Medaxone Mechanism of Action

Pharmacotherapeutic group: Antibacterials for systemic use, Other beta-lactam antibacterials, Third-generation cephalosporins. ATC code: J01DD04.
Pharmacology: Pharmacodynamics: Mechanism of action: The bactericidal activity of ceftriaxone results from inhibition of bacterial cell wall synthesis. Ceftriaxone exerts in vitro activity against a wide range of gram-negative and gram-positive micro-organisms. Ceftriaxone is highly stable to most ß-lactamases, both penicillinases and cephalosporinases, of gram-positive and gram-negative bacteria. Ceftriaxone is usually active against the following micro-organisms in vitro and in clinical infections.
Gram-positive aerobes: Staphylococcus aureus (methicillin-sensitive), Staphylococci coagulase-negative, Streptococcus pyogenes (ß-hemolytic, group A), Streptococcus agalactiae (ß-hemolytic, group B), ß-hemolytic Streptococci (non-group A or B), Streptococcus viridans, Streptococcus pneumoniae.
Note: Methicillin-resistant Staphylococcus spp. is resistant to cephalosporins, including ceftriaxone. In general, Enterococcus faecalis, Enterococcus faecium and Listeria monocytogenes are resistant.
Gram-negative aerobes: Acinetobacter lwoffi, Acinetobacter anitratus (mostly A. baumanii)*, Aeromonas hydrophila, Alcaligenes faecalis, Alcaligenes odorans, Alcaligenes-like bacteria, Borrelia burgdorferi, Capnocytophaga spp., Citrobacter diversus (including C. amalonaticus), Citrobacter freundii*, Escherichia coli, Enterobacter aerogenes*, Enterobacter cloacae*, Enterobacter spp. (other)*, Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Hafnia alvei, Klebsiella oxytoca, Klebsiella pneumoniae**, Moraxella catarrhalis (former Branhamella catarrhalis), Moraxella osloensis, Moraxella spp. (other), Morganella morganii, Neisseria gonorrhoea, Neisseria meningitidis, Pasteurella multocida, Plesiomonas shigelloides, Proteus mirabilis, Proteus penneri*, Proteus vulgaris*, Pseudomonas fluorescens*, Pseudomonas spp. (other)*, Providentia rettgeri*, Providentia spp. (other), Salmonella typhi, Salmonella spp. (non-typhoid), Serratia marcescens*, Serratia spp. (Other)*, Shigella spp., Vibrio spp., Yersinia enterocolitica, Yersinia spp. (other).
*Some isolates of these species are resistant to ceftriaxone, mainly due to the production of the chromosomally encoded ß-lactamase.
**Some isolates of these species are resistant due to production of extended spectrum, plasmid-mediated ß-lactamase.
Note: Many strains of the previously mentioned micro-organisms that are multiple resistant to other antibiotics, e.g. amino-penicillins and ureido-penicillins, older cephalosporins and aminoglycosides, are susceptible to ceftriaxone. Treponema pallidum is sensitive in vitro and in animal experiments. Clinical investigations indicate that primary and secondary syphilis respond well to ceftriaxone therapy. With a few exceptions clinical P. aeruginosa isolates are resistant to ceftriaxone.
Anaerobic organisms: Bacteroides spp. (bile-sensitive)*, Clostridium spp. (excluding C. difficile), Fusobacterium nucleatum, Fusobacterium spp. (other), Gaffkia anaerobica (formerly Peptococcus), Peptostreptococcus spp.
*Some isolates of these species are resistant to ceftriaxone due to ß-lactamase-production.
Note: Many strains of ß-lactamase-producing Bacteroides spp. (notably B. fragilis) are resistant. Clostridium difficile is resistant.
Susceptibility to ceftriaxone can be determined by the disk diffusion test or by the agar or broth dilution test using standardized techniques for susceptibility testing such as those recommended by the National Committee for Clinical Laboratory Standards (NCCLS). The NCCLS issued the following interpretative breakpoints for ceftriaxone: (See Table 1.)

Click on icon to see table/diagram/image

Micro-organisms should be tested with the ceftriaxone disk since it has been shown by in vitro tests to be active against certain strains resistant to cephalosporin class disks.
Where NCCLS recommendations are not in daily use, alternative, well standardized, susceptibility-interpretative guidelines such as those issued by DIN, ICS and others may be substituted.
Pharmacokinetics: Absorption: Intramuscular administration: Following intramuscular injection, mean peak plasma ceftriaxone levels are approximately half those observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single intramuscular dose of 1g is about 81 mg/l and is reached in 2-3 hours after administration. The area under the plasma concentration-time curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.
Intravenous administration: After intravenous bolus administration of ceftriaxone 500 mg and 1g, mean peak plasma ceftriaxone levels are approximately 120 and 200 mg/l respectively. After intravenous infusion of ceftriaxone 500 mg, 1g and 2g, the plasma ceftriaxone levels are approximately 80, 150 and 250 mg/l respectively.
Distribution: The volume of distribution of ceftriaxone is 7-12 l. Concentrations well above the minimal inhibitory concentrations of most relevant pathogens are detectable in tissue including lung, heart, biliary tract/liver, tonsil, middle ear and nasal mucosa, bone, and in cerebrospinal, pleural, prostatic and synovial fluids. An 8-15% increase in mean peak plasma concentration (Cmax) is seen on repeated administration; steady state is reached in most cases within 48-72 hours depending on the route of administration.
Penetration into particular tissues: Ceftriaxone penetrates the meninges. Penetration is greatest when the meninges are inflamed. Mean peak ceftriaxone concentrations in CSF in patients with bacterial meningitis are reported to be up to 25% of plasma levels compared to 2% of plasma levels in patients with uninflamed meninges. Peak ceftriaxone concentrations in CSF are reached approximately 4-6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is excreted in the breast milk at low concentrations (see Use in Pregnancy & Lactation).
Protein binding: Ceftriaxone is reversibly bound to albumin. Plasma protein binding is about 95% at plasma concentrations below 100 mg/l. Binding is saturable and the bound portion decreases with rising concentration (up to 85% at a plasma concentration of 300 mg/l).
Biotransformation: Ceftriaxone is not metabolised systemically; but is converted to inactive metabolites by the gut flora.
Elimination: Plasma clearance of total ceftriaxone (bound and unbound) is 10-22 ml/min. Renal clearance is 5-12 ml/min. 50-60% of ceftriaxone is excreted unchanged in the urine, primarily by glomerular filtration, while 40-50% is excreted unchanged in the bile. The elimination half-life of total ceftriaxone in adults is about 8 hours.
Patients with renal or hepatic impairment: In patients with renal or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only minimally altered with the half-life slightly increased (less than two fold), even in patients with severely impaired renal function.
The relatively modest increase in half-life in renal impairment is explained by a compensatory increase in non-renal clearance, resulting from a decrease in protein binding and corresponding increase in non-renal clearance of total ceftriaxone.
In patients with hepatic impairment, the elimination half-life of ceftriaxone is not increased, due to a compensatory increase in renal clearance. This is also due to an increase in plasma free fraction of ceftriaxone contributing to the observed paradoxical increase in total drug clearance, with an increase in volume of distribution paralleling that of total clearance.
Older people: In older people aged over 75 years the average elimination half-life is usually two to three times that of young adults.
Paediatric population: The half-life of ceftriaxone is prolonged in neonates. From birth to 14 days of age, the levels of free ceftriaxone may be further increased by factors such as reduced glomerular filtration and altered protein binding. During childhood, the half-life is lower than in neonates or adults.
The plasma clearance and volume of distribution of total ceftriaxone are greater in neonates, infants and children than in adults.
Linearity/non-linearity: The pharmacokinetics of ceftriaxone are non-linear and all basic pharmacokinetic parameters, except the elimination half-life, are dose dependent if based on total drug concentrations, increasing less than proportionally with dose. Non-linearity is due to saturation of plasma protein binding and is therefore observed for total plasma ceftriaxone but not for free (unbound) ceftriaxone.
Pharmacokinetic/pharmacodynamic relationship(s): As with other beta-lactams, the pharmacokinetic-pharmacodynamic index demonstrating the best correlation with in vivo efficacy is the percentage of the dosing interval that the unbound concentration remains above the minimum inhibitory concentration (MIC) of ceftriaxone for individual target species (i.e. %T >MIC).
Toxicology: Preclinical safety data: There is evidence from animal studies that high doses of ceftriaxone calcium salt led to formation of concrements and precipitates in the gallbladder of dogs and monkeys, which proved to be reversible. Animal studies produced no evidence of toxicity to reproduction and genotoxicity. Carcinogenicity studies on ceftriaxone were not conducted.