Beta Lactamase Inhibitors

Beta-lactamase inhibitors have little or no intrinsic antibacterial activity but protect a partner beta-lactam from hydrolysis. They fall into three generations: first (clavulanic acid, sulbactam, tazobactam), covalent inhibitors with a beta-lactam core and good activity against class A enzymes; second (avibactam, relebactam, durlobactam), diazabicyclooctanes that also block class A, C and some class D enzymes; and a boronic acid inhibitor (vaborbactam) active against class A, especially KPC.

Mechanism. The inhibitor forms a stable acyl-enzyme complex with serine beta-lactamases. First generation inhibitors are consumed (suicide inhibition); avibactam and its relatives form reversible complexes that recycle. None inhibit class B metallo-beta-lactamases (NDM, VIM, IMP).

Pharmacokinetics. The partner and inhibitor need matched half-lives. All are renally cleared and are given by infusion; clavulanic acid also has an oral form with variable food dependence.

Matching to the mechanism.

• ESBL (CTX-M): a carbapenem is preferred for bacteraemia; piperacillin-tazobactam is less reliable.
• AmpC (Enterobacter, Citrobacter freundii, Klebsiella aerogenes): cefepime if susceptible, or a carbapenem; tazobactam and clavulanate are weak against AmpC.
• KPC: ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam.
• OXA-48: ceftazidime-avibactam.
• Metallo-beta-lactamases (NDM, VIM, IMP): ceftazidime-avibactam plus aztreonam, aztreonam-avibactam or cefiderocol, with specialist input.
• Acinetobacter baumannii (carbapenem-resistant): high-dose sulbactam-based regimens (ampicillin-sulbactam or sulbactam-durlobactam).

Stewardship. Reserve the newer combinations for confirmed or highly probable resistant infection with susceptibility data, as resistance to avibactam and vaborbactam combinations has appeared. They are costly and often unavailable in East Africa, so local carbapenemase type and supply determine options.

Renal adjustment. All newer combinations require stepwise reduction at estimated clearance under 50 mL/min (for example, ceftazidime-avibactam 1.25 g every 8 hours at clearance 31 to 50 mL/min). Exact steps are agent-specific and should be taken from the current product information.

Contraindications. Hypersensitivity to the partner or inhibitor. History of cholestatic jaundice with amoxicillin-clavulanate. Imipenem-relebactam is avoided with valproate.

Common and serious effects.

• Clavulanate: diarrhoea, nausea, cholestatic hepatitis (delayed, often in older men and courses over 14 days).
• Tazobactam: effects follow the piperacillin partner, including acute kidney injury when combined with vancomycin.
• Avibactam, vaborbactam, relebactam, durlobactam: headache, infusion-site reactions, raised transaminases, positive Coombs test, diarrhoea; seizure risk follows the carbapenem partner.

Interactions. Carbapenem partners lower valproate levels; probenecid raises avibactam and tazobactam exposure; methotrexate clearance is reduced.

Monitoring. Renal function (dose adjusts with changes), liver tests in prolonged courses, full blood count, seizure threshold in renal impairment.

Special groups. Pregnancy: amoxicillin-clavulanate and piperacillin-tazobactam are acceptable (clavulanate may be avoided in threatened preterm rupture of membranes because of necrotising enterocolitis reports); data on newer combinations are limited and they are used only when no alternative exists. Children: weight-based dosing for amoxicillin-clavulanate and piperacillin-tazobactam; newer combinations have limited paediatric licensing.