Ciprobay Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: Ciprofloxacin has in vitro activity against a wide range of Gram-negative and Gram-positive organisms. The bactericidal action of ciprofloxacin results from inhibition of bacterial type II topoisomerases (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination.
Mechanism of resistance: In vitro resistance to ciprofloxacin is commonly due to target site mutations in topoisomerase IV and DNA gyrase through multiple-step mutations. Single mutations may result in reduced susceptibility rather than clinical resistance, but multiple mutations generally result in clinical resistance to ciprofloxacin and cross-resistance across the fluoroquinolone class.
Resistance mechanisms that inactivate other antibiotics such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may affabect susceptibility to ciprofloxacin. Plasmid-mediated resistance encoded by the qnr gene has been reported. Resistance mechanisms that inactive penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines may not interfere with the antibacterial activity of ciprofloxacin. Organisms resistant to these drugs may be susceptible to ciprofloxacin.
The minimal bactericidal concentration (MBC) generally does not exceed the minimal inhibitory concentration (MIC) by more than a factor of 2.
In vitro susceptibility to ciprofloxacin: The prevalence of acquired resistance may vary geographically and with time for selected species and local information of resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought where the local prevalence of resistance is such that utility of the agent, in at least some types of infections, is questionable.
The bacterial genus and species listed as follows have been shown to commonly be susceptible to ciprofloxacin in vitro: Aerobic Gram-positive microorganisms: Bacillus anthracis, Staphylococcus aureus (methicillin-susceptible isolates), Staphylococcus saprophyticus, Streptococcus spp.
Aerobic Gram-negative microorganisms: Aeromonas spp., Brucella spp., Citrobacter koseri, Francisella tularensis, Haemophilus ducreyi, Haemophilius influenzae, Legionella spp., Moraxella catarrhalis, Neisseria meningitidis, Pasteurella spp., Salmonella spp., Shigella spp., Vibrio spp., Yersinia pestis.
Anaerobic microorganisms: Mobiluncus.
Other microorganisms: Chlamydia trachomatis, Chlamydia pneumoniae, Mycoplasma hominis, Mycoplasma pneumoniae.
The following microorganisms show varying degrees of susceptibility to ciprofloxacin: Acinetobacter baumannii, Burkholderia cepacia, Campylobacter spp., Citrobacter freudii, Enterococcus faecalis, Enterobacter aerogenes, Enterobacter clocae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Morganella morganii, Neisseria gonorrhoeae, Proteus mirabilis, Proteus vulgaris, Providencia spp., Pseudomonas aeruginosa, Pseudomonas fluorescens, Serratia marcescens, Peptostreptococcus spp., Propionibacterium acnes. The following microorganisms are considered inherently resistant to ciprofloxacin: Staphylococcus aureus (methicillin-resistant) and Stenotrophomonas maltophilia, Actinomyces, Enteroccus faecium, Listeria monocytogenes, Mycoplasma genitalium, Ureaplasma urealitycum, Anaerobic microorganisms (Excepted Mobiluncus, Peptostreptococus, Propionibacterium acnes).
Pharmacokinetics: Absorption: Film-coated tablet: Following oral administration of single doses of 250 mg, 500 mg, and 750 mg of Ciprofloxacin (Ciprobay) film-coated tablets, ciprofloxacin is absorbed rapidly and extensively, mainly from the small intestine, reaching maximum serum concentrations 1-2 hours later.
The absolute bioavailability is approximately 70-80%. Maximum serum concentrations (C_max) and total areas under serum concentration vs. time curves (AUC) increased in proportion to dose.
Solution for infusion: Following an intravenous infusion of ciprofloxacin the mean maximum serum concentrations were achieved at the end of infusion. Pharmacokinetics of ciprofloxacin were linear over the dose range up to 400 mg administered intravenously.
Distribution: The protein binding of ciprofloxacin is low (20-30%), and the substance is present in plasma largely in a non-ionized form. Ciprofloxacin can diffuse freely into the extravascular space. The large steady-state distribution volume of 2-3 L/kg body weight shows that ciprofloxacin penetrates in tissues resulting in concentrations which clearly exceed the corresponding serum levels.
Metabolism: Small concentrations of four metabolites have been reported, and were identified as: desethyleneciprofloxacin (M 1), sulphociprofloxacin (M 2), oxociprofloxacin (M 3) and formylciprofloxacin (M 4). M 1 to M 3 display in vitro antimicrobial activity comparable to, or inferior to that of nalidixic acid. M 4, with the smallest quantity, is largely equivalent to norfloxacin in terms of in vitro antimicrobial activity.
Elimination: Ciprofloxacin is largely excreted unchanged both renally and, to a smaller extent, non-renally.
Children: In a study in children, C_max and AUC were not age-dependent. No notable increase in C_max and AUC upon multiple dosing (10 mg/kg/TID) was observed. In ten children with severe sepsis, less than 1 year of age, C_max was 6.1 mg/L (range 4.6-8.3 mg/L) after a 1-hour intravenous infusion at a dose level of 10 mg/kg; and 7.2 mg/L (range 4.7-11.8 mg/L) for children between 1 and 5 years of age. The AUC-values were 17.4 mg*h/L (range 11.8-32.0 mg*h/L) and 16.5 mg*h/L (range 11.0-23.8 mg*h/L) in the respective age groups. These values are within the range reported for adults at therapeutic doses. Based on population, pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life in children is approximately 4-5 hours and the bioavailability of the oral suspension approximately 60%.
Toxicology: Preclinical safety data: Acute toxicity: The acute toxicity of ciprofloxacin after oral administration can be classified as very low. Depending on the individual species, the LD₅₀ after intravenous infusion is 125-290 mg/kg.
Chronic Toxicity: Chronic tolerability studies over 6 months: Oral administration: Doses up to and including 500 mg/kg and 30 mg/kg were tolerated without damage by rats and monkeys, respectively. Changes in the distal renal tubules were again observed in some monkeys in the highest-dose group (90 mg/kg).
Parenteral administration: In monkeys slightly elevated urea and creatinine concentrations and changes in the distal renal tubules were recorded in the highest-dose group (20 mg/kg).
Carcinogenicity: In carcinogenicity studies in mice (21 months) and rats (24 months) with doses up to approximately 1000 mg/kg body weight/day in mice and 125 mg/kg body weight/day in rats (increased to 250 mg/kg body weight/day after 22 weeks), there was no evidence of a carcinogenic potential at any dose level.
Reproduction toxicology: Fertility studies in rats: Fertility, the intrauterine and postnatal development of the young, and the fertility of F1 generation were not affected by ciprofloxacin.
Embryotoxicity studies: These yielded no evidence of any embryotoxic or teratogenic action of ciprofloxacin.
Perinatal and postnatal development in rats: No effects on the perinatal or postnatal development of the animals were detected. At the end of the rearing period histological investigations did not show any sign of articular damage in the young.
Mutagenicity: Eight in vitro mutagenicity tests have been conducted with ciprofloxacin.
Although two of the eight in vitro assays (i.e. the Mouse Lymphoma Cell Forward Mutation Assay and the Rat Hepatocyte Primary Culture DNA Repair Assay [UDS]) were positive, all of the in vivo test systems covering all relevant endpoints gave negative results.
Special tolerability studies: Articular tolerability studies: As it is also known for other gyrase inhibitors, ciprofloxacin causes damage to the large, weight-bearing joints in immature animals.
The extent of the cartilage damage varies according to age, species, and dose; the damage can be reduced by taking the weight off the joints. Studies with mature animals (rat, dog) revealed no evidence of cartilage lesions. In a study in young beagle dogs ciprofloxacin at high doses (1.3 to 3.5 times the therapeutic dose) caused articular changes after two weeks of treatment, which were still observed after five months. At therapeutic doses no effects were observed.