxicillin 400 mg and clavulanate potassium 57 mg per 5 mL (50 mL, 75 mL, 100 mL) [contains phenylalanine 7 mg/5 mL; orange-raspberry flavor]

Augmentin ES-600®: Amoxicillin 600 mg and clavulanic potassium 42.9 mg per 5 mL (75 mL, 125 mL, 200 mL) [contains phenylalanine 7 mg/5 mL; orange flavor]

Tablet: 500: Amoxicillin trihydrate 500 mg and clavulanate potassium 125 mg; 875: Amoxicillin trihydrate 875 mg and clavulanate potassium 125 mg

Augmentin®:

250: Amoxicillin trihydrate 250 mg and clavulanate potassium 125 mg

500: Amoxicillin trihydrate 500 mg and clavulanate potassium 125 mg

875: Amoxicillin trihydrate 875 mg and clavulanate potassium 125 mg

Tablet, chewable: 200: Amoxicillin trihydrate 200 mg and clavulanate potassium 28.5 mg [contains phenylalanine]; 400: Amoxicillin trihydrate 400 mg and clavulanate potassium 57 mg [contains phenylalanine]

Augmentin®:

125: Amoxicillin trihydrate 125 mg and clavulanate potassium 31.25 mg [lemon-lime flavor]

200: Amoxicillin trihydrate 200 mg and clavulanate potassium 28.5 mg [contains phenylalanine 2.1 mg/tablet; cherry-banana flavor]

250: Amoxicillin trihydrate 250 mg and clavulanate potassium 62.5 mg [lemon-lime flavor]

400: Amoxicillin trihydrate 400 mg and clavulanate potassium 57 mg [contains phenylalanine 4.2 mg/tablet; cherry-banana flavor]

Tablet, extended release (Augmentin XR™): Amoxicillin 1000 mg and clavulanic acid 62.5 mg


References

American Thoracic Society, "Guidelines for the Initial Management of Adults With Community-Acquired Pneumonia: Diagnosis, Assessment of Severity, and Initial Antimicrobial Therapy," Am Rev Respir Dis , 1993, 148(5):1418-26.

Ancill RJ, Ballard JH, and Capewell MA, "Urinary Tract Infections in Geriatric Inpatients: A Comparative Study of Amoxicillin-Clavulanic Acid and Co-trimoxazole," Curr Ther Res , 1987, 41(4):444-8.

Donowitz GR and Mandell GL, "Beta-Lactam Antibiotics," N Engl J Med , 1988, 318(7):419-26 and 318(8):490-500.

Gan VN, Kusmiesz H, Shelton S, et al, "Comparative Evaluation of Loracarbef and Amoxicillin-Clavulanate for Acute Otitis Media," Antimicrob Agents Chemother , 1991, 35(5):967-71.

Hoberman A, Paradise JL, Burch DJ, et al, "Equivalent Efficiency and Reduced Occurrence of Diarrhea From a New Formulation of Amoxicillin/Clavulanate Potassium (Augmentin®) for Treatment of Acute Otitis Media in Children," Pediatr Infect Dis J , 1997, 16(5):463-70.

Reed MD, "Clinical Pharmacokinetics of Amoxicillin and Clavulanate," Pediatr Infect Dis J , 1996, 15(10):949-54.

Thoene DE and Johnson CE, "Pharmacotherapy of Otitis Media," Pharmacotherapy , 1991, 11(3):212-21.

Todd PA and Benfield P, "Amoxicillin/Clavulanic Acid. An Update of Its Antibacterial Activity, Pharmacokinetic Properties, and Therapeutic Use," Drugs , 1990, 39(2):264-307.

Wright AJ, "The Penicillins," Mayo Clin Proc , 1999, 74(3):290-307.

Wynn RL and Bergman SA, "Antibiotics and Their Use in the Treatment of Orofacial Infections, Part I and Part II," Gen Dent , 1994, 42(5):398-402, 498-502.


International Brand Names

 Alti-Amoxi-Clav (CA); Apo-Amoxi-Clav® (CA); Augmentin® (CA); Clavulin® (CA); ratio-AmoxiClav (CA)


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