Continuing Education Activity

Amoxicillin is one of the most commonly used antibiotics in the primary care setting. It is an amino-penicillin, created by adding an extra amino group to penicillin to battle antibiotic resistance. Amoxicillin covers a wide variety of gram-positive bacteria, with some added gram-negative coverage compared to penicillin. Like penicillin, it covers most Streptococcus species and has improved coverage of Listeria monocytogenes and Enterococcus spp. It also has coverage over Haemophilus influenzae, some Escherichia coli, Actinomyces spp., Clostridium species, Salmonella spp., Shigella spp., and Corynebacteria species. This activity covers amoxicillin, a beta-lactam antimicrobial that interprofessional team members need to review its indications, coverage, contraindications, and adverse event profile to manage patients with infectious disease optimally.

Objectives:

• Outline the indications for initiating amoxicillin as an anti-infective strategy for patient care.
• Identify the mechanism of action of amoxicillin and its target coverage.
• Summarize the adverse effects of amoxicillin.
• Explain the importance of antimicrobial stewardship and how it affects antimicrobial selection to improve care coordination among the interprofessional team when initiating amoxicillin antimicrobial therapy.

Indications

Amoxicillin is one of the most commonly used antibiotics in the primary care setting. It is an amino-penicillin, created by adding an extra amino group to penicillin to battle antimicrobial resistance. Amoxicillin covers a wide variety of gram-positive bacteria, with some added gram-negative coverage compared to penicillin. Like penicillin, it covers most Streptococcus species and is also effective against Listeria monocytogenes and Enterococcus species. It also covers Haemophilus influenza, some Escherichia coli, Actinomyces species, Clostridium species, Salmonella species, Shigella species, and Corynebacteria species.

FDA-approved Indications

• Amoxicillin is indicated in treating infections due to susceptible (only beta-lactamase–negative) isolates of the selected bacteria in the conditions listed below.

• Ear, nose, and throat infections: Treatment of tonsillitis, pharyngitis, and otitis media in adults and pediatric patients ≥12 years of age. The microbiological spectrum is infections due to beta-lactamase-negative Streptococcus species (alpha- and beta-hemolytic isolates only), Streptococcus pneumoniae, Staphylococcus species, or Haemophilus influenza.[1]

• Helicobacter pylori eradication: Triple therapy for Helicobacter pylori with clarithromycin, amoxicillin, and lansoprazole to eradicate Helicobacter pylori reduces the risk of duodenal ulcer recurrence. Dual treatment with amoxicillin and lansoprazole is also FDA approved to eradicate Helicobacter pylori infection.[2]

• Lower respiratory tract infections: Treatment of lower respiratory tract infection due to beta-lactamase-negative Streptococcus species (alpha- and beta-hemolytic strains only), pneumococcus, Staphylococcus species, or Haemophilus influenzae. For community-acquired pneumonia, IDSA recommends a combination of amoxicillin and macrolide.[3]

• Acute Bacterial Sinusitis: Treating infections due to beta-lactamase-negative Streptococcus species (alpha- and beta-hemolytic isolates only), Streptococcus pneumoniae, Staphylococcus species, or Haemophilus influenzae.[4]

• Skin and skin structure infections: Immediate release: Treatment of skin and skin structure infections due to beta-lactamase-negative Streptococcus species (alpha and beta-hemolytic strains only), Staphylococcus species, or Escherichia coli.[5]

• Urinary tract infection: Treatment of the genitourinary tract infections. Organisms include beta-lactamase-negative Escherichia coli, Proteus mirabilis, or Enterococcus faecalis.[6]

• The Centers for Disease Control and Prevention (CDC) recommends using amoxicillin for post-exposure prophylaxis for anthrax(second-line agent).[7]      

Off-label Clinical Uses

• Lyme disease (if doxycycline contraindications are present)[8]

• Infectious endocarditis prophylaxis(cardiac conditions associated with the high risk such as the presence of prosthetic cardiac valve or congenital heart disease)[9]

• Periodontitis in combination with metronidazole[10] 

• Actinomycosis[11]

Mechanism of Action

Amoxicillin is in the class of beta-lactam antimicrobials. Beta-lactams act by binding to penicillin-binding proteins that inhibit a process called transpeptidation (the cross-linking process in cell wall synthesis), leading to activation of autolytic enzymes in the bacterial cell wall. This process leads to lysis of the cell wall, thus destroying the bacterial cell. This type of activity is referred to as bactericidal killing.[12]

Amoxicillin administration can also be in combination with a beta-lactamase inhibitor. Some examples of these are clavulanic acid and sulbactam. These beta-lactamase inhibitors work by binding irreversibly to the catalytic site of an organism’s beta-lactamase enzyme, which causes resistance to the original beta-lactam ring of amoxicillin. These drugs do not have inherent bactericidal activity; however, they may broaden amoxicillin's spectrum to organisms that produce the beta-lactamase enzyme when combined with amoxicillin.[13]

Administration

Bactericidal antimicrobials, such as amoxicillin, often are most effective in a “time-dependent” manner rather than a “concentration-dependent” manner. Time-dependent refers to the time that serum concentrations exceed the minimum-inhibitor-concentration (MIC) for the microorganism. Therefore, they are often dosed more frequently, rather than the concentration-dependent drugs, which can be dosed, for example, daily. The more “around-the-clock” dosing provides minor variation in peak and trough serum concentrations.[14]

Amoxicillin is an oral antimicrobial; whereas, ampicillin (which is structurally similar) can be given orally, intravenously, or intramuscularly. Amoxicillin comes in immediate-release or extended-release tablets. It also comes in a chewable tablet or a suspension. It may be mixed (after thoroughly shaking) and administered with formula, milk, water, fruit juice, ginger ale, or other cold drinks if given in suspension. The administration should take place immediately after mixing. Patients should not crush Extended-release tablets, and the administration should be within 1 hour after finishing a meal. Amoxicillin is sometimes preferred over penicillin in children because of its taste.

Dosing

• In adults, 750-1750 mg/day in divided doses every 8-12 hours.
• In Pediatric Patients > 3 Months of Age, 20-45 mg/kg/day in divided doses every 8-12 hours.
• Dosing for H. pylori Infection: Triple therapy: 1 gram amoxicillin, 500 mg clarithromycin, and 30 mg lansoprazole, all given twice daily (every 12 hours) for 14 days.
• Dual therapy: 1 gram amoxicillin and 30 mg lansoprazole, each given three times daily.

Dosing in Renal Impairment

• Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe.
• Severely impaired patients with a glomerular filtration rate of < 30 mL/min should not receive an 875-mg dose.
• Patients with a glomerular filtration rate of 10 to 30 mL/min should receive 500 mg or 250 mg every 12 hours, depending on the severity of the infection.
• Patients with a glomerular filtration rate less than 10 mL/min should receive 500 mg or 250 mg every 24 hours, depending on the severity of the infection.
• Hemodialysis patients should receive 500 mg or 250 mg every 24 hours, depending on the severity of the infection. They should receive an additional dose both during and at the end of dialysis.

Geriatric Consideration

• It is important to note that it is excreted in most people by the kidney, and some renal adjustment and extra caution may be necessary for renal insufficiency. Because elderly patients are more likely to have decreased renal function, the clinician should adjust the dose. It is reported to be partially dialyzable, and therefore, immediate-release tablets can be an option for dosing after hemodialysis.[15]

Pregnancy

• Amoxicillin is a pregnancy category B drug under the old FDA classification system, which means there have been no studies demonstrating clear risk. Amoxicillin is widely used in pregnant women. Based on available data, amoxicillin is usually considered compatible for use during pregnancy. The dose and duration of amoxicillin therapy in pregnant and postpartum women are the same as in nonpregnant adults.[16]

Breastfeeding

• An exclusively breastfed infant would be expected to receive a maximum daily dosage of about 0.1 mg/kg of amoxicillin with a maternal dose of 500 mg three times daily. This amounts to 0.25 to 0.5% of a typical infant amoxicillin dosage. As discussed above, amoxicillin produces low levels in milk that are not expected to cause adverse effects in breastfed infants. Occasionally, rash and disruption of the infant's gastrointestinal flora, resulting in diarrhea or thrush, have been reported. Consequently, amoxicillin is acceptable in nursing mothers.[17]

Adverse Effects

Common Adverse Drug Reactions: Amoxicillin is well-tolerated, but some common complaints can be gastrointestinal (GI) symptoms, such as nausea, vomiting, and diarrhea.

Superinfections: Mucocutaneous candidiasis, clostridium difficile associated diarrhea. Of note, patients who take amoxicillin may have less diarrhea than those who take ampicillin because of better absorption in the gut.[18]

Nephrotoxicity: Crystalluria, interstitial nephritis[19][20]

Hypersensitivity Reactions: Amoxicillin can lead to type-I, II, III, or IV reactions. It is essential to differentiate between a type-I and type-IV hypersensitivity reaction because one may be more dangerous than the other. A type-I hypersensitivity reaction is an IgE-mediated response to a sensitized patient that triggers widespread histamine release leading to an urticarial-like pruritic rash or severe anaphylaxis. A type-IV hypersensitivity reaction is not mediated by histamine release and is more papular or morbilliform and often not itchy. Professionals suggest that almost all patients that receive amoxicillin inadvertently for infectious mononucleosis develop a maculopapular rash caused by a type IV-mediated hypersensitivity reaction. These types of reactions are not known to cause anaphylaxis.[21]

Hepatotoxicity: instances of idiosyncratic liver injury have been reported in persons receiving amoxicillin.  The serum enzyme pattern associated with the liver injury is the hepatocellular pattern with marked elevations in AST and ALT. There are minimal elevations in alkaline phosphatase. Most patients recover rapidly after withdrawal of amoxicillin and rapid recovery after withdrawal. The cause of the liver injury associated with amoxicillin use is hypersensitivity. Rare cases of acute liver failure and vanishing bile duct syndrome have been reported. Corticosteroids have often been used to treat the allergic manifestations of penicillin-related immunoallergic hepatitis. Likelihood score: B (highly likely but rare cause of clinically apparent liver injury).[22]

Postmarketing Adverse Drug Reactions

Gastrointestinal: black hairy tongue, pseudomembranous colitis, hemorrhagic colitis[23]

Neurological: reversible hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, aseptic meningitis[24]

Hematological: hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and neutropenia[25]

Dermatological: serum sickness-like reactions, erythematous maculopapular rashes, exfoliative dermatitis, toxic epidermal necrolysis, hypersensitivity vasculitis[26]

Contraindications

• Any previous anaphylactic or serious skin reaction (for example, Stevens-Johnson syndrome) to amoxicillin or any other beta-lactam is a contraindication to amoxicillin. These reactions may have crossover sensitivity with cephalosporins or carbapenems. However, it is important to note that newer data has suggested a much lower cross-reactivity with cephalosporins and carbapenems than once suspected.

• An important consideration is determining if the patient’s allergic rash is a type-I or a type-IV hypersensitivity reaction. Occasionally patients will report a childhood allergy to amoxicillin, which is, in fact, a type-IV-mediated hypersensitivity reaction, often in the setting of infectious mononucleosis; this is not a contraindication to giving repeat amoxicillin. However, a type-1 mediated hypersensitivity reaction is a contraindication given that a repeat exposure puts the patient at risk for anaphylaxis.

• Skin testing has been approved to help assist in hypersensitivity to penicillins. Reports are that the risk of an allergic reaction in a patient with a positive skin test is roughly four percent. In contrast, a negative skin test has a relatively high sensitivity in ruling out a type-I hypersensitivity reaction.[27]

Monitoring

• It is essential to be aware of hypersensitivity reactions, and the patient should understand to notify their physician of any rashes.[27]

• In a patient on a short-term course of amoxicillin, no specific laboratory monitoring parameters are suggested. However, during prolonged administration, such as for osteomyelitis, it is essential to monitor renal and hepatic function and hematologic function periodically throughout treatment.[22]

• Mild diarrhea is often tolerable. However, prolonged diarrhea with fever and abdominal pain should prompt evaluation by a clinician for CDAD.[28]

• Penicillins in high doses can cause seizures which is a concern, especially in patients with renal failure.[29]

Toxicity

A prospective study of 51 pediatric patients at a poison-control center proposed that less than 250 mg/kg of amoxicillin overdosages are not associated with significant clinical symptoms(Product labeling FDA).

Clinical Features

• Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin.[19][20]

• Crystalluria leading to renal failure has been reported after amoxicillin overdosage in adult and pediatric patients.[30]

Management

• In case of overdose, discontinue medication, treat symptomatically.

• Maintain airway, breathing, and circulation.

• Clinicians should ensure adequate fluid intake to reduce the risk of amoxicillin crystalluria.

• Renal impairment appears to be reversible with the cessation of drug administration.

• Amoxicillin may be removed from circulation by hemodialysis.[31][15]

• For updated information about the overdose of amoxicillin, call a poison control center (1-800-222-1222)

Enhancing Healthcare Team Outcomes

Amoxicillin is a common antimicrobial often prescribed by nurse practitioners, primary care providers, and internists. The drug is safe, but it is essential always to get a good history of allergy before prescribing the medication. Due to the widespread use of amoxicillin, all healthcare providers should understand the mechanism, resistance patterns, adverse drug reactions, and toxicity management.[27][32]

The clinician usually initiates amoxicillin therapy for appropriate indication. However, a pharmacist should verify the dosing and duration are correct for the infection being treated and confirm that no drug interactions could impede treatment. Nursing staff can counsel on administration, verify adherence. Additionally, nurses should educate the patient not to discontinue amoxicillin when they start to feel better. If the nurse or pharmacist encounters any issues, they should address them with the prescriber immediately.

In case of significant overdose, triage nurses should admit the patient. Emergency physicians need to evaluate and manage nephrotoxicity. Nephrologist consultation is necessary for hemodialysis. Consult a medical toxicologist or poison control center for the latest information.[33] Infectious disease specialists should ensure proper management of pseudomembranous colitis resulting from irrational amoxicillin use. Additionally, infectious disease specialists should emphasize the importance of antimicrobial stewardship. Antimicrobial stewardship is a coordinated program that encourages the proper use of antimicrobials, enhances patient outcomes, decreases microbial resistance, and reduces the spread of infections caused by multidrug-resistant organisms.[34]

As depicted above, clinicians(MDs, DOs, NPs, PAs), specialists, pharmacists, nurses, and other healthcare providers should collaborate to maximize efficacy and minimize adverse drug reactions related to amoxicillin therapy. This type of interprofessional team approach and antimicrobial stewardship will improve the likelihood of more favorable patient outcomes.[35] [Level 2]