Amoxicillin Clavulanate

Amoxicillin clavulanate is the most widely used oral beta-lactam and beta-lactamase inhibitor combination. It extends amoxicillin to beta-lactamase producing Haemophilus, Moraxella, Staphylococcus aureus (methicillin-susceptible), Bacteroides and many Enterobacterales.

Classification. Aminopenicillin plus clavulanic acid. Ratios differ between products; always prescribe by the amoxicillin component with the clavulanate ratio.

Mechanism. Amoxicillin blocks penicillin-binding proteins; clavulanate irreversibly inhibits many class A beta-lactamases but not AmpC or metallo-beta-lactamases.

Spectrum. Streptococci, pneumococci, Enterococcus faecalis, MSSA, Haemophilus, Moraxella, Pasteurella, Bacteroides and anaerobes, and Escherichia coli, Klebsiella and Proteus where resistance is low. Not active against MRSA, Pseudomonas, ESBL producers or atypical organisms.

Pharmacokinetics. Oral bioavailability of amoxicillin 70 to 90% and clavulanate 60%; clavulanate is best absorbed at the start of a meal. Half-life 1 to 1.5 hours. Eliminated by kidneys.

No loading dose. Prescribe by amoxicillin and clavulanate content. The clavulanate dose should not exceed 125 mg a dose in adults to limit diarrhoea; two 250/125 tablets are not equal to one 500/125 tablet.

Adults, oral.

• 500/125 mg every 8 hours; or 875/125 mg every 12 hours; or 2 g/125 mg (extended release) every 12 hours for pneumonia with resistant pneumococci.
• Maximum 3 g amoxicillin daily orally in usual practice.

Indications and durations:

• acute sinusitis 5 to 7 days
• community-acquired pneumonia when anaerobes or beta-lactamase producing Haemophilus are likely 5 to 7 days
• exacerbation of COPD 5 days
• bite wounds 5 to 7 days (3 days preemptive)
• mild diabetic foot and cellulitis with deeper involvement 7 days
• dental abscess 5 days
• urinary infection with susceptible organism 5 to 7 days
• aspiration pneumonia 5 to 7 days

Adults, IV (where available). 1.2 g (1 g/200 mg) every 8 hours; severe infection every 6 hours; maximum 4.8 g combination daily.

Children. Dose by amoxicillin: 25 to 45 mg/kg/day divided every 12 hours using 14:1 formulations (45 mg/kg/day for otitis media, up to 90 mg/kg/day for resistant pneumococcal disease with 14:1 ratio); 20 to 40 mg/kg/day every 8 hours using 4:1 ratio. IV 30 mg/kg (amoxicillin) every 8 hours, maximum 1 g a dose.

Alternatives. Doxycycline, cefuroxime, ceftriaxone plus metronidazole, ciprofloxacin or moxifloxacin in allergy or resistance.

Contraindications. Penicillin hypersensitivity; previous jaundice or hepatic dysfunction caused by amoxicillin clavulanate.

Hepatotoxicity. Cholestatic hepatitis is the most frequent drug-induced liver injury in several series; onset up to 6 weeks after stopping. Risk is higher in men, those over 55 years, courses over 14 days and repeat courses.

Other adverse effects. Diarrhoea (clavulanate-related), nausea, candidiasis, rash, Clostridioides difficile infection, anaphylaxis, Stevens-Johnson syndrome, interstitial nephritis, crystalluria at very high dose, cytopenias.

Interactions. Methotrexate, warfarin (INR rise), allopurinol (rash), mycophenolate (lower trough levels), probenecid, oral typhoid vaccine.

Common prescribing errors. Using for viral infection, substituting tablets of different ratios, giving the extended release form to children, continuing beyond 14 days, and prescribing for presumed UTI without susceptibility.

Special groups. - Pregnancy: acceptable; avoid in preterm prelabour rupture of membranes because of possible neonatal necrotising enterocolitis. - Breastfeeding: acceptable. - Older adults: higher liver injury risk; use shortest course. - Kidney impairment: creatinine clearance over 30 mL/min no change; 10 to 30 mL/min 500/125 mg every 12 hours (no 875 mg tablets); under 10 mL/min 500/125 mg every 24 hours.

IV: 1.2 g then 600 mg every 12 hours for 10 to 30 mL/min; 1.2 g then 600 mg every 24 hours under 10 mL/min. Haemodialysis: extra dose after the session. - Liver impairment: use with caution and monitor liver tests; avoid in severe cholestatic disease. - Region: widely used in East Africa; counterfeits and mislabelled ratios occur, so check the product label.

Preparation. Take at the start of a meal. Dispersible and suspension forms: shake and measure with a calibrated syringe. IV: reconstitute in water for injection and give by slow injection over 3 to 4 minutes or infuse over 30 to 40 minutes.

Baseline and monitoring. - Baseline: allergy history, creatinine, liver tests in prolonged therapy. - During treatment: review at 48 to 72 hours; liver tests and blood count in courses over 14 days; stool monitoring for Clostridioides difficile infection. - No therapeutic drug monitoring.

Stop rules. Stop for jaundice, rash with mucosal involvement, anaphylaxis or severe diarrhoea.

Referral and escalation. Refer for liver injury, failure at 48 to 72 hours, deep infection needing source control and suspected resistant organisms.