Amoxicillin (Clavulanate Potassium): Drug Whys
By Mike McEvoy
Generic Name: Amoxicillin/clavulanate potassium (multiple manufacturers)
Common Brand Name: Augumentin (GlaxoSmithKline — U.S.)
Popularity: 28th most commonly prescribed drug between 2002 – 2010 (U.S.)
Treatment Uses – For treatment of lower respiratory infections, otitis media (OM), sinusitis, skin and skin structure infections, urinary tract infections (UTIs), community-acquired pneumonia (CAP), and acute bacterial sinusitis.
Effective for cat bites and infections following colorectal surgery. Has been used with good results in treatment of post infective (reactive) arthritis as well as short-term treatment of ulcerative colitis. Amoxicillin/clavulanate is not recommended for treatment of gonorrhea due to antibiotic resistance patterns.
Amoxicillin/clavulanate is the drug of choice for children with acute otitis media (AOM) as well as kids with treatment failures using amoxicillin alone. It is also the treatment of choice for patients with a perforated eardrum (tympanic membrane).
The current standard of care for treating acute sinusitis is symptom relief (saline irrigations, decongestants) and reassurance. Antibiotic therapy is reserved for patients meeting criteria for acute bacterial sinusitis with at least moderately severe symptoms (lasting greater than seven days, with maxillary pain in the face or teeth and purulent nasal secretions/discharge) or for those with severe rhinosinusitis symptoms, regardless of duration of illness.
In acute bacterial sinusitis, the use of first-line agents (amoxicillin, trimethoprim-sulfamethoxazole) has equivalent clinical benefits plus significant cost savings compared to second- and third-line agents (fluoroquinolones, azithromycin, clarithromycin, second- and third-generation cephalosporins).
Choosing appropriate, more narrow-spectrum antibiotics lowers risk for infections from antibiotic-resistant bacteria, in addition to cost savings and equal efficacy. Another very reasonable treatment is no antibiotic; 69 percent of acute sinusitis cases resolve without antibiotics.
Dosing and Administration – Dosing varies both by the condition and severity of illness. For adults with mild to moderate cases of AOM, sinusitis, skin/tissue infections, or UTI, oral dosing is recommended at 500 milligrams (of amoxicillin component) every 12 hours or 250 milligrams every 8 hours.
Severe cases of AOM, sinusitis, UTIs, lower respiratory infections and severe skin/tissue infections should be treated with 875 milligrams every 12 hours or 500 milligrams every 8 hours. CAP dosing is recommended at 2,000 milligrams of extended release amoxicillin/clavulanate every 12 hours for seven to 10 days.
Pediatric dosing is tricky; the clavulanic acid component can be harmful to youngsters. Children under 40 kilograms (88 pounds) should not be given the 250 milligram film-coated tablets of amoxicillin/clavulanate due to the higher amount of clavulanic acid when compared to the chewable 250 milligram tablet.
Safety of extended release amoxicillin/clavulanate in children under 16 years of age has not been established. Weight-based dosing with amoxicillin/clavulanate immediate release chewable tablets or liquid suspension ranging from 20 to 90 milligrams (of amoxicillin component) per kilogram per day depending on the indication and severity of infection is recommended. Prescribers should consult a formulary reference.
Amoxicillin/clavulanate should be taken before or at the start of meals; taking it on an empty stomach decreases absorption of extended release tablets. Both immediate and extended release tablets taken on a full stomach will have decreased absorption of the clavulanate.
What is important with amoxicillin/clavulanate, like all antibiotics, is assuring even intervals between doses. Twice daily dosing should be spaced 12 hours apart; three times daily dosing taken 8 hours apart, and daily doses taken the same time each day. This will assure a steady state of antibiotic levels, yielding the best effects against the organisms they are intended to treat.
Dose adjustments of amoxicillin/clavulanate are necessary in patients with impaired renal function. For patients not on dialysis, 250 to 500 milligrams of amoxicillin/125 milligrams of clavulanic acid every 12 to 24 hours depending on the degree of renal insufficiency is recommended.
Hemodialysis patients should be given a maintenance dose of 250 to 500 milligrams of amoxicillin/125 milligrams of clavulanic acid every 24 hours with a supplemental dose both during and at the end of dialysis.
Peritoneal dialysis patients should receive 50 to 75 percent of the normal dose of clavulanic acid with 250 milligrams of amoxicillin every 12 hours. The extended release (containing 1000 milligrams of amoxicillin) and 875 milligram tablets should not be given to patients with significant renal insufficiency (creatinine clearance less than 30 mL/minute) or renal failure. Amoxicillin/clavulanate should be used with caution in patients with hepatic (liver) insufficiency.
Overdoses of amoxicillin/clavulanate do not typically cause serious or severe symptoms. Gastrointestinal distress is the most often seen. This can lead to fluid and electrolyte disturbances from vomiting or diarrhea. Treatment should be supportive.
Hemodialysis removes both amoxicillin and clavulanic acid and would likely be helpful in major overdoses. As in all overdoses, the possibility of multidrug ingestion should be considered, especially if symptoms are severe.
Pharmacology/Pharmacokinetics/Stability – After oral administration of amoxicillin/clavulanate, peak concentrations appear in the bloodstream within 1 to 2 hours. The combination of the two drugs does not appear to affect the absorption of either drug. Both amoxicillin and clavulanic acid are extensively metabolized in the liver.
The kidneys excrete 50 percent to 70 percent of amoxicillin and 25 percent to 40 percent of clavulanic acid; most of it excreted unchanged in the first 6 hours. The remainder can be found in bile, sputum, and virtually all other body fluids.
Amoxicillin/clavulanate does cross the placenta. There are limited human and animal data suggesting little to no risk of fetal harm. Based on lack of data, amoxicillin/clavulanate should be used during pregnancy only if clearly indicated.
A single, small study of women with premature rupture of membranes (PROM) found that prophylaxis with amoxicillin/clavulanate may be associated with an increased risk of necrotizing enterocolitis (NEC) in newborns.
Amoxicillin/clavulanate is excreted in breast milk; the World Health Organization considers amoxicillin/clavulanate to be compatible with breastfeeding. Infants of nursing mothers should be monitored for gastrointestinal disturbances (diarrhea or thrush infections) as well as allergic reactions.
Amoxicillin is a beta-lactam antibiotic with antibiotic activity against many microbes, but is very susceptible to inactivation by beta lactamases, and therefore ineffective against bacteria that produce these enzymes.
The addition of clavulanic acid, a beta-lactamase inhibitor, protects amoxicillin from being degraded by beta lactamases, extending the antibiotic activity of amoxicillin alone. Amoxicillin and clavulanic acid are also synergistic when given together. In other words, the combined effects are more powerful than either component given alone. This allows for greater effectiveness at lower doses.
Amoxicillin/clavulanate comes in multiple forms including immediate release tablets, extended release tablets, chewable tablets, and powder for oral suspension. The chewable tablet should either be chewed or crushed and mixed with food before swallowing. Liquid suspensions for oral administration can be prepared and may be flavored with a proprietary apple, banana cream, bubble gum, cherry, or watermelon flavor, if desired.
Suspensions must be refrigerated in between uses, and well shaken in the container before each use. Shelf life for suspensions is 10 days when refrigerated after which they should be discarded. Tablets should be stored at room temperature (77 F). An intravenous form of amoxicillin/clavulanate is available outside the United States.
Cautions and Warnings – Amoxicillin/clavulanate is a penicillin antibiotic and should not be used by patients with a history of penicillin allergy. There is a relatively low incidence of cross-allergy with beta-lactam and cephalosporin antibiotics, but amoxicillin/clavulanate should be used cautiously in patients with these allergies. Amoxicillin/clavulanate can produce false positive results in urine tests for glucose.
Important Side Effects and Interactions – The most commonly reported side effect of amoxicillin/clavulanate is diarrhea, often associated with abdominal cramps, with a reported incidence of 2.9 percent to 14.5 percent. Nausea (2.1 percent to 3 percent), vomiting (1 percent to 2.2 percent) and rash (1.1 percent to 3 percent) are also common side effects.
Diarrhea is a somewhat troubling symptom and when very frequent and watery, requires extra vigilance since amoxicillin along with clindamycin, ampicillin, and the cephalosporins tend to be the worst offenders in an uncommon but dangerous antibiotic induced pseudomembranous colitis (PMC).
This can occur up to several weeks after treatment with an antibiotic and is, in the U.S., frequently associated with a toxin produced by Clostridium difficile. Some cases respond to discontinuation of the antibiotic, but often treatment with an antibiotic effective against C-difficile is necessary.
There are 52 drugs and drug classes specifically reported to interact with amoxicillin/clavulanate. Several are worth noting. Fair documentation exists for amoxicillin/clavulanate induced increases in clotting times when patients are also taking anticoagulants. Decreased effectiveness of some oral contraceptives (leading to unwanted pregnancies when other birth control methods are not used) also occurs, as does toxic levels of methotrexate when doses are not adjusted (in patients taking any penicillin). No food-drug interactions involving amoxicillin/clavulanate have been reported.
Average Costs – U.S.
• 875/125 and 500/125 milligram tablets
Patient cost: $2.50 and $2.30 each*
Large Hospital cost: $0.83 and $1.39 each
*(Wal Mart® and Target don't include this med in their $4/month programs)
- MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed May, 2012).
- Albany Medical Center Pharmacy, Albany, New York.