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Pharmacology: Pharmacodynamics: 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 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.
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): (See Table 1.)
Click on icon to see table/diagram/imagePrevalence 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 table shows the cases whose resistance patterns are known to vary in the European Union: Acute Otitis Media Tympanostomy Tubes (AOMT): (See Table 2.)
Click on icon to see table/diagram/imageAcute Otitis Externa (AOE): (See Table 3.)
Click on icon to see table/diagram/imagePharmacokinetics: Auricular use: Blood samples in two studies of AOMT 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 Plus in the ear is unlikely to result in pharmacokinetically or clinically relevant systemic levels of ciprofloxacin and/or fluocinolone acetonide.
Toxicology: Preclinical safety data: The toxicity of ciprofloxacin has been deeply studied. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Adverse effects on the central nervous system and potential to damage cartilage as well as tendons have been described in human and preclinical studies. In juvenile and prenatal animals exposed to quinolones, effects on immature cartilage have been observed. However, these toxic effects have been observed after oral or IV administration at doses that cannot be achieved after otic administration.
Since no relevant toxicity 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 of hearing loss should be expected with its clinical use.
