Beta-lactamase inhibitors

1. Beta lactamase Inhibitors
Jagir R. Patel
Asst Professor
Dept. pharmacology

2.  Beta-lactamases are a family of enzymes involved in
bacterial resistance to beta-lactam antibiotics.
 They are the agents which resembles to beta lactam molecules
Beta lactamase inhibitors
Clavulanic acid
Sulbactam
Tazobactam
Avibactam
Relebactam
Definition & Classification

3. Mechanism of action
 B-lactamases are a family of enzymes produced by many gram-
positive and gram-negative bacteria that inactivate B-lactam
antibiotics by opening the B-lactam ring. Beta-lactamases (β-
lactamases, also known as Penicillinase) that provide multi-
resistance to β-lactam antibiotics.
 Beta lactam inhibitors binds to β-lactamase enzyme and
inactivate them

4. Clavulanic acid
 Clavulanic acid is a β-lactam drug Obtained from Streptomyces
 Clavuligerus that functions as a mechanism-based β-lactamase
inhibitor.
 While not effective by itself as an antibiotic
 It inhibits a wide variety (class II to class V) of B-lactamases (but
not class I cephalosporinase) produced by both gram-positive
and gram-negative bacteria.
 when combined with penicillin-group antibiotics, it can
overcome antibiotic resistance in bacteria that secrete β-
lactamase, which otherwise inactivates most penicillins.

5. Cont..
Progressive, inhibitor
Initially reversible binding with B-
lactamase
covalent later-inhibition increasing with time.
After binding to enzymes it itself gets inactivated hence
they are called “Suicide inhibitors”

6. Cont.…
 Clavulanic acid has rapid oral absorption and a bioavailability of
60%; can be injected.
 it is eliminated mainly by glomerular filtration and its excretion is
not affected by Probenecide.
 It is largely hydrolyzed and decarboxylated before excretion,
 while amoxicillin is primarily excreted unchanged by tubular
secretion.

7. combinations
 Clavulanic acid + Amoxicillin
 Its elimination t1/2 of 1 hr and tissue distribution matches
amoxicillin with which it is used
 Spectrum: β-lactamase producing strains like S.aureus, E.coli,
H.influenza, and gonococci.
 Given oral or i.m. or i.v.
 Side effects : same as Amoxicillin alone
 Indications: skin infections, otitis, respiratory infections, UTI.

8. Clavulanic acid + Ticarcillin
 Given i.m. or i.v.
 Absorption: Absorption from GI: Ticarcillin: Poorly absorbed;
clavulanate potassium: Well absorbed.

Distribution: Protein-binding: Ticarcillin 45-65%; clavulanic acid
22-30%. Both distributed into bone, blister and peritoneal fluid.
Both cross placenta and distributed into breast milk. Ticarcillin:
Low distribution into CSF, higher when meninges are inflamed.

Metabolism: Clavulanate potassium: Extensively metabolized;
Ticarcillin: Limited metabolism.

Excretion: Excreted unchanged in urine: Ticarcillin 60-70%;
clavulanic acid 35-45%.

9. Cont..
 Interactions: Probenecide decreases clearance of Ticarcillin.
 Indications
 Mixed nosocomial infections due to aerobic gram negative bacilli,
S.aureus and Bacteriosides spp. Gynecological infections

10. Sulbactam
 It is a semisynthetic B-lactamase inhibitor, related chemically as
well as in activity to clavulanic acid. It is also a progressive
inhibitor.
 on weight basis, it is 2-3 times less potent than clavulanic acid for
most types of the enzyme, but the same level of inhibition can be
obtained at the higher concentrations achieved clinically.
 Absorption: Poorly absorbed from the GI tract.
 Distribution: Distributed into breast milk. Protein binding: 38%.
 Excretion: Half-life elimination: 1-1.3 hr. About 75-85% is
excreted unchanged in the urine within 8 hr.

11. Cont..
Interactions: Probenecid may increase the serum concentrations of
sulbactam.
Ampicillin + Sulbactam (1gm+0.5gm)
 i.v.= Gynecological infections
 Intra-abdominal infections
 Skin and skin structure infections
 Acute pelvic inflammatory disease

12. Tazobactam
 It is similar to Sulbactam. Its pharmacokinetics matches with
Piperacillin with which it has been combined for use in severe
infections
 Absorption: Time to peak plasma concentration: Immediately
after completion of IV infusion.
 Distribution: Widely distributed into body tissues and fluids; both
cross the placenta; distributed into milk (Piperacillin). Plasma
protein binding: Approx 30%.
 Metabolism: Piperacillin: Metabolized to a desethyl metabolite.
Tazobactam: Metabolized to a single metabolite that lacks
pharmacological and antibacterial activities.
 Excretion: Via kidney by glomerular filtration and tubular
secretion as unchanged in urine. Plasma half-life: 0.7-1.2 hr.

13. Cont…
 Interaction : the neuromuscular blockade of vecuronium and
non-depolarising muscle relaxants.
 Indications Piperacillin + Tazobactam
 Nosocomial pneumonia
 Empiric therapy for febrile neutropenic patients
 Complicated intra-abdominal infections
 Complicated urinary tract infections; Skin and soft tissue
infections

14. Avibactam
 Avibactam is a non-β-lactam β-lactamase inhibitor
 A new drug application for Avibactam in combination with
Ceftazidime
 Ceftazidime / Avibactam was developed for the treatment of
certain multidrug-resistant Gram-(−) infections.
 Ceftazidime / Avibactam is used for the treatment of complicated
intra-abdominal infections.
 It is also used for the treatment of complicated urinary tract
infections including acute pyelonephritis , in adult patients.
 As with all other antibacterial, combination should be used only
to treat infections that are proven or strongly suspected to be
caused by susceptible bacteria to avoid development
of antimicrobial resistance.

15. Cephalosporins + Sulbactam
Cefotaxime + Sulbactam
Interactions: Concomitant admin of cephalosporins and
aminoglycoside antibiotics.
Oral: Genitourinary infections; Lower respiratory tract infections
 Cefoperazone + Sulbactam
 For susceptible infections