Clinical Uses of Clavulanate
Clavulanate is a β-lactamase inhibitor combined with β-lactam antibiotics (primarily amoxicillin) to restore activity against β-lactamase-producing bacteria that would otherwise be resistant to the β-lactam alone. 1
Primary Mechanism and Function
- Clavulanate acts as a "suicide" inhibitor of bacterial β-lactamase enzymes, preventing these enzymes from destroying penicillins and thereby extending the antibacterial spectrum of the companion β-lactam antibiotic 2, 3
- Clavulanic acid alone has minimal intrinsic antibacterial activity; its therapeutic value lies entirely in protecting the companion antibiotic from enzymatic degradation 2, 4
FDA-Approved Clinical Indications
The FDA approves amoxicillin-clavulanate for infections caused by β-lactamase-producing organisms only 1:
Respiratory Infections
- Lower respiratory tract infections caused by β-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis 1
- Acute bacterial sinusitis caused by β-lactamase-producing H. influenzae and M. catarrhalis 1
Ear Infections
- Acute bacterial otitis media caused by β-lactamase-producing H. influenzae and M. catarrhalis 1
Skin and Soft Tissue Infections
- Skin and skin structure infections caused by β-lactamase-producing Staphylococcus aureus, Escherichia coli, and Klebsiella species 1
Urinary Tract Infections
- Urinary tract infections caused by β-lactamase-producing E. coli, Klebsiella species, and Enterobacter species 1
Critical Limitation
- When susceptibility testing shows the organism is susceptible to amoxicillin alone (indicating no β-lactamase production), amoxicillin-clavulanate should NOT be used 1
- Using the combination unnecessarily increases adverse effects (particularly gastrointestinal) and violates antimicrobial stewardship principles 5, 6
Specialized Use in Drug-Resistant Tuberculosis
Carbapenem Combination (Only Approved TB Use)
- In multidrug-resistant tuberculosis (MDR-TB), clavulanate should ONLY be used when combined with carbapenems (imipenem or meropenem), where it enhances carbapenem activity against Mycobacterium tuberculosis 7
- The American Thoracic Society/CDC/ERS/IDSA guidelines conditionally recommend including a carbapenem with clavulanic acid in MDR-TB regimens 7
- Since clavulanate is only available co-formulated with amoxicillin, amoxicillin-clavulanate must be administered to deliver the required 125 mg clavulanate with each carbapenem dose 7
Strong Contraindication in MDR-TB Without Carbapenem
- Amoxicillin-clavulanate should NOT be included in MDR-TB treatment regimens except when providing clavulanate for carbapenem use (strong recommendation) 7
- In adjusted analyses, patients receiving amoxicillin-clavulanate without carbapenems had significantly worse outcomes: lower treatment success (aOR 0.6,95% CI 0.5-0.8) and higher mortality (aOR 1.7,95% CI 1.3-2.1) 7
Common Pitfalls to Avoid
Dosing-Related Adverse Effects
- Gastrointestinal side effects, particularly diarrhea, become significantly more problematic when clavulanate exceeds 10 mg/kg/day 6
- Three-times-daily dosing causes significantly more GI adverse effects than twice-daily dosing 6
- The 14:1 ratio formulation (90 mg/kg/day amoxicillin with 6.4 mg/kg/day clavulanate) causes less diarrhea than other ratios 8
Inappropriate Combination Therapy
- Do not combine amoxicillin-clavulanate with linezolid—these agents are not recommended together, though each may be used separately in specific MDR-TB regimens 5
- Combining antibiotics without proven synergy increases adverse effects without clinical benefit and contributes to antimicrobial resistance 5
Penicillin Allergy Alternatives
- For adults with penicillin allergy, use doxycycline or respiratory fluoroquinolones (levofloxacin or moxifloxacin) instead 8
- For children with non-type I penicillin allergy, use clindamycin plus a third-generation oral cephalosporin 8
- Third-generation cephalosporins (cefdinir, cefuroxime, cefpodoxime) are highly unlikely to cross-react with penicillin allergy 8