Amoxicillin-Clavulanate: Drug Class, Dosing, Side Effects, Contraindications, and Renal Adjustments
Drug Classification
Amoxicillin-clavulanate is a β-lactam/β-lactamase inhibitor combination antibiotic that pairs amoxicillin (a semisynthetic aminopenicillin) with clavulanic acid (a β-lactamase inhibitor) to provide broad-spectrum coverage against β-lactamase-producing organisms 1, 2.
- The combination is active against both β-lactamase producer and nonproducer strains, including Gram-positive cocci (Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus), Gram-negative cocci (Neisseria gonorrhoeae, Moraxella catarrhalis), Gram-negative bacilli (Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae), and anaerobes 3.
Adult Dosing
Standard-Dose Regimens
For mild to moderate infections, the standard adult dose is 500 mg amoxicillin/125 mg clavulanate every 8 hours OR 875 mg/125 mg twice daily for 7-10 days 1.
- For respiratory tract infections without risk factors, 625 mg (500 mg amoxicillin/125 mg clavulanate) three times daily is recommended 1.
- For non-severe pneumonia, 625 mg three times daily or 875 mg/125 mg twice daily for 7-10 days is appropriate 1.
High-Dose Regimens
For infections caused by resistant pathogens or in patients with specific risk factors, use 2000 mg amoxicillin/125 mg clavulanate twice daily 1.
High-dose therapy is indicated for patients with 1:
- Recent antibiotic use within the past 4-6 weeks
- Failed previous antibiotic therapy
- Moderate to severe infections
- Age over 65 years
- Immunocompromised status
- High prevalence of resistant bacteria (>10% penicillin-resistant S. pneumoniae)
- Smokers or exposure to secondhand smoke
- Close contact with children in daycare
Severe Infections Requiring IV Therapy
For hospital-treated severe pneumonia, administer 1.2 g IV three times daily 1.
- Switch from IV to oral formulation as soon as clinically appropriate 1.
Specific Indications
For acute bacterial sinusitis with risk factors, use 625 mg three times daily for 5-7 days 1.
- For animal or human bite infections, use 875 mg/125 mg twice daily 1.
- Treatment duration for sinusitis is 5-7 days, which is as effective as 10 days in most cases 1.
Pediatric Dosing
Standard-Dose Regimen
For children with uncomplicated infections, administer 45 mg/kg/day of amoxicillin with 6.4 mg/kg/day of clavulanate divided into 2 doses 1, 4.
High-Dose Regimen
For children with risk factors, use 80-90 mg/kg/day of amoxicillin with 6.4 mg/kg/day of clavulanate divided into 2 doses 1, 4.
High-dose therapy is indicated for children with 4:
- Age under 2 years
- Daycare attendance
- Recent antibiotic treatment within 30 days
- Incomplete Haemophilus influenzae type b vaccination
- Moderate to severe illness
- Geographic area with high prevalence of penicillin-resistant S. pneumoniae (>10%)
The maximum dose is 4000 mg/day of amoxicillin component regardless of weight 1, 4.
Age-Based Oral Dosing
- Children 1-12 months: 2.5 ml of 125/31 suspension three times daily 4
- Children 1-6 years: 5 ml of 125/31 suspension three times daily 4
- Children 7-12 years: 5 ml of 250/62 suspension three times daily 4
- Children 12-18 years: 1 tablet (250/125) three times daily 4
IV Dosing for Children
For pediatric patients requiring IV therapy, administer 30 mg/kg three times daily (every 8 hours) based on the amoxicillin component 5.
- The standard IV dose is 100-200 mg/kg/day of the amoxicillin component, divided every 6-8 hours 5.
- Administration should be given as IV infusion over 15-30 minutes 5.
Treatment Duration
For most pediatric respiratory infections, treat for 10 days 4.
- For bacterial pneumonia, continue treatment for 10 days 4.
- Clinical improvement should be evident within 48-72 hours; if no improvement or worsening occurs, reevaluate the diagnosis and consider switching antibiotics 1, 4.
Common Side Effects
The most frequently reported adverse events are mild gastrointestinal disturbances, particularly diarrhea 2.
- Diarrhea is generally less frequent with twice-daily than with three-times-daily dosing 2.
- The 14:1 ratio of amoxicillin to clavulanate in the high-dose formulation is less likely to cause diarrhea than other amoxicillin-clavulanate preparations 1, 4.
- Other common adverse effects include nausea, vomiting, and rash 4.
- In children, diaper dermatitis (51% vs 35% placebo) and thrush may occur 4.
Serious adverse reactions include anaphylactic reactions, severe cutaneous adverse reactions, and Clostridioides difficile-associated diarrhea (CDAD) 6.
Common Pitfall to Avoid
Do not prescribe amoxicillin-clavulanate to patients with infectious mononucleosis, as skin rash occurs frequently in these patients 6.
Contraindications
Amoxicillin-clavulanate is contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate, or any β-lactam antibacterial drug 6.
- It is also contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin-clavulanate 6.
Alternative Treatments for Penicillin Allergy
For adults allergic to penicillin, use doxycycline or respiratory fluoroquinolones (levofloxacin or moxifloxacin) 1.
- For children with non-type I penicillin allergy, use clindamycin plus a third-generation oral cephalosporin 1.
Renal Dose Adjustments
In patients with renal insufficiency, prolong the dosing interval according to creatinine clearance to avoid drug accumulation 4.
- For adults and pediatric patients aged 3 months and older weighing greater than 40 kg, dosage adjustments are required based on creatinine clearance 6.
- The dose should be significantly reduced in children with altered renal function due to the renal elimination of both amoxicillin and clavulanic acid 4.
Critical Dosing Consideration
For patients weighing over 40 kg, dose as an adult rather than using pediatric weight-based calculations 1.
- Verify that adult dosing is used for patients ≥40 kg to avoid dosing errors 1.
Important Clinical Considerations
Serum levels of amoxicillin increase linearly with the dose, and the difference in the incidence of adverse effects between lower and higher doses is generally negligible 4.
- The high-dose formulation (90/6.4 mg/kg/day) eradicated penicillin-resistant S. pneumoniae with MICs of 2-4 mg/L in clinical trials, with clinical response rates of 76-95% 4.
- The high-dose formulation provides a 14:1 ratio of amoxicillin to clavulanate, which achieves middle ear fluid concentrations adequate to overcome penicillin-resistant S. pneumoniae 4.
Reassessment Protocol
If there is no improvement after 72 hours, consider changing the antibiotic or reevaluating the diagnosis with cultures, computed tomography, or endoscopy 1.