β-Lactamase Inhibitor Combinations in Multidrug-Resistant Infections

Multidrug resistance among Gram-negative pathogens poses a critical threat to global health, driven in large part by bacterial production of β-lactamases that hydrolyse and inactivate β-lactam antibiotics. To counteract this mechanism, β-lactamase inhibitors (BLIs) have been paired with established β-lactams to restore or enhance their efficacy. Contemporary combinations include ceftazidime-avibactam, meropenem-vaborbactam and imipenem-cilastatin-relebactam, each targeting distinct spectra of β-lactamase classes. Avibactam and vaborbactam are potent against class A carbapenemases such as KPC, whereas relebactam also inhibits class C (AmpC) enzymes. Optimising pharmacokinetics and pharmacodynamics (PK/PD) through extended or continuous infusions has improved target attainment in severe infections, including pneumonia, osteomyelitis and bloodstream infections. These regimens have demonstrated clinical success against carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa high-risk clones, reducing mortality and toxicity compared with older therapies. The strategic deployment of BLIs has underscored the need for ongoing surveillance of emerging resistance mechanisms, such as overexpression of blaKPC or carriage of GES variants, and highlights the imperative for novel inhibitors to address class B metallo-β-lactamases.

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β-Lactamase Inhibitor Combinations in Multidrug-Resistant Infections publication trend

The graph below shows the total number of articles in β-lactamase inhibitor combinations in multidrug-resistant infections across all publications each year (not limited to Nature Index journals).

Technical terms

β-Lactamase: an enzyme produced by bacteria that hydrolyses the β-lactam ring of antibiotics, rendering them ineffective.

β-Lactamase inhibitor (BLI): a molecule that binds to β-lactamases, preventing them from deactivating β-lactam antibiotics.

Carbapenemase: a subclass of β-lactamases capable of hydrolysing carbapenems, a class of last-resort antibiotics.

Minimum inhibitory concentration (MIC): the lowest concentration of an antimicrobial agent that inhibits visible growth of a microorganism in vitro.

Pharmacokinetics/pharmacodynamics (PK/PD): the study of drug concentration over time and its relationship to antimicrobial effect.

Extended-spectrum β-lactamase (ESBL): an enzyme variant that hydrolyses a broad range of β-lactam antibiotics, including penicillins and cephalosporins.

Enterobacterales: an order of Gram-negative bacteria that includes clinically relevant genera such as Escherichia, Klebsiella and Enterobacter species.

References

1. Ceftazidime/Avibactam and Meropenem/Vaborbactam for the Management of Enterobacterales Infections: A Narrative Review, Clinical Considerations, and Expert Opinion. Antibiotics (2023).
2. Real-world use of imipenem/cilastatin/relebactam for the treatment of KPC-producing Klebsiella pneumoniae complex and difficult-to-treat resistance (DTR) Pseudomonas aeruginosa infections: a single-center preliminary experience. Frontiers in Microbiology (2024).
3. bla KPC-2 overexpression and bla GES-5 carriage as major imipenem/relebactam resistance mechanisms in Pseudomonas aeruginosa high-risk clones ST463 and ST235, respectively, in China. Antimicrobial Agents and Chemotherapy (2023).
4. Relebactam restores susceptibility of resistant Pseudomonas aeruginosa and Enterobacterales and enhances imipenem activity against chromosomal AmpC-producing species: analysis of global SMART 2018–2020. BMC Microbiology (2023).