Amoxicillin (Amoxil): Drug Whys


Generic name: Amoxicillin (multiple manufacturers)
Common brand name: Amoxil (GlaxoSmithKline – U.S.)
Popularity: Third most commonly prescribed drug between 2002 – 2007 (U.S.)
Class: Penicillin antibiotic

Treatment Uses – For treatment of ear, nose, throat, lower respiratory, skin or subcutaneous, and urinary tract or lower genitourinary infections, as well as tonsillitis. Prophylaxis (prevention) of infective endocarditis (IE) in high risk patients undergoing surgical or dental procedures. Has been effective for treatment of acute infective exacerbations of chronic obstructive pulmonary disease (COPD). Used as part of a multi-drug regimen (including omeprazole and clarithromycin) for eradication of Helicobacter pylori (to reduce risk of duodenal ulcer recurrence).

For treatment of susceptible infections caused by streptococci, E. coli, E. faecalis, P. mirabilis, and H. influenza. Amoxicillin is an available option to complete post exposure prophylaxis against anthrax after two to three weeks treatment with a first-line antibiotic. Amoxicillin had been used to treat gonorrhea, but antibiotic resistance has made it ineffective and no longer recommended. Either oral amoxicillin or azithromycin are preferred for treatment of chlamydial infections during pregnancy. Amoxicillin is also used to treat Lyme disease, Typhoid Fever, post-infective arthritis, Whipple's disease, and as infective prophylaxis in premature rupture of membranes (PROM) during pregnancy.

Amoxicillin is a semisynthetic antibiotic derived from penicillin (actually a chemical analog of ampicillin). It has a spectrum of antimicrobial activity nearly indistinguishable from ampicillin. Amoxicillin seems to have a lower incidence of diarrhea than ampicillin. Comparable doses of amoxicillin produce higher blood and urine drug levels than ampicillin.

The American Heart Association recommends prophylaxis with antibiotics for some dental procedures and a few highly invasive or surgical procedures (usually involving biopsy or debridement of infected tissue) to prevent infective endocarditis (IE or bacterial infection of the heart) for patients with underlying cardiac conditions of high risk. Note that these recommendations were totally overhauled in 2007 based on very clear evidence that the cumulative lifetime risk of developing IE with normal dental hygiene measures (such as teeth brushing and flossing) far exceeded the risks of most surgical and dental procedures for which antibiotic prophylaxis was recommended.

The latest recommendations suggest antibiotic prophylaxis only for patients with prosthetic heart valves, prior history of bacterial endocarditis, heart transplant recipients who develop heart valve dysfunction, unrepaired cyanotic congenital heart diseases (CHD) such as tetrology of Fallot (TOF), single ventricle, and transposition. Prophylaxis is also recommended for the first six months following repair of CHD with prosthetic materials and for life if there are residual defects at the site of, or adjacent to, a CHD repair. Prophylaxis is not recommended for conditions of negligible risk as these are thought equivalent to the general population risk: atrial septal defect (ASD) or repaired ASD/VSD, or PDA (Patent Ductus Arteriosus), previous CABG (Coronary Artery Bypass Grafting), MVP without regurgitation, innocent heart murmurs, previous rheumatic fever or Kawasaki disease without valve dysfunction, and all implanted pacemakers and defibrillators. At least one well-conducted and highly credible study raised serious question whether dental procedures predispose any patient to endocarditis and whether prophylaxis with antibiotics is necessary for dental work. There is little evidence that antibiotic prophylaxis helps to prevent IE. When advised, amoxicillin is the preferred antibiotic for endocarditis prophylaxis.

Another use for amoxicillin is treatment of uncomplicated acute bacterial sinusitis (rhinosinusitis). Our present era of multiple antibiotic resistant organisms caused by years of antibiotic overuse have taught us to reserve treatment for acute sinusitis patients with at least moderately severe symptoms meeting criteria for diagnosis of acute bacterial sinusitis (symptoms for more than seven days, maxillary pain in the face or teeth, and purulent nasal drainage). In such patients, multiple studies demonstrate similar clinical benefit of first-line agents (such as amoxicillin or trimethoprim-sulfamethoxazole) coupled with significantly less cost and decreased risk for emergence and spread of antibiotic resistant bugs when compared to second-line agents. Another very reasonable treatment is no antibiotic, which will resolve 69 percent of acute sinusitis cases.

Dosing and Administration – Dosing varies both by the condition and severity being treated. For adults, oral doses range from 250 milligrams three times daily to 1000 milligrams (1 gram) every 12 hours. When used for endocarditis prophylaxis in patients undergoing dental or certain other surgical procedures, the normal adult dose is 2 grams orally taken 30 to 60 minutes before the procedure. Pediatric oral dosing ranges from 20 to 50 milligrams per kilogram per day divided every eight hours while neonatal dosing is typically 30 milligrams per kilogram per day divided every 12 hours.

Amoxicillin comes in multiple forms including tablets, capsules, chewable tablets, liquid, powder for oral suspension, and tablets for oral suspension. The chewable tablet should be either chewed or crushed and mixed with food before swallowing. Oral liquid should be well shaken in the container before each use and can be mixed with baby formula, milk, water, or other drinks. The tablets for oral suspension should not be chewed or swallowed but placed in a glass to which 2 teaspoons of water are added (only water, no other liquid should be used). Drink the entire mixture once dissolved completely. An intravenous form of amoxicillin is available outside the United States, which can also be nebulized for treatment of pulmonary infections.

Regular release forms of amoxicillin can be taken without regard to meals. While food may decrease the total amount of amoxicillin absorbed, the effect is not clinically significant. Extended release amoxicillin tablets should be taken within one hour of finishing a meal and should not be crushed or chewed.

As with any antibiotic, it is critical to assure even intervals between doses. Three times daily dosing should be spaced evenly eight hours apart; twice daily spaced 12 hours apart; and daily doses taken the same time each day. This assures a steady state of antibiotic levels in the body and yields the desired effects against bacteria (see explanation of MIC below).

Dose adjustments of amoxicillin should be considered in patients with significantly impaired renal function. For patients not on dialysis, usual doses are spaced at longer intervals, depending on the degree of kidney dysfunction. An alternative to longer dosing intervals would be lower doses. As amoxicillin is removed by dialysis (the half-life is reduced by a factor of two by hemodialysis and somewhat less by peritoneal dialysis), supplemental doses are necessary both during and at the end of dialysis.

In overdoses, amoxicillin can be removed from the body by hemodialysis. Of note, overdoses less than 250 milligrams per kilogram of patient body weight have not been known to cause significant clinical effects and therefore, do not mandate emptying the stomach.

Pharmacology/Pharmacokinetics/Stability – After oral administration of amoxicillin, peak concentrations appear in the bloodstream within one to two hours. Although nearly 89 percent of an oral dose is absorbed, there appears to be a drop off in absorption at higher doses. Roughly 2 grams of amoxicillin appear to be the maximal amount of drug able to be absorbed from a single dose. The standard normally used to treat infection with antibiotics is called the minimal inhibitory concentration (MIC), representing the lowest antibiotic concentration needed to inhibit growth of an organism. MICs vary with different organisms, sites of infection, and antibiotics. Maintaining an antibiotic level above the MIC at the site of an infection requires meticulous attention to dosing intervals.

The kidneys excrete roughly 60 percent of amoxicillin. The remainder can be found in bile, sputum, and virtually all other body fluids. Amoxicillin is excreted in breast milk; the American Academy of Pediatrics considers amoxicillin to be safe for use by nursing mothers. There have not been any documented risks to the fetus or adverse pregnancy outcomes caused by amoxicillin.

Amoxicillin is chemically an analog of ampicillin. Antibiotics fall into three major classes according to their mechanism of action: cell walls, protein synthesis, or nucleic acid synthesis. Cell wall agents attack bacterial cell walls. Protein synthesis and nucleic acid agents inhibit the ability of bacteria to synthesize these important components. Amoxicillin is a cell wall agent.

Amoxicillin is available in multiple forms from multiple manufacturers with varying storage requirements. Capsules and tablets come in a variety of colors, shapes, and sizes.

Cautions and Warnings – Amoxicillin 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 should be used cautiously in patients with these allergies. Patients with mononucleosis are at extremely high risk of developing erythematous skin rash when given ampicillin-class antibiotics and should not be given amoxicillin. Amoxicillin can produce false positive results in urine tests for glucose.

Prolonged use of amoxicillin can result in superinfections from bacteria or fungus. These include CDAD (C. difficile-associated diarrhea).

Important Side Effects and Interactions – Despite widespread use, there are few data of specific incidence of amoxicillin side effects in the medical literature. The most commonly reported side effect of amoxicillin is diarrhea, often associated with abdominal cramps. Nausea, vomiting and rash are also common amoxicillin side effects. Diarrhea is a somewhat troubling symptom and, especially when very frequent and watery, requires extra vigilance as amoxicillin (along with clindamycin, ampicillin, and the cephalosporins) tend to be the worst offenders in an uncommon but very dangerous antibiotic induced pseudomembranous colitis (PMC). Other rare side effects have included hemorrhagic colitis as well as kidney and liver toxicity. Brown, yellow, or gray staining of the teeth has been reported to occur rarely and usually involves pediatric patients. Tooth discoloration is typically improved or removed by brushing or dental cleaning.

Twenty-four drugs are reported to interact with amoxicillin, none of which have good documentation. Fair documentation exists for amoxicillin to increase clotting times in patients taking anticoagulants, decrease effectiveness of some oral contraceptives (leading to unwanted pregnancies when other birth control methods are not used), and result in toxic levels of methotrexate when doses are not adjusted. No food-drug interactions involving amoxicillin have been reported.

Average Costs – U.S.
250 mg /500 mg tablets and 875 mg capsule (generic)
Patient cost: $ 0.30/0.38 and 0.67 each*
Large Hospital cost: $0.06/0.08 and 0.42 each
*($4.00 at Wal Mart® and Target for 1 month or $10.00 for 90 day supply)


References:

  • MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed June, 2008).
  • Albany Medical Center Pharmacy, Albany, New York.

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