Clavulanic Acid
Beta lactamase inhibitor in combination with amoxicillin
Clavulanic acid is a β lactamase inhibitor derived from the soil fungus Streptomyces clavuligerus. It has practically no antibacterial activity of its own, but it blocks bacterial β lactamases and thereby considerably broadens the spectrum of combined aminopenicillins. Clavulanic acid is approved exclusively in fixed combinations with amoxicillin (Augmentan, Amoxi Clavulan, numerous generics), and rarely with ticarcillin (inpatient, no longer marketed in Germany). The oral amoxicillin clavulanic acid fixed combination has been one of the most frequently prescribed antibiotic combinations in Europe since the 1980s.
The combination of amoxicillin and clavulanic acid pairs the broad spectrum of an aminopenicillin with protection against enzymatic breakdown. This extends the indication spectrum to β lactamase producing strains of Staphylococcus aureus (except MRSA), Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae and Bacteroides fragilis. In the guidelines of the Deutsche Gesellschaft für Allgemeinmedizin and the Paul Ehrlich Society, the combination is a second or first line choice for certain respiratory, skin, dental and urogenital infections.
Mechanism of Action
β lactamases are bacterial enzymes that hydrolyse the β lactam ring of penicillins and cephalosporins and thereby inactivate them. Many clinically relevant pathogens possess chromosomal or plasmid encoded β lactamases, for example Staphylococcus aureus (penicillinase), Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli and Klebsiella pneumoniae. Clavulanic acid itself has a β lactam ring, binds irreversibly to the active site of β lactamase and inactivates the enzyme by covalent modification. This principle is known as suicide inhibition.
Against certain classes of β lactamase, however, clavulanic acid is ineffective or inadequate. These include advanced classes of extended spectrum β lactamases (ESBLs), AmpC β lactamases and carbapenemases. In practice this means that for correspondingly resistant pathogens other β lactamase inhibitors such as avibactam, vaborbactam or relebactam must be combined with cephalosporins or carbapenems.
The pharmacokinetics largely parallel those of amoxicillin. The oral bioavailability of clavulanic acid is about 60 percent and its half life is 1 hour. Elimination is predominantly renal and partly biliary. Tissue penetration into lung, middle ear, paranasal sinuses, skin, prostate and bile is ensured at therapeutically relevant concentrations.
Indications
- Acute otitis media in the case of treatment failure on amoxicillin monotherapy or when β lactamase producing pathogens are suspected
- Acute bacterial rhinosinusitis of moderate severity
- Community acquired pneumonia of outpatient, moderately severe course
- Exacerbation of chronic bronchitis particularly in COPD with β lactamase producing pathogens
- Uncomplicated and complicated urinary tract infection, pyelonephritis with correspondingly susceptible pathogens
- Skin infections, bite and puncture wounds (human and animal bites with the typical mixed spectrum of Pasteurella, staphylococci, anaerobes)
- Odontogenic infections such as abscesses, root canal inflammation, soft tissue infections
- Gynaecological infections and sequential therapy after parenteral antibiosis
- Chronic osteomyelitis with β lactamase producers as part of combination therapy
Dosage and Administration
Adults and adolescents from 40 kg: 500 mg amoxicillin plus 125 mg clavulanic acid three times daily or 875 mg amoxicillin plus 125 mg clavulanic acid twice daily. For severe infections parenterally 2.2 g amoxicillin clavulanic acid every 8 to 12 hours intravenously.
Children under 40 kg: 25 to 45 mg amoxicillin per kg per day, divided into 2 to 3 single doses, with clavulanic acid correspondingly 6.25 to 10 mg per kg per day. Paediatric suspensions are formulated by age and body weight.
Administration is at the start of a meal, which improves the absorption of clavulanic acid and enhances gastrointestinal tolerability. Swallow tablets with adequate fluid and shake the suspension well before use.
Renal impairment: extend the dosing interval or reduce the dose when creatinine clearance is below 30 ml/min. Hepatic impairment: no formal adjustment; a history of Augmentan induced hepatitis is a contraindication. Elderly patients: careful dose adjustment in reduced renal function.
Side Effects
Very common and common: diarrhoea (more frequent than with amoxicillin alone, as clavulanic acid has an additional motility promoting effect), nausea, vomiting, abdominal pain, rash, vaginal candidiasis, headache.
Uncommon: urticaria, pruritus, elevated liver transaminases, pseudomembranous colitis due to Clostridioides difficile, blood count changes such as eosinophilia, thrombocytosis, reversible leukopenia, candidal infections.
Rare to very rare: anaphylaxis, Stevens Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), haemolytic anaemia, cholestatic hepatitis with or without jaundice, acute renal failure. Cholestatic hepatitis is a specific complication of clavulanic acid and typically occurs 1 to 6 weeks after the end of therapy, mainly in elderly men and with longer treatment duration.
Pseudo allergic exanthem: in infectious mononucleosis (Epstein Barr virus) a maculopapular exanthem occurs in almost all treated patients; this is not a true penicillin allergy but should be documented. Amoxicillin clavulanic acid should be avoided when EBV infection is clinically suspected.
Interactions
- Allopurinol: increased risk of rash with concurrent use
- Methotrexate: reduced renal elimination, increased toxicity risk
- Oral anticoagulants (warfarin, phenprocoumon): INR fluctuations, close monitoring
- Probenecid: slows renal elimination of amoxicillin, raises plasma levels
- Mycophenolate mofetil: reduced mycophenolate plasma levels, relevant in transplant recipients
- Bacteriostatic antibiotics (tetracyclines, macrolides, sulphonamides): antagonism of the bactericidal action
- Oral contraceptives: a theoretical reduction in efficacy is clinically debated; in diarrhoea during antibiosis use an additional barrier method
Special Notes
Hepatitis: cholestatic hepatitis is a rare but important complication of amoxicillin clavulanic acid. A prior hepatitis on this combination is a contraindication to re exposure. The risk is increased in elderly men and with longer therapy. Jaundice, pale stools, dark urine and pruritus must be evaluated medically without delay.
Penicillin allergy: contraindicated in type I immediate reactions to penicillins or cephalosporins. In unclear history, perform allergy testing before therapy. Mild exanthem reactions in the past are not an absolute contraindication, but clear counselling and observation are important.
Antibiotic stewardship: amoxicillin clavulanic acid is not a trivial therapy. The combination should be used only on a clear indication; in uncomplicated streptococcal infections or community acquired pneumonia, amoxicillin monotherapy is often sufficient. The current S3 guideline of the DEGAM advises restrained prescribing.
Pregnancy: aminopenicillins including amoxicillin clavulanic acid are well studied in pregnancy and permitted with a clear indication. Breastfeeding: small amounts transfer into breast milk; breastfeeding is possible, with diarrhoea or thrush possible in the infant.
Monitoring: during longer therapy check liver and kidney values and a full blood count. In patients at risk of Clostridioides difficile association, watch for bloody mucoid stools. Counsel the patient on completing the full course even after symptoms resolve, to avoid resistance.
You might also be interested in
- Amoxicillin, oral aminopenicillin, the main partner in the combination
- Sultamicillin, oral ampicillin sulbactam prodrug
- Ampicillin, aminopenicillin in inpatient therapy
- Cefpodoxime, oral third generation cephalosporin
- Clarithromycin, macrolide in penicillin allergy
Frequently Asked Questions
Why do I need clavulanic acid in addition to amoxicillin?
Clavulanic acid protects amoxicillin from enzymatic breakdown by bacterial β lactamases. Without this protection, amoxicillin would be ineffective against many pathogens such as staphylococci, Haemophilus or Moraxella. The combination retains the full spectrum of amoxicillin and extends it to β lactamase producing strains.
Why do I get diarrhoea so often?
Clavulanic acid has an intrinsic motility promoting effect on the gut, and the antibiotic also alters the intestinal flora. As a result, diarrhoea is considerably more frequent on amoxicillin clavulanic acid than on amoxicillin alone. Probiotics such as Saccharomyces boulardii or lactobacilli can ease the symptoms, and plenty of fluids helps. Bloody diarrhoea requires immediate medical evaluation.
Can I combine amoxicillin clavulanic acid with alcohol?
The combination is not strictly contraindicated and antibiotic efficacy is not substantially influenced by moderate alcohol intake. During an acute infection the body is nonetheless weakened and additional strain from alcohol is not advisable. In pre existing liver disease or suspected hepatitis during therapy, avoid alcohol throughout the whole treatment course.
What is Augmentan hepatitis?
A rare, usually cholestatic liver inflammation on amoxicillin clavulanic acid. It typically occurs 1 to 6 weeks after the end of therapy and is more common in elderly men and with longer treatment duration. Symptoms include jaundice, dark urine, pale stools and pruritus. With timely diagnosis the prognosis is usually good, but re exposure is contraindicated for life.
Sources
- EMA, European Medicines Agency
- AWMF, S3 guidelines on respiratory and urinary tract infections
- Paul Ehrlich Society for Chemotherapy
- Gelbe Liste, clavulanic acid drug profile
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