Clavulanic acid

Clavulanic acid is not an antibiotic in the usual sense: it is a beta-lactamase inhibitor. Beta-lactamases are enzymes that certain bacteria produce to destroy antibiotics of the penicillin family. Clavulanic acid itself has a beta-lactam ring, which lodges in the active site of the enzyme and inactivates it. It is called a suicide inhibitor: the chemical reaction blocks the enzyme permanently, sacrificing the clavulanic acid molecule in the process.

On its own, it has no useful therapeutic action. It does nothing to improve activity against bacteria that do not produce beta-lactamase, because its role is limited to protecting the antibiotic it is paired with. That antibiotic, amoxicillin, works by binding to penicillin-binding proteins and inhibiting transpeptidation, the step that assembles the bacterial cell wall. Deprived of a solid wall, the bacterium does not survive.

Many bacteria have become resistant to amoxicillin by producing beta-lactamases that degrade it before it can act. By neutralising these enzymes, clavulanic acid restores the activity of amoxicillin and extends its reach to resistant strains. That is the whole logic of the combination: an antibiotic that attacks the bacterium, and a partner that protects it from degradation.

This protection has a precise limit. Clavulanic acid contributes nothing against bacteria that do not produce beta-lactamase, since there is then no enzyme to neutralise. The value of the combination therefore rests entirely on enzyme-producing bacteria. That is why the medicine always comes as a co-formulation, with amoxicillin and clavulanic acid combined in a single tablet.

Each dose is taken at the start of a meal. This timing improves the absorption of clavulanic acid and reduces digestive upset, which the leaflet recommends easing by taking the medicine with a meal or a snack. Both molecules are eliminated quickly: after oral intake, the half-life is about 1.3 hours for amoxicillin and 1 hour for clavulanic acid. This rapid elimination requires doses spread across the day, every eight or every twelve hours depending on the chosen schedule.

Taking the doses regularly maintains an effective concentration against the bacterium. The prescribed duration must be followed to the end, without stopping treatment as soon as symptoms improve. Stopping too early allows the least susceptible bacteria to survive and encourages resistance. Any change is decided with the doctor or pharmacist, never alone.

The digestive tract is the first affected. In trials conducted before marketing, diarrhoea or loose stools affected 9% of patients, nausea 3%, rashes and urticaria 3%, vomiting 1% and vaginitis 1%. Diarrhoea is more frequent with the combination than with amoxicillin alone.

This diarrhoea depends on the dose and on the timing of the doses. In a paediatric trial on otitis media, it occurred in 14.3% of children on a twelve-hourly schedule, compared with 34.3% on an eight-hourly schedule. The risk of Clostridioides difficile colitis, an inflammation of the colon linked to disruption of the gut flora, is moderately increased. Severe or persistent diarrhoea warrants medical advice.

The amoxicillin-clavulanic acid combination is among the most frequent causes of drug-induced liver injury, through an idiosyncratic mechanism. The injury is cholestatic in type: it hinders the flow of bile and shows up as a rise in alkaline phosphatase and bilirubin. It remains rare and unpredictable, and more often affects older men.

The delay in time makes this signal difficult to link to the medicine. The signs typically appear two to three weeks after the start of treatment, sometimes up to twelve weeks, therefore well after the tablets have finished. Yellowing of the skin or eyes, dark urine or unusual tiredness should prompt a consultation.

Several medicines alter the effect of the combination or have their own effect altered. Probenecid increases and prolongs the blood concentrations of amoxicillin when used concomitantly. In people on an oral anticoagulant, prolongations of prothrombin time have been reported, which calls for vigilance over coagulation. The combination can also reduce the effectiveness of oral contraceptives.

Follow-up depends on the length of treatment. For a short course, it remains limited. Beyond a week to ten days, periodic monitoring of hepatic, renal and haematological function is recommended. This laboratory follow-up is decided with the doctor, according to the individual’s condition and the other treatments in progress.