Continuing Education Activity

Amoxicillin is a widely utilized beta-lactam antimicrobial drug approved by the U.S. Food and Drug Administration (FDA) for use in the primary care setting. Amoxicillin is an aminopenicillin created by adding an extra amino group to penicillin to battle antibiotic resistance. This drug is indicated for the treatment of infections caused by susceptible isolates of selected bacteria, specifically those that are beta-lactamase–negative, including ear, nose, and throat infections, Helicobacter pylori eradication, lower respiratory and urinary tract infections, acute bacterial sinusitis, and skin and structure infections.

Amoxicillin is effective against a wide range of gram-positive bacteria, offering additional coverage against some gram-negative organisms compared to penicillin. Amoxicillin's spectrum of activity includes coverage against Streptococcus species, with heightened efficacy against Listeria monocytogenes and Enterococcus spp. Furthermore, amoxicillin also demonstrates effectiveness against Haemophilus influenzae, select Escherichia coli strains, Actinomyces spp., Clostridium species, Salmonella spp., Shigella spp., and Corynebacteria spp. This activity delves into the indications, mechanism of action, administration, contraindications, and adverse event profiles associated with amoxicillin. This activity equips clinicians with a comprehensive understanding of amoxicillin to optimally enhance their ability to manage infectious diseases in patients.

Objectives:

• Differentiate between the spectrum of activity of amoxicillin and other antimicrobial agents, understanding its coverage against various gram-positive and some gram-negative organisms compared to penicillin.

• Implement effective antimicrobial stewardship practices by selecting amoxicillin judiciously, considering its efficacy against specific bacteria causing the infection, and minimizing the risk of contributing to antimicrobial resistance.

• Select amoxicillin as a preferred agent for susceptible bacterial infections, considering its effectiveness against common pathogens and safety profile.

• Collaborate with other healthcare professionals to promote antimicrobial stewardship, enhancing outcomes and treatment efficacy for patients who might benefit from amoxicillin therapy.

Indications

Amoxicillin is a widely utilized beta-lactam antimicrobial drug approved by the U.S. Food and Drug Administration (FDA) for use in the primary care setting. Amoxicillin is an aminopenicillin created by adding an extra amino group to penicillin to battle antibiotic resistance. The medication is effective against a wide range of gram-positive bacteria, offering additional coverage against some gram-negative organisms compared to penicillin. Amoxicillin's spectrum of activity includes coverage against Streptococcus species, with heightened efficacy against Listeria monocytogenes and Enterococcus spp. Furthermore, amoxicillin also demonstrates effectiveness against Haemophilus influenzae, select Escherichia coli strains, Actinomyces spp., Clostridium species, Salmonella spp., Shigella spp., and Corynebacteria spp.

FDA-Approved Indications

Amoxicillin is indicated for treating infections caused by susceptible isolates of selected bacteria, specifically beta-lactamase–negative, in the conditions listed below.

• Ear, nose, and throat infections: Amoxicillin is approved for the treatment of tonsillitis, pharyngitis, and otitis media in adults and pediatric patients aged 12 and older. The microbiological spectrum covers infections caused by beta-lactamase–negative Streptococcus species (alpha- and beta-hemolytic isolates only), Streptococcus pneumoniae, Staphylococcus species, or H influenzae.[1]

• Helicobacter pylori eradication: H pylori eradication involves triple therapy using clarithromycin, amoxicillin, and lansoprazole to reduce the risk of duodenal ulcer recurrence. In addition, dual treatment with amoxicillin and lansoprazole is FDA-approved for eradicating H pylori infection.[2]

• Lower respiratory tract infections: Amoxicillin is prescribed for treating lower respiratory tract infections caused by beta-lactamase–negative Streptococcus species (limited to alpha- and beta-hemolytic strains), Pneumococcus or Staphylococcus species, or H influenzae. In cases of community-acquired pneumonia, the Infectious Diseases Society of America (IDSA) recommends a combination therapy comprising amoxicillin and a macrolide antibiotic.[3]

• Acute bacterial sinusitis: The treatment for acute bacterial sinusitis involves addressing infections caused by beta-lactamase–negative Streptococcus species (limited to alpha- and beta-hemolytic isolates), S pneumoniae, Staphylococcus species, or H influenzae.[4]

• Skin and skin structure infections: Amoxicillin in the immediate-release formulation is prescribed to treat skin infections caused by beta-lactamase–negative Streptococcus species (restricted to alpha- and beta-hemolytic strains), Staphylococcus species, or E coli.[5]

• Urinary tract infection: Amoxicillin is indicated for treating genitourinary tract infections caused by beta-lactamase–negative E coli, Proteus mirabilis, or Enterococcus faecalis.[6]

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

Off-label Uses

• Amoxicillin is often used for Lyme disease if there are contraindications for doxycycline.[8]

• Infectious endocarditis prophylaxis is recommended for individuals with high-risk cardiac conditions, such as a prosthetic cardiac valve or congenital heart disease, using amoxicillin.[9]

• Amoxicillin, combined with metronidazole, is used to treat periodontitis.[10] 

• Amoxicillin is often used for the treatment of actinomycosis.[11]

Mechanism of Action

Amoxicillin belongs to the class of beta-lactam antimicrobials. Beta-lactams bind to penicillin-binding proteins, inhibiting transpeptidation — a crucial step in cell wall synthesis involving cross-linking. This action activates autolytic enzymes in the bacterial cell wall, resulting in cell wall lysis and bacterial cell destruction. This mechanism is known as bactericidal killing.[12]

Amoxicillin administration can be combined with a beta-lactamase inhibitor, such as clavulanic acid or sulbactam. These inhibitors function by irreversibly binding to the catalytic site of the organism's beta-lactamase enzyme, preventing resistance to the original beta-lactam ring of amoxicillin. Although these inhibitors lack inherent bactericidal activity, their combination with amoxicillin may broaden its spectrum to include organisms producing the beta-lactamase enzyme.[13]

Pharmacokinetics

Absorption: Amoxicillin exhibits stability in the presence of gastric acid and is rapidly absorbed after oral administration, with average peak blood levels typically reached within 1 to 2 hours.

Distribution: Amoxicillin displays significant tissue and fluid diffusion throughout the body, with the exception of the brain and spinal fluid, except in cases where meningeal inflammation is present. Amoxicillin exhibits approximately 20% plasma protein binding.

Metabolism: The metabolism of amoxicillin involves oxidation, hydroxylation, and deamination processes. Amoxicillin is a substrate of organic anion transporters (OATs), specifically OATs 1 and 3.[14][15]

Elimination: Amoxicillin has an approximate half-life of 61.3 minutes, and about 60% of the administered dose is excreted in the urine within 6 to 8 hours. Co-administration of probenecid can delay amoxicillin excretion, as the majority of the drug is eliminated unchanged in the urine.

Administration

Bactericidal antimicrobials, such as amoxicillin, exhibit their greatest efficacy in a "time-dependent" manner rather than a "concentration-dependent" one. In the context of time-dependent action, the emphasis is on the duration during which serum concentrations exceed the minimum inhibitory concentration (MIC) for the targeted microorganism. Consequently, these antimicrobials are often administered more frequently than concentration-dependent drugs, which may have daily dosing regimens. The more frequent, "around-the-clock" dosing strategy aims to minimize variations in peak and trough serum concentrations.[16][17]

Available Dosage Forms

Amoxicillin is administered orally and is available in various forms, including immediate-release or extended-release tablets, chewable tablets, and suspension. After thorough shaking, the medication can be mixed and administered with formula, milk, water, fruit juice, ginger ale, or other cold drinks. Immediate administration is recommended after mixing. Extended-release tablets should not be crushed, and administration should occur within 1 hour after completing a meal. Amoxicillin, with a more palatable taste, is often preferred over penicillin in pediatric patients. In contrast, ampicillin is versatile, structurally similar, and suitable for oral, intravenous, or intramuscular administration.

Amoxicillin Dosages 

• Adults: For adults, the recommended dosage of amoxicillin is 750 to 1750 mg/d, divided into doses and administered every 8 to 12 hours.

• Pediatric: For pediatric patients 3 months and older, the recommended amoxicillin dosage is 20 to 45 mg/kg/d, divided into doses and administered every 8 to 12 hours.

• H pylori infection (triple therapy): For the treatment of H pylori infection, the recommended dosing for triple therapy involves administering 1 g of amoxicillin, 500 mg of clarithromycin, and 30 mg of lansoprazole twice daily (every 12 hours) for 14 days.

• H pylori infection (dual therapy): For dual therapy against H pylori infection, the recommended dosing is 1 g of amoxicillin and 30 mg of lansoprazole, each administered 3 times daily.

Specific Patient Populations

Hepatic impairment: The product labeling does not recommend dosage adjustments for individuals with hepatic impairment.

Renal impairment: Patients with impaired renal function typically do not necessitate a dose reduction unless the impairment is severe. However, individuals with severe renal impairment, defined by a glomerular filtration rate of <30 mL/min, should not receive an 875-mg amoxicillin dose. Patients with a glomerular filtration rate of 10 to 30 mL/min should receive 500 mg or 250 mg of amoxicillin every 12 hours, depending on the severity of the infection. Patients with a glomerular filtration rate <10 mL/min should receive 500 or 250 mg of amoxicillin every 24 hours, depending on the severity of the infection. Hemodialysis patients should be prescribed 500 or 250 mg of amoxicillin every 24 hours, with the dosage adjusted based on the infection severity. An additional dose is recommended both during and after dialysis.

Pregnancy considerations: Amoxicillin is classified as a pregnancy category B drug under the former FDA classification system, indicating a lack of studies demonstrating clear risk. This medication is widely used in pregnant women, and available data generally support its compatibility during pregnancy. The recommended dose and duration of amoxicillin therapy for pregnant and postpartum women align with those for nonpregnant adults.[18]

Breastfeeding considerations: An exclusively breastfed infant is anticipated to receive a maximum daily dosage of approximately 0.1 mg/kg of amoxicillin when the mother takes 500 mg thrice daily. This represents only 0.25% to 0.5% of a typical infant amoxicillin dosage. As discussed above, low levels of amoxicillin in breast milk are generally not anticipated to induce adverse effects in breastfed infants. Infrequent reports include rash and disturbances in the infant's gastrointestinal flora, leading to diarrhea or thrush. As a result, amoxicillin is considered acceptable for use in nursing mothers.[19]

Older patients: Notably, as amoxicillin is predominantly excreted through the kidneys, renal adjustments and additional caution may be warranted, especially in cases of renal insufficiency. Because older patients are more likely to have decreased renal function, the clinician should adjust the dosage. Amoxicillin is reportedly partially dialyzable; therefore, immediate-release tablets can be an option for dosing after hemodialysis.[20]

Pediatric patients: The therapeutic efficacy and safety of amoxicillin have been established for treating skin and soft tissue infections, respiratory tract infections, and genitourinary tract infections in pediatric patients. In neonates and infants, the elimination of amoxicillin may be delayed due to their incompletely developed renal function. Thus, dosage adjustments are necessary for pediatric patients aged 12 weeks or younger (3 months or younger). Oral amoxicillin exhibits potential as a safe substitute for parenteral ampicillin in neonatal sepsis regimens that include aminoglycosides, particularly in cases where hospitalization is not feasible.[21]

Adverse Effects

Common Adverse Drug Reactions

Although generally well-tolerated, amoxicillin may lead to common gastrointestinal symptoms, including nausea, vomiting, and diarrhea. Additional adverse drug reactions associated with amoxicillin are listed below.

Superinfections: Mucocutaneous candidiasis and Clostridium difficile–associated diarrhea (CDAD) are potential adverse effects of amoxicillin. Notably, individuals taking amoxicillin may experience less diarrhea than those taking ampicillin due to better absorption in the gut.[22]

Nephrotoxicity: Amoxicillin may cause crystalluria and interstitial nephritis.[23][24]

Hypersensitivity reactions: Amoxicillin has the potential to cause hypersensitivity reactions categorized as type I, II, III, or IV. Differentiating between a type-I and type-IV reaction is crucial due to varying danger levels. A type-I hypersensitivity reaction involves an IgE-mediated response in sensitized patients, inducing widespread histamine release, resulting in an urticarial-like pruritic rash or severe anaphylaxis. In contrast, a type-IV hypersensitivity reaction is not mediated by histamine release and typically presents as a more papular or morbilliform rash, often without itching. Notably, almost all patients receiving amoxicillin inadvertently for infectious mononucleosis may develop a maculopapular rash attributed to a type IV–mediated hypersensitivity reaction. Notably, reactions of this type are not associated with anaphylaxis.[25]

Hepatotoxicity: Cases of idiosyncratic liver injury have been reported in individuals receiving amoxicillin. The associated serum enzyme pattern reveals a hepatocellular pattern characterized by significant elevations in aspartate transaminase (AST) and alanine transaminase (ALT), with minimal increases in alkaline phosphatase. Most patients experience rapid recovery upon withdrawal of amoxicillin. The cause of liver injury associated with amoxicillin use is attributed to hypersensitivity. Although rare, cases of acute liver failure and vanishing bile duct syndrome have been reported. Corticosteroids are often used to treat allergic reactions caused by penicillin-related immunoallergic hepatitis, which is a rare cause of clinically apparent liver injury, with a likelihood score of B.[26]

Postmarketing Adverse Drug Reactions

Gastrointestinal: Gastrointestinal effects may include black hairy tongue, pseudomembranous colitis, and hemorrhagic colitis.[27]

Neurological: Neurological effects may encompass reversible hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, and aseptic meningitis.[28]

Hematological: Hematological effects may include hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and neutropenia.[29]

Dermatological: Dermatological effects may manifest as serum sickness-like reactions, erythematous maculopapular rashes, exfoliative dermatitis, toxic epidermal necrolysis, and hypersensitivity vasculitis.[30]

Drug-Drug Interactions

• Concomitant use of probenecid diminishes the renal tubular secretion of amoxicillin, leading to increased and prolonged amoxicillin blood levels.[31]

• Amoxicillin can induce abnormal prolongation of prothrombin time (increased INR) in patients taking oral anticoagulants, requiring meticulous monitoring and potential dosage adjustments for anticoagulation.[32]

• Concurrent administration of amoxicillin and allopurinol increases the incidence of rashes compared to amoxicillin alone.[33]

• Amoxicillin may alter intestinal flora, leading to reduced estrogen reabsorption and potentially diminishing the efficacy of combined oral estrogen or progesterone contraceptives.[34][35]

• Chloramphenicol, macrolides, sulfonamides, and tetracyclines can interfere with the bactericidal effects of penicillin, although the clinical significance of this interaction is not extensively documented.[36] In general, clinicians are advised to avoid combining bacteriostatic and bactericidal drugs.

• Intravesical BCG therapy should not be administered concomitantly with antibiotics, including amoxicillin, to mitigate the potential risk of interference with the clinical response to intravesical BCG.[37]

Drug-Laboratory Test Interactions

High urine concentrations of amoxicillin can cause false-positive reactions in urine glucose tests using certain detection methods. Clinicians should consider using alternative enzymatic glucose oxidase-based tests.

Contraindications

Understanding contraindications and nuances related to amoxicillin use is crucial for healthcare professionals. This overview explores contraindications stemming from previous anaphylactic reactions, considerations of crossover sensitivity, and the differentiation between type-I and type-IV hypersensitivity reactions in patients, offering insights into skin testing as a diagnostic tool.

• Prior occurrences of anaphylactic reactions or severe skin responses, such as Stevens-Johnson syndrome, to amoxicillin or other beta-lactams are a contraindication to amoxicillin.[38] These reactions may have crossover sensitivity with cephalosporins or carbapenems. Recent data suggests significantly lower cross-reactivity with these agents than once suspected.

• A critical consideration is distinguishing between type-I and type-IV hypersensitivity reactions when evaluating allergic rashes. Occasionally, patients may report a childhood allergy to amoxicillin, which is, in fact, a type-IV–mediated hypersensitivity reaction, which is often associated with infectious mononucleosis. Importantly, this is not a contraindication for administering repeat amoxicillin. However, a type-I–mediated hypersensitivity reaction constitutes a contraindication due to the risk of anaphylaxis upon repeat exposure.

• Skin testing is approved to aid in identifying hypersensitivity to penicillins, with reports indicating that the risk of an allergic reaction in patients with a positive skin test is approximately 4%. In contrast, a negative skin test exhibits a relatively high sensitivity in excluding a type-I hypersensitivity reaction.[39]

Monitoring

Ensuring the safe and effective use of amoxicillin involves attentive oversight. The essential monitoring considerations encompass hypersensitivity reactions, laboratory parameters during different courses of treatment, and potential adverse effects of amoxicillin, which require clinician evaluation. It is crucial to be vigilant for hypersensitivity reactions, and patients should promptly notify their physician of any developing rashes.[39] No specific laboratory monitoring parameters are suggested for patients on a short-term course of amoxicillin. However, during prolonged administration, such as for osteomyelitis, it is essential to periodically monitor renal and hepatic function and hematologic function throughout the treatment.[26] Although mild diarrhea is often tolerable, prolonged diarrhea with fever and abdominal pain should prompt evaluation by a clinician for CDAD.[40] High doses of penicillin can induce seizures, raising concerns, especially in patients with renal failure.[41]

Toxicity

A prospective study of 51 pediatric patients at a poison control center suggested that amoxicillin overdoses of less than 250 mg/kg are not associated with significant clinical symptoms, as per the FDA product labeling.

Signs and Symptoms of Overdose

• Interstitial nephritis leading to oliguric renal failure has been reported in a small number of patients following overdosage with amoxicillin.[23][24]

• Crystalluria leading to renal failure has been reported in both adult and pediatric patients following amoxicillin overdosage.[42]

Management of Overdose

• In case of amoxicillin overdose, clinicians should discontinue amoxicillin therapy and provide supportive care to patients.

• Clinicians should maintain the patient's airway, breathing, and circulation.

• Healthcare providers should ensure the patient maintains adequate fluid intake to mitigate 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.[43][20]

• Individuals should contact a poison control center at 1-800-222-1222 for updated information about an amoxicillin overdose.

Enhancing Healthcare Team Outcomes

Amoxicillin is a commonly prescribed antimicrobial by nurse practitioners, primary care providers, and internists. Although amoxicillin is considered a safe drug, it is crucial to obtain a thorough history of allergies before prescribing the drug. Due to the widespread use of amoxicillin, healthcare providers should have a comprehensive understanding of its mechanism, resistance patterns, adverse drug reactions, and toxicity management.[39][44]

Amoxicillin therapy is typically initiated by the clinician for the appropriate indication. However, a pharmacist must verify the dosing and duration, ensuring accuracy for the specific infection being treated. The pharmacist should also confirm that no drug interactions could impede the treatment's effectiveness. The nursing staff can provide counseling on administration and verify adherence. In addition, nurses should educate patients not to discontinue amoxicillin when they feel better. If the nurse or pharmacist encounters any issues, they should promptly address them with the prescriber.

In case of a significant overdose, triage nurses should admit the patient. Emergency physicians are responsible for evaluating and managing nephrotoxicity. Nephrologist consultation becomes necessary for hemodialysis. Consultation with a medical toxicologist or poison control center is recommended for the latest information.[45] Infectious disease specialists play a crucial role in ensuring the proper management of pseudomembranous colitis resulting from inappropriate amoxicillin use. In addition, they should emphasize the importance of antimicrobial stewardship—a coordinated program that promotes the appropriate use of antimicrobials, improves patient outcomes, diminishes microbial resistance, and mitigates the spread of infections caused by multidrug-resistant organisms.[46]

As illustrated above, clinicians (MDs, DOs, NPs, PAs), specialists, pharmacists, nurses, and other healthcare providers should collaborate to maximize the efficacy and minimize adverse drug reactions related to amoxicillin therapy. This interprofessional team approach and antimicrobial stewardship will enhance the likelihood of more favorable patient outcomes.[47]