Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: anti-infectives, other anti-infectives, ATC code: S03 AA 07 
Mechanism of action
CILOXAN contains the fluoroquinolone ciprofloxacin. The bactericidal and bacteriostatic effect of ciprofloxacin results from interference with DNA gyrase, an enzyme used by the bacterium for the synthesis of DNA. As a result, the vital information of the bacterial chromosomes can no longer be transmitted, causing a breakdown in the metabolism of the bacteria. Ciprofloxacin is active in vitro against a broad spectrum of Gram-positive and Gram-negative bacteria.

PK/PD relationship
The efficacy of an antibacterial agent in the cornea depends not only on the MIC90 for the organism, but on the drug content in the stromal cells. Metal ions in eye irrigation solutions can markedly decrease the bioavailability of fluoroquinolones. As a result, the clinical efficacy of ciprofloxacin against deep ocular infections may not be as good as laboratory antimicrobial susceptibility testing would indicate due to the drug's interaction with the metal ions.

Clinical efficacy against specific pathogens
See “Susceptibility to ciprofloxacin” below.

Antibacterial effect against other relevant pathogens
See “Mechanism of resistance” below.
Mechanism of resistance


CIL API OCT21 V3                                          Belgium update Oct 2020 Resistance to fluoroquinolones, particularly ciprofloxacin, requires significant genetic changes in one or more of five major bacterial mechanisms: a) enzymes for DNA synthesis, b) protective proteins, c) cell permeability, d) drug efflux, or e) plasmid-mediated aminoglycoside 6'-N-acetyltransferase, AAC (6')-Ib.

Fluoroquinolones, including ciprofloxacin, differ in chemical structure and mechanism of action from aminoglycosides, β-lactam antibiotics, macrolides, tetracyclines, sulfonamides, trimethoprim and chloramphenicol. Therefore, organisms resistant to these drugs may be susceptible to ciprofloxacin.

Breakpoints:
There are no official breakpoints for topical use of ciprofloxacin. Use is made of breakpoints based on systemic administration, but it is doubtful whether they apply to topical use. The EUCAST clinical MIC breakpoints for this antibiotic are the following:

Staphylococcus species           S ≤1 mg/l, R ≥1 mg/l
Streptococcus pneumoniae         S ≤0.125 mg/l, R ≥2 mg/l
Haemophilus influenzae           S ≤0.5 mg/l, R ≥0.5 mg/l
Moraxella catarrhalis            S ≤0.5 mg/l, R ≥0.5 mg/l
Pseudomonas aeruginosa           S ≤0.5 mg/l, R ≥1 mg/l

Susceptibility to ciprofloxacin
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. If necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. Bacterial species recovered from external eye infections are listed below.

Commonly susceptible species
Aerobic Gram-positive microorganisms
Corynebacterium accolens
Corynebacterium auris
Corynebacterium propinquum
Corynebacterium pseudodiphtheriticum
Corynebacterium striatum
Staphylococcus aureus (methicillin-susceptible – MSSA)
Staphylococcus capitis
Staphylococcus epidermidis (methicillin-susceptible – MSSE)
Staphylococcus hominis
Staphylococcus saprophyticus
Staphylococcus warneri
Streptococcus pneumoniae
Streptococcus viridans group
Aerobic Gram-negative microorganisms
Acinetobacter species
Haemophilus influenzae
Moraxella catarrhalis
Pseudomonas aeruginosa
Serratia marcescens

CIL API OCT21 V3                                         Belgium update Oct 2020 Species for which acquired resistance may be a problem
Aerobic Gram-positive microorganisms:
Staphylococcus aureus (methicillin-resistant – MRSA)
Staphylococcus epidermidis (methicillin-resistant – MRSE)
Staphylococcus lugdunensis
Aerobic Gram-negative microorganisms:
None
Other microorganisms
None

Inherently resistant organisms
Aerobic Gram-positive microorganisms:
Corynebacterium jeikium
Aerobic Gram-negative microorganisms:
None
Other microorganisms
None

Paediatric patients
Ocular use
The safety and efficacy of CILOXAN 3 mg/ml eye drops were determined in 230 children aged between 0 and 12 years. No serious adverse reactions have been reported in this patient population.

Otic use
The safety and efficacy of CILOXAN 3 mg/ml ear drops were determined in 193 children aged between 0 and 12 years. No serious adverse reactions have been reported in this patient population.


Data from clinical trials
Clinical trial data are summarised in section 4.8.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Ocular use:
Ciprofloxacin is rapidly absorbed into the eye after topical ocular administration of CILOXAN 3 mg/ml eye drops, solution. In rabbits, maximum concentrations were reached in most tissues within 0.5 to 2 hours. Systemic concentrations are low after topical administration. Plasma levels of ciprofloxacin in humans after 2 drops of 0.3% ciprofloxacin solution every 2 hours for two days and then every four hours for 5 days ranged from non-quantifiable (<1.0 ng/ml) to 4.7 ng/ml. The mean peak ciprofloxacin plasma level obtained in this study is approximately 450 times less than that observed after a single oral administration of 250 mg ciprofloxacin. The systemic pharmacokinetic properties of ciprofloxacin have been well studied. Ciprofloxacin is widely distributed to body tissues.
The apparent volume of distribution at steady state is 1.7 to 5.0 l/kg. Serum protein binding is 20-40%.
The half-life of ciprofloxacin in serum is 3-5 hours. Both ciprofloxacin and its four primary metabolites are excreted in urine and faeces. Renal clearance is approximately two-thirds of total serum clearance, with the biliary and faecal routes of excretion accounting for the remaining percentages. In patients with renal impairment, the elimination half-life of ciprofloxacin is only moderately increased due to extrarenal routes of elimination. Similarly, the elimination half-life is only slightly longer in patients with severe hepatic impairment.

Ocular pharmacokinetics and systemic exposure levels of ciprofloxacin after topical ocular CIL API OCT21 V3                                       Belgium update Oct 2020 administration of CILOXAN 3 mg/g eye ointment have not been studied.

Otic use:
In children with otitis media with tympanostomy tubes treated with ciprofloxacin 3 mg/ml solution (3 drops 3 times daily for 14 days), no plasma concentrations of ciprofloxacin were detected (limit of quantification 5 ng/ml) [Force, RW 1995]. In children with purulent otitis with perforated eardrum treated with ciprofloxacin 2 mg/ml solution (twice daily for 7 to 10 days), no circulating plasma concentration of ciprofloxacin was detected up to the quantification limit of 5 ng/ml. No significant systemic passage of ciprofloxacin is expected under normal use.

No pharmacokinetic data are available with regard to use in children.