Forgram Mechanism of Action

Antibacterial.
Pharmacology: After 500 mg and 1.5 b bolus IV injection in healthy subjects, mean peak plasma concentrations were 0.15 and 0.28 mg/mL, respectively.
Following IM injection, mean peak plasma concentrations were about half those achieved after IV administration of an equivalent dose. After 2 hrs, mean plasma concentrations by the 2 routes were similar.
In surgical patients and those with bacterial infections, mean plasma concentrations 24 hrs after the first dose of 2 g ceftriaxone were between 0.012 and 0.02 mg/mL. Peak plasma concentrations ranged from 0.18 and 0.25 mg/mL. Steady-state mean plasma concentration following repeated administration of 2g every 24 hrs was 0.015 mg/mL.
In neonates with bacterial meningitis given 50 mg/kg IV boluses, mean plasma concentrations after 1-2 hrs were 0.12 mg/mL in those less than 1 week of age, and 0.1 mg/mL if >1 week.
Repeated 12-hrly IV dosing (eg, 1 g every 12 hrs) causes accumulation with peak trough levels up to 50% higher than after the 1st dose. Repeated dosing at 24-hr intervals (eg, 2 g every 24 hrs) results in mean maximum plasma concentrations at 8% higher and grade tissue penetration than the twice-daily dosing schedule.
In studies which have examined the kinetics of both total and free ceftriaxone, apparent volume of distribution of total ceftriaxone during the terminal elimination phase increased with increasing dose, but the volume of distribution of the free ceftriaxone remained relatively constant. Volume of distribution of infants >1 month old compared with adults is 3-fold larger, as is the plasma clearance. Elimination half-life in healthy adults is about 6-9 hrs.
Ceftriaxone penetrates well into most tissues and body fluids including cerebrospinal fluid (inflamed and non-inflamed meninges), sputum, pleural, peritoneal, blister and ascitic fluids; tears, bile, gallbladder tissue, bone, myometrium, endometrium and salpinges tissues, synovial fluid, prostate, nasal mucosa, tonsil and middle ear mucosa. Ceftriaxone is the first systemic cephalosporins to adequately penetrate into the vitreous humor. Ceftriaxone is highly protein bound (95%).
Ceftriaxone is eliminated unchanged by the kidneys and liver, 56% of a dose of ¹⁴C-labeled ceftriaxone appeared in the urine, and 14% as microbiologically inactive, material in the feces. Structure of the metabolites have not been identified.
The percentage of ceftriaxone recovered in the bile during constant infusion varied from 11-65%. Renal clearance is governed mainly by glomerular filtration of unchanged drug. In neonates, 70% of a dose is eliminated in the urine compared with 40-50% in adults.
Microbiology: Mechanism of Action: Ceftriaxone sodium, a semisynthetic broad-spectrum "third generation" cephalosporin antibiotic, exert its bactericidal activity by interfering with the synthesis of the bacterial cell wall. It binds to penicillin-binding protein 3 responsible for the synthesis of peptidoglycan, a heteropolymeric structure that gives the cell wall its mechanical stability.
The 1st 2 steps in cell wall synthesis (ie, formation of an acetylmuranyl pentapeptide followed by alternating linkage to acetylglucosamine to form peptidoglycan chains) are unaffected by penicillins or cephalosporins. It is the final step in this process, in which strands of peptidoglycan are cross-linked by peptide side chains, that is inhibited by ceftriaxone. This transpeptidation reaction is mediated by the transpeptidase enzyme and occurs at the surface of the cell membrane. Ceftriaxone, because of its similarity to the terminal D-alanine-D-alanine of the pentapeptide, binds covalently to the active site of the transpeptidase enzyme and inhibits it, causing spheroplast formation and eventual lysis of the bacterial cell membrane resulting bacterial death.
Spectrum of Activity: Ceftriaxone is active in vitroagainst the following organisms:
Gram-Positive Aerobes: Staphylococcus aureus (including penicillinase-producing strains), Streptococcus pneumoniae, Streptococcus pyogenes, Viridians group Streptococci.
Gram-Negative Aerobes: Acinetobacter calcoaceticus, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae (including ampicillin resistant and β-lactamase producing strains), Morganella morganii, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Salmonella spp (including Salmonella typhi).
Anaerobes: Bacteroides fragilis, Clostridium spp, Peptostreptococcus spp.
Note: Methicillin-resistant Staphylococci are resistant to cephalosporins, including ceftriaxone. Most strains of Group D Streptococci and Enterococci are resistant. Most strains of Clostridium difficile are resistant.
The following microorganisms are sensitive to ceftriaxone in vitro but the clinical significance is unknown:
Gram-Positive Aerobes: Streptococcus agalactiae.
Gram-Negative Aerobes: Citrobacter diversus, Citrobacter freundii, Providencia spp (including Providencia rettgerri), Shigella spp.
Anaerobes: Bacteroides bivius, Bacteroides melaninogenicus.