Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Third-generation cephalosporins, ATC code: J01DD16.

Mechanism of action
Cefditoren exerts its antibacterial action by inhibiting bacterial cell wall synthesis due to its affinity for penicillin-binding proteins (PBPs).
Mechanisms of resistance
Bacterial resistance to cefditoren may be due to one or more of the following mechanisms: • hydrolysis by beta-lactamases. Cefditoren may be efficiently hydrolysed by certain of the extended-spectrum beta-lactamases (ESBLs) and by the chromosomally-encoded (AmpC) beta lactamases that may be induced or stably derepressed in certain aerobic gram-negative bacterial species
• reduced affinity of penicillin-binding proteins for cefditoren
• outer membrane impermeability, which restricts access of cefditoren to penicillin binding proteins in gram-negative organisms
• active substance efflux pumps.

More than one of these mechanisms of resistance may co-exist in a single bacterial cell. Depending on the mechanism(s) present, bacteria may express cross-resistance to several or all other beta-lactams and/or antibacterial active substances of other families.
Gram-negative micro-organisms containing inducible chromosomally encoded beta-lactamases, like Enterobacter spp., Serratia spp., Citrobacter spp., and Providentia spp., should be regarded as resistant for cefditoren pivoxil in spite of apparent in vitro susceptibility.
Breakpoints
The recommended MIC breakpoints for cefditoren, which allow susceptible micro-organisms to be distinguished from intermediately susceptible micro-organisms, and intermediately susceptible organisms from resistant micro-organisms are: Susceptible ≤ 0.5 μg/ml, Resistant ≥ 2 μg/ml (or > 1 μg/ml according to recent criteria).
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly susceptible species
Aerobic Gram-positive bacteria:
Groups C and G streptococci
Staphylococcus aureus methicillin - susceptible *
Streptococcus agalactiae
$
Streptococcus pneumoniae*
Streptococcus pyogenes*
Aerobic Gram-negative bacteria:
Haemophilus influenzae*
Moraxella catarrhalis*
Anaerobic bacteria:
Clostridium perfringes
Peptostreptococcus spp.
Inherently resistant organisms
Aerobic Gram-positive bacteria:
Enterococcus spp.
Staphylococcus aureus methicillin - resistant (MRSA)+
Aerobic Gram-negative bacteria:
Acinetobacter baumanii
Pseudomonas aeruginosa
Anaerobic bacteria:
Bacteroides fragilis group
Clostridium difficile
Other:
Chlamydia spp.
Mycoplasma spp.
Legionella spp.

+ MRSA have acquired resistance to cephalosporins but are included here for convenience.
*Clinical efficacy has been demonstrated for the susceptible micro-organisms in the approved clinical indications.
$
Some strains that show high level resistance to penicillin may show a decreased susceptibility to cefditoren. Cefotaxime and ceftriaxone resistant strains should not be considered susceptible.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
Following oral administration, cefditoren pivoxil is absorbed in the gastrointestinal tract and is hydrolysed to cefditoren by the action of esterases. The absolute bioavailability of orally administered cefditoren is approximately 15-20%.
The presence of food in the gastrointestinal tract increases the absorption of cefditoren pivoxil, with the Cmax and the AUC approximately 50% and 70% higher compared to fasting values.
A 200 mg dose administered with food gives a mean Cmax of 2.6 μg/ml after approximately 2.5 hours, while a 400 mg dose gives a mean Cmax value of 4.1 μg/ml in approximately the same time period.
Distribution
Plasma protein binding to cefditoren is 88%.
The volume of distribution at steady state is not significantly different from that calculated after a single dose administration and is relatively independent of the administered dose (40-65 litres).
After a single dose administration of 400 mg, penetration in bronchial mucosa and in bronchial secretion was 60% and 20% respectively of the plasma concentration. After the same dose, cefditoren concentrations in skin blister fluid reached 40% and 56% of plasma AUC after 8 and 12 hours, respectively.
Biotransformation / Elimination
Following multiple dose administration, pharmacokinetic parameters were similar to those obtained after single dose administration, with no accumulation detected.
Up to 18% of the administered dose of cefditoren is recovered by excretion in urine without being metabolised.
The plasma elimination half-life of cefditoren is between 1 and 1.5 hours. Total clearance adjusted by bioavailability is approximately 25-30 l/h, while renal clearance is approximately 80-90 ml/min.
Studies with labelled cefditoren in healthy volunteers suggest that the non-absorbed fraction is eliminated in faeces, where the majority of the administered cefditoren appears as inactive metabolites.
Cefditoren pivoxil is not detected in faecal extracts or in urine. The pivalate portion is eliminated through renal excretion as the conjugated pivaloylcarnitine.

Special populations
Gender
Pharmacokinetics of cefditoren pivoxil do not show clinically relevant differences between males and females.
Elderly
Plasma levels of cefditoren in elderly subjects (over 65 years) show Cmax and AUC that are approximately 26% and 33% higher than in younger adults. However, no dose adjustment is required except in cases of advanced hepatic and/or renal insufficiency.
Renal insufficiency
After multiple dose of cefditoren pivoxil 400 mg to patients with moderate to severe renal impairment Cmax was 2-fold and AUC between 2.5 and 3-fold than those observed in normal healthy volunteers (see section 4.2 Posology and Method of Administration). There are no data available for patients undergoing dialysis.
Hepatic insufficiency
In mild hepatic insufficiency (Child-Pugh A) to moderate hepatic insufficiency (Child-Pugh B), multiple doses of 400 mg cefditoren pivoxil gave a slight increase in pharmacokinetic parameters compared to normal subjects. No data are available in patients with severe insufficiency (Child-Pugh C) (See section 4.2 Posology and Method of Administration).

Pharmacokinetic/Pharmacodynamic relationship
With a dosage of 200 mg twice daily, plasma concentrations exceed the minimum inhibitory concentrations (MIC90) for Moraxella catarrhalis, Haemophilus influenzae, Streptococcus pyogenes and penicillin-susceptible Streptococcus pneumoniae strains for at least 50% of the dose interval. The dosage of 400 mg twice daily, also provides a time above the minimum inhibitory concentrations which is enough to exceed the MIC90 of Streptococcus pneumonia resistant to penicillin.