Drug class: Aminopenicillins
VA class: AM052
Chemical name: [2R-(2α,3Z,5α)]-3-(2-Hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic acid monopotassium salt mixt. with [2S-[2α,5α,6β(S*)]]-6-[[Amino(4-hydroxyphenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid trihydrate
Molecular formula: C₁₆H₁₉N₃O₅S•3H₂O C₈H₈KNO₅
CAS number: 74469-00-4

Amoxicillin and Clavulanate Potassium is also contained as an ingredient in the following combinations:
Amoxicillin and Clavulanate Potassium

Medically reviewed by Drugs.com on Jan 23, 2024. Written by ASHP.

Introduction

Antibacterial; β-lactam antibiotic; fixed combination containing amoxicillin (an aminopenicillin) and clavulanate potassium (a β-lactamase inhibitor).^{1 61}

Uses for Amoxicillin/Clavulanate

Otitis Media

Treatment of acute otitis media (AOM) caused by β-lactamase producing H. influenzae or M. catarrhalis.^{1 3 61 67 74 77 78 81 82 88 89 92 93 94 95 96 98 99 101 115} AAP, AAFP, CDC, and others recommend the fixed combination of amoxicillin and clavulanate (amoxicillin/clavulanate) instead of amoxicillin for initial treatment of AOM in those with severe illness (moderate to severe otalgia or fever ≥39°C)¹¹⁵ or when the infection is suspected of being caused by β-lactamase-producing Haemophilus influenzae or Moraxella catarrhalis.^{74 76 77 78 81 89 115}

Treatment of persistent or recurrent AOM caused by H. influenzae (including β-lactamase-producing strains), M. catarrhalis (including β-lactamase-producing strains), or Streptococcus pneumoniae (penicillin MIC ≤2 mcg/mL) in pediatric patients.^{76 79 81 89 90 91 97 115} Drug of choice for retreatment of AOM that has not responded to other anti-infectives^{81 89 90 100 107 115} (e.g., no response to amoxicillin within 48–72 hours).¹¹⁵ Not indicated for AOM caused by S. pneumoniae with penicillin MIC ≥4 mcg/mL.³

Has been used for management of otitis media with effusion^{† [off-label]} (OME).^{68 94 102 107} Anti-infectives not usually recommended;^{102 103 104 105 107 116} they provide only limited benefit in enhancing resolution of effusion and may promote resistance.^{103 104 105 106 107} AAP, AAFP, and others recommend watchful waiting for 3 months from date of effusion onset or diagnosis in those 2 months to 12 years of age who are not at risk for speech, language, or learning problems; some suggest a short course of anti-infectives may be considered for possible short-term benefits when parent and/or caregiver expresses a strong aversion to impending surgery.¹¹⁶ If anti-infectives are used for treatment, amoxicillin/clavulanate or amoxicillin recommended.^{102 107}

Pharyngitis and Tonsillitis

Treatment of symptomatic patients who have multiple, recurrent episodes of pharyngitis known to be caused by S. pyogenes (group A β-hemolytic streptococci)^{† [off-label]}.^{75 76 80}

Not a drug of choice for treatment of streptococcal pharyngitis and tonsillitis,^{61 75 76 80} but one of several possible alternatives recommended by AAP, IDSA , and AHA when multiple episodes occur and the patient fails to respond to drugs of choice (oral penicillin V, IM penicillin G benzathine, oral amoxicillin).^{75 76 80}

Consider that multiple, recurrent episodes of symptomatic pharyngitis occurring within several months to years may indicate that the patient is a streptococcal carrier experiencing repeated episodes of nonstreptococcal (e.g., viral) pharyngitis;^{75 80} treatment not usually recommended for streptococcal pharyngeal carriers.^{75 76 80}

Respiratory Tract Infections

Treatment of acute sinusitis and lower respiratory tract infections caused by susceptible H. influenzae^{1 2 5 17 53 67 68 69} or M. catarrhalis.^{1 2 5 17 53 59}

Treatment of acute sinusitis or community-acquired pneumonia (CAP) caused by or suspected to be caused by β-lactamase-producing pathogens (i.e., H. influenzae, M. catarrhalis, H. parainfluenzae, Klebsiella pneumoniae, oxacillin-susceptible Staphylococcus aureus).^{4 61 305} Treatment of acute sinusitis or CAP caused by or suspected of being caused by S. pneumoniae with reduced penicillin susceptibility (i.e., penicillin MIC 2 mcg/mL).⁴ Not indicated for treatment of infections caused by S. pneumoniae with penicillin MIC ≥4 mcg/mL.⁴

ATS and IDSA recommend a regimen of amoxicillin/clavulanate with a macrolide (azithromycin or clarithromycin) as one of several options for empiric treatment of CAP in adult outpatients with comorbidities (e.g., chronic heart, lung, liver, or renal disease; diabetes mellitus; alcoholism; malignancy; asplenia).³⁰⁵

Skin and Skin Structure Infections

Treatment of skin or skin structure infections (e.g., abscesses, cellulitis, impetigo) caused by β-lactamase-producing S. aureus, Escherichia coli, or Klebsiella.^{1 2 5 33 42}

Urinary Tract Infections (UTIs)

Treatment of UTIs caused by β-lactamase-producing E. coli, Klebsiella, or Enterobacter.^{1 2 5 14 17 27 28 32 41 43 44 45 47 49 51 53 111}

Useful for outpatient treatment of recurrent UTIs or UTIs acquired in hospitals or nursing homes likely to be caused by drug-resistant S. aureus, Enterococcus, or gram-negative bacilli.¹¹¹ In severe gram-negative infections, consider concomitant use of an aminoglycoside (amikacin, gentamicin, tobramycin).¹¹¹

Tuberculosis

Has been suggested as an alternative for use in multiple-drug regimens for treatment of active tuberculosis^{† [off-label]} in patients with multidrug-resistant Mycobacterium tuberculosis (MDR-TB),^{20 31 66}

ATS, CDC, IDSA, and others state that amoxicillin/clavulanate is not recommended for inclusion in multiple-drug regimens used for the treatment of MDR-TB because of lack of evidence of clinical benefit.³⁰⁶ However, because of synergistic effects reported between clavulanate and meropenem, these experts state that amoxicillin/clavulanate should be included in multiple-drug regimens whenever a carbapenem is used for the treatment of MDR-TB.³⁰⁶

Bite Wounds

Has been used for empiric treatment of animal or human bites^{† [off-label]}.^{76 109} Active against many likely bite pathogens, including anaerobes, Staphylococcus, Eikenella corrodens, Pasteurella multocida.^{108 110}

Alternative for treatment of infections caused by P. multocida^{† [off-label]} or E. corrodens^†.¹¹¹

Pelvic Inflammatory Disease

Has been used for treatment of acute pelvic inflammatory disease^† (PID).^{46 52}

Not included in CDC recommendations for treatment of PID.³⁴⁴

Related/similar drugs

prednisone, amoxicillin, albuterol, doxycycline, cephalexin, ciprofloxacin, azithromycin

Amoxicillin/Clavulanate Dosage and Administration

Administration

Oral Administration

The various film-coated, scored, and chewable tablets and the oral suspension containing 125, 200, 250, or 400 mg of amoxicillin/5 mL may be administered without regard to meals.¹ However, administration with meals results in optimal absorption of clavulanate potassium and may minimize adverse GI effects.^{1 2 17 37 41 48 53 61}

Extended-release tablets containing 1 g of amoxicillin⁴ and the oral suspension containing 600 mg of amoxicillin/5 mL³ should be administered at the start of a meal to enhance absorption and minimize adverse GI effects.

Chewable tablets should be thoroughly chewed before swallowing.

In adults who have difficulty swallowing tablets, the oral suspension containing 125 or 250 mg of amoxicillin/5 mL may be substituted for 500-mg film-coated tablets or the oral suspension containing 200 or 400 mg of amoxicillin/5 mL may be substituted for 875-mg scored tablets.¹

When 500-mg film-coated tablets are indicated, do not substitute 250-mg film-coated tablets and do not substitute chewable tablets.²

When extended-release tablets containing 1 g of amoxicillin are indicated, do not substitute film-coated, scored, or chewable tablets.⁴

Reconstitution

Reconstitute oral suspension at the time of dispensing.^{1 3} Tap bottle to thoroughly loosen powder and then add the amount of water specified on the bottle in 2 portions; agitate vigorously after each addition.^{1 3}

Agitate suspension well prior to administration of each dose.^{1 3}

Dosage

Available as fixed combination containing amoxicillin and clavulanate potassium (amoxicillin/clavulanate);^{1 2 3 4} dosage expressed in terms of amoxicillin.^{1 2 3 4}

Not all preparations of amoxicillin/clavulanate are interchangeable since they contain different amounts of clavulanic acid.^{1 3}

Powders for oral suspension contain a 4:1, 7:1, or 14:1 ratio of amoxicillin to clavulanic acid;^{1 3} chewable tablets contain a 4:1 or 7:1 ratio of the drugs;¹ film-coated tablets contain a 2:1 or 4:1 ratio of the drugs;² scored tablets contain a 7:1 ratio of the drugs;¹ and extended-release tablets contain a 16:1 ratio of the drugs.⁴

Pediatric Patients

Children weighing <40 kg should not receive film-coated tablets containing 250 mg of amoxicillin since this preparation contains a high dose of clavulanic acid.¹

The oral suspension containing 125 mg of amoxicillin/5 mL is the only preparation recommended for use in neonates and infants <12 weeks (3 months) of age.¹

Acute Otitis Media (AOM)

AOM in Neonates and Infants <12 Weeks (3 Months) of Age

Oral

Oral suspension: Manufacturer recommends 30 mg/kg daily given in divided doses every 12 hours for 10 days using the oral suspension containing 125 mg/5 mL.¹

AOM in Children ≥12 Weeks of Age Weighing <40 kg

Oral

Oral suspension: Manufacturer recommends 45 mg/kg daily given in divided doses every 12 hours for 10 days using the suspension containing 200 or 400 mg/5 mL; alternatively, 40 mg/kg daily given in divided doses every 8 hours using the suspension containing 125 or 250 mg/5 mL.¹

Chewable tablets: Manufacturer recommends 45 mg/kg daily given in divided doses every 12 hours for 10 days using the chewable tablets containing 200 or 400 mg; alternatively, 40 mg/kg daily given in divided doses every 8 hours using chewable tablets containing 125 or 250 mg.¹

AOM in Children Weighing ≥40 kg

Oral

Film-coated tablets: Manufacturer recommends one 250-mg tablet every 8 hours or one 500-mg tablet every 12 hours for 10 days.^{1 2}

Oral suspension: Manufacturer recommends 500 mg every 12 hours for 10 days using the suspension containing 125 or 250 mg/5 mL.¹

AOM with Severe Illness or When β-Lactamase-producing Strains are Suspected

Oral

90 mg/kg daily given in divided doses every 12 hours recommended by AAP and AAFP.¹¹⁵

Usual duration is 10 days; optimal duration is uncertain.¹¹⁵ AAP and AAFP recommend 10 days in those <6 years of age and in those with severe disease and state 5–7 days may be appropriate in those ≥6 years of age with mild to moderate AOM.¹¹⁵

AOM that Failed to Respond to Amoxicillin

Oral

90 mg/kg daily given in divided doses every 12 hours recommended by AAP and AAFP.¹¹⁵

Usual duration is 10 days; optimal duration is uncertain.¹¹⁵ AAP and AAFP recommend 10 days in those <6 years of age and in those with severe disease and state 5–7 days may be appropriate in those ≥6 years of age with mild to moderate AOM.¹¹⁵

Persistent or Recurrent AOM

Infections in Children ≥3 Months of Age Weighing <40 kg

Oral

Oral suspension: Manufacturer recommends 90 mg/kg daily given in divided doses every 12 hours for 10 days using the suspension containing 600 mg/5 mL.³

Pharyngitis and Tonsillitis

Oral

40 mg/kg daily (up to 750 mg daily) in 3 divided doses for 10 days for treatment of multiple, recurrent episodes of pharyngitis known to be caused by S. pyogenes^†.⁸⁰

Respiratory Tract Infections

Infections in Neonates and Infants <12 weeks (3 months) of Age

Oral

Oral suspension: 30 mg/kg daily given in divided doses every 12 hours using the suspension containing 125 mg/5 mL.¹

Infections in Children ≥12 Weeks of Age Weighing <40 kg

Oral

Oral suspension: 45 mg/kg daily given in divided doses every 12 hours using the suspension containing 200 or 400 mg/5 mL; alternatively, 40 mg/kg daily given in divided doses every 8 hours using the suspension containing 125 or 250 mg/5 mL.¹

Chewable tablets: 45 mg/kg daily given in divided doses every 12 hours using chewable tablets containing 200 or 400 mg; alternatively, 40 mg/kg daily given in divided doses every 8 hours using chewable tablets containing 125 or 250 mg.¹

Infections in Children Weighing ≥40 kg

Oral

Film-coated or scored tablets: One 500-mg tablet every 8 hours or one 875-mg tablet every 12 hours.¹

Oral suspension: 500 mg every 8 hours using the suspension containing 125 or 250 mg/5 mL^{1 2} or 875 mg every 12 hours using the suspension containing 200 or 400 mg/5 mL.^{1 2}

Skin and Skin Structure Infections

Infections in Neonates and Infants <12 Weeks (3 Months) of Age

Oral

Oral suspension: 30 mg/kg daily in divided doses every 12 hours using the suspension containing 125 mg/5 mL.¹

Infections in Children ≥12 Weeks of Age Weighing <40 kg

Oral

Oral suspension: 25 mg/kg daily in divided doses every 12 hours using the suspension containing 200 or 400 mg/5 mL; alternatively, 20 mg/kg daily in divided doses every 8 hours using the suspension containing 125 or 250 mg/5 mL.¹ For severe infections, 45 mg/kg daily in divided doses every 12 hours using the suspension containing 200 or 400 mg/5 mL; alternatively, 40 mg/kg daily in divided doses every 8 hours using the suspension containing 125 or 250 mg/5 mL.¹

Chewable tablets: 25 mg/kg daily in divided doses every 12 hours using chewable tablets containing 200 or 400 mg.¹ For severe infections, 45 mg/kg daily given in divided doses every 12 hours using chewable tablets containing 200 or 400 mg.¹

Infections in Children Weighing ≥40 kg

Oral

Film-coated or scored tablets: One 250-mg tablet every 8 hours or one 500-mg tablet every 12 hours.^{1 2} For severe infections, one 500-mg tablet every 8 hours or one 875-mg tablet every 12 hours.¹

Oral suspension: 500 mg every 12 hours using the suspension containing 125 or 250 mg/5 mL.¹

Urinary Tract Infections (UTIs)

Infections in Neonates and Infants <12 Weeks (3 Months) of Age

Oral

Oral suspension: 30 mg/kg daily in divided doses every 12 hours using the suspension containing 125 mg/5 mL.¹

Infections in Children ≥12 Weeks of Age Weighing <40 kg

Oral

Oral suspension: 25 mg/kg daily in divided doses every 12 hours using the suspension containing 200 or 400 mg/5 mL; alternatively, 20 mg/kg daily in divided doses every 8 hours using the suspension containing 125 or 250 mg/5 mL.¹ For severe infections, 45 mg/kg daily in divided doses every 12 hours using the suspension containing 200 or 400 mg/5 mL; alternatively, 40 mg/kg daily in divided doses every 8 hours using the suspension containing 125 or 250 mg/5 mL.¹

Chewable tablets: 25 mg/kg daily in divided doses every 12 hours using chewable tablets containing 200 or 400 mg.¹ For severe infections, 45 mg/kg daily given in divided doses every 12 hours using chewable tablets containing 200 or 400 mg.¹

Infections in Children Weighing ≥40 kg

Oral

Film-coated or scored tablets: One 250-mg tablet every 8 hours or one 500-mg tablet every 12 hours.^{1 2} For severe infections, one 500-mg tablet every 8 hours or one 875-mg tablet every 12 hours.¹

Oral suspension: 500 mg every 12 hours using the suspension containing 125 or 250 mg/5 mL.¹

Adults

Respiratory Tract Infections

Oral

Scored tablets: one 875-mg-tablet every 12 hours.²

Oral suspension: 875 mg every 12 hours using the suspension containing 200 or 400 mg/5 mL.¹

Community-acquired Pneumonia

Oral

Extended-release tablets: Two 1-g tablets every 12 hours for 7–10 days.⁴

Sinusitis

Oral

Extended-release tablets: Two 1-g tablets every 12 hours for 10 days.⁴

Acute Otitis Media (AOM)

Oral

Film-coated tablets: One 500-mg tablet every 12 hours or one 250-mg tablet every 8 hours.² For severe infections, one 875-mg tablet every 12 hours or one 500-mg tablet every 8 hours.²

Oral suspension: 500 mg every 12 hours using the suspension containing 125 or 250 mg/5 mL.¹ For severe infections, 875 mg every 12 hours using the suspension containing 200 or 400 mg/5 mL.¹

Pharyngitis and Tonsillitis

Oral

500 mg twice daily for 10 days for treatment of multiple, recurrent episodes of pharyngitis known to be caused by S. pyogenes^†.⁸⁰ Adult dosage was extrapolated from pediatric dosage and has not been evaluated in clinical studies.⁸⁰

Skin and Skin Structure Infections

Oral

Film-coated or scored tablets: One 500-mg tablet every 12 hours or one 250-mg tablet every 8 hours.² For severe infections, one 875 mg-tablet every 12 hours or one 500-mg tablet every 8 hours.²

Oral suspension: 500 mg every 12 hours using the suspension containing 125 or 250 mg/5 mL.¹ For severe infections, 875 mg every 12 hours using the suspension containing 200 or 400 mg/5 mL.¹

Urinary Tract Infections (UTIs)

Oral

Film-coated or scored tablets: One 500-mg tablet every 12 hours or one 250-mg tablet every 8 hours.² For severe infections, one 875-mg tablet every 12 hours or one 500-mg tablet every 8 hours.²

Oral suspension: 500 mg every 12 hours using the suspension containing 125 or 250 mg/5 mL.¹ For severe infections, 875 mg every 12 hours using the suspension containing 200 or 400 mg/5 mL.¹

Special Populations

Hepatic Impairment

Select dosage with caution and monitor hepatic function.^{1 2 3 4} (See Hepatic Effects under Cautions.)

Renal Impairment

Dosage adjustment necessary in patients with moderate to severe renal impairment.^{2 5 17 63 65}

Do not use scored tablets containing 875 mg of amoxicillin in those with severe renal impairment and GFR <30 mL/minute.²

Do not use extended-release tablets containing 1 g of amoxicillin in those with Cl_cr <30 mL/minute or in hemodialysis patients.⁴

Geriatric Patients

No dosage adjustments except those related to renal impairment.⁴ (See Renal Impairment under Dosage and Administration.)

Cautions for Amoxicillin/Clavulanate

Contraindications

• Known hypersensitivity to any penicillin.^{1 2 3 4}

• Previous history of cholestatic jaundice or hepatic dysfunction associated with amoxicillin/clavulanate.^{1 2 3 4}

• Use of extended-release tablets containing 1 g of amoxicillin in those with Cl_cr <30 mL/minute or in hemodialysis patients.⁴

Warnings/Precautions

Warnings

Superinfection/Clostridioides difficile-associated Colitis

Possible emergence and overgrowth of nonsusceptible bacteria or fungi.^{1 2 3 4} Discontinue and institute appropriate therapy if superinfection occurs.^{1 2 3 4}

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of C. difficile.^{1 2 3 4 302} C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including amoxicillin/clavulanate, and may range in severity from mild diarrhea to fatal colitis.^{1 2 3 4 302} Consider CDAD if diarrhea develops during or after therapy and manage accordingly.^{1 2 3 4 302}

If CDAD suspected or confirmed, discontinue anti-infectives not directed against C. difficile as soon as possible.^{1 2 3 4 302} Initiate appropriate anti-infective therapy directed against C. difficile (e.g., fidaxomicin, vancomycin, metronidazole), appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), and surgical evaluation as clinically indicated.^{1 2 3 4 302}

Hepatic Effects

Rare reports of hepatic dysfunction (e.g., increases in serum AST, ALT, bilirubin, and/or alkaline phosphatase), especially in geriatric patients, males, or with prolonged therapy.^{1 2 3 4}

Hepatic dysfunction may occur during or several weeks following discontinuance of therapy.^{1 2 3 4}

Hepatic dysfunction may be severe, but usually is reversible.^{1 2 3 4} Histologic findings indicate predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes.^{1 2 3 4}

Fatalities has been reported rarely,^{1 2 3 4 71} most frequently in those with serious underlying diseases or concomitant drug therapy.^{1 2 3 4}

Assess hepatic function periodically during prolonged therapy.^{1 2 3 4}

Use with caution if there is evidence of hepatic dysfunction.^{1 2 3 4}

Sensitivity Reactions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity reactions reported with penicillins.^{1 2 3 4}

Prior to initiation of therapy, make careful inquiry regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other drugs.^{1 2 3 4} Partial cross-allergenicity occurs among penicillins and other β-lactam antibiotics including cephalosporins and cephamycins.^{1 2 3 4}

If hypersensitivity reaction occurs, discontinue immediately and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, maintenance of an adequate airway and oxygen).^{1 2 3 4}

General Precautions

Renal Effects

Acute interstitial nephritis and hematuria reported rarely.^{1 2 3 4}

Assess renal function periodically during prolonged therapy.^{1 2 3 4}

Hematologic Effects

Adverse hematologic effects (e.g., anemia, hemolytic anemia, leukopenia, agranulocytosis, thrombocytopenia, thrombocytopenic purpura) reported with penicillins.^{1 2 3 4} Usually reversible when drug discontinued; may be a hypersensitivity reaction.^{1 2 3 4}

Assess hematologic function periodically during prolonged therapy.^{1 2 3 4}

Mononucleosis

Possible increased risk of erythematous rash in patients with mononucleosis; use in these patients not recommended.^{1 2 3 4 22 23}

Phenylketonuria

Chewable tablets containing 200 or 400 mg of amoxicillin contain aspartame (NutraSweet), which is metabolized in the GI tract to provide 2.1 or 4.2 mg of phenylalanine, respectively.¹

Oral suspensions containing 200 400, or 600 mg of amoxicillin/5 mL contain aspartame (NutraSweet), which is metabolized in the GI tract to provide 7 mg of phenylalanine/5 mL.^{1 3}

Other commercially available preparations do not contain aspartame;^{1 2 4} these other preparations should be used in individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine.¹

Potassium and Sodium Content

Chewable tablets containing 125 or 250 mg of amoxicillin contain 0.16 or 0.32 mEq of potassium, respectively; chewable tablets containing 200 or 400 mg of amoxicillin contain 0.14 or 0.29 mEq of potassium, respectively.¹

Each 5 mL of oral suspension containing 125 or 250 mg of amoxicillin contains 0.16 or 0.32 mEq of potassium, respectively.¹ Each 5 mL of oral suspension containing 200 or 400 mg of amoxicillin contains 0.14 or 0.29 mEq of potassium, respectively.¹ Each 5 mL of oral suspension containing 600 mg of amoxicillin contains 0.23 mEq of potassium.³

Each film-coated or conventional tablet containing 250, 500, or 875 mg of amoxicillin contains 0.63 mEq of potassium.²

Each extended-release tablet containing 1 g of amoxicillin contains 12.6 mg (0.32 mEq) of potassium and 29.3 (1.27 mEq) of sodium.⁴

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of amoxicillin/clavulanate and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.^{1 2 3 4}

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.^{1 2 3 4} In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.^{1 2 3 4}

Use of Fixed Combinations

Consider cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination.

When prescribing, preparing, and dispensing amoxicillin/clavulanate, consider that dosage of the fixed combination usually is expressed as the amoxicillin component.^{1 2 3 4}

Specific Populations

Pregnancy

Category B.^{1 2 3 4}

Lactation

Distributed into milk; use with caution.^{1 2 3 4}

Pediatric Use

Renal clearance of amoxicillin may be delayed in neonates and young infants because of incompletely developed renal function.¹ Dosage adjustments necessary in those <12 weeks (3 months) of age compared with older infants and children.¹ (See Pediatric Patients under Dosage and Administration.)

Adverse effects profile similar to adults.¹ In children 2 months to 12 years of age receiving oral suspension, diarrhea occurs less frequently with dosing every 12 hours compared with every 8 hours.¹

Safety and efficacy of oral suspension containing 600 mg of amoxicillin/5 mL not established in children <3 months of age.³

Safety and efficacy of extended-release tablets containing 1 g of amoxicillin not established in children <16 years of age.⁴

Geriatric Use

Possible increased incidence of hepatic dysfunction compared with younger adults.^{1 2 3 4} (See Hepatic Effects under Cautions.)

Studies using extended-release tablets containing 1 g of amoxicillin indicate no substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.⁴

Substantially eliminated by kidneys.⁴ Monitor renal function since geriatric patients more likely to have decreased renal function.^{17 63 65}

Consider that extended-release tablets containing 1 g of amoxicillin contain 29.3 mg (1.27 mEq) of sodium.⁴

Hepatic Impairment

Use with caution;^{1 2 3 4} assess hepatic function periodically during prolonged therapy.^{1 2 3 4}

Renal Impairment

Substantially eliminated by kidneys; risk of dose-dependent adverse effects may be greater in those with impaired renal function.^{17 63 65}

Evaluate renal function periodically during prolonged therapy.^{1 2 3 4}

Dosage adjustments necessary in moderate or severe renal impairment.^{2 5 17 63 65}

Tablets containing 875 mg of amoxicillin should not be used in those with severe renal impairment (GFR <30 mL/minute).²

Pharmacokinetics of extended-release tablets not evaluated in renal impairment;⁴ extended-release tablets contraindicated in those with Cl_cr <30 mL/minute and in hemodialysis patients.⁴

Common Adverse Effects

Adverse GI effects (e.g., diarrhea or loose stools,^{1 2 3 4 17 27 32 33 41 42 44 49} nausea,^{1 2 3 4 27 32 42 53} vomiting),^{1 2 3 4 27 32 42 53} hypersensitivity reactions (e.g., rash,^{1 2 3 4 46} urticaria).^{1 2 3 4}

Adverse GI effects may be more frequent with amoxicillin/clavulanate than with amoxicillin alone.⁵ Severe diarrhea may occur less frequently in adults if 875 mg given every 12 hours rather than 500 mg every 8 hours.¹

Drug Interactions

Specific Drugs and Laboratory Tests

Amoxicillin/Clavulanate Pharmacokinetics

Absorption

Bioavailability

Both amoxicillin and clavulanate potassium well absorbed following oral administration.^{1 2 3 4 5 30 41 53 62 62}

Amoxicillin plasma concentrations attained with amoxicillin/clavulanate are similar to those attained with equivalent doses of amoxicillin alone.^{1 2 3 4 5 61 62}

A single chewable tablet containing 250 mg of amoxicillin and 62.5 mg of clavulanate potassium or 2 chewable tablets containing 125 mg of amoxicillin and 31.25 mg of clavulanate potassium are bioequivalent to 5 mL of the oral suspension containing 250 mg of amoxicillin/5 mL.¹

A single chewable tablet containing 400 mg of amoxicillin and 57 mg of clavulanate potassium is bioequivalent to 5 mL of the oral suspension containing 400 mg of amoxicillin/5 mL.¹

Food

Food has minimal or no effect on bioavailability of oral amoxicillin;^{1 2 3 4 5 6 48 61 62} bioavailability of clavulanate may be increased when taken with food.^{1 2 3 4}

Optimal absorption of both amoxicillin and clavulanic acid occurs when extended-release tablets containing 1 g of amoxicillin are taken at the start of a standardized meal.⁴ With this preparation, absorption of amoxicillin is decreased in the fasted state and absorption of clavulanate is decreased when taken with a high-fat meal.⁴

Distribution

Extent

Amoxicillin readily distributed into most tissues and fluids following oral administration,^{1 2 3 4} including lungs,^{5 17} bronchial secretions⁷² maxillary sinus secretions,⁷ bile,⁵ pleural fluid,^{5 17 53} peritoneal fluid,^{41 53 55} sputum,⁵ and middle ear fluid.^{1 3}

Animal studies indicate clavulanic acid well distributed into body tissues.^{1 2 3 4 5}

Only low amoxicillin concentrations attained in CSF.^{5 17 41 53}

Both amoxicillin and clavulanate potassium cross the placenta.^{5 7 19 53}

Both amoxicillin^{1 2 3 4 5 21} and clavulanate potassium distribute into human milk.^{5 7 21 53}

Plasma Protein Binding

Amoxicillin: 17–20%.^{1 2 3 4 5 6}

Clavulanic acid: 22–30%.^{1 2 3 4 41}

Elimination

Metabolism

Amoxicillin probably metabolized to some extent in the liver.⁵

Clavulanic acid may be extensively metabolized.^{5 17 40 62}

Elimination Route

Amoxicillin eliminated principally in urine^{1 2 3 4 5} by both glomerular filtration and tubular secretion;⁵ clavulanate eliminated by renal and nonrenal routes.^{4 5 62}

Approximately 50–80% of amoxicillin^{1 2 3 4 5} and 25–50% of clavulanic acid dose excreted unchanged in urine.^{1 2 3 4}

Half-life

Amoxicillin: 1–1.4 hours.^{1 2 3 4 39 41 57}

Clavulanic acid: 0.78–1.2 hours.^{1 2 3 4 17 39 41 50 57 62}

Special Populations

Serum concentrations and half-life of amoxicillin increased in patients with renal impairment.^{5 6 17 63 65} Half-life of clavulanic acid increased slightly in patients with renal impairment.⁵

Renal clearance may be delayed in neonates and young infants because of incompletely developed renal function.¹

Stability

Storage

Oral

For Suspension

≤25°C.^{1 3} Following reconstitution, refrigerate and discard after 10 days.^{1 3}

Tablets

Scored, film-coated, chewable, or extended-release tablets: ≤25°C.^{1 2 4}

Actions and Spectrum

• Amoxicillin/clavulanate is a fixed combination of amoxicillin trihydrate (a β-lactam antibacterial classified as an aminopenicillin) and the potassium salt of clavulanic acid (a β-lactamase inhibitor).^{17 35 41 61}

• Clavulanic acid synergistically expands activity of amoxicillin against β-lactamase-producing bacteria^{1 5 8 10 11 12 13 15 16 17 25 34 35 37 41 46 53 58 60 61} by irreversibly and competitively inhibiting β-lactamases.^{5 8 10 16 17 34 35 37 54 60 70}

• Usually bactericidal.^{10 11 13 15 17 35 53}

• Active against bacteria susceptible to amoxicillin alone and also active against many β-lactamase-producing bacteria resistant to amoxicillin alone.^{5 11 13 17 25 29 35 38 41 53 54 60 61}

• Gram-positive aerobes: Active in vitro and in clinical infections against Staphylococcus (including β-lactamase-producing strains),^{1 4 5 17 35 37 42 108} Streptococcus pneumoniae,^{1 4 17 35} S. pyogenes (group A β-hemolytic streptococci),⁵ and Enterococcus faecalis.⁵

• Gram-negative aerobes: Active in vitro and in clinical infections against β-lactamase-producing strains of Haemophilus influenzae,^{4 5 13 17 1 35 38} H. parainfluenzae,⁴ Klebsiella pneumoniae,^{1 4 5} Moraxella catarrhalis,^{4 17 35 59 108} and Escherichia coli.^{15 17 28 1 29 35} Also active in vitro against Eikenella corrodens¹⁰⁸ and Pasteurella multocida.^{108 110}

• Active in vitro and in clinical infections against Mycobacteria tuberculosis, including multidrug-resistant strains.^{24 26 31 66} Active in vitro against some anaerobic bacteria, including Peptostreptococcus,^{1 4 108} Bacteroides,^{1 4 10 15 17 25 35} Fusobacterium,^{1 4 108} and Prevotella.¹⁰⁸

• Resistance reported in some gram-negative bacteria (e.g., Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa, some strains of E. coli).^{5 17 35 37 41 42 49 53}

Advice to Patients

• Advise patients that antibacterials (including amoxicillin/clavulanate) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).^{1 2 3 4}

• Importance of taking each dose with a meal or snack to decrease the risk of adverse GI effects.^{1 2 3 4}

• Importance of contacting clinician if diarrhea occurs that is severe or lasts longer than 2 or 3 days.^{1 2 3 4}

• Importance of completing the entire prescribed course of treatment, even if feeling better after a few days.^{1 2 3 4}

• Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with amoxicillin/clavulanate or other antibacterials in the future.^{1 2 3 4}

• Importance of keeping oral suspension refrigerated; shaking the suspension well prior to withdrawal of each dose; using a dosing spoon or medicine dropper and rinsing it well after each use; and discarding any unused suspension.^{1 3}

• Advise individuals with phenylketonuria and other individuals who must restrict their intake of phenylalanine that 200- and 400-mg chewable tablets and oral suspensions containing 200, 400, or 600 mg of amoxicillin/5 mL contain aspartame (NutraSweet), which is metabolized in the GI tract to phenylalanine.^{1 3}

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{1 2 3 4}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 2 3 4}

• Importance of advising patients of other important precautionary information.^{1 2 3 4} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Frequently asked questions

• Amoxicillin rash: When should I be concerned?
• What are the best antibiotics for pneumonia?
• Does AMOX-CLAV treat an abcessed tooth?
• Can Amox-Clav tablets be crushed?

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