Aminopenicillins

Aminopenicillins (amoxicillin and ampicillin) add an amino group to the penicillin side chain, which improves penetration through Gram-negative porins and extends activity to enterococci, Listeria, Haemophilus influenzae and some Enterobacterales. They remain destroyed by beta-lactamases, so the inhibitor combination (amoxicillin-clavulanate, ampicillin-sulbactam) is used where beta-lactamase producers are likely.

Mechanism. PBP binding with time-dependent killing.

Pharmacokinetics. Amoxicillin has bioavailability of 70 to 90 percent unaffected by food, with a half-life of about 1 hour. Oral ampicillin absorbs poorly (30 to 50 percent) and is reduced by food, so it is reserved for intravenous use. Both are renally cleared and reach good levels in lung, urine, bile and (with inflamed meninges) CSF.

Resistance. Widespread TEM-1 production in E. coli, Klebsiella and H. influenzae; ampicillin-resistant E. faecium; PBP alterations in pneumococci. Salmonella Typhi and many E. coli urinary isolates in sub-Saharan Africa show high resistance, so local data should decide empirical use.

• Amoxicillin: preferred oral agent; higher serum levels, less frequent dosing and lower gastrointestinal upset than ampicillin.
• Ampicillin: intravenous agent for Listeria, enterococcal infection, neonatal sepsis and meningitis.
• Combinations: amoxicillin-clavulanate (oral 500/125 mg every 8 hours or 875/125 mg every 12 hours; intravenous formulations where available) and ampicillin-sulbactam 3 g (2 g/1 g) IV every 6 hours.

Adult regimens.

• Community pneumonia, non-severe: amoxicillin 500 mg to 1 g orally every 8 hours for 3 to 5 days if stable.
• Acute sinusitis, otitis media, exacerbation of COPD: amoxicillin 500 mg every 8 hours for 5 days (higher doses for resistant pneumococci).
• Helicobacter pylori eradication: amoxicillin 1 g orally every 12 hours as part of a combination regimen for 10 to 14 days.
• Endocarditis prophylaxis in high-risk patients before dental procedures: amoxicillin 2 g orally once, 30 to 60 minutes before.
• Listeria meningitis: ampicillin 2 g IV every 4 hours for 21 days, with gentamicin in the first week.
• Enterococcal endocarditis: ampicillin 2 g IV every 4 hours with ceftriaxone 2 g every 12 hours for 6 weeks, or with an aminoglycoside.
• Neonatal sepsis: ampicillin with gentamicin, dosed by weight and gestation.
• Children: amoxicillin 25 to 30 mg/kg every 12 hours; high dose 80 to 90 mg/kg daily in two divided doses for otitis media and pneumonia where pneumococcal resistance is a concern.

Selection. Amoxicillin is first line for mild respiratory infection and enterococcal infection. It is no longer reliable empirical therapy for urinary infection or typhoid where resistance is common. Add an inhibitor for beta-lactamase producers, aspiration, bites, sinusitis and diabetic foot infection.

Contraindications. Prior immediate hypersensitivity to any penicillin; history of cholestatic jaundice with amoxicillin-clavulanate.

Serious and common effects. Diarrhoea (clavulanate accelerates gut motility), maculopapular rash (nearly universal in infectious mononucleosis and with allopurinol; not IgE-mediated), anaphylaxis, cholestatic hepatitis (clavulanate, delayed up to 6 weeks after treatment), C. difficile infection, crystalluria at very high doses.

Interactions. Methotrexate, warfarin (INR rise), allopurinol (rash), mycophenolate (lower active metabolite), probenecid.

Monitoring. Renal function; liver tests in courses over 14 days; INR when co-prescribed with warfarin.

Special groups.

• Pregnancy and breastfeeding: acceptable. It is used for asymptomatic bacteriuria in pregnancy when the isolate is susceptible.
• Renal impairment: amoxicillin 500 mg every 12 hours at creatinine clearance 10 to 30 mL/min, and every 24 hours under 10 mL/min; extend ampicillin intervals to 6 to 12 hours (clearance 10 to 50 mL/min) or 12 to 24 hours (under 10 mL/min).
• Older adults: higher risk of clavulanate hepatotoxicity.