Otological preparations: corticosteroids and antiinfectives in combination. ATC Code:
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.
Pharmacokinetics: Auricular use:
Given the concentration of the formulation as drops and the maximum daily dose to be administered, topical application in the ear is unlikely to result in pharmacokinetically or clinically relevant systemic levels of ciprofloxacin.
The absorption of fluocinolone acetonide after topical administration is generally low, and varies ostensibly according to the application site. There are no data on absorption following ototopical application.
Toxicology: Preclinical Safety Data:
The toxicity of ciprofloxacin has been deeply studied. Adverse effects on CNS and potential to damage cartilage as well as tendons have been described in human and preclinical studies. However, these toxic effects have been observed after oral or IV administration at doses that cannot be achieved after otic administration.
Regarding fluocinolone acetonide, reversible hypothalamic-pituitary-adrenal (HPA) axis suppression has occurred in some patients receiving topical corticosteroid at total doses higher than 2 g. However, no HPA axis suppression has been described after otically administered corticosteroids. Considering the low total dose after the treatment with Cetraxal Plus, it is unlikely that the systemic exposure of this drug could lead to measurable changes in cortisol levels.
Since no relevant signs of ototoxicity were observed after intratympanic administration of Cetraxal Plus during 28 days in guinea pigs, the ototopical use of this product should be considered safe and no risk for hearing loss should be expected with its clinical use.
Ciprofloxacin: Mechanism of Resistance:
The mutation in genes encoding ciprofloxacin targets (gyr A, gyrN, parC, parE) represent the main mechanism of ciprofloxacin resistance in P. aeruginosa
. 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.
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.
Based on present data the following table represents susceptibility of ciprofloxacin to the leading pathogens in the approved indication. (See table.)
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