Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Aspire Pharma Ltd, Unit 4, Rotherbrook Court, Bedford Road, Petersfield, Hampshire, GU32 3QG, United Kingdom
Pharmacotherapeutic group: Sensory organs. Otologicals. Antiinfectives.
ATC code: S02AA15
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.
No pharmacodynamic relationship has been described for topical administration. With local pharmaceutical forms, the concentration attained in situ are far higher than plasma concentrations.
In-vitro resistance to ciprofloxacin can be acquired through a stepwise process by target site mutations in both DNA gyrase and topoisomerase IV. The degree of cross-resistance between ciprofloxacin and other fluoroquinolones that results is variable. Single mutations may not result in clinical resistance, but multiple mutations generally result in clinical resistance to many or all active substances within the class.
Impermeability and/or active substance efflux pump mechanisms of resistance may have a variable effect on susceptibility to fluoroquinolones, which depends on the physiochemical properties of the various active substances within the class and the affinity of transport systems for each active substance. All in-vitro mechanisms of resistance are commonly observed in clinical isolates. Resistance mechanisms that inactivate other antibiotics such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may affect susceptibility to ciprofloxacin.
Plasmid-mediated resistance encoded by qnr-genes has been reported.
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.
Epidemiological cut-off values according to EUCAST. ECOFF â€mg/ml
Enterobacteriaceae – 0.125 mg/l
Staphylococcus spp. - 1 mg/l
Pseudomonas aeruginosa – 0.5 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.
Based on present data the following table represents susceptibility of ciprofloxacin to the leading pathogens in the approved indication.
Aerobic Gram positive micro-organisms: Staphylococcus aureus
Aerobic Gram negative micro-organisms: Pseudomonas aeruginosa
NB: With local pharmaceutical forms, the concentrations attained in situ are far higher than plasma concentrations. Some doubts remain as to the kinetics of concentrations in situ, the local physical and chemical conditions which may modify the activity of the antibiotic and the stability of the product in situ.
The plasma concentrations of ciprofloxacin were not measured following administration of 0.25 ml Cetraxal 0.2% (total dose: 0.5 mg ciprofloxacin). It is expected that systemic plasma levels will be no detectable or very low, although no significant systemic passage of ciprofloxacin is expected under normal condition of use. Even if the entire amount of ciprofloxacin was absorbed following bilateral ear administration (1mg total dose) it is doubtful that a detectable plasma concentration of this drug would result in a human considering 180L as volume of distribution of ciprofloxacin (EUCAST information) and 5ng/ml as the detection limit.
No significant findings were seen in carcinogenicity or reproductive and developmental toxicity studies. Ciprofloxacin is well tolerated when applied to both intact and abraded skin in the external ear canal.
In test animals, toxicity was only observed at doses which are high above compared to the highest dose used in the ear.
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested following oral administration. The degree of cartilage involvement was found to be dependent on age, species and dosage. With 30 mg/kg ciprofloxacin the effect on the joint was minimal.
While the joints of some species of juvenile animals are sensitive to the degenerative effects of fluoroquinolones (primarily the dog), young adult guinea pigs dosed in the middle ear with ciprofloxacin for one month exhibited no drug related structural or functional changes of the cochlear hair cells and no lesions in the ossicles.
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