• act by breaking the beta-lactam ring that allows penicillin-like antibiotics to work.
  • Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.
  • Beta-lactamase producing bacteria
  • Staphylococcus
    • MRSA(Methicillin-resistant Staphylococcus aureus)
  • Enterobacteriaceae:
    • Klebsiella pneumoniae, Citrobacter, Proteus vulgaris, Salmonella, Shigella, Escherichia coli
  • Haemophilus influenzae
  • Neisseria gonorrhoeae
  • Pseudomonas aeruginosa
  • Mycobacterium tuberculosis

Medical uses

  • the most important use of beta-lactamase inhibitors is in the treatment of infections known or believed to be caused by gram-negative bacteria, as beta-lactamase production is an important contributor to beta-lactam resistance in these pathogens.
  • In contrast, most beta-lactam resistance in gram-positive bacteria is due to variations in penicillin-binding proteins that lead to reduced binding to the beta-lactam.
  • The gram-positive pathogen Staphylococcus aureus produces beta-lactamases, but beta-lactamase inhibitors play a lesser role in the treatment of these infections because the most resistant strains (methicillin-resistant Staphylococcus aureus) also use variant penicillin-binding proteins.

Mechanism of action

Currently, available beta-lactamase inhibitors are effective against

Based on their catalytic activities, β-lactamases are classified as

  • serine β-lactamases (SBLs, Ambler class A, C, and D) and
  • Metallo-β-lactamases (MBLs, Ambler class B)
  • Ambler Class A beta-lactamases (tazobactam, clavulanate, and sulbactam) or against
  • Ambler Class A, C and some Class D beta-lactamases (avibactam).
  • Unlike the case of beta-lactam antibiotics, the inhibitors act as suicide substrates (tazobactam and sulbactam) which ultimately leads to the degradation of the beta-lactamase
  • Avibactam, on the other hand, does not contain a beta-lactam ring (non-beta-lactam beta-lactamase inhibitor) and instead binds reversibly.
  • Ambler Class B beta-lactams cleave beta-lactams by a mechanism similar to that of metalloproteases. As no covalent intermediate is formed, the mechanism of action of marketed beta-lactamase inhibitors is not applicable. Thus the spread of bacterial strains expressing Metallo beta-lactamases such as the New Delhi Metallo-beta-lactamase 1 has engendered considerable concern.

Commonly used agents

  • Currently marketed β-lactamase inhibitors are not sold as individual drugs.
  • Instead, they are co-formulated with a β-lactam antibiotic with a similar serum half-life.
  • This is done not only for dosing convenience but also to minimize resistance development that might occur as a result of varying exposure to one or the other drug.
  • The main classes of β-lactam antibiotics used to treat gram-negative bacterial infections include (in approximate order of intrinsic resistance to cleavage by β-lactamases) penicillins (especially aminopenicillins and ureidopenicillins), 3rd generation cephalosporins, and carbapenems.
  • Individual β-lactamase variants may target one or many of these drug classes, and only a subset will be inhibited by a given β-lactamase inhibitor.
  • β-lactamase inhibitors expand the useful spectrum of these β-lactam antibiotics by inhibiting the β-lactamase enzymes produced by bacteria to deactivate them.

β-lactamase inhibitors with the β-lactam core:

  • Clavulanic acid or clavulanate, usually combined with amoxicillin (Augmentin) or ticarcillin (Timentin)
    • Sulbactam, usually combined with ampicillin or Cefoperazone 
    • Tazobactam, usually combined with piperacillin
    • Ceftolozane plus tazobactam (Zerbaxa) à novel fifth-generation cephalosporin antibiotic ceftolozane and the established β-lactamase inhibitor tazobactam
  • Non-β-lactam β-lactamase inhibitors:
    • Avibactam, approved in combination with ceftazidime (Avycaz), currently undergoing clinical trials for combination with ceftaroline à complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI)
    • Relebactam (previously known as MK-7655) is undergoing Phase III clinical trials as a treatment for pneumonia and bacterial infections (as of March 1, 2016).
    • Vaborbactam plus meropenem -> complicated UTI -> as an injectable solution with each vial containing 1 g of meropenem and 1 g of tazobactam

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