Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use, Third-generation cephalosporins, ATC code: J01DD04.

Mechanism of action
Ceftriaxone inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins (PBPs). This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death.

Resistance
Bacterial resistance to ceftriaxone may be due to one or more of the following mechanisms: -     hydrolysis by beta-lactamases, including extended-spectrum beta-lactamases (ESBLs), carbapenemases and Amp C enzymes that may be induced or stably derepressed in certain aerobic Gram-negative bacterial species.
-     reduced affinity of penicillin-binding proteins for ceftriaxone.
-     outer membrane impermeability in Gram-negative organisms.
-     bacterial efflux pumps.

Susceptibility testing breakpoints
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST v. 7.1, valid from 2017-03-10) are as follows: 
Dilution Test (MIC, mg/L)
Pathogen
Susceptible                 Resistant
Enterobacteriaceae                                          ≤1                            >2 Staphylococcus spp.                                         a.                            a.
Streptococcus spp. (Groups A, B, C and G)                   b.                            b.
Streptococcus pneumoniae                                    ≤ 0.5c.                       >2 Viridans group Streptococci                                 ≤ 0.5                         > 0.5 Haemophilus influenzae                                      ≤ 0.12c.                      > 0.12 Moraxella catarrhalis                                       ≤1                            >2 Neisseria gonorrhoeae                                       ≤ 0.12                        > 0.12 Neisseria meningitidis                                      ≤ 0.12c.                      > 0.12 Non-species related                                         ≤ 1d.                         >2 
 a. Susceptibility inferred from cefoxitin susceptibility.
b. Susceptibility inferred from penicillin susceptibility.
c. Isolates with a ceftriaxone MIC above the susceptible breakpoint are rare and, if found, should be re-tested and, if confirmed, should be sent to a reference laboratory.
d. Breakpoints apply to a daily intravenous dose of 1 g x 1 and a high dose of at least 2 g x 1.


Clinical efficacy against specific pathogens
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severeinfections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of ceftriaxone in at least some types of infections is questionable.
Commonly susceptible species
Gram-positive aerobes

Staphylococcus aureus (methicillin-susceptible)a
Staphylococci coagulase-negative (methicillin-susceptible)a
Streptococcus pyogenes (Group A)
Streptococcus agalactiae (Group B)
Streptococcus pneumoniae
Viridans Group Streptococci

Gram-negative aerobes
Borrelia burgdorferi
Haemophilus influenzae
Haemophilus parainfluenzae
Moraxella catarrhalis
Neisseria gonorrhoea
Neisseria meningitidis
Proteus mirabilis
Providencia spp.
Treponema pallidum
Species for which acquired resistance may be a problem
Gram-positive aerobes

Staphylococcus epidermidisb
Staphylococcus haemolyticusb
Staphylococcus hominisb

Gram-negative aerobes
Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloacae
Escherichia colic
Klebsiella pneumoniaec
Klebsiella oxytocac
Morganella morganii
Proteus vulgaris
Serratia marcescens
Anaerobes
Bacteroides spp.
Fusobacterium spp.
Peptostreptococcus spp.
Clostridium perfringens
Inherently resistant organisms
Gram-positive aerobes

Enterococcus spp.
Listeria monocytogenes

Gram-negative aerobes
Acinetobacter baumannii
Pseudomonas aeruginosa
Stenotrophomonas maltophilia
Anaerobes
Clostridium difficile

Others:
Chlamydia spp.
Chlamydophila spp.
Mycoplasma spp.
Legionella spp.
Ureaplasma urealyticum
 a
All methicillin-resistant staphylococci are resistant to ceftriaxone.
b
Resistance rates > 50% in at least one region c
ESBL producing strains are always resistant

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
After intravenous bolus administration of ceftriaxone 500 mg and 1 g, mean peak plasma ceftriaxone levels are approximately 120 and 200 mg/l respectively. After intravenous infusion of ceftriaxone, 1 g and 2 g, the plasma ceftriaxone levels are approximately, 150 and 250 mg/l respectively. 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 1 g 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.

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 section 4.6).

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 clearanceis 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
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).