What is the appropriate dosing regimen of amoxicillin‑clavulanate 625 mg in adults, including adjustments for renal impairment and contraindications?

Amoxicillin-Clavulanate 625 mg Dosing Guidelines for Adults

Amoxicillin-clavulanate 625 mg (500 mg amoxicillin/125 mg clavulanate) is dosed as one tablet three times daily for 7–14 days, depending on the infection type, with respiratory infections typically requiring 14 days and most other infections 7–10 days. 1

Standard Dosing Regimens by Indication

Respiratory Tract Infections

• Bronchiectasis exacerbations: 625 mg three times daily for 14 days when treating beta-lactamase-producing Haemophilus influenzae or Moraxella catarrhalis. 1
• Acute bacterial rhinosinusitis: 625 mg three times daily for 5–7 days in adults without risk factors; extend to 10 days if risk factors present (recent antibiotic use, age >65, comorbidities). 1, 2
• Community-acquired pneumonia (outpatient with comorbidities): 625 mg three times daily plus azithromycin 500 mg day 1, then 250 mg daily for 5–7 days total. 3 Never use amoxicillin-clavulanate as monotherapy for pneumonia—atypical pathogen coverage is mandatory. 3
• Chronic rhinosinusitis: 625 mg three times daily for 3 weeks (21 days) demonstrated comparable efficacy to ciprofloxacin in clinical trials. 1, 4

Alternative Dosing for Respiratory Infections

• 875 mg/125 mg twice daily is an acceptable alternative for respiratory infections, with equivalent clinical success rates (93% vs 88%, p=0.76) and significantly less severe diarrhea (1% vs 2%, p<0.05) compared to three-times-daily dosing. 1, 4, 5

Non-Respiratory Infections

• Skin and soft tissue infections: 625 mg three times daily for 7–10 days. 4
• Animal or human bites: 625 mg three times daily for 7–10 days. 4
• Urinary tract infections: 625 mg three times daily for 7 days (uncomplicated). 4

Critical Dosing Considerations

When to Use High-Dose Regimens Instead

• Switch to 2000 mg/125 mg twice daily (not the 625 mg formulation) when treating adults with recent antibiotic exposure (past 4–6 weeks), moderate-to-severe disease, age >65, comorbidities, or regional penicillin-resistant S. pneumoniae prevalence >10%. 2
• High-dose formulations achieve 90–92% predicted clinical efficacy versus 83–88% for standard doses in these populations. 2

Treatment Duration Algorithm

• Minimum 5 days for respiratory infections in adults, continuing until afebrile for 48–72 hours with no more than one sign of clinical instability. 3
• 7–10 days for most bacterial infections to prevent treatment failure and resistance development. 4
• 14 days for bronchiectasis exacerbations and infections with Pseudomonas aeruginosa. 1
• 14–21 days only when Legionella pneumophila, Staphylococcus aureus, or gram-negative enteric bacilli are identified. 3

Reassessment Timepoints

• At 3–5 days: If no clinical improvement in adults with sinusitis, escalate to high-dose amoxicillin-clavulanate or switch to a respiratory fluoroquinolone. 2
• At 72 hours: Lack of improvement or worsening warrants diagnostic reconsideration, possible imaging, and ENT referral. 2

Renal Impairment Adjustments

Dosing by Creatinine Clearance

• CrCl >30 mL/min: No adjustment needed; use standard 625 mg three times daily. 2
• CrCl 10–30 mL/min: Reduce to 625 mg twice daily. 6, 7
• CrCl <10 mL/min: Reduce to 625 mg once daily. 6, 7
• Hemodialysis patients: 625 mg once daily, with an additional 625 mg dose after each dialysis session (both amoxicillin and clavulanate are significantly removed by dialysis, with fractional removal of 0.64–0.65). 6

Pharmacokinetic Rationale

• Amoxicillin clearance decreases more dramatically than clavulanate clearance in renal impairment, causing the amoxicillin-to-clavulanate ratio to increase from 4.9 in normal renal function to 14.7 in dialysis patients. 7
• Non-renal clearance of both components is reduced in end-stage renal disease, suggesting some degree of hepatic impairment. 6

Contraindications and Cautions

Absolute Contraindications

• History of cholestatic jaundice or hepatic dysfunction associated with prior amoxicillin-clavulanate use. 8
• Confirmed penicillin allergy (IgE-mediated hypersensitivity). 2
• Infectious mononucleosis (high risk of maculopapular rash). 8

Relative Contraindications

• Recent antibiotic use within 90 days: Select an agent from a different antibiotic class to reduce resistance risk. 3
• Regions with >25% pneumococcal macrolide resistance: Do not use amoxicillin-clavulanate monotherapy for pneumonia; combination therapy is mandatory. 3

Special Populations

• Elderly patients (>65 years): Consider high-dose formulations due to increased risk of resistant organisms and comorbidities. 2
• Pregnancy: Category B; generally safe but use only when clearly needed. 8
• Hepatic impairment: Use with caution; monitor liver function tests. 6

Common Pitfalls to Avoid

• Do not substitute two 250 mg/125 mg tablets for one 500 mg/125 mg tablet—this results in excessive clavulanate dosing (250 mg vs 125 mg) and significantly increases gastrointestinal adverse effects without added antimicrobial benefit. 4
• Do not use amoxicillin-clavulanate monotherapy for pneumonia—atypical pathogens account for 10–40% of cases and require macrolide or doxycycline coverage. 3
• Do not extend therapy beyond 7–8 days in clinically improving patients without specific indications (Legionella, S. aureus, gram-negative bacilli). 3, 4
• Do not delay reassessment—failure to improve by 72 hours suggests resistant organisms, complications, or incorrect diagnosis. 2

Adverse Effects and Tolerability

• Gastrointestinal effects are the most common adverse events, occurring in approximately 9% of patients, with diarrhea reported in 40–43% and severe diarrhea in 7–8%. 4, 9
• Twice-daily dosing (875 mg/125 mg) causes significantly less severe diarrhea than three-times-daily dosing (1% vs 2%, p<0.05). 4
• Clavulanate dose is restricted to 125 mg in adult formulations due to tolerability issues. 8

Drug Interactions

• Avoid concurrent aminoglycosides in patients with renal dysfunction or when using other nephrotoxic drugs to minimize nephrotoxicity risk. 4
• Antacids, calcium, iron, and magnesium supplements may reduce absorption; separate administration by 2–3 hours. 3