Penicillins And Others

• Beta-lactamase inhibitors

  • Relebactam

    • Relebactam

     

    • Overview and Mechanism of Action

      • Relebactam is presently available as I combination product which includes imipenem and cilastatin, used to treat complicated urinary tract infections (UTI's), pyelonephritis, and complicated interabdominal infections in adults.²

        • According to FDA labeling, this combination would be indicated for patients 18 years of age and older who have limited or no alternative treatment options, for treatment of the aforementioned infections due to susceptible Gram-negative bacteria (2019).⁷

        • In June, 2020. The FDA approved Recarbrio for treatment of the adults with hospital-acquired and ventilator-associated bacterial pneumonia caused by the following susceptible Gram-negative bacteria: Citrobacter calcoaceticus-baumanii complex, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens.⁸

      • Relebactam is a diazabicyclooctane beta-lactamase inhibitor very closely related to avibactam and is administered in combination with imipenem and cilastatin.⁴ 

        • The triple drug combination, imipenem/cilastatin/relebactam is sold as Recarbrio.³

        • Structurally, it is avibactam with an added piperidine ring, which makes relebactam positively charged at physiological pH.¹

          • Relebactam includes of piperidine rain that reduces transport of the drug out of bacterial cells by producing of positive charge.^2,6

      • This structural change reduces the efflux of the inhibitor from bacteria, thereby increasing its activity against organisms like Pseudomonas that have robust efflux pumps.

        • Relebactam’s mechanism of action is the same as that noted with avibactamin that it forms a reversible acyl-enzyme complex with serine beta-lactamases, inhibiting the enzyme without being permanently inactivated.¹

          • Thus, in contrast to some other beta-lactamase inhibitors, once relebactam de-acylates from the active site, it can reform the 5 membered ring, regaining capability to bind to target beta-lactamases.²

      • Relebactam is a potent inhibitor of Ambler Class A β-lactamases (including KPC and ESBLs) and Class C (AmpC) β-lactamases.²

        •  It is particularly effective at restoring imipenem's activity against many resistant isolates of P. aeruginosa and KPC-producing Enterobacterales.⁵  

          • Similar to avibactam, relebactam is not active against Class B (MBL) enzymes or the majority of Class D carbapenemases like OXA-48.

          • Attribution Table about corresponds to Table 1. From reference (9) below: Sidjabat H Kamolvit W Wailan A Paterson D Multi-drug-resistant Gram-negative bacteria. Microbiology Australia 34(1) 43-46. 20 March 2013. https://www.publish.csiro.au/ma/Fulltext/ma13014

       

    • Pharmacokinetics

      • Absorption

        • Relebactam is administered intravenously.¹⁰

      • Distribution

        • Plasma protein binding is modest at approximately 22%, and it has a volume of distribution of about 19 L.²

      • Metabolism

        • Relebactam does not undergo significant metabolism and is found mostly as the unchanged drug in human plasma.²  

      • Excretion

        • Elimination is mainly renal, with over 90% of the dose excreted unchanged in the urine.²  

          • Elimination half-life is approximately 1.2 to 1.8 hours.²

          • Renal clearance is the primary elimination pathway, necessitating dosage adjustments in patients with impaired renal function.³

    • Therapeutic Uses

      • Complicated urinary tract infections (cUTIs), including pyelonephritis, caused by susceptible organisms (especially E. coli, Klebsiella, Enterobacter species that produce ESBL or AmpC enzymes, or some carbapenemase producers).¹  

      • Complicated intra-abdominal infections (cIAIs), in combination with metronidazole for anaerobic coverage, particularly when caused by organisms like ESBL-producing Enterobacteriaceae where imipenem alone might have been degraded without the inhibitor.¹

      • Hospital-acquired and ventilator-associated pneumonia (HABP/VABP)¹

        • Relebactam expands the imipenem spectrum to include many imipenem-resistant Gram-negatives.

          • Recarbrio is useful in hospital pneumonia due to non-susceptible P. aeruginosa or CRE.

            • The RESTORE-IMI 1 and 2 trials demonstrated its efficacy in these settings.^1,11

August, 2025