Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ophthalmologicals; anti-infectives
MAX DRO API MAY21 V5                                                   UK SmPC (JAN 2021) ATC code: S01CA01

Mechanism of Action
Maxitrol ophthalmic suspension has a dual effect: suppression of inflammation symptoms by the corticosteroidal component dexamethasone, and an anti-infective effect due to the presence of two antibiotics, polymyxin B and neomycin.

Dexamethasone is a synthetic glucorticoid with potent anti-inflammatory activity. Polymyxin B is a cyclic lipopeptide that penetrates the cell wall of gram-negative bacilli to destabilize the cytoplasmic membrane. It is generally less active against gram-positive bacteria.
Neomycin is an aminoglycoside antibiotic that primarily exerts its effect on bacterial cells by inhibiting polypeptide assembly and synthesis on the ribosome.

Mechanism of Resistance
Resistance of bacteria to polymyxin B is of chromosomal origin and is uncommon. A modification of the phospholipids of the cytoplasmic membrane appears to play a role.
Resistance to neomycin occurs by several different mechanisms including (1) alterations of the ribosomal subunit within the bacterial cell; (2) interference with the transport of neomycin into the cell, and (3) inactivation by an array of adenylating, phosphorylating, and acetylating enzymes. Genetic information for production of inactivating enzymes may be carried on the bacterial chromosome or on plasmids.
Breakpoints
Each gram of MAXITROL ophthalmic suspension contains 6000 IU polymyxin B sulphate and 3500 IU neomycin sulphate. The breakpoints and the in vitro spectrum as mentioned below are based on the dual activity of either polymyxin B or neomycin. The breakpoints listed here are based upon acquired resistance for specific species found in ocular infections and the ratio in International Units of polymyxin B to neomycin in MAXITROL ophthalmic suspension:
Resistance breakpoints: >5:2.5 to >40:20 depending upon the bacterial species 
Susceptibility
The information listed below provides guidance on the approximate probabilities on the susceptibility of microorganisms to polymyxin B or neomycin in MAXITROL ophthalmic suspension. The presentation below lists bacterial species recovered from external ocular infections of the eye.

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 combination of polymyxin B or neomycin as in MAXITROL ophthalmic suspension in at least some types of infections is questionable.

COMMONLY SUSCEPTIBLE SPECIES
Aerobic Gram-positive microorganisms
Bacillus cereus
Bacillus megaterium
Bacillus pumilus
Bacillus simplex
Corynebacterium accolens
Corynebacterium bovis
Corynebacterium macginleyi

MAX DRO API MAY21 V5                                                    UK SmPC (JAN 2021) Corynebacterium propinquum
Corynebacterium pseudodiphtheriticum
Staphylococcus aureus (methicillin susceptible - MSSA)
Staphylococcus capitis
Staphylococcus epidermidis (methicillin susceptible - MSSE)
Staphylococcus pasteuri
Staphylococcus warneri
Streptococcus mutans

Aerobic Gram-negative microorganisms
Haemophilus influenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Moraxella lacunata
Pseudomonas aeruginosa
Serratia species

SPECIES FOR WHICH ACQUIRED RESISTANCE MIGHT BE A PROBLEM
Staphylococcus epidermidis (methicillin resistant - MRSE)
Staphylococcus hominis
Staphylococcus lugdunensis
INHERENTLY RESISTANT ORGANISMS
Aerobic Gram-positive microorganisms
Enterococci faecalis
Staphylococcus aureus (methicillin resistant - MRSA)
Streptococcus mitis
Streptococcus pneumoniae
Anaerobic Bacteria
Propionibacterium acnes

Dexamethasone is a moderately powerful corticosteroid having good penetration in ocular tissue. Corticosteroids have an anti-inflammatory as well as a vasoconstrictive effect. They suppress the inflammatory response and symptoms in various disorders without basically curing these disorders.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Dexamethasone, like other corticosteroids, is absorbed rapidly after oral administration and has a biological half-life of about 190 minutes. Sufficient absorption may occur after topical application to the skin and eye to produce systemic effects. Intraocular penetration of dexamethasone occurs in significant amounts and contributes to the effectiveness of dexamethasone in anterior segment inflammatory disease.
Polymyxin B sulphate is not absorbed from the gastrointestinal tract or through intact skin, although the intact corneal epithelium prevents penetration into the corneal stroma, therapeutic concentrations do enter the stroma after epithelial damage. Good stromal penetration occurs after epithelial abrasion following topical instillation, subconjunctival injection, or corneal bath. No significant polymyxin B penetration into the vitreous is demonstrable after parenteral or local administration of the drug.
Neomycin is poorly absorbed from the gastrointestinal tract and after topical administration an insufficient amount is absorbed to produce systemic effects. Absorption has been 

MAX DRO API MAY21 V5                                                    UK SmPC (JAN 2021) reported to occur from wounds and inflamed skin. After absorption neomycin is rapidly excreted by the kidneys in active form.