Penicillins And others

• Beta-lactamase inhibitors

  • Tazobactam

    • Tazobactam

    • Overview

      • Tazobactam exhibit the broad spectrum of activity against many Ambler Class A β-lactamases, including:

        • TEM-1: TEM-1 has been identified as the most common plasma-encoded beta-lactamase in Gram-negative bacteria (class A enzyme).³

          • "TEM" was so named because the isolate was obtained from a fecal culture of an Athenian patient named Temoniera in 1963.⁶

        • SHV-1:  SHV-1 Is a class A beta-lactamase with a spectrum of activity similar to TEM-1 but with better activity against ampicillin.⁴ 

          • SHV-1 has been found in several species of enterobacteria.

          • The SHV-1 beta-lactamase has been found at high frequency (up to 80%-90%) in Klebsiella pneumoniae.⁴

        • and a wide range of clinically important ESBLs.

          • Extended-spectrum β-lactamases (ESBLs) are described as are rapidly evolving beta-lactamase group sharing ability to hydrolyze third-generation cephalosporins and aztreonam but remain sensitive to inhibition by clavulanic acid.⁵ 

            • ESBLs represent mutations from genes for TEM-1, TEM-2 and SHV-1.⁵ 

        • Tazobactam does not exhibit activity against Class B or most Class C enzymes.

    • Mechanism of Action

      • Tazobactam is a synthetic penicillanic acid sulfone, structurally related to sulbactam.

        • Tazobactam contains a 1,2,3-triazole side chain on the beta-lactam ring.¹

          • Tazobactam irreversibly inhibits many class A beta-lactamases by the same suicide-substrate mechanism as clavulanate and sulbactam.^1,2    

            • By binding and permanently disabling the enzyme, it protects partner beta-lactams from hydrolysis.

      • Tazobactam has negligible intrinsic antibacterial activity on its own.

        • It is currently used in combination with the ureidopenicillin piperacillin and with the cephalosporin ceftolozane.

          • While tazobactam is a potent inhibitor of most plasmid-mediated beta-lactamases (TEM, SHV, CTX-M ESBLs, etc.), it is not effective against some AmpC enzymes and not at all active against metallo-beta-lactamases.

    • Pharmacokinetics

      • Tazobactam is only given parenterally (typically IV).

        • Tazobactam is administered intravenously, ensuring 100% bioavailability.⁷

          • In the combination piperacillin/tazobactam (Zosyn), the ratio is 8:1 (pip:tazo).⁸

          • After IV infusion, tazobactam’s pharmacokinetic profile is similar to that of piperacillin. Its half-life is about 0.7–1.0 hour.⁹ 

            • Tazobactam’s volume of distribution and clearance are roughly equivalent whether given alone or with piperacillin indicating minimal pharmacokinetic interaction between the two.⁹ 

              • About 56–64% of a tazobactam dose is excreted unchanged in urine in 24 hours.⁹ 

              • The remainder is likely eliminated as a single metabolite That appears to lack both pharmacological and antibacterial activities.¹⁰

            • Like other Beta-lactamase inhibitors, tazobactam is primarily renally cleared and accumulates in renal impairment (dose adjustment needed).¹¹ 

              • Tazobactam also is a component of ceftolozane/tazobactam (ratio 2:1) – in that combination its kinetics remain linear and predictable, with similar reliance on renal elimination.

              •  Ceftolozane/tazobactam combinations appear well tolerated by those patients with renal impairment.¹²

    • Therapeutic Uses: Piperacillin-tazobactam is considered a broad-spectrum antibiotic combination.

      • Intra-abdominal infections:

        • This category includes appendicitis with perforation, intra-abdominal abscesses, cholangitis.

        • Piperacillin-tazobactam covers gut Gram-negative rods which includes many beta-lactamase–producing E. coli, Klebsiella) and anaerobes (Bacteroides fragilis), in addition to enterococci, making it a one-drug regimen for polymicrobial abdominal infections.¹

      • Complicated skin and soft tissue infections

        • This category includes diabetic foot infections, infected ulcers, where broad coverage of Gram-positives, Gram-negatives, and anaerobes is needed.¹³

      • Gynecologic infections

        • The indications include postpartum endometritis or pelvic infection, where mixed flora are involved.⁸

      • Serious hospital-acquired pneumonia

        •  Piperacillin-tazobactam has activity against Pseudomonas aeruginosa (including many strains that produce beta-lactamases) and other nosocomial pathogens.

          •  This combination is used for ventilator-associated pneumonia or severe aspiration pneumonia.

          • In combination with an aminoglycoside, it has been used in febrile neutropenia and other high-risk infections.¹

      • Urinary tract infections (complicated)

        • Piperacillin-tazobactam covers (ESBL) Extended-Spectrum Beta-lactamase-producing organisms causing pyelonephritis or urosepsis when carbapenems are to be avoided.