Traxulev Mechanism of Action

Pharmacology: Pharmacodynamics: The bactericidal activity of Ceftriaxone and Sulbactam is due to the Ceftriaxone component and the ability of Ceftriaxone to interfere with the biosynthesis of the peptidoglycan component of the bacterial cell wall by binding to and inactivating penicillin-binding proteins (PBPs).
Ceftriaxone induces filamentation in Escherichia coli and Pseudomonas aeruginosa, it binds primarily to PBP 3 which is responsible for formation of cross-wall or septum of dividing bacilli.
Ceftriaxone has a high degree of stability against the beta-lactamases, both penicillinases and cephalosporinases produced by both gram -ve and gram +ve bacteria but not against chromosomally and plasmid mediated ESBL's produced by some strains of Klebsiella, Escherichia coli, Enterobacter spp and Serratia spp.
Sulbactam irreversibly blocks the destruction of beta-lactam ring of Ceftriaxone by these wide variety of ESBLs and chromosomally mediated beta-lactamases by attaching to these enzymes and acting as a suicide substrate that forms a stable intermediate, rendering the enzyme inactive.
Sulbactam is a broader-spectrum beta-lactamase inhibitor than clavulanic acid. Sulbactam does not induce chromosomal beta-lactamases like clavulanic acid, nor does it select for derepressed beta-lactamase-producing bacteria. Thus the full potential of Ceftriaxone against Klebsiella, Pseudomonas, Escherichia coli is restored by addition of Sulbactam.
Antimicrobial spectrum of Ceftriaxone-Sulbactam: The combination of Ceftriaxone sodium and Sulbactam sodium is active against all the organisms sensitive to Ceftriaxone. In addition, it demonstrates synergistic activity (reduction in minimum inhibitory concentrations, for the combination versus those of each component) in a variety of organisms.
Pharmacokinetics: Ceftriaxone and Sulbactam can be administered IM or IV.
Following intramuscular administration, peak serum concentrations of Ceftriaxone and Sulbactam are seen between 15 minutes to 2 hrs. The maximum plasma concentration of Ceftriaxone after a single IM dose of 1.0 g is about 81 mg/L and is reached 2-3 hrs after the dose while that of Sulbactam sodium is 6-24 mg/L and is reached approximately 1 hr after the dose. Hence effective amount of beta-lactamases are destroyed by the time peak concentration of Ceftriaxone is reached allowing full potential of action of Ceftriaxone against ESBL producing Klebsiella, E. coli. Serum concentrations have been shown to be proportional to the amount of dose administered. The area under curve (AUC) after IM administration is equivalent to that after IV administration of an equivalent dose, indicating 100% bioavailability of intramuscularly administered Ceftriaxone sodium. On intravenous administration Ceftriaxone sodium diffuses into the tissue fluid where if given in the recommended doses bactericidal concentrations are maintained for up to 24 hrs. Ceftriaxone is highly bound to human serum protein by about 83-90%.
Distribution: The volume of distribution of Ceftriaxone sodium is 7-12 L and that of Sulbactam is 18-27.6 L. Ceftriaxone sodium penetrates well into the extravascular spaces, tissue fluid and the synovial fluid of inflamed joints. The concentrations in most extracellular foci reach or exceed several times the MIC of most pathogens for at least 24 hours after a single administration.
Ceftriaxone sodium reaches therapeutically effective concentrations in patients with bacterial meningitis which are at least ten-fold the MICs of common pathogens such as, Enterobacteriaceae, H. influenzae, Meningococci, Pneumococci, and group B Streptococci.
Ceftriaxone crosses placenta and is distributed in the amniotic fluid. It is also distributed in the milk.
Metabolism and excretion: Ceftriaxone is not metabolised in the body and is eliminated unchanged via two pathways, urine and bile. 40-50% of parenterally administered dose is excreted into the urine within 48 hours as active drug. Thus, high concentrations are attained in urine, whatever is not excreted via kidney is excreted through bile.
Metabolism of sulbactam is less than 25%. 70-80% of Sulbactam is excreted by the kidney biliary excretion is minimal and renal excretion is blocked by probenecid. Sulbactam and Ceftriaxone can be removed by hemodialysis.
Impaired renal function and Hepatic insufficiency: Ceftriaxone is excreted via both renal and biliary pathways therefore patients with renal failure normally require no adjustments of dose however concentration of the drug should be monitored in such patients and if there is evidence of drug accumulation then dosage adjustments should be made accordingly. Dosage adjustments are not necessary in patients with hepatic dysfunction, however, in patients with both hepatic dysfunction and significant renal failure, dosage should not exceed more than 2 gm daily with close monitoring of serum concentrations.