Sianem Mechanism of Action

Pharmacology: SIANEM IV INJECTION is a fixed combination of Imipenem monohydrate, a semisynthetic carbapenem antibiotics of the thienamycin class, and Cilastatin sodium, the dehydropeptidase I (DHP I) competitive inhibitor present on the proximal renal tubular cells. Imipenem is hydrolyzed in vivo to an inactive metabolite by DHP I. Concurrent administration of Cilastatin prevents this renal metabolism of Imipenem, resulting in increased serum concentrations of active Imipenem better than administered alone. This will impact Imipenem's broad spectrum antibacterial activity.
Pharmacodynamics: Imipenem is a carbapenem antibiotics. It has a very broad spectrum of antibacterial activity. The antibacterial activity of Imipenem results from the inhibition of cell wall synthesis with a high affinity to penicillin binding proteins (PBPs) of susceptible microorganisms. The inhibition of mucopeptide synthesis leading to the formation of defective bacterial cell wall and cell death. Imipenem has bactericidal activity against Gram-positive and Gram-negative aerobic bacteria, anaerobic bacteria, β-lactamase-producing bacteria. Imipenem is also active against Pseudomonas aeruginosa, Serratia spp., and Enterobacter spp.
Cilastatin sodium has no direct antibacterial activity. When administered concomitantly it increases Imipenem activity by inhibiting DHP I on the brush border of proximal renal tubular cells. The resulting urinary and serum concentrations of active imipenem are higher than Imipenem administration alone. Cilastatin has no antimicrobial effect and does not affect the action of imipenem. Imipenem is active in vitro against the following microorganisms: Gram-positive Aerobic Bacteria: Cocci: penicillinase-and nonpenicillinase-producing strains of Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, Streptococcus pyrogenes (group A β-hemolytic streptococci), Streptococcus agalactiae (group B β-hemolytic streptococci), Streptococcus viridians, Enterococcus faecalis (Streptococcus faecalis), Enterococcus durans (Streptococcus durans), Group C, G, and H Streptococci. But most strains of Enterococcus faecium (Streptococcus faecium) are considered resistant to the drug.
Bacilli: Nocardia asteroides, Listeria monocytogenes.
Gram-negative Aerobic Bacteria: Neisseria spp.: Neisseria meningitidis, penicillinase- and nonpenicillinase-producing strains of Neisseria gonorrhoeae.
Haemophilus spp.: Penicillinase- and nonpenicillinase-producing strains of Haemophilus influenzae, strains of Haemophilus influenza resistant to ampicillin, penicillinase- and nonpenicillinase-producing strains of Haemophilus parainfluenzae, Haemophilus ducreyi.
Enterobacteriaceae spp.: Citrobacter diversus, Citrobacter freundii, Enterobacter agglomerans, Enterobacter cloacae, Enterobacter aerogenes, Escherichia coli, Hafnia alvei, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii (Proteus morganii), Proteus mirabilis, Proteus vulgaris, Providencia rettgeri (Proteus rettgeri), Providencia stuartii, Serratia liquefaciens, Serratia marcescens, Salmonella spp., Shigella spp., Yersinia enterocolitica, Yersinia pseudotuberculosis.
Pseudomonas spp.: Pseudomonas aeruginosa.
Other Gram-negative aerobic bacteria: Acinetobacter spp., Moraxella catarrhalis (Branhamella catarrhalis), Gardnerella vaginalis (Haemophilus vaginalis).
Gram-positive Anaerobic Bacteria: Actinomyces spp., Bifidobacterium spp., Clostridium perfringens, some strains of Clostridium difficile, Eubacterium spp., Lactobacillus spp., Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp.
Gram-negative Anaerobic Bacteria: Bacteriodes fragilis, Bacteroides distasonis, Bacteroides thetaiotaomicron, Bacteroides vulgates, Fusobacterium spp.
Other organism: Mycobacterium species (in vitro), but no clinical studies.
Pharmacokinetics: Neither Imipenem nor Cilastatin sodium is appreciably absorbed from GI tract and, therefore, they must be given parenterally. Imipenem is widely distributed into the following tissues and fluids; sputum, saliva, aqueous humor, bone, bile, fallopian tube, myometrium, endometrium, pleural, peritoneal, interstitial and skin. Only low concentrations of Imipenem diffuse into CSF following IV administration (1-10%). However if meningitis occurs, the diffusion will be higher. Imipenem crosses the placenta and is distributed into milk. After IV administration for 20 minutes, peak plasma level, highest at 20% of Imipenem and 40% of Cilastatin, are bound to plasma proteins. In adults with normal renal function, the elimination half-life of IV Imipenem is 0.85-1.3 hours. The serum half-life of both Imipenem and Cilastatin are prolonged in patients with impaired renal function. If Imipenem is administered alone, the drug is partially hydrolyzed in the kidneys by dehydropeptidase I (DHP I) to a microbiologically inactive nephrotoxic metabolites, with only 5 to 43% of a dose excreted in the urine as unchanged active drug. However, when Cilastatin sodium is administered for inhibit dehydropeptidase I (DHP I) enzyme concurrently with Imipenem in 1:1 ratio as a solution, approximately 70% of Imipenem dose and 75% of Cilastatin dose are excreted as unchanged in urine within 10 hours. A 1:1 ratio of Imipenem to Cilastatin ensures that dehydropeptidase I (DHP I) is inhibited up to 8-10 hours. Imipenem is also metabolized to some extent by a nonrenal mechanism which is unrelated to dehydropeptidase I (DHP I). Approximately 20-30% of Imipenem dose is inactivated by nonspecific hydrolysis of the β-lactam ring. Cilastatin is partially metabolized in the kidney to N-acetylcilastatin, which is also an effective inhibitor of dehydropeptidase I (DHP I). Approximately 70-80% of IV dose of Cilastatin is excreted in urine as unchanged and 12% is excreted as N-acetylcilastatin. Both Imipenem and Cilastatin are removed by hemodialysis and peritoneal dialysis.