Amoxicillin‑Clavulanate (Co‑Amoxiclav): Comprehensive Clinical Guide
Indications
Amoxicillin‑clavulanate is first‑line therapy for acute bacterial rhinosinusitis, acute otitis media, community‑acquired pneumonia, and exacerbations of chronic bronchitis when β‑lactamase‑producing organisms (Haemophilus influenzae, Moraxella catarrhalis) or drug‑resistant Streptococcus pneumoniae are suspected. 1, 2
- Acute bacterial rhinosinusitis (ABRS): Prescribe only when symptoms persist ≥10 days without improvement, severe symptoms (fever ≥39°C with purulent discharge) last ≥3–4 consecutive days, or "double sickening" (initial improvement followed by worsening) occurs. 2
- Acute otitis media (AOM): Use in children <2 years, those with bilateral AOM, severe presentation, recent antibiotic exposure (past 30 days), or daycare attendance. 1
- Community‑acquired pneumonia (CAP): Indicated for outpatient children <5 years with presumed bacterial pneumonia, especially with incomplete Haemophilus influenzae type b vaccination or concurrent purulent otitis media. 1
- Skin/soft tissue infections: Effective for animal or human bite wounds requiring coverage of oral anaerobes and Pasteurella species. 3
Adult Dosing Regimens
Standard‑Dose (Uncomplicated Infections)
875 mg/125 mg orally twice daily for 5–7 days is the preferred regimen for uncomplicated ABRS, providing 90–92% predicted clinical efficacy against the principal pathogens. 2, 3
- Alternative: 500 mg/125 mg three times daily for 7–10 days for respiratory tract infections without risk factors. 3
- Shorter courses (5–7 days) are equally effective as 10‑day regimens and cause fewer adverse effects in uncomplicated adult ABRS. 2, 3
High‑Dose (Risk‑Factor Patients)
2 g/125 mg orally twice daily when any of the following are present: 2, 3
- Recent antibiotic use (past 4–6 weeks)
- Age >65 years
- Daycare exposure (close contact with children attending daycare)
- Moderate‑to‑severe symptoms
- Comorbidities (diabetes, chronic cardiac/hepatic/renal disease)
- Immunocompromised state
- Geographic area with >10% prevalence of penicillin‑resistant S. pneumoniae
- Frontal or sphenoidal sinusitis
This high‑dose regimen achieves 90–92% predicted efficacy against drug‑resistant S. pneumoniae and β‑lactamase‑producing organisms. 2, 3
Renal Dosing Adjustments
For patients on hemodialysis: 875 mg/125 mg once daily immediately after each dialysis session (typically three times per week). 2
- Rationale: Both amoxicillin and clavulanate are removed during dialysis; post‑dialysis dosing maintains therapeutic levels throughout the interdialytic interval. 2
- Do not use standard twice‑daily dosing in end‑stage renal disease—it leads to drug accumulation and increased gastrointestinal adverse effects. 2
Pediatric Dosing Regimens
High‑Dose (First‑Line for Most Infections)
90 mg/kg/day (amoxicillin component) + 6.4 mg/kg/day (clavulanate) divided into 2 doses for 10–14 days is strongly recommended as initial therapy for children ≥3 months. 1, 3
- Maximum single dose: 2 g amoxicillin per dose regardless of weight. 1
- This 14:1 ratio formulation causes less diarrhea than other amoxicillin‑clavulanate preparations while maintaining efficacy. 1, 3
Standard‑Dose (Uncomplicated Cases Without Risk Factors)
45 mg/kg/day (amoxicillin component) divided into 2 doses for 10–14 days may be used when disease is uncomplicated and no risk factors are present. 1, 3
Age‑Based Oral Dosing (Alternative Approach)
- <1 year (1–12 months): 2.5 mL of 125/31 suspension three times daily. 1
- 1–6 years: 5 mL of 125/31 suspension three times daily. 1
- 7–12 years: 5 mL of 250/62 suspension three times daily. 1
- 12–18 years: 1 tablet (250/125) three times daily. 1
Intravenous Dosing (Severe Infections)
30 mg/kg three times daily IV for pediatric patients of all ages requiring parenteral therapy. 1
High‑Dose Indications in Children
Use the 90 mg/kg/day regimen when any of the following are present: 1, 3
- Age <2 years
- Daycare attendance
- Recent antibiotic use (past 4–6 weeks)
- Incomplete Haemophilus influenzae type b vaccination (<3 injections)
- Concurrent purulent otitis media
- Moderate‑to‑severe illness
- Geographic area with >10% prevalence of penicillin‑resistant S. pneumoniae
Treatment Duration
Adults
- Uncomplicated ABRS: 5–7 days (equally effective as 10 days with fewer adverse effects). 2, 3
- General guideline: Continue until symptom‑free for 7 consecutive days (typically 10–14 days total). 2
Children
- Minimum 10–14 days for most pediatric infections, including ABRS and AOM. 1, 3
- Continue for 7 days after the patient becomes free of signs and symptoms. 1
Specific Conditions
- Bacterial pneumonia: 10 days. 1
- Acute otitis media: 10 days for children <2 years; shorter courses may be considered for older children without risk factors. 1
Reassessment & Treatment Failure Protocol
Adults
- Reassess at 3–5 days: If no clinical improvement (persistent purulent drainage, unchanged facial pain, or worsening), switch immediately to a respiratory fluoroquinolone (levofloxacin 500 mg once daily for 10–14 days or moxifloxacin 400 mg once daily for 10 days). 2
- Reassess at 7 days: Persistent or worsening symptoms warrant diagnostic reconsideration, exclusion of complications (orbital cellulitis, meningitis, intracranial abscess), and possible imaging or ENT referral. 2
- Do not extend amoxicillin‑clavulanate beyond 3–5 days without improvement—early discontinuation prevents unnecessary exposure and bacterial proliferation. 2
Children
- Reassess at 72 hours: Lack of improvement or clinical worsening requires escalation to high‑dose amoxicillin‑clavulanate (if not already prescribed) or switching to an alternative agent. 1, 2
- If no improvement after 72 hours on high‑dose therapy, consider:
Red‑Flag Situations Requiring Urgent ENT Referral
- No improvement after 7 days of appropriate second‑line therapy. 2
- Any worsening of symptoms (increasing facial pain, fever, purulent drainage). 2
- Signs of complications: severe headache, visual changes, periorbital swelling/erythema, proptosis, diplopia, altered mental status, cranial nerve deficits. 2
- Recurrent sinusitis (≥3 episodes per year) suggesting underlying allergic rhinitis, immunodeficiency, or anatomic abnormality. 2
Penicillin Allergy: Alternative Agents
Non‑Severe (Non‑Type I) Penicillin Allergy
Second‑ or third‑generation cephalosporins for 10 days are preferred because cross‑reactivity is negligible: 2
- Cefuroxime‑axetil
- Cefpodoxime‑proxetil
- Cefdinir
- Cefprozil
Severe (Type I/Anaphylactic) Penicillin Allergy
Respiratory fluoroquinolones provide 90–92% predicted efficacy against multidrug‑resistant pathogens: 2
- Levofloxacin 500 mg once daily for 10–14 days (adults)
- Moxifloxacin 400 mg once daily for 10 days (adults)
Reserve fluoroquinolones for documented severe β‑lactam allergy or treatment failure—do not use as routine first‑line therapy to prevent resistance development. 2
Suboptimal Alternative
Doxycycline 100 mg once daily for 10 days yields only 77–81% predicted efficacy with a 20–25% bacteriologic failure rate due to limited H. influenzae coverage. 2
- Contraindicated in children <8 years due to risk of tooth enamel discoloration. 2
- Use only when fluoroquinolones and cephalosporins are contraindicated or unavailable. 2
Agents to Avoid
- Macrolides (azithromycin, clarithromycin): 20–25% resistance rates in S. pneumoniae and H. influenzae; explicitly contraindicated by the American Academy of Pediatrics. 2
- Trimethoprim‑sulfamethoxazole: 50% resistance in S. pneumoniae, 27% in H. influenzae. 2
- First‑generation cephalosporins (cephalexin): Inadequate coverage because ~50% of H. influenzae strains produce β‑lactamase. 2
Adjunctive Therapies (Add to All Patients)
Intranasal corticosteroids (mometasone, fluticasone, or budesonide) twice daily significantly reduce mucosal inflammation and accelerate symptom resolution; supported by strong evidence from multiple randomized controlled trials. 2
- Saline nasal irrigation 2–3 times daily provides symptomatic relief and aids mucus clearance. 2
- Analgesics (acetaminophen or ibuprofen) for pain and fever control. 2
- Decongestants (oral or topical): Limit topical agents to ≤3 days to avoid rebound congestion. 2
Systemic corticosteroid injections have no role in uncomplicated acute bacterial sinusitis—intranasal corticosteroids are the appropriate anti‑inflammatory therapy. 2
Safety & Adverse Effects
Common Adverse Effects
- Diarrhea: Occurs in 40–43% of patients; severe diarrhea in 7–8%. 2
- Nausea, vomiting, rash: Reported but generally mild to moderate. 1, 4
- The 14:1 ratio high‑dose formulation (90/6.4 mg/kg/day) causes less diarrhea than other amoxicillin‑clavulanate preparations. 1
Serious Adverse Effects (Rare)
- Hepatotoxicity: Cholestatic jaundice and hepatitis have been reported; monitor liver function in prolonged therapy. 5
- Hypersensitivity reactions: Rash, urticaria, anaphylaxis (rare). 5
Drug Interactions
- Probenecid: Increases amoxicillin serum concentrations by decreasing renal tubular secretion. 5
- Oral contraceptives: May reduce efficacy; advise additional contraceptive measures. 5
Critical Pitfalls to Avoid
- Do not prescribe antibiotics for symptoms <10 days unless severe features (fever ≥39°C with purulent discharge for ≥3 consecutive days) are present—98–99.5% of acute rhinosinusitis is viral. 2
- Ensure minimum treatment duration: ≥5 days for adults, ≥10 days for children to prevent relapse. 2, 3
- Verify suspension concentration (125/31 vs. 250/62) before calculating volume to avoid dosing errors. 1
- Do not combine amoxicillin‑clavulanate with a second antibiotic (e.g., levofloxacin)—switch, don't add. 2
- Always administer antibiotics immediately after dialysis in ESRD patients; dosing before dialysis results in drug removal and subtherapeutic levels. 2
- Gastrointestinal adverse effects are more common with amoxicillin‑clavulanate than other antibiotics—counsel patients and consider taking with food to reduce nausea. 2, 5
Watchful Waiting Strategy
For uncomplicated ABRS with reliable follow‑up, initial observation without antibiotics is appropriate; initiate therapy only if no improvement by day 7 or if symptoms worsen at any time. 2
- Number needed to treat (NNT) with antibiotics is 10–15 to achieve one additional cure compared with placebo, reflecting the high rate of spontaneous recovery. 2
- Symptomatic treatment with analgesics, intranasal corticosteroids, and saline irrigation is appropriate during the observation period. 2
Special Populations
Pregnancy & Lactation
- Pregnancy Category B: No evidence of fetal harm in animal studies; use when clearly needed. 5
- Lactation: Excreted in breast milk in small amounts; generally considered compatible with breastfeeding. 5
Immunocompromised Patients
- Consider high‑dose regimens and obtain sinus cultures (direct aspiration or endoscopic sampling) if no improvement after 7 days of appropriate therapy. 2
- Evaluate for opportunistic infections (e.g., fungal sinusitis) if symptoms persist despite adequate antibacterial therapy. 2
Pharmacokinetics & Pharmacodynamics
- Amoxicillin serum levels increase linearly with dose; the difference in adverse effects between lower and higher doses is generally negligible. 1
- High‑dose amoxicillin (80–90 mg/kg/day) exceeds the minimum inhibitory concentration (MIC) for intermediately resistant S. pneumoniae and many highly resistant serotypes. 1
- Clavulanic acid is a "suicide" inhibitor of bacterial β‑lactamase enzymes, preventing destruction of amoxicillin by these enzymes. 5
- Absorption is not affected by food; taking with food may reduce gastrointestinal adverse effects. 5
Resistance Considerations
- Amoxicillin‑clavulanate has a low propensity to select resistance mutations and a favorable PK/PD profile predictive of high bacteriological efficacy, accounting for its longevity in clinical use. 6
- Routine antibiotic use for viral rhinosinusitis is the primary driver of community antimicrobial resistance—withholding antibiotics in viral cases is essential to preserve antibiotic effectiveness. 2
- Reserve fluoroquinolones appropriately to prevent resistance development; use only after β‑lactam failure or in documented severe allergy. 2