Continuing Education Activity

Amoxicillin-clavulanate is an antibiotic commonly used in emergency departments and primary care offices worldwide. This drug combination offers broader coverage by combining amoxicillin, a penicillin derivative effective against gram-positive and gram-negative bacteria, with clavulanic acid, which counteracts β-lactamase–producing strains. This medication is effective against methicillin-sensitive Staphylococcus aureus (MSSA) and Neisseria species. Indications for amoxicillin-clavulanate administration also include community-acquired pneumonia (CAP), chronic group A streptococci carriers, and small intestinal bacterial overgrowth (SIBO); the efficacy of amoxicillin-clavulanate in treating SIBO approximates 50%. Amoxicillin-clavulanate is also indicated for treating acute bacterial rhinosinusitis; the Infectious Diseases Society of America (IDSA) and the American Academy of Otolaryngology's Head and Neck Surgery guidelines recommend this combination medication over amoxicillin alone.

Healthcare professionals play a critical role in antimicrobial stewardship by prescribing amoxicillin-clavulanate appropriately to prevent resistance. Understanding this drug's indications, contraindications, and associated adverse reactions aids in optimizing dosage regimens. Monitoring for interactions and understanding clinical toxicology is essential for safe and effective patient care. Familiarity with the pharmacological features of amoxicillin-clavulanate enables informed decision-making, contributing to improved patient outcomes.

Objectives:

• Assess the antimicrobial coverage of amoxicillin-clavulanate based on its mechanism of action.

• Identify the indications for amoxicillin-clavulanate administration.

• Identify the adverse reactions associated with amoxicillin-clavulanate administration.

• Implement effective collaboration and communication among interprofessional team members to optimize amoxicillin-clavulanate administration, improve patient outcomes, and prevent antimicrobial resistance.

Indications

Amoxicillin-clavulanate is one of the most frequently prescribed antimicrobial combinations in emergency departments and primary care offices worldwide. Amoxicillin is a penicillin derivative and has similar activity against gram-positive and gram-negative bacteria, including Listeria monocytogenes, Haemophilus influenzae, Moraxella catarrhalis, Corynebacterium diphtheria, Escherichia coli, and Klebsiella pneumoniae, in addition to various Streptococcus, Enterococcus, Salmonella, Shigella, and Borrelia species. With the addition of clavulanic acid, the coverage extends to all β-lactamase-producing strains of these organisms and methicillin-sensitive Staphylococcus aureus (MSSA), Neisseria species, Proteus species, Pasteurella multocida, and Capnocytophaga canimorsus, among others.[1][2] 

The American Thoracic Society and Infectious Diseases Society of America guidelines provide initial treatment strategies for patients with community-acquired pneumonia. For patients with comorbidities, these guidelines recommend combination therapy involving amoxicillin-clavulanate or cephalosporin combined with a macrolide or doxycycline. Alternatively, monotherapy with a respiratory fluoroquinolone is also considered appropriate.[3] The American College of Gastroenterology guidelines suggest using amoxicillin-clavulanate to treat small intestinal bacterial overgrowth (SIBO). However, its efficacy is only about 50% for this indication.[4] According to the Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for Acute Bacterial Rhinosinusitis (ABRS), amoxicillin-clavulanate is preferred over amoxicillin alone as the initial antibiotic therapy.[5] The American Academy of Otolaryngology's Head and Neck Surgery guidelines also endorse amoxicillin-clavulanate for treating ABRS.[6] The IDSA recommends using amoxicillin-clavulanate in specific scenarios for chronic group A Streptococcus (GAS) carriers. These indications include a community outbreak of acute rheumatic fever, acute post-streptococcal glomerulonephritis, or invasive group A streptococcal (GAS) infection; an outbreak of GAS pharyngitis within a closed or partially closed community; for individuals with a family or personal history of acute rheumatic fever; or when tonsillectomy is considered for patients who are Streptococcus carriers.[7]

FDA-Approved Indications

Amoxicillin-clavulanate is approved by the United States Food and Drug Administration to treat the conditions listed below.[8][3][9][10][6][11][12][13][14]

• Aspiration pneumonia
• Community-acquired pneumonia
• Acute bacterial rhinosinusitis
• Urinary tract infection
• Acute otitis media
• Skin or soft tissue infection

Off-Label Uses

Amoxicillin-clavulanate may help manage the conditions listed below.[15][7][16][17][18][19][20][21][22][23][24][25] These indications have not been approved by the FDA.

• Bite wounds
• Group A streptococcal infections
• Impetigo
• Acute exacerbations of chronic obstructive pulmonary disease and bronchiectasis
• Diabetic foot infections
• Odontogenic infections
• Peritonsillar cellulitis or abscess
• Thoracic empyema (Actinomyces naeslundii)
• Pasteurella multocida bacteremia
• Bacillus anthracis (anthrax) postexposure prophylaxis

Mechanism of Action

Amoxicillin is a broad-spectrum β-lactam penicillin derivative that targets and kills bacteria by inhibiting the biosynthesis of the peptidoglycan layer of the bacterial cell wall. This outermost layer of the cell wall is responsible for the structural integrity of the cell. Peptidoglycan synthesis involves the facilitation of DD-transpeptidases, a type of penicillin-binding protein (PBP). Amoxicillin works by binding to these PBPs and inhibiting peptidoglycan synthesis, which interrupts the construction of the cell wall and ultimately leads to the destruction, or lysis, of the bacteria.[1][26]

Various bacterial species have progressively developed resistance to standard β-lactam antimicrobials by producing enzymes called β-lactamases. These enzymes target and hydrolyze the β-lactam ring, a key component of penicillin and similar antimicrobials. Clavulanic acid is a β-lactamase inhibitor often combined with amoxicillin to extend its coverage and reduce resistance. Clavulanate has minimal antimicrobial activity but prevents bacterial degradation of β-lactams by binding and deactivating β-lactamases, ensuring amoxicillin's antimicrobial mechanism remains intact.[1][26][27]

Pharmacokinetics

Absorption: No significant difference has been observed between patients taking amoxicillin after fasting or with meals. However, clavulanate potassium absorption is increased when taken with food.

Distribution: Amoxicillin is approximately 18% bound to serum proteins, and clavulanic acid is about 25% bound. Additionally, amoxicillin is transported by organic anion transporters (OATs) 1 and 3. Amoxicillin diffuses readily into most body tissues and fluids, except the brain and spinal fluid. Amoxicillin and clavulanic acid have been detected in middle ear effusions.

Metabolism: Amoxicillin is primarily eliminated unchanged in the urine. Between 50% and 85% of the oral dose is eliminated within 6 hours. The metabolism of amoxicillin involves various processes, including oxidation, hydroxylation, and deamination. In contrast, clavulanate is metabolized considerably, and between 25% and 40% of the drug is excreted unchanged in the urine.[28][29][30]

Elimination: After oral administration of amoxicillin and clavulanate potassium, the approximate half-life is 1.3 hours for amoxicillin and 1 hour for clavulanic acid.

Administration

Available Dosage Forms and Strengths

Amoxicillin-clavulanate is only available in oral formulations and, like most bactericidal antibiotics, needs to be administered at regularly scheduled intervals to minimize differences in the peak and trough concentrations. This approach maintains consistent serum concentrations above the minimum inhibitory concentration (MIC) needed to destroy the targeted organism, generally accomplished with administration every 8 to 12 hours.[31] Amoxicillin-clavulanate is available as immediate or extended-release tablets, chewable tablets, and reconstituted suspensions. Taking this antimicrobial with food is recommended to enhance absorption and minimize any adverse gastrointestinal symptoms.[10][26]

The oral suspension is available for reconstitution in the following combinations. For better palatability in the pediatric population, apple, banana cream, bubble gum, cherry, or watermelon flavoring may be supplemented. Before interchanging strengths, dosage forms should be verified to contain the same amoxicillin-to-clavulanic acid ratio. The amoxicillin 600 mg and potassium clavulanate 42.9 mg combination is not interchangeable with other immediate-release formulations. To maximize its longevity and effectiveness, the reconstituted solution should be refrigerated and shaken well before administration.

• Amoxicillin 125 mg and potassium clavulanate 31.25 mg per 5 mL
• Amoxicillin 200 mg and potassium clavulanate 28.5 mg per 5 mL
• Amoxicillin 250 mg and potassium clavulanate 62.5 mg per 5 mL
• Amoxicillin 400 mg and potassium clavulanate 57 mg per 5 mL
• Amoxicillin 600 mg and potassium clavulanate 42.9 mg per 5 mL

Oral tablets are available in the following combinations. Before interchanging strengths, dosage forms should be verified to contain the same amoxicillin-to-clavulanic acid ratio. The combination of amoxicillin 1000 mg and potassium clavulanate 62.5 mg is not interchangeable with other immediate-release formulations. Amoxicillin 250 mg and potassium clavulanate 125 mg tablets are not recommended for pediatric patients due to the higher amount of clavulanate than other strengths.

• Amoxicillin 250 mg and potassium clavulanate 125 mg
• Amoxicillin 500 mg and potassium clavulanate 125 mg
• Amoxicillin 875 mg and potassium clavulanate 125 mg
• Amoxicillin 200 mg and potassium clavulanate 28.5 mg (chewable)
• Amoxicillin 400 mg and potassium clavulanate 57 mg (chewable)
• Amoxicillin 1000 mg and potassium clavulanate 62.5 mg (12-hour, extended-release)

Adult Dosage

• Immediate-release: 500 mg every 8 to 12 hours, or 875 mg every 12 hours
• Extended-release: 2 g every 12 hours

Pediatric Dosage

• Weight over 40 kg: 250 or 500 mg every 8 hours, or 500 or 875 mg every 12 hours
• 12 weeks and older: Amoxicillin 20 to 40 mg/kg/day divided every 8 hours, or 25 to 45 mg/kg/day divided every 12 hours
• Neonates and infants: Amoxicillin 30 mg/kg/day divided every 12 hours. The 125 mg per 5 mL oral suspension is recommended for these patients.

Specific Patient Populations

Hepatic impairment: This medication should be discontinued if signs or symptoms of hepatitis (eg, hepatic dysfunction, cholestatic jaundice) occur. Clinicians should monitor liver function in patients with hepatic impairment. The product label has no information regarding this patient population.[32]

Renal impairment: As the kidney primarily eliminates amoxicillin from the body, dosage adjustment is recommended for patients with severe renal impairment (CrCL<30 mL/min).[33]

Pregnancy considerations: Amoxicillin-clavulanate is a Pregnancy Category B medication.

Breastfeeding considerations: Amoxicillin is excreted in human milk and may lead to sensitization of nursing infants. Restlessness, diarrhea, or rash may occur occasionally. Amoxicillin-potassium clavulanate should be administered cautiously to a patient who is breastfeeding.[34]

Pediatric patients: See above.

Older patients: The dosage of amoxicillin-clavulanate for older adults should be based on renal function and any concomitant medications.[35]

Adverse Effects

Amoxicillin-clavulanate is generally safe and well-tolerated in the general population, with the vast majority of adverse effects being mild gastrointestinal symptoms, including: 

• Diarrhea
• Nausea
• Vomiting
• Abdominal discomfort

The incidence of diarrhea is higher in patients receiving amoxicillin-clavulanate than with amoxicillin alone.[36] Additionally, there is a moderately increased risk of secondary Clostridioides difficile colitis compared to other antimicrobial classes. Women taking this medication can also develop vaginitis secondary to vaginal mycosis or candidiasis.[37]

Dermatologic effects are less common and generally associated with hypersensitivity reactions. These reactions range from simple pruritis or urticaria to severe and life-threatening manifestations, such as anaphylaxis, Steven-Johnson syndrome, or toxic epidermal necrolysis. Classically, a morbilliform rash will present shortly after initiation of amoxicillin in patients misdiagnosed with streptococcal pharyngitis when they actually have infectious mononucleosis.[26][38][39][40]

Rare complications of amoxicillin-clavulanate administration include:[41][42][43]

• Prolonged prothrombin time
• Vasculitis
• Thrombocytopenia
• Cholestatic jaundice
• Elevated serum alkaline phosphatase
• Hepatitis
• Hepatotoxicity

High-dose penicillins can cause seizures, which is particularly concerning for patients with poor renal function.

Drug-Drug Interactions

• Probenecid (Risk D): Concurrent use of probenecid and amoxicillin-clavulanate results in prolonged and elevated blood concentrations of amoxicillin. Therefore, coadministration of probenecid is not recommended.
• Oral Anticoagulants: Coadministration of amoxicillin and oral anticoagulants may lead to abnormally prolonged prothrombin time. Appropriate monitoring and dose adjustment of oral anticoagulants are recommended to achieve the desired level of anticoagulation.
• Allopurinol: Coadministration may increase the incidence of allergic or hypersensitivity reactions associated with amoxicillin administration.
• Combined Oral Contraceptives: Amoxicillin-clavulanate administration may hinder the intestinal flora involved in estrogen reabsorption, reducing the efficacy of oral estrogen/progesterone combination contraceptives.

Contraindications

Liver Disease 

There are no guidelines for dosage adjustments for patients with hepatic impairment, but extreme caution is necessary for this population. This medication is contraindicated for any patient with a prior history of amoxicillin or clavulanic acid-induced hepatic dysfunction.[42]

Hypersensitivity Reactions 

The administration of amoxicillin to patients with a history of hypersensitivity reactions to amoxicillin, clavulanic acid, or other β-lactam antimicrobials is contraindicated. As amoxicillin is a penicillin derivative, there is a high likelihood of crossover hypersensitivity in patients with a documented penicillin allergy. In this population, clinicians should consider alternative antibiotics.[41]

Warning and Precautions

• Renal impairment: Caution is warranted when treating patients on hemodialysis or with severe renal impairment (CrCL <30 mL/min). As this antibiotic is primarily eliminated renally, individuals with kidney disease require dose adjustments and closer monitoring.[33]

• Drug-induced enterocolitis syndrome (DIES): The FDA recently listed drug-induced enterocolitis syndrome (DIES) as a potential complication of amoxicillin-clavulanate administration. Drug-induced enterocolitis syndrome (DIES) is a non-IgE-mediated hypersensitivity reaction involving the gastrointestinal system that typically occurs 2 to 4 hours after taking certain drugs. Amoxicillin and amoxicillin-clavulanate are frequently implicated. Symptoms include vomiting, abdominal pain, diarrhea, pallor, and dehydration, which can be severe and lead to hypovolemic shock. Neutrophilic leukocytosis is common. DIES primarily affects pediatric patients. If DIES is suspected, the offending drug should be discontinued, and appropriate treatment should be initiated immediately.[44]

• Phenylketonuria: Administering aspartame-containing formulations of amoxicillin-clavulanic acid should be avoided for patients with this genetic disorder. Aspartame is metabolized into various components in the gastrointestinal tract, including phenylalanine. Excessive aspartame can cause elevated phenylalanine levels in patients with PKU. Aspartame-free formulations should be prioritized to prevent potential neurological complications associated with elevated phenylalanine levels.[45]

Monitoring

Patients taking amoxicillin-clavulanate require close monitoring for hypersensitivity and secondary infections, such as C difficile colitis or candidiasis. Intermittent hepatic, renal, and hematologic function testing is indicated for prolonged treatment exceeding  10 days.[42] Clinicians should regularly obtain liver function markers in patients with hepatic impairment up to several weeks after discontinuing amoxicillin-clavulanate.[43]

Toxicity

Nephrotoxicity 

Excessive amoxicillin and clavulanate potassium doses may cause interstitial nephritis and oliguric renal failure. Crystalluria, which can progress to renal failure, has also been reported. Higher doses of intravenous amoxicillin (HDIVA) can lead to acute kidney injury.[46] Immediate discontinuation of amoxicillin-clavulanate is crucial for suspected overdoses. Symptomatic treatment and supportive care should be provided as necessary. Maintaining adequate fluid intake and promoting diuresis are essential to reduce the risk of crystalluria. Hemodialysis may be considered to enhance clearance, particularly in patients with severe overdose or renal impairment.

Hepatotoxicity 

Amoxicillin-clavulanate is an excellent antimicrobial but is one of the most frequent causes of idiosyncratic drug-induced hepatic injury.[47] Men and patients older than 50 are at increased risk compared to women. Other potential contributors to liver disease include genetic polymorphisms, antiretroviral therapy, and concomitant use of medications that affect the cytochrome P450 pathway. Symptoms generally begin 2 to 3 weeks after initiation but may occur sooner or be delayed up to 12 weeks. Treatment involves immediate discontinuation of the offending agent and limiting the use of other hepatotoxic drugs. N-acetylcysteine and corticosteroids can also considered. However, the benefits of these medications are likely marginal. Administration of a bile acid sequestrant, such as cholestyramine, may provide symptomatic relief from pruritis. The majority of patients achieve a full, albeit prolonged, recovery. Additionally, a few may develop liver failure and require a transplant to survive.[42][43][48][49]

Enhancing Healthcare Team Outcomes

All drug-related reactions, including drug-induced hepatic injury, have the potential to lead to significant morbidity or mortality if not appropriately identified and managed. Open and effective interprofessional communication is essential among all medical team members. Proper management begins in the primary care office or emergency department, with physicians maintaining broad differentials and a high index of suspicion through clinical gestalt and information gained from a thorough history and appropriate physical exam and subsequent laboratory testing. Patients with drug-induced hepatic injury secondary to antimicrobial use may present with liver injury days to weeks after completing a course of antibiotics, and a direct correlation may not be straightforward. If there is suspicion of drug-induced hepatic injury, identifying and discontinuing the offending agent is the primary goal of treatment. The involvement of a specialist, such as a hepatologist, can be beneficial, especially when there is a concern for acute liver failure or chronic liver disease or the diagnosis remains unclear after the initial evaluation. Furthermore, early transport to liver transplant facilities can be advantageous in patients with evidence of liver failure or who are at high risk.[50] Other treatment modalities include corticosteroids and N-acetylcysteine. However, the benefits are likely marginal, and their use should be in conjunction with a specialist.[49]

In summary, proactive instead of reactive methods are always more effective. Proper antimicrobial stewardship can decrease unnecessary use of antimicrobials, reduce the incidence of drug-related adverse effects, and limit the rate of antimicrobial resistance. This stewardship is only one aspect of amoxicillin-clavulanate management by an interprofessional team. Information sharing between emergency medicine and primary care physicians can help identify suspected adverse reactions early and improve appropriate antimicrobial selection for individuals undergoing treatment. The pharmacist can check dose and duration, provide antibiogram data, and assess for drug interactions that may interfere with therapy. Nurses can administer the medication, counsel the patient on proper administration, and monitor for adverse events and therapeutic effectiveness. When a severe adverse reaction has occurred, the early involvement of a specialist can limit the severity of the disease and increase the chance of a complete and uneventful recovery. All these exemplify an interprofessional team approach that improves the odds of optimal patient outcomes. An interprofessional team approach and communication among clinicians (MDs, DOs, NPs, PAs), infectious disease specialists, pharmacists, and nurses are crucial to reducing adverse effects and antimicrobial resistance and enhancing patient outcomes associated with amoxicillin-clavulanate therapy.