Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Otological preparations: corticosteroids and anti-infectives in combination. ATC Code: S02CA05.

Fluocinolone acetonide

Fluocinolone acetonide is a synthetic fluorinated corticosteroid with anti-inflammatory, antipruritic, and vasoconstrictive properties. Early anti-inflammatory effects of topical corticosteroids include the inhibition of macrophage and leukocyte movement and activity in the inflamed area by reversing vascular dilation and permeability. Later inflammatory processes such as capillary production, collagen deposition, keloid (scar) formation also are inhibited by corticosteroids.

Ciprofloxacin
Mechanism of action

As a fluoroquinolone antibacterial agent, the bactericidal action of ciprofloxacin results from the inhibition of both type II topoisomerase (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair and recombination.

Mechanism of resistance
The mutation in genes encoding ciprofloxacin targets (gyr A, gyrN, parC, parE) represent the main mechanism of ciprofloxacin resistence in P. aeruginoa. Another mechanism of resistance described is overexpression of the efflux pumps, in particular Mex (Multiple EffluX) gene. The single mutations do not necessarily result in clinical resistance, but multiple mutations generally result in clinical resistance. Nevertheless, the high concentration of delivered antibiotic, when topical administration is used, is always well above the MIC of the relevant organisms. This makes the emergence of bacterial resistance extremely improbable. The possibility for the emergence of resistance seems to be vastly lower when topical routes of administration are used as compared with drugs that are administered systemically.

Breakpoints

For most topical agents there are limited pharmacological data and no data relating treatment to outcome. For this reason EUCAST proposes that epidemiological cut-off values (ECOFFs) are used to indicate susceptibility to topical agents.

EUCAST Clinical Breakpoint for ciprofloxacin (Table v.5.0, valid from 2015-01-01): 
Microorganisms                Sensible (S)                  Resistant (R) Staphylococcus species        S ≤ 1 mg/l                    R ≥ 1 mg/l Streptococcus                 S ≤ 0.125 mg/l                R ≥ 2 mg/l pneumoniae
Haemophilus influenza and     S ≤ 0.5 mg/l                  R ≥ 0.5 mg/l Moraxella catarrhalis
Pseudomonas species           S ≤ 0.5 mg/l                  R ≥ 1 mg/l 
Prevalence of resistance may vary according to geographical zone and weather for the selected microorganisms. Local information on resistance should be available, particularly in the case of serious infections. This information only provides an approximate orientation as to the probability of the microorganism being sensitive to this antibiotic.


The following tables show the cases whose resistance patterns are known to vary in the European Union:

Acute Otitis Media with Tympanostomy Tubes (AOMT)

COMMONLY SUSCEPTIBLE SPECIES
Aerobic Gram-positive micro-organisms:
Staphylococcus aureus (methicillin-susceptible)
Streptococcus pneumoniae
Aerobic Gram negative micro organisms:
Haemophilus influenzae
Moraxella catarrhalis
Pseudomonas aeruginosa
SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM
Aerobic Gram-positive micro-organisms:
Staphylococcus aureus (methicillin-resistant)

Acute Otitis Externa (AOE)

COMMONLY SUSCEPTIBLE SPECIES
Aerobic Gram-positive micro-organisms:
Staphylococcus aureus (methicillin-susceptible)
Aerobic Gram negative micro organisms:
Pseudomonas aeruginosa
SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM
Aerobic Gram-positive micro-organisms:
Staphylococcus aureus (methicillin-resistant)

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Auricular use

Blood samples were taken in two studies of AOMT (acute otitis media with tympanostomy tubs) to determine the plasma levels of ciprofloxacin and/or fluocinolone acetonide. Pharmacokinetic analysis showed no or negligible plasma level of the active ingredients demonstrating that topical application of Cetraxal in the ear is unlikely to result in pharmacokinetically or clinically relevant systemic levels of ciprofloxacin and/or fluocinolone acetonide.