VA Class:AM111

AHFS Class:

• Aminopenicillins 8:12.16.08

Generic Name(s):

• Amoxicillin and Clavulanate Potassium

• Amoxicillin

• Clavulanate Potassium

Chemical Name:

• [2 R -(2α,3 Z ,5α)]-3-(2-Hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic acid monopotassium salt mixt. with [2 S -[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

• [2 S -[2α,5α,6β( S *)]]-6-[[Amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid trihydrate

• [2 R -(2α,3 Z ,5α)]-3-(2-Hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0] heptane-2-carboxylic acid monopotassium salt

Molecular Formula:

• C₁₆H₁₉N₃O₅S•3H₂O C₈H₈KNO₅

Amoxicillin and clavulanate potassium (amoxicillin/clavulanate) is a fixed combination of amoxicillin trihydrate (an aminopenicillin antibiotic) and the potassium salt of clavulanic acid (a β-lactamase inhibitor);68,69,318,1437,1446,1448,1457 clavulanic acid synergistically expands amoxicillin's spectrum of activity against many strains of β-lactamase-producing bacteria.143,311,312,313,314,316,317,318,1298,1437,1445,1446,1448,1449,1457,1467,1486,1498,1501

The fixed combination of amoxicillin and clavulanate potassium (amoxicillin/clavulanate) is used orally for the treatment of lower respiratory tract infections,318,1437,1457,1475,1486,1488 otitis media,318,1437,1457,1475,1656,1659,2180,2310,2361,2362,2364,2398,2430,2432,2529 sinusitis,1437,1475,2529 skin and skin structure infections,318,1437,1444,1457,1459,1475,1482,1488 and urinary tract infections315,318,1312,1313,1437,1443,1457,1460,1461,1462,1466,1468,1470,1474,1475,1477,1486,1488,1500,2254 caused by susceptible organisms.

Amoxicillin/clavulanate is used principally for the treatment of infections caused by susceptible β-lactamase-producing strains of Moraxella catarrhalis , Escherichia coli , Haemophilus influenzae , Klebsiella , and Staphylococcus aureus .1437,1486,2529 Although amoxicillin/clavulanate also may be effective in the treatment of infections caused by non-β-lactamase-producing organisms susceptible to amoxicillin alone,1437 most clinicians state that an aminopenicillin used alone is preferred to the combination drug for the treatment of these infections and that amoxicillin/clavulanate should be reserved for use in the treatment of infections caused by, or suspected of being caused by, β-lactamase-producing organisms when an aminopenicillin alone would be ineffective.1457,1512,1513

Prior to initiation of therapy with amoxicillin/clavulanate, appropriate specimens should be obtained for identification of the causative organism and in vitro susceptibility tests.1437,2529 Amoxicillin/clavulanate may be started pending results of susceptibility tests if the infection is believed to be caused by β-lactamase-producing bacteria susceptible to the drug,1473 but should be discontinued if the organism is found to be resistant to the drug.1473,2529 If the infection is found to be caused by non-β-lactamase-producing organisms susceptible to aminopenicillins, some clinicians suggest that therapy generally should be changed to an aminopenicillin alone, unless this is impractical.1513

Gram-positive Aerobic Bacterial Infections

Amoxicillin/clavulanate has been effective for the treatment of abscesses, cellulitis, and impetigo caused by susceptible penicillinase-producing and nonpenicillinase-producing Staphylococcus aureus and S. epidermidis , Streptococcus pyogenes (group A β-hemolytic streptococci), or Corynebacterium .1444,1459 Results of several controlled studies indicate that amoxicillin/clavulanate is as effective as cefaclor in the treatment of these infections.1444,1459 However, natural penicillins are generally the drugs of choice for the treatment of infections caused by nonpenicillinase-producing staphylococci or group A β-hemolytic streptococci866,867,906,1089,1513,1732,2318,2343 and penicillinase-resistant penicillins are generally the drugs of choice for the treatment of infections caused by susceptible penicillinase-producing staphylococci.61,64,67,80,580,865,906,942,943,1172,1512,1513,1732

Amoxicillin/clavulanate should not be used in the treatment of infections caused by methicillin-resistant staphylococci, even though results of in vitro susceptibility tests may indicate that the organism is susceptible to the drug.1473,1512

Gram-negative Aerobic Bacterial Infections

Haemophilus Infections

Amoxicillin/clavulanate generally has been effective for the treatment of otitis media or upper and lower respiratory tract infections such as bronchopneumonia,2529 sinusitis,2529 and acute exacerbations of chronic bronchitis caused by susceptible H. influenzae .318,1437,1486,1511,1656,1659,1660 Amoxicillin/clavulanate usually is the drug of choice for empiric anti-infective therapy of otitis media and sinusitis in communities with a high incidence of ampicillin-resistant H. influenzae or M. catarrhalis 1437,1656,1657,1659,1664 and for infections that fail to respond to other regimens.1656,1661,1664 (See Uses: Acute Otitis Media.)

Moraxella catarrhalis Infections

Infections caused by β-lactamase-producing M. catarrhalis have been reported with increasing frequency.1657,1658,1660,1661,1662,1663,1696 This organism recently has been recognized as a common cause of otitis media and maxillary sinusitis in children and of bronchitis and pneumonia in adults, especially those with chronic lung disease.1657,1658,1660,1661,1662,1663,1664,1696 Rarely, septicemia, endocarditis, urethritis, meningitis, neonatal ophthalmia, and conjunctivitis caused by M. catarrhalis have been reported.1657,1658,1661,1662,1696 Amoxicillin/clavulanate generally has been effective when used in the treatment of upper and lower respiratory tract infections caused by M. catarrhalis ,318,1437,1465,1486,1499,1657,1658,2529 and many clinicians consider it a drug of choice for infections caused by the organism.1732,2337,2343

Amoxicillin/clavulanate generally has been effective when used for the treatment of acute otitis media or acute maxillary sinusitis caused by M. catarrhalis .1656,1657,1659,1664,2529 In several controlled studies, amoxicillin/clavulanate was more effective than cefaclor for the empiric treatment of acute otitis media in children 2 months to 12 years of age.1656,1659 Although adverse GI effects occurred more frequently with amoxicillin/clavulanate than with cefaclor,165,1659 amoxicillin/clavulanate appears to be more active than cefaclor against β-lactamase-producing M. catarrhalis .1656,1657,1659,1661 Some clinicians suggest that amoxicillin/clavulanate is a drug of choice for the empiric treatment of otitis media and sinusitis in communities with a high incidence of β-lactamase-producing M. catarrhalis .1656,1657,1659,1664

Gonorrhea

Amoxicillin/clavulanate has been used with some success for the treatment of uncomplicated gonorrhea† caused by penicillinase-producing strains of N. gonorrhoeae (PPNG) or nonpenicillinase-producing strains of the organism.318,1457,1478,1481,1486,1495,1496,1497,1504,1505,1510 Regimens consisting of a single oral dose of amoxicillin (3 g) and clavulanic acid (125-500 mg) with or without oral probenecid (1 g) have been effective in some cases for the treatment of uncomplicated gonorrhea caused by PPNG or nonpenicillinase-producing N. gonorrhoeae .318,1457,1478,1481,1486,1495,1505 However, CDC has not recommended use of penicillins for the treatment of gonococcal infections for over 30 years because of the widespread prevalence of PPNG resistant to penicillins.265,344 Ceftriaxone is the drug of choice for the treatment of gonococcal infections.344

Urinary Tract Infections

Amoxicillin/clavulanate has been effective for the treatment of uncomplicated or complicated urinary tract infections (UTIs) caused by susceptible organisms, including E. coli , Klebsiella , Enterobacter , or P. mirabilis .315,318,1312,1313,1437,1443,1457,1460,1461,1462,1466,1468,1470,1472,1474,1475,1477,1486,1488,1500 Because amoxicillin/clavulanate is active in vitro against many urinary pathogens resistant to amoxicillin or ampicillin alone, some clinicians suggest that the combination drug may be preferred over ampicillin or amoxicillin alone for the initial treatment of UTIs;1312,1443,1461,1474,1500 however, further studies are needed to evaluate the relative efficacy of amoxicillin/clavulanate and other anti-infectives used for the treatment of UTIs.1486,1511

Other Gram-negative Aerobic Bacterial Infections

Amoxicillin/clavulanate has been used in the treatment of infections caused by Eikenella corrodens † or Pasteurella multocida †.1732

Anaerobic and Mixed Aerobic-Anaerobic Bacterial Infections

Amoxicillin/clavulanate has been used with some success for the treatment of anaerobic and mixed aerobic-anaerobic bacterial infections† including intra-abdominal and gynecologic infections such as endometritis, salpingitis, pelvic cellulitis, and acute pelvic inflammatory disease.1457,1467,1482 Although oral amoxicillin/clavulanate has been effective in the treatment of these infections, including infections caused by Bacteroides fragilis ,1467,1482 further study is needed to evaluate efficacy of the drug in the treatment of anaerobic and mixed aerobic-anaerobic bacterial infections and to determine if serum and tissue concentrations of amoxicillin and clavulanic acid obtained following oral administration of the drug are adequate for the treatment of these infections.1486

Acute Otitis Media

Amoxicillin/clavulanate is used for the treatment of acute otitis media (AOM) caused by S. pneumoniae †, H. influenzae (including β-lactamase-producing strains), or M. catarrhalis (including β-lactamase-producing strains).1437,1656,1659,2180,2310,2361,2362,2364,2389,2398,2418,2429,2430,2432,2434,2450,2550 Amoxicillin usually is considered the drug of first choice for initial treatment of AOM, unless the patient has severe illness (moderate to severe otalgia or fever 39°C or higher)2550 or the infection is suspected of being caused by β-lactamase-producing bacteria resistant to the drug, in which case amoxicillin/clavulanate is recommended for initial treatment.1656,1657,1661,1664,2180,2181,2250,2310,2343,2361,2362,2398,2400,2433,2446,2479,2482,2550 The American Academy of Pediatrics (AAP), American Academy of Family Physicians (AAFP), CDC, and others state that, despite the increasing prevalence of multidrug-resistant S. pneumoniae and presence of β-lactamase-producing H. influenzae or M. catarrhalis in many communities, amoxicillin remains the anti-infective of first choice for treatment of uncomplicated AOM since it is highly effective, has a narrow spectrum of activity, is well distributed into middle ear fluid, is well tolerated, has an acceptable taste, and is inexpensive.2178,2314,2343,2398,2403,2404,2413,2414,2433,2476,2479,2482,2550 Amoxicillin (when given in a dosage of 80-90 mg/kg daily) usually is effective in the treatment of AOM caused by S. pneumoniae , including infections involving strains with intermediate resistance to penicillins, and also usually is effective in the treatment of AOM caused by most strains of H. influenzae .2398,2403,2433,2475,2550

Alternatives for initial treatment of AOM in patients with a history of non-type I hypersensitivity reactions to penicillins include oral cephalosporins (cefdinir, cefpodoxime, cefuroxime axetil) or parenteral ceftriaxone.2343,2361,2398,2400,2414,2441,2550 Alternatives for patients with type I penicillin hypersensitivity include oral macrolides (azithromycin, clarithromycin, fixed combination of erythromycin and sulfisoxazole), oral co-trimoxazole, or oral clindamycin (especially in those with infections known or presumed to be caused by penicillin-resistant S. pneumoniae) .2550

Amoxicillin/clavulanate (given in a dosage of 80-90 mg/kg of amoxicillin and 6.4 mg/kg of clavulanate daily) is the drug of choice for retreatment in patients who fail to respond to an initial amoxicillin regimen (given in a dosage of 80-90 mg/kg daily).2314,2343,2361,2398,2400,2414,2441,2550 The AAP and AAFP recommend that amoxicillin/clavulanate be substituted if there has been no response to amoxicillin within 48-72 hours.2550 A 3-day regimen of IM or IV ceftriaxone also is recommended for retreatment, especially in those who have severe illness (moderate to severe otalgia or fever 39°C or higher)2550 and in those who are vomiting or cannot otherwise tolerate an oral regimen.2550

Pharyngitis and Tonsillitis

Although not considered a drug of choice for the treatment of pharyngitis and tonsillitis caused by S. pyogenes † (group A β-hemolytic streptococci), amoxicillin/clavulanate is recommended as one of several possible alternatives for the treatment of symptomatic patients who have multiple, recurrent episodes of pharyngitis known to caused by S. pyogenes †.2318,2343 Natural penicillins (i.e., 10 days of oral penicillin V or a single IM dose of penicillin G benzathine) is the treatment of choice for streptococcal pharyngitis and tonsillitis,2235,2318,2343 although oral amoxicillin often is used instead of penicillin V in small children because of a more acceptable taste.2318,2343

If there is recurrence of signs and symptoms of pharyngitis shortly after the initial recommended regimen is completed (i.e., within a few weeks) and presence of S. pyogenes is detected, retreatment with the original regimen or another regimen of choice is indicated; if compliance with a 10-day oral regimen is a concern, IM penicillin G benzathine should be used for retreatment.2318,2343 Some clinicians suggest use of an alternative agent (e.g., Amoxicillin/clavulanate, clindamycin, macrolide) for retreatment.2343 However, if there are multiple, recurrent episodes of symptomatic pharyngitis within a period of months to years, it may be difficult to determine whether these are true episodes of S. pyogenes infection or whether the patient is a long-term streptococcal pharyngeal carrier who is experiencing repeated episodes of nonstreptococcal pharyngitis (e.g., viral pharyngitis) in whom treatment is not usually indicated.2318,2343 Continuous anti-infective prophylaxis (secondary prophylaxis) to prevent the recurrence of streptococcal pharyngitis is not recommended in these circumstances, unless the patient has a history of rheumatic fever.2318,2343 Instead, use of an alternative regimen is recommended by some clinicians.2318 Although there are no controlled clinical studies evaluating efficacy, the IDSA suggests that symptomatic individuals with multiple, recurrent episodes of documented S. pyogenes pharyngitis receive a regimen of oral amoxicillin clavulanate, oral clindamycin, or IM penicillin G benzathine (with or without oral rifampin).2318

For additional information on treatment ofS. pyogenes pharyngitis, see Pharyngitis and Tonsillitis under Uses in the Natural Penicillins General Statement 8:12.16.04.

Reconstitution and Administration

The fixed combination of amoxicillin and clavulanate potassium (amoxicillin/clavulanate) is administered orally.1437,2529 Chewable tablets should be thoroughly chewed before swallowing.1576 Amoxicillin/clavulanate has also been given IV,1440,1485,1490 but a parenteral dosage form of the drug is not available in the US.

Because GI absorption of amoxicillin and clavulanate potassium is not affected by food following oral administration of conventional preparations of amoxicillin/clavulanate, these preparations may be administered orally without regard to meals.1437 However, administration of oral amoxicillin/clavulanate with meals may minimize adverse GI effects.318,1449,1457,1469,1486 Extended-release tablets of amoxicillin/clavulanate should be administered at the beginning of a meal to enhance GI absorption of amoxicillin and clavulanate and to minimize adverse GI effects; amoxicillin absorption from extended-release tablets is decreased when administered in a fasting state, and clavulanate absorption is decreased when these tablets are administered with a high-fat meal.2529

Amoxicillin/clavulanate powder for oral suspension should be reconstituted at the time of dispensing by adding the amount of water specified on the bottle to provide a suspension containing 125 mg of amoxicillin and 31.25 mg of clavulanic acid per 5 mL, 200 mg of amoxicillin and 28.5 mg of clavulanic acid per 5 mL, 250 mg of amoxicillin and 62.5 mg of clavulanic acid per 5 mL, or 600 mg of amoxicillin and 42.9 mg of clavulanic acid per 5 mL.1437 After tapping the bottle to thoroughly loosen the powder for oral suspension, the water should be added to the powder in 2 portions and the suspension agitated well after each addition.1437 The suspension should be agitated well just prior to administration of each dose.1437

Dosage

Dosage of amoxicillin/clavulanate generally is expressed in terms of the amoxicillin content of the fixed combination.1437 Although commercially available amoxicillin/clavulanate contains amoxicillin as the trihydrate and/or the sodium salt and clavulanic acid as the potassium salt, potency of amoxicillin is calculated on the anhydrous basis and potency of clavulanate potassium is expressed in terms of clavulanic acid.1437

Amoxicillin/clavulanate is commercially available for oral administration as a powder for oral suspension containing a 4:1, 7:1, or 14:1 ratio of amoxicillin to clavulanic acid; as chewable tablets containing a 4:1 or 7:1 ratio of the drugs; as film-coated tablets containing a 2:1 or 4:1 ratio of the drugs; as scored tablets containing a 7:1 ratio of the drugs; and as extended-release tablets containing a 16:1 ratio of the drugs.1437,2529

Commercially available amoxicillin/clavulanate powders for oral suspension should not be considered interchangeable since they contain different amounts of clavulanic acid. 2364 The powder for oral suspension containing 600 mg of amoxicillin and 42.9 mg of clavulanic acid per 5 mL (Augmentin ES-600^®) is indicated only for the treatment of persistent or recurrent acute otitis media (AOM) in certain pediatric patients 3 months to 12 years of a safety and efficacy of this preparation in younger children or in adolescents or adults have not been established.2364 Because commercially available amoxicillin/clavulanate film-coated tablets containing 250 mg of amoxicillin contain 125 mg of clavulanic acid and commercially available chewable tablets containing 250 mg of amoxicillin contain 62.5 mg of clavulanic acid, these preparations should not be considered interchangeable.1437 In addition, since the 250- and 500-mg film-coated tablets of the drug both contain the same amount of clavulanic acid, two 250-mg film-coated tablets are not equivalent to one 500-mg film-coated tablet.1437 Because extended-release tablets of amoxicillin/clavulanate contain different ratios of the drugs, the extended-release tablets are not equivalent to conventional or chewable tablets of the drug.2529

Children weighing less than 40 kg should not receive the 250-mg film-coated tablets since this formulation contains a higher dose of clavulanic acid.1437 (See Dosage: Pediatric Dosage, under Dosage and Administration.) Safety and efficacy of the extended-release tablets have not been established in pediatric patients younger than 16 years of age.2529

Adult Dosage

The usual adult oral dosage of amoxicillin/clavulanate is one 250-mg film-coated tablet (containing 250 mg of amoxicillin and 125 mg of clavulanic acid) every 8 hours or one 500-mg film-coated tablet (containing 500 mg of amoxicillin and 125 mg of clavulanic acid) every 12 hours.1437 For more severe infections and infections of the respiratory tract, the usual adult oral dosage is one 500-mg film-coated tablet (containing 500 mg of amoxicillin and 125 mg of clavulanic acid) every 8 hours or one 875-mg scored tablet (containing 875 mg of amoxicillin and 125 mg of clavulanic acid) every 12 hours.1437 Alternatively, adults who have difficulty swallowing tablets may receive the oral suspension containing 125 or 250 mg of amoxicillin/5 mL instead of the 500-mg film-coated tablet or may receive the oral suspension containing 200 or 400 mg of amoxicillin/5 mL instead of the 875-mg scored tablet.1437

The usual oral dosage of amoxicillin/clavulanate extended-release tablets for the treatment of acute bacterial sinusitis in patients 16 years of age and older is 2 tablets (containing 1 g of amoxicillin and 62.5 mg of clavulanic acid in each tablet) every 12 hours for 10 days.2529 The usual oral dosage of the extended-release tablets for the treatment of community-acquired pneumonia (CAP) in patients 16 years of age and older is 2 tablets (containing 1 g of amoxicillin and 62.5 mg of clavulanic acid in each tablet) every 12 hours for 7-10 days.2529 Dosage adjustment for extended-release tablets of the combination based solely on age is not necessary in geriatric patients.2529

Pediatric Dosage

Children weighing 40 kg or more may receive the usual adult oral dosage of amoxicillin/clavulanate.1437

The usual dosage of amoxicillin/clavulanate in neonates and infants younger than 12 weeks of age is 30 mg/kg of amoxicillin daily given in divided doses every 12 hours.1437 Because experience with the oral suspension containing 200 mg of amoxicillin/5 mL is limited in this age group, the manufacturer recommends that the oral suspension containing 125 mg of amoxicillin/5 mL be used in neonates and infants younger than 12 weeks of age.1437

For the treatment of sinusitis, lower respiratory tract infections, and more severe infections in pediatric patients 12 weeks of age and older, the usual dosage of amoxicillin/clavulanate is 45 mg/kg of amoxicillin daily in divided doses every 12 hours administered as the oral suspension containing 200 or 400 mg of amoxicillin/5 mL or as chewable tablets containing 200 or 400 mg of amoxicillin.1437 Alternatively, these infections in this age group can be treated with a dosage of 40 mg/kg of amoxicillin daily in divided doses every 8 hours administered as the oral suspension containing 125 or 250 mg of amoxicillin/5 mL or as chewable tablets containing 125 or 250 mg of amoxicillin.1437

For the treatment of less severe infections in pediatric patients 12 weeks of age or older, the usual dosage of amoxicillin/clavulanate is 25 mg/kg of amoxicillin daily in divided doses every 12 hours administered as the oral suspension containing 200 or 400 mg of amoxicillin/5 mL or as chewable tablets containing 200 or 400 mg of amoxicillin.1437 Alternatively, less severe infections in this age group can be treated with a dosage of 20 mg/kg of amoxicillin daily in divided doses every 8 hours administered as the oral suspension containing 125 or 250 mg of amoxicillin/5 mL or as chewable tablets containing 125 or 250 mg of amoxicillin.1437

Acute Otitis Media

For the treatment of acute otitis media (AOM) in pediatric patients, the recommended dosage of amoxicillin/clavulanate is 90 mg/kg of amoxicillin and 6.4 mg/kg of clavulanate daily given in 2 divided doses†.2364,2398,2414,2475,2495,2550 The drug usually is given for 10 days,1437,2398,2400,2414,2475,2479 but the optimal duration of therapy is uncertain.2550 The American Academy of Pediatrics (AAP) and American Academy of Family Physicians (AAFP) recommend that a 10-day regimen be used for treatment of AOM in children younger than 6 years of age and in those with severe disease, but that a duration of 5-7 days may be appropriate in those 6 years of age or older with mild to moderate AOM.2550

Although amoxicillin/clavulanate can be administered in a dosage of 40-45 mg/kg of amoxicillin daily given in 2 or 3 divided doses for 10 days for the treatment of AOM,1437,2398,2479 the AAP, AAFP, US Centers for Disease Control and Prevention (CDC), and others recommend use of the higher dosage.2343,2361,2398,2400,2414,2441,2550 The higher dosage is especially important in patients with AOM known or suspected of being caused by Streptococcus pneumoniae with reduced susceptibility to penicillins, patients with primary treatment failure or persistent or recurrent AOM after treatment with amoxicillin, and in patients who have received anti-infective therapy within the previous few months.2343,2361,2398,2400,2414,2441

When amoxicillin/clavulanate is administered in the higher dosage for the treatment of AOM in pediatric patients, commercially available formulations containing a 7:1 or 14:1 ratio of amoxicillin to clavulanic acid should be used since these formulations provide a lower daily dosage of clavulanate potassium and minimize the risk of adverse GI effects associated with the clavulanate potassium component.2398,2494,2495 When the oral suspension containing 600 mg of amoxicillin and 42.9 mg of clavulanic acid per 5 mL is used for the treatment of persistent or recurrent AOM in pediatric patients weighing less than 40 kg, the usual dosage is 90 mg/kg of amoxicillin daily given in divided doses every 12 hours for 10 days.2364

Pharyngitis and Tonsillitis

If amoxicillin/clavulanate is used for the treatment of symptomatic patients who have multiple, recurrent episodes of pharyngitis known to be caused by Streptococcus pyogenes † (group A β-hemolytic streptococci) (see Uses: Pharyngitis and Tonsillitis), the Infectious Diseases Society of America (IDSA) recommends that children receive 40 mg/kg of amoxicillin daily (maximum 750 mg daily) given in 3 equally divided doses for 10 days.2318 Adults should receive amoxicillin/clavulanate in a dosage of 500 mg of amoxicillin twice daily for 10 days; the IDSA states that this dosage has not been specifically studied in adults and was extrapolated from the pediatric dosage.2318

Dosage in Renal and Hepatic Impairment

In patients with renal impairment, doses and/or frequency of administration of amoxicillin/clavulanate should be modified in response to the degree of renal impairment.318,1508,1554 Some clinicians suggest that modification of usual dosage is unnecessary in adults with creatinine clearances greater than 30 mL/minute.1508 These clinicians recommend that adults with creatinine clearances of 15-30 mL/minute receive the usual dose of conventional preparations of the drug every 12-18 hours, adults with creatinine clearances of 5-15 mL/minute receive the usual dose every 20-36 hours, and adults with creatinine clearances less than 5 mL/minute receive the usual dose every 48 hours.1508 However, other clinicians suggest that use of amoxicillin/clavulanate should be avoided in patients with creatinine clearances less than 30 mL/minute until more data are available on use of the drug in these patients.1513

Some clinicians suggest that adults undergoing hemodialysis receive a 500-mg tablet containing 500 mg of amoxicillin and 125 mg of clavulanic acid halfway through each dialysis period and an additional 500-mg tablet after each dialysis period.1508

The pharmacokinetics of extended-release tablets of amoxicillin/clavulanate have not been studied in patients with renal impairment, and the manufacturer states that this preparation is contraindicated in patients with severe impairment (creatinine clearance less than 30 mL/minute and those undergoing hemodialysis).2529 The extended-release tablets should be dosed cautiously in patients with hepatic impairment and liver function should be monitored at frequent intervals.2529

Adverse Effects

Adverse effects reported with the fixed combination of amoxicillin and clavulanate potassium (amoxicillin/clavulanate) are generally dose related and similar to those reported with amoxicillin alone.318,1437,1457,1458,1486 For information on adverse effects reported with amoxicillin and other aminopenicillins, see Cautions in the Aminopenicillins General Statement 8:12.16.08.

With the exception of adverse GI effects, which have been reported more frequently with amoxicillin/clavulanate than with amoxicillin alone, the frequency and severity of adverse effects reported with the fixed-combination are generally similar to those reported with amoxicillin alone.318,1458,1486 The manufacturers state that adverse effects reported with oral amoxicillin/clavulanate are generally mild and transient and have required discontinuance of therapy in less than 3% of patients receiving the drug.1437

GI effects are the most frequent adverse reactions to oral amoxicillin/clavulanate.318,1312,1437,1457,1469,1475,1486,1488 Diarrhea or loose stools318,1312,1437,1443,1444,1457,1459,1461,1470,1475,1488,1500 has been reported in about 9% of patients receiving the drug,318,1437,1457 and nausea1312,1437,1443,1459,1475,1482,1486,1488 and vomiting1312,1437,1443,1459,1475,1486,1488 have been reported in 1-5% of patients.1437,1486 Abdominal discomfort,1437,1486,1500 anorexia,1486 and flatulence,1437 dyspepsia,1437 gastritis,1437 stomatitis,1437 glossitis,1437 black or hairy tongue,1437 and enterocolitis1437 also have been reported. The frequency of nausea and vomiting appears to be related to the dose of clavulanic acid since these effects have been reported in up to 40% of patients when a 250-mg dose of clavulanic acid rather than a 125-mg dose was used in conjunction with amoxicillin.1448,1457 Administration of oral amoxicillin/clavulanate with meals reportedly decreases the frequency and severity of adverse GI effects,318,1449,1457,1469,1486,2529 and therefore patients should be advised to take the drug with a meal or snack.2529

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly known as Clostridium difficile ).302 C. difficile -associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis; CDAD) may occur during or following discontinuance of amoxicillin/clavulanate.1437 C. difficile produces toxins A and B which contribute to development of CDAD.302 If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued as soon as possible.302 Patients should be managed with appropriate anti-infective therapy directed against C. difficile (e.g., fidaxomicin, vancomycin, metronidazole), supportive therapy (e.g., fluid and electrolyte management, protein supplementation), and surgical evaluation as clinically indicated.302,1437

Rash1437,1467,1475,1477,1482,1488 and urticaria1437 have been reported in approximately 3% of patients receiving amoxicillin/clavulanate.1437 Other adverse effects that have been reported in 1% or less of patients receiving the drug include candidal vaginitis,1312,1437,1443,1461,1470,1486,1480 dizziness,1486,1500 headache,1437,1488 fever,1486 and slight thrombocytosis.1437

Moderate increases in serum concentrations of AST (SGOT) and/or ALT (SGPT),1437,1486 alkaline phosphatase, and/or bilirubin have been reported in patients receiving amoxicillin/clavulanate.1437 Hepatic dysfunction has been reported most frequently in geriatric patients, males, or in patients receiving prolonged therapy with the drug.1437 Histologic findings on liver biopsies have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes.1437 The onset of manifestations of hepatic dysfunction may occur during or several weeks following discontinuance of amoxicillin/clavulanate therapy and usually is reversible.1437 However, fatal cholestatic hepatitis has been reported rarely;1437,1814 these generally have been cases associated with serious underlying diseases or concomitant drug therapy.1437

Although not reported to date with amoxicillin/clavulanate,1515 positive direct antiglobulin (Coombs') test results have been reported in patients who received therapy with ticarcillin and clavulanic acid.1516 In one study in immunocompromised patients, positive direct antiglobulin test results occurred during 44% of the courses of therapy with ticarcillin and clavulanic acid and concomitant tobramycin.1516 Positive reactions occurred within 48 hours after initiation of therapy and reverted to negative within 2-4 months after completion of therapy.1516 These reactions appear to result from nonimmunologic adsorption of proteins onto erythrocytes in the presence of clavulanic acid; this nonimmunologic mechanism is similar to that observed with cephalosporins.1516 Nonimmunologic adsorption of proteins onto erythrocyte membranes and positive direct antiglobulin test results also occurred in vitro when erythrocytes obtained from healthy individuals were exposed to clavulanic acid; however, exposure of erythrocytes to ticarcillin alone under various conditions did not result in a positive reaction.1516

Precautions and Contraindications

Amoxicillin/clavulanate shares the toxic potentials of the penicillins, including the risk of hypersensitivity reactions, and the usual precautions of penicillin therapy should be observed.1437 Prior to initiation of therapy with amoxicillin/clavulanate, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other drugs.1437 There is clinical and laboratory evidence of partial cross-allergenicity among penicillins and other β-lactam antibiotics including cephalosporins and cephamycins.781,1437

Renal, hepatic, and hematologic function should be evaluated periodically during prolonged therapy with amoxicillin/clavulanate.1437

Because C. difficile -associated diarrhea and colitis has been reported with the use of nearly all anti-infective agents, including amoxicillin/clavulanate, it should be considered in the differential diagnosis of patients who develop diarrhea during or after amoxicillin/clavulanate therapy.302,1437 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.302 Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued; however, it is important to contact a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.302

Because a high percentage of patients with infectious mononucleosis have developed rash during therapy with aminopenicillins,812,815,1437 amoxicillin/clavulanate should not be used in patients with the disease.1437 amoxicillin/clavulanate is contraindicated in patients who are hypersensitive to any penicillin.1437

Commercially available amoxicillin/clavulanate chewable tablets containing 200 or 400 mg of amoxicillin and amoxicillin/clavulanate oral suspension containing 200 400, or 600 mg of amoxicillin per 5 mL contain aspartame, which is metabolized in the GI tract to phenylalanine following oral administration.1437,2364 Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned1649,1650,1651,1652,1653 that each 200- or 400-mg chewable tablet of amoxicillin/clavulanate provides 2.1 or 4.2 mg of phenylalanine, respectively, and each 5 mL of amoxicillin/clavulanate oral suspension containing 200, 400, or 600 mg of amoxicillin provides 7 mg of phenylalanine.1437,2364 While these preparations should not be used in patients with phenylketonuria, other commercially available preparations of amoxicillin/clavulanate do not contain aspartame.1437

For information on the potassium and sodium content of various amoxicillin/clavulanate preparations, see Chemistry and Stability: Chemistry.

For a more complete discussion of these and other precautions associated with the use of amoxicillin, see Cautions: Precautions and Contraindications in the Aminopenicillins General Statement 8:12.16.08.

Pediatric Precautions

Adverse effects reported in pediatric patients receiving amoxicillin/clavulanate are similar to those reported in adults.1437

In a clinical study in pediatric patients 2 months to 12 years of age with acute otitis media who received amoxicillin/clavulanate oral suspension, the incidence of diarrhea was lower in those who received the drug in a dosage of 45 mg/kg of amoxicillin daily in divided doses every 12 hours than in those who received the drug in a dosage of 40 mg/kg of amoxicillin daily in divided doses every 8 hours.1437 Diarrhea occurred in 14.3% of those receiving the twice-daily regimen and 34.3% of those receiving the 3-times-daily regimen, and 3.1% of those receiving the twice-daily regimen and 7.6% of those receiving the 3-times-daily regimen had severe diarrhea or were withdrawn from the study with diarrhea.1437 It is not known whether a similar difference in the incidence of diarrhea occurs when amoxicillin/clavulanate chewable tablets are administered in a twice-daily or 3-times-daily regimen.1437

Safety and efficacy of the extended-release tablets of amoxicillin/clavulanate have not been established in pediatric patients younger than 16 years of age.2529

Mutagenicity and Carcinogenicity

Studies have not been performed to date to evaluate the mutagenic or carcinogenic potential of amoxicillin/clavulanate.1437

Pregnancy, Fertility, and Lactation

Pregnancy

Safe use of amoxicillin/clavulanate during pregnancy has not been definitely established.1437 There are no adequate or controlled studies using amoxicillin/clavulanate in pregnant women, and the drug should be used during pregnancy only when clearly needed.1437

Aminopenicillins are generally poorly absorbed when given orally during labor.1437 Although the mechanism is unclear and the clinical importance has not been determined to date, studies using oral ampicillin indicate that, when administered during pregnancy, the drug interferes with metabolism and enterohepatic circulation of steroids resulting in decreased urinary concentrations of estrogen metabolites.1437 The manufacturers state that this effect could also occur with amoxicillin/clavulanate.1437 IV administration of ampicillin to guinea pigs has decreased uterine tone and decreased the frequency, height, and duration of uterine contractions; however, it is not known whether use of amoxicillin/clavulanate in humans during labor or delivery could have any immediate or delayed adverse effects on the fetus, prolong the duration of labor, or increase the likelihood of forceps delivery, other obstetrical intervention, or resuscitation of the neonate.1437

Fertility

Reproduction studies in mice and rats using doses up to 10 times the usual human dose have not revealed evidence of impaired fertility or harm to the fetus.1437

Lactation

Because amoxicillin and clavulanic acid are distributed into milk, amoxicillin/clavulanate should be used with caution in nursing women.1437,1514

Allopurinol

Because an increased incidence of rash reportedly occurs in patients with hyperuricemia who are receiving allopurinol and concomitant amoxicillin or ampicillin compared with those receiving amoxicillin, ampicillin, or allopurinol alone,712,774,812,829,1153 some clinicians suggest that concomitant use of the drugs should be avoided if possible.712 The manufacturers state that there are no data to date on concomitant administration of allopurinol and amoxicillin/clavulanate.1437

Probenecid

Oral probenecid administered shortly before or concomitantly with the fixed combination of amoxicillin and clavulanate potassium (amoxicillin/clavulanate) slows the rate of renal tubular secretion of amoxicillin and produces higher and prolonged serum concentrations of amoxicillin.1437,1485,1491 However, concomitant administration of probenecid with amoxicillin/clavulanate does not affect the area under the serum concentration-time curve (AUC), half-life, or peak serum concentration of clavulanic acid.1437,1485,1491

Laboratory Test Interferences

Ampicillin reportedly interferes with urinary glucose determinations using cupric sulfate (e.g., Benedict's solution, Clinitest^®),759,1437 but does not affect glucose oxidase methods (e.g., Clinistix^®, Tes-Tape^®).759 Since this laboratory test interference could also occur with amoxicillin, glucose oxidase methods should be used when urinary glucose determinations are indicated in patients receiving the fixed combination of amoxicillin and clavulanate potassium (amoxicillin/clavulanate).1437

Although not reported to date with amoxicillin/clavulanate, positive direct antiglobulin (Coombs') test results have been reported in patients who received ticarcillin and clavulanic acid and appear to be caused by clavulanic acid.1516 (See Cautions: Adverse Effects.) This reaction may interfere with hematologic studies or transfusion cross-matching procedures and should be considered in patients receiving amoxicillin/clavulanate.1516

Mechanism of Action

The fixed combination of amoxicillin and clavulanate potassium (amoxicillin/clavulanate) usually is bactericidal in action.311,312,314,316,318,1446,1486 Concurrent administration of clavulanic acid does not alter the mechanism of action of amoxicillin.1446,1498 However, because clavulanic acid has a high affinity for and binds to certain β-lactamases that generally inactivate amoxicillin by hydrolyzing its β-lactam ring, concurrent administration of the drug with amoxicillin results in a synergistic bactericidal effect which expands the spectrum of activity of amoxicillin against many strains of β-lactamase-producing bacteria that are resistant to amoxicillin alone.143,311,312,314,316,318,1311,1446,1449,1498 For information on the mechanism of action of penicillins, see Mechanism of Action in the Natural Penicillins General Statement 8:12.16.04.

In vitro studies indicate that clavulanic acid generally inhibits staphylococcal penicillinases,143,318,1315,1445,1446,1449,1489,1501,1667β-lactamases produced by Bacteroides fragilis ,143,1315,1446,1449,1501,1667β-lactamases produced by Moraxella catarrhalis ,1662,1667,1668 and β-lactamases classified as Richmond-Sykes types II, III (TEM-type), IV, and V.143,316,318,1311,1315,1446,1449,1457,1489,1501,1667 Clavulanic acid can inhibit some cephalosporinases produced by Proteus vulgaris , Bacteroides fragilis , and Burkholderia cepacia , but generally does not inhibit inducible, chromosomally mediated cephalosporinases classified as Richmond-Sykes type I.316,318,1311,1445,1446,1449,1501,1667

Clavulanic acid generally acts as an irreversible, competitive inhibitor of β-lactamases.143,311,317,1445,1464,1501 The mechanism by which clavulanic acid binds to and inhibits β-lactamases varies depending on the specific β-lactamase involved.1445,1449,1464,1486,1501 Because clavulanic acid is structurally similar to penicillins and cephalosporins, it initially acts as a competitive inhibitor and binds to the active site on the β-lactamase.1445,1464,1501 An inactive acyl intermediate is then formed but it is only transiently inactive since the intermediate can be hydrolyzed, resulting in restoration of β-lactamase activity and release of clavulanic acid degradation products.1445,1464,1501 With many types of β-lactamases, however, subsequent reactions occur that lead to irreversible inactivation of the β-lactamase.1445,1464,1501

Synergism does not generally occur between amoxicillin and clavulanic acid if resistance to aminopenicillins is intrinsic (i.e., results from the presence of a permeability barrier in the outer membrane of the organism or alterations in the properties of the penicillin-binding proteins).316,318 Synergism between the drugs also does not generally occur against organisms that are susceptible to amoxicillin alone; however, a slight additive effect has been reported in vitro with amoxicillin and clavulanic acid against some non-β-lactamase-producing strains of Staphylococcus aureus and Haemophilus influenzae and some strains of Streptococcus pneumoniae and group A β-hemolytic streptococci.312,318 This additive effect may result from clavulanic acid's intrinsic antibacterial activity, but this activity generally is inadequate for the drug to be therapeutically useful alone.143,312,313,317,318,1446,1486

Clavulanic acid, like cefoxitin and imipenem, can induce production of chromosomally mediated type I cephalosporinases in certain gram-negative bacteria that possess these enzymes (e.g., some strains of Enterobacter , Pseudomonas aeruginosa , Morganella morganii ).1665,1666,1667,1669,1670 Concomitant use of clavulanic acid with a β-lactam antibiotic that is inactivated by inducible β-lactamases theoretically could result in an antagonistic effect against organisms that possess these enzymes.1665,1666,1669,1670 However, high concentrations of clavulanic acid generally are required to induce production of these β-lactamases and the clinical importance of this effect has not been determined.1666,1670

Spectrum

The fixed combination of amoxicillin and clavulanate potassium (amoxicillin/clavulanate) is active in vitro against organisms susceptible to amoxicillin alone.312,318,1311,1438,1446,1450,1454,1457,1486 In addition, because clavulanic acid can inhibit certain β-lactamases that generally inactivate amoxicillin, amoxicillin/clavulanate is active in vitro against many β-lactamase-producing organisms that are resistant to amoxicillin alone.311,312,314,316,318,1298,1437,1446,1450,1453,1454,1473,1486,1489,1494,1501

Clavulanic acid alone has some antibacterial activity and is active in vitro against some gram-positive and gram-negative bacteria including Moraxella catarrhalis , Bacteroides fragilis , Haemophilus influenzae , Legionella , Neisseria gonorrhoeae , and Staphylococcus aureus .311,312,317,318,1446,1449,1486 However, high concentrations of clavulanic acid are necessary to inhibit most susceptible organisms and the drug is not therapeutically useful alone.143,311,312,313,316,317,318,1438,1446,1486

In Vitro Susceptibility Testing

The Clinical and Laboratory Standards Institute) states that, for streptococci (including Streptococcus pneumoniae ), results of in vitro susceptibility tests using penicillin can be used to predict susceptibility to amoxicillin/clavulanate and, for non-β-lactamase-producing enterococci, results of in vitro susceptibility tests using penicillin or ampicillin can be used to predict susceptibility to amoxicillin/clavulanate.2365 However, to determine susceptibility of staphylococci, Enterobacteriaceae, and Haemophilus to amoxicillin/clavulanate, CLSI recommends that disk-diffusion and dilution susceptibility tests be performed using appropriate combinations of amoxicillin/clavulanate.2365 For information on interpretive criteria specified for ampicillin, see Spectrum: In Vitro Susceptibility Testing, in the Aminopenicillins General Statement 8:12.16.08.

To test in vitro susceptibility to amoxicillin/clavulanate, a 2:1 ratio of amoxicillin to clavulanic acid generally is used for both disk-diffusion and agar or broth dilution procedures.2365

Results of in vitro susceptibility tests with amoxicillin/clavulanate may be affected by inoculum size312,318,1311,1447 or test media.1446,1466,1483 However, results of the tests are not generally affected by pH changes between 6 and 8 or the presence of serum.312,318,1446

CLSI, the manufacturers, and most clinicians recommend that strains of staphylococci resistant to penicillinase-resistant penicillins also be considered resistant to amoxicillin/clavulanate, although results of in vitro susceptibility tests may indicate that the organism is susceptible to the drug.1311,1437,1513,2365 In addition, CLSI recommends that non-β-lactamase-producing strains of Haemophilus influenzae that are resistant to ampicillin (BLNAR H. influenzae ) be considered resistant to amoxicillin/clavulanate despite the fact that results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug.2365

Disk Susceptibility Tests

When disk-diffusion procedures are used to test susceptibility to amoxicillin/clavulanate, a disk containing 20 mcg of amoxicillin and 10 mcg of clavulanic acid is used.2365

When disk-diffusion susceptibility tests are performed according to CLSI standardized procedures using CLSI interpretive criteria, Staphylococcus with growth inhibition zones of 20 mm or greater are considered susceptible to amoxicillin/clavulanate and those with zones of 19 mm or less are resistant to the drug.2365

When disk-diffusion susceptibility tests are performed according to CLSI standardized procedures, Enterobacteriaceae with growth inhibition zones of 18 mm or greater are susceptible to amoxicillin/clavulanate, those with zones of 14-17 mm have intermediate susceptibility, and those with zones of 13 mm or less are resistant to the drug.2365

When disk-diffusion susceptibility testing for Haemophilus is performed according to CLSI standardized procedures, Haemophilus with growth inhibition zones of 20 mm or greater are considered susceptible to amoxicillin/clavulanate and those with zones of 19 mm or less are resistant to the drug.2365

Dilution Susceptibility Tests

For dilution susceptibility testing (agar or broth dilution), CLSI recommends that a 2:1 ratio of amoxicillin to clavulanic acid be used with each dilution and that the MIC of amoxicillin/clavulanate be reported as mcg/mL of amoxicillin and mcg/mL of clavulanic acid.2365 The MIC of amoxicillin/clavulanate has also been reported as mcg of amoxicillin plus mcg of clavulanic acid per mL (i.e., mcg of “Augmentin” per mL)1472,1473,1499 or in terms of the MIC of amoxicillin in the presence of a specified concentration of clavulanic acid.1298,1446,1447

When dilution tests are performed using CLSI standardized procedures and a 2:1 ratio of amoxicillin to clavulanic acid with each dilution, Staphylococcus with MICs of 4 mcg/mL or less of amoxicillin and 2 mcg/mL or less of clavulanic acid are considered susceptible to amoxicillin/clavulanate and those with MICs of 8 mcg/mL or greater of amoxicillin and 4 mcg/mL or greater of clavulanic acid are resistant to the drug.2365

When broth dilution susceptibility for S. pneumoniae (from nonmeningeal sites only) is performed using CLSI standardized procedure and cation-adjusted Mueller-Hinton broth (supplemented with 2-5% lysed horse blood), S. pneumoniae with MICs of 2 mcg/mL or less of amoxicillin and 1 mcg/mL or less of clavulanic acid are considered susceptible to amoxicillin/clavulanate, those with MICs of 4 mcg/mL of amoxicillin and 2 mcg/mL of clavulanic acid have intermediate susceptibility, and those with MICs of 8 mcg/mL or greater of amoxicillin and 4 mcg/mL or greater of clavulanic acid are resistant to amoxicillin/clavulanate.2365

When dilution susceptibility tests are performed according to CLSI standardized procedures using CLSI interpretive criteria, Enterobacteriaceae with MICs of 8 mcg/mL or less of amoxicillin and 4 mcg/mL or less of clavulanic acid are susceptible to amoxicillin/clavulanate, those with MICs of 16 mcg/mL of amoxicillin and 8 mcg/mL of clavulanic acid are considered to have intermediate susceptibility, those with MICs of 16 mcg/mL of amoxicillin and 8 mcg/mL of clavulanic acid have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater of amoxicillin and 16 mcg/mL or greater of clavulanic acid are resistant to the drug.2365

When susceptibility of Haemophilus is tested in a broth dilution procedure according to CLSI standardized procedures using HTM, Haemophilus with MICs of 4 mcg/mL or less of amoxicillin and 2 mcg/mL or less of clavulanic acid are susceptible to amoxicillin/clavulanate and those with MICs of 8 mcg/mL or greater of amoxicillin and 4 mcg/mL or greater of clavulanic acid are resistant to the drug.2365

Gram-positive Aerobic Bacteria

Amoxicillin/clavulanate is active in vitro against most gram-positive aerobic cocci, including penicillinase-producing and nonpenicillinase-producing strains of Staphylococcus aureus ,318,1311,1437,1446,1449,1459,1506 S. epidermidis ,1437 and S. saprophyticus ;1437 group A β-hemolytic streptococci;318,1311,1437,1446 Streptococcus pneumoniae ;1311,1437,1446 Enterococcus faecalis ;318,1311,1437,1446 and viridans streptococci.1437 Amoxicillin/clavulanate is active in vitro against many strains of penicillinase-producing staphylococci that are resistant to amoxicillin alone;318,1311,1437,1446,1449,1506 however, staphylococci resistant to penicillinase-resistant penicillins are generally also resistant to amoxicillin/clavulanate.318,1311,1446

In one in vitro study using dilutions containing a 2:1 ratio of amoxicillin to clavulanic acid, the MIC₉₀ (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of amoxicillin/clavulanate for both penicillinase-producing and nonpenicillinase-producing strains of S. aureus was 8 mcg/mL of amoxicillin and 4 mcg/mL of clavulanic acid1311 and the MIC₉₀ of the drug for group A β-hemolytic streptococci, S. pneumoniae , and E. faecalis was 0.03-1 mcg/mL of amoxicillin and 0.015-0.5 mcg/mL of clavulanic acid.1311 In a similar in vitro study, the MIC₉₀ for penicillinase-producing S. aureus was 1.33 mcg/mL of amoxicillin and 0.67 mcg/mL of clavulanic acid.1506

Gram-negative Aerobic Bacteria

Neisseria

Amoxicillin/clavulanate is active in vitro against most strains of Neisseria meningitidis 1311 and penicillinase-producing and nonpenicillinase-producing N. gonorrhoeae .318,1437,1446,1450,1480,1481,1497,1504 Although penicillinase-producing N. gonorrhoeae (PPNG) are usually resistant to amoxicillin alone, these strains usually are susceptible in vitro to amoxicillin/clavulanate.318,1450,1480,1497,1501

The MIC₉₀ of amoxicillin/clavulanate for N. meningitidis is reportedly 0.12 mcg/mL of amoxicillin and 0.06 mcg/mL of clavulanic acid.1311 In one in vitro study using dilutions containing a 2:1 ratio of amoxicillin to clavulanic acid, the MIC of amoxicillin/clavulanate for nonpenicillinase-producing N. gonorrhoeae ranged from 0.08-2.7 mcg/mL of amoxicillin and 0.04-1.3 mcg/mL of clavulanic acid and the MIC for PPNG ranged from 0.67-2.7 mcg/mL of amoxicillin and 0.33-1.3 mcg/mL of clavulanic acid.1497

Haemophilus

Amoxicillin/clavulanate is active in vitro against most β-lactamase-producing and non-β-lactamase-producing strains of Haemophilus influenzae ,318,1311,1437,1446,1450,1451,1453 H. parainfluenzae ,1451 and H. ducreyi .314 However, strains of non-β-lactamase-producing Haemophilus that are resistant to aminopenicillins may also be resistant to amoxicillin/clavulanate.318,1453

In one in vitro study using dilutions containing a 2:1 ratio of amoxicillin to clavulanate potassium, the MIC of amoxicillin/clavulanate for non-β-lactamase-producing strains of H. influenzae was 0.06-0.5 mcg/mL of amoxicillin and 0.03-0.25 mcg/mL of clavulanic acid and the MIC of the drug for β-lactamase-producing strains was 0.5-2 mcg/mL of amoxicillin and 0.25-1 mcg/mL of clavulanic acid.1311 In another in vitro study using β-lactamase-producing H. influenzae type b, the MIC of amoxicillin alone ranged from 6.25-12.5 mcg/mL and the MIC of clavulanic acid alone ranged from 12.5-25 mcg/mL, but the MIC of amoxicillin/clavulanate was 0.36 mcg/mL of amoxicillin and 0.36 mcg/mL of clavulanic acid.1453

Moraxella catarrhalis

Amoxicillin/clavulanate is active in vitro against both β-lactamase-producing and non-β-lactamase-producing strains of Moraxella catarrhalis .318,1446,1450,1473,1499,1655,1662,1663 The MIC₉₀ of amoxicillin plus clavulanate acid is 0.005 mcg/mL for non-β-lactamase-producing strains of M. catarrhalis and 0.125-0.25 mcg/mL for β-lactamase-producing strains.1473,1655,1663 In an in vitro study of β-lactamase-producing M. catarrhalis , the MIC of amoxicillin alone was 25-50 mcg/mL, the MIC of clavulanic acid alone was 2.5-12.5 mcg/mL, and the MIC of amoxicillin plus clavulanate acid was 0.02-0.05 mcg/mL.1499

Enterobacteriaceae

Amoxicillin/clavulanate is active in vitro against Enterobacteriaceae that are susceptible to amoxicillin alone (e.g., some strains of Escherichia coli , Proteus mirabilis , Salmonella , Shigella ).316,318,1311,1313,1437,1438,1446,1494,1506 In addition, amoxicillin/clavulanate is active in vitro against many β-lactamase-producing strains of Citrobacter diversus , K. pneumoniae , P. mirabilis , and P. vulgaris and some strains of β-lactamase-producing E. coli and Enterobacter that are resistant to amoxicillin alone.316,318,1311,1313,1437,1438,1446,1449,1494,1506

In one in vitro study using dilutions containing a 2:1 ratio of amoxicillin to clavulanic acid, the MIC₉₀ of amoxicillin/clavulanate for E. coli was 32 mcg/mL of amoxicillin and 16 mcg/mL of clavulanic acid, the MIC₉₀ for Klebsiella and P. vulgaris was 8 mcg/mL of amoxicillin and 4 mcg/mL of clavulanic acid, and the MIC₉₀ for C. diversus and P. mirabilis was 1-2 mcg/mL of amoxicillin and 0.5-1 mcg/mL of clavulanic acid.1311

Although rare strains of C. freundii , Enterobacter cloacae , Morganella morganii , Providencia , and Serratia are inhibited in vitro by high concentrations of amoxicillin/clavulanate, most strains of these organisms are considered resistant to the drug.318,1311,1446,1447,1472,1486,1506

Other Gram-negative Aerobic Bacteria

Amoxicillin/clavulanate has some in vitro activity against Legionella , although the drug may not be effective clinically.318,1476 In one in vitro study using CYEA media containing 2.5 mcg/mL of clavulanic acid, L. pneumophila , L. micdadei , and L. bozemanii were inhibited by 0.003 mcg/mL of amoxicillin plus clavulanate potassium.1476 In another in vitro study using L. pneumophila and Mueller-Hinton agar, the MIC of amoxicillin alone was 1.95 mcg/mL, the MIC of clavulanic acid alone was 0.2-0.4 mcg/mL, and the MIC of amoxicillin plus clavulanate potassium was 0.61 mcg/mL.1452

Amoxicillin and clavulanic acid is generally inactive against Pseudomonas ;311,316,318,1311,1438,1447,1449 however, the drug may be active in vitro against Burkholderia pseudomallei .1732

Anaerobic Bacteria

Amoxicillin/clavulanate is active in vitro against gram-positive anaerobic bacteria including Clostridium , Peptococcus , and Peptostreptococcus .1437

Amoxicillin/clavulanate is active in vitro against Prevotella melaninogenica and P. oralis .1437 Although the Bacteroides fragilis group (e.g., B. fragilis , B. distasonis , B. ovatus , B. thetaiotamicron , B. vulgatus ) usually is resistant to amoxicillin alone, amoxicillin/clavulanate is active in vitro against many strains of these organisms.311,316,318,1298,1437,1446 In one in vitro study, the MIC of amoxicillin in the presence of 0.75 mcg/mL of clavulanic acid was 0.5-1 mcg/mL for B. fragilis , B. ovatus , B. thetaiotamicron , and B. vulgatus and 4 mcg/mL for B. distasonis .1298

Mycobacterium

Although the clinical importance has not been determined to date, amoxicillin/clavulanate is active in vitro against some strains of Mycobacterium tuberculosis 1247 and M. fortuitum .1310 M. tuberculosis and M. fortuitum are β-lactamase producers and are generally resistant to amoxicillin alone.1247,1310 In one in vitro study using dilutions containing a 2:1 ratio of amoxicillin to clavulanic acid, the MIC of amoxicillin/clavulanate for M. tuberculosis was 1-2 mcg/mL of amoxicillin and 0.5-1 mcg/mL of clavulanic acid and the minimum bactericidal concentration (MBC) of the drug was 1-4 mcg/mL of amoxicillin and 0.5-2 mcg/mL of clavulanic acid.1247 In another study using M. fortuitum , the MIC of amoxicillin/clavulanate for most strains was 4-16 mcg/mL of amoxicillin and 2-8 mcg/mL of clavulanic acid, although some strains had an MIC of 32 mcg/mL or greater of amoxicillin and 16 mcg/mL or greater of clavulanic acid.1310

Resistance

Gram-negative aerobic bacilli that produce Richmond-Sykes type I chromosomally mediated β-lactamases (e.g., Citrobacter freundii , Enterobacter cloacae , Serratia marcescens , Pseudomonas aeruginosa ) are generally resistant to amoxicillin/clavulanate, since clavulanic acid does not inhibit most type I β-lactamases.318,1311,1446,1449,1457,1459,1470,1483,1486 Strains of E. coli with chromosomally mediated β-lactamases are also resistant to amoxicillin/clavulanate.318,1448,1488

Strains of E. cloacae 149,150,1314,1479,1493 and Providencia stuartii 1314 that appear to be resistant to amoxicillin/clavulanate but susceptible to ampicillin in vitro have been reported rarely.

Pharmacokinetics

Crossover studies using fixed combinations of amoxicillin and clavulanate potassium, amoxicillin alone, and clavulanate potassium alone indicate that concomitant administration of clavulanate potassium does not affect the pharmacokinetics of amoxicillin; however, concomitant administration of amoxicillin reportedly may increase GI absorption and renal elimination of clavulanate potassium compared with administration of clavulanate potassium alone.1437,1439,1455,1457,1502,1507

For additional information on absorption, distribution, and elimination of amoxicillin, see Pharmacokinetics in the Aminopenicillins General Statement 8:12.16.08 and in Amoxicillin 8:12.16.08.

Absorption

Amoxicillin trihydrate and clavulanate potassium are both generally stable in the presence of acidic gastric secretions1437 and are well absorbed following oral administration of the fixed combination of amoxicillin and clavulanate potassium (amoxicillin/clavulanate).318,1437,1439,1457,1470,1486,1507 Peak serum concentrations of amoxicillin and of clavulanic acid are generally attained within 1-2.5 hours following oral administration of a single dose of conventional preparations of amoxicillin/clavulanate in fasting adults or a single dose of extended-release tablets in adults fed a standardized meal.1437,1439,1455,1471,1492,1502

Following oral administration of a single conventional tablet containing 250 mg of amoxicillin and 125 mg of clavulanic acid in healthy, fasting adults, peak serum concentrations of amoxicillin and of clavulanic acid average 3.7-4.8 mcg/mL and 2.2-3.5 mcg/mL, respectively.318,1437,1457,1502 Following oral administration of a single conventional tablet containing 500 mg of amoxicillin and 125 mg of clavulanic acid in healthy, fasting adults, peak serum concentrations of amoxicillin average 6.5-9.7 mcg/mL and peak serum concentrations of clavulanic acid average 2.1-3.9 mcg/mL.318,1437,1439,1455,1456,1471,1507 The manufacturer states that serum concentrations of the drugs achieved following oral administration of a single chewable tablet containing 250 mg of amoxicillin and 62.5 mg of clavulanic acid or 2 chewable tablets each containing 125 and 31.25 mg of the drugs, respectively, are similar to those achieved following oral administration of a single equivalent dose of the oral suspension.1437 The manufacturer also states that serum concentrations of amoxicillin achieved following oral administration of conventional preparations or extended-release tablets of amoxicillin/clavulanate are similar to those achieved following oral administration of equivalent doses of amoxicillin alone.1437

Following oral administration of a single dose of 250 mg of amoxicillin and 62.5 mg of clavulanic acid as an oral suspension, peak serum concentrations of amoxicillin average 6.9 mcg/mL and peak concentrations of clavulanic acid average 1.6 mcg/mL.1437,2529 In one study in children 2-5 years of age with urinary tract infections, oral administration of a single dose of 125 mg of amoxicillin and 31.75 mg of clavulanic acid as an oral suspension resulted in serum concentrations of amoxicillin that averaged 9.4, 9.7, and 6.5 mcg/mL and serum concentrations of clavulanic acid that averaged 2.1, 4.4, and 2.5 mcg/mL at 30, 60, and 90 minutes, respectively, after the dose.1470

Studies in healthy adults using conventional preparations of amoxicillin/clavulanate indicate that presence of food in the GI tract does not affect oral absorption of either amoxicillin or clavulanic acid following administration of fixed-combination preparations of the drugs.1437,1469,1502,1507 However, amoxicillin and clavulanate are optimally absorbed from extended-release tablets of the combination when administered orally at the beginning of a standardized meal (612 kcal, 89.3 g carbohydrate, 24.9 g fat, and 14 g protein); administration of the extended-release tablets with a high-fat meal is not recommended because clavulanate absorption is decreased, and administration of these tablets in the fasting state is not recommended because amoxicillin absorption is decreased.2529 GI absorption of the drugs from extended-release tablets is not affected by administration simultaneously with or 2 hours before a magnesium and aluminum-containing antacid (Maalox^®).2529

Distribution

Following administration of amoxicillin/clavulanate, amoxicillin and clavulanic acid are both distributed into the lungs,318 pleural fluid,318,1486 and peritoneal fluid.1457,1486,1490 Low concentrations (i.e., less than 1 mcg/mL) of each drug are attained in sputum318,1457,1486 and saliva.1457,1486

In one study in fasting children who received a single amoxicillin dose of 35 mg/kg given as amoxicillin/clavulanate oral suspension, concentrations of amoxicillin and of clavulanic acid in middle ear effusions averaged 3 and 0.5 mcg/mL, respectively, 2 hours after the dose.1437

Only minimal concentrations of amoxicillin or clavulanic acid are attained in CSF following oral administration of amoxicillin/clavulanate in patients with uninflamed meninges; higher concentrations may be attained when meninges are inflamed.318,1457,1486,1514 In one study in patients with uninflamed meninges who received a single 250-mg oral dose of clavulanic acid as the sodium salt, concentrations of clavulanic acid in CSF obtained 1-6 hours after the dose ranged from 0-0.2 mcg/mL.1517 In 2 patients with continuous CSF drainage after neurosurgical procedures who received a similar oral dose of the drug, peak CSF concentrations of clavulanic acid were 2.4 and 0.4 mcg/mL, respectively, and occurred approximately 4 hours after the dose; concurrent serum concentrations of clavulanic acid were 2.3 and 0.3 mcg/mL, respectively.1517

Amoxicillin is 17-20% bound to serum proteins.36,37,64,81,226,428,491 In vitro or in vivo following oral administration, clavulanic acid is reportedly 22-30% bound to serum proteins at a concentration of 1-100 mcg/mL.312,1437,1457,1540

Amoxicillin73,439 and clavulanic acid1486 readily cross the placenta. Amoxicillin and clavulanic acid are distributed into milk in low concentrations.61,73,496,498,1514

Elimination

Serum concentrations of amoxicillin and clavulanic acid both decline in a biphasic manner and half-lives of the drugs are similar.318,1455,1457,1471,1492,1507 Following oral administration of conventional preparations or extended-release tablets of amoxicillin/clavulanate in adults with normal renal function, amoxicillin has an elimination half-life of 1-1.3 hours1455,1457,1485,1492 and clavulanic acid has a distribution half-life of 0.28 hours1471 and an elimination half-life of 0.78-1.2 hours.318,1437,1455,1457,1471,1485,1492,1507 In one study in children 2-15 years of age, the elimination half-lives of amoxicillin and of clavulanic acid averaged 1.2 and 0.8 hours, respectively.1440

The metabolic fate of clavulanate potassium has not been fully elucidated; however, the drug appears to be extensively metabolized.318,1456,1507 In rats and dogs, the major metabolite of clavulanic acid is 1-amino-4-hydroxybutan-2-one; this metabolite has also been found in human urine following administration of clavulanic acid.1507 Clavulanic acid is excreted in urine principally by glomerular filtration.1457,1491,1507 Studies in dogs and rats using radiolabeled clavulanic acid indicate that 34-52, 25-27, and 16-33% of a dose of the drug is excreted in urine, feces, and respired air, respectively.1507

Following oral administration of a single oral dose of amoxicillin/clavulanate in adults with normal renal function, approximately 50-73 and 25-45% of the amoxicillin and clavulanic acid doses, respectively, are excreted unchanged in urine within 6-8 hours.318,1437,1456,1457,1471,1502,1507 In one study in healthy adults who received a single oral dose of 250 mg of amoxicillin and 125 mg of clavulanic acid, urinary concentrations of amoxicillin and of clavulanic acid averaged 381 and 118 mcg/mL, respectively, in urine collected over the first 2 hours after the dose.1502

Serum concentrations of amoxicillin and of clavulanic acid are higher and the serum half-lives prolonged in patients with renal impairment.318,1508,1554 In one study in patients with creatinine clearances of 9 mL/minute, the serum half-lives of amoxicillin and of clavulanic acid were 7.5 and 4.3 hours, respectively.1508

Oral probenecid administered shortly before or with amoxicillin/clavulanate competitively inhibits renal tubular secretion of amoxicillin and produces higher and prolonged serum concentrations of the drug; however, probenecid does not appreciably affect the pharmacokinetics of clavulanic acid.1437,1485,1491 (See Drug Interactions: Probenecid.)

Amoxicillin63,73,81,428,451,473,601,1437,1508,1554 and clavulanic acid1437,1508,1554 are both removed by hemodialysis. The manufacturers state that clavulanic acid is also removed by peritoneal dialysis.1514 Only minimal amounts of amoxicillin appear to be removed by peritoneal dialysis.509

Chemistry and Stability

Chemistry

Amoxicillin and clavulanate potassium (amoxicillin/clavulanate) is a fixed combination of amoxicillin trihydrate and the potassium salt of clavulanic acid.318,1437,1446,1448,1457 Amoxicillin is an aminopenicillin.68,89,575 (See Amoxicillin 8:12.16.08.) The fixed combination also is commercially available as extended-release tablets containing the sodium salt and the trihydrate of amoxicillin and the potassium salt of clavulanic acid. Clavulanic acid is a β-lactamase inhibitor produced by fermentation of Streptomyces clavuligerus .143,317,318,1437,1445,1446,1448,1449,1498,1501 Clavulanic acid contains a β-lactam ring and is structurally similar to penicillins and cephalosporins;311,1437,1498 however, the β-lactam ring in clavulanic acid is fused with an oxazolidine ring rather than with a thiazolidine ring as in penicillins or a dihydrothiazine ring as in cephalosporins.1457,1498,1501 Although clavulanic acid has only weak antibacterial activity when used alone, the combined use of clavulanic acid and certain penicillins or cephalosporins (e.g., amoxicillin, ampicillin, carbenicillin, cefoperazone, cefotaxime, penicillin G, ticarcillin) results in a synergistic effect that expands the spectrum of activity of the penicillin or cephalosporin against many strains of β-lactamase-producing bacteria.143,311,312,313,314,316,317,318,1298,1437,1445,1446,1448,1449,1457,1467,1486,1498,1501 Clavulanic acid and its salts currently are commercially available in the US only in fixed combination with other drugs.

Amoxicillin/clavulanate is commercially available for oral administration as film-coated tablets containing a 2:1 or 4:1 ratio of amoxicillin to clavulanic acid; as scored tablets containing a 7:1 ratio of amoxicillin to clavulanic acid; as chewable tablets containing a 4:1 or 7:1 ratio of amoxicillin to clavulanic acid; as extended-release tablets containing a 16:1 ratio of the drugs;2529 or a powder for oral suspension containing a 4:1, 7:1, or 14:1 ratio of the drugs.1437

2364 Although commercially available amoxicillin/clavulanate contains amoxicillin as the trihydrate and clavulanic acid as the potassium salt, potency of amoxicillin is calculated on the anhydrous basis and potency of clavulanate potassium is expressed in terms of clavulanic acid.1437

Amoxicillin occurs as a white, practically odorless, crystalline powder and is sparingly soluble in water.1 Clavulanate potassium occurs as an off-white, crystalline powder and is very soluble in water and slightly soluble in alcohol at room temperature.1514 Clavulanic acid has a pK_a of 2.7.

Each amoxicillin/clavulanate film-coated tablet containing 250 or 500 mg of amoxicillin and 125 mg of clavulanic acid or each scored tablet containing 875 mg of amoxicillin and 125 mg of clavulanic acid contains 0.63 mEq of potassium.1437 Following reconstitution as directed, each 5 mL of amoxicillin/clavulanate oral suspension containing 125, 200, 250, 400, or 600 mg of amoxicillin contains 0.16, 0.14, 0.32, 0.29, or 0.23 mEq of potassium, respectively.1437,2364 Each amoxicillin/clavulanate chewable tablet containing 125, 200, 250, 400 mg, or 600 of amoxicillin contains 0.16, 0.14, 0.32, or 0.29 mEq of potassium, respectively.1437 Each amoxicillin/clavulanate extended-release tablet containing 1 g of amoxicillin contains 0.32 mEq of potassium and 1.27 mEq of sodium.2529 When reconstituted as directed, the oral suspensions have a pH of 4.8-6.8.1514

Amoxicillin/clavulanate chewable tables containing 200, 400, or 600 mg of amoxicillin and amoxicillin/clavulanate oral suspension containing 200 or 400 mg of amoxicillin per 5 mL contain aspartame; following metabolism of aspartame in the GI tract, each 200- or 400-mg chewable tablet provides 2.1 or 4.2 mg of phenylalanine, respectively, and each 5 mL of amoxicillin/clavulanate oral suspension containing 200, 400, or 600 mg of amoxicillin provides 7 mg of phenylalanine.1437,2364

Stability

Commercially available amoxicillin/clavulanate film-coated tablets, scored tablets, chewable tablets, extended-release tablets, and powder for oral suspension should be stored in tight containers at a temperature of 25°C or lower;1437,2364 exposure to excessive humidity should be avoided.1514,1576

Following reconstitution, oral suspensions of amoxicillin/clavulanate should be stored at 2-8°C, and any unused suspension should be discarded after 10 days.1437

Additional Information

For further information on chemistry and stability, mechanism of action, spectrum, resistance, pharmacokinetics, uses, cautions, drug interactions, and laboratory test interferences of amoxicillin, see the Aminopenicillins General Statement 8:12.16.08 and see Amoxicillin 8:12.16.08.

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