Beta lactamase inhibitors

Beta-lactamase inhibitors

1. Beta lactamase Inhibitors Jagir R. Patel Asst Prof essor 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 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 C lavuligerus  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..

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