Ciprofloxacin

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Anti infectives for systemic use -> Antibacterials for systemic use

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Antibiotics

Pharmaceuticals -> Antibiotics (Quinolones)

log Kow = 0.28 (non-ionized)

2.3

<1mg/mL

Water Solubility: approx 36 mg/ml @ 25 °C /Ciprofloxacin hydrochloride/

Soluble in dilute (0.1N) hydrochloric acid; practically insoluble in ethanol

In water, 30,000 mg/L at 20 °C

1.35e+00 g/L

Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents; Antibacterial Agents; Quinolones; Fluoroquinolones

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Ear, nose and throat medicines [c]

255-257 °C

225-257 °C, decomposes

255 - 257 °C

Ciprofloxacin hydrochloride ophthalmic solution should be stored in tight, light-resistant containers at 2-25 °C. When stored as directed, the commercially available ophthalmic solution has an expiration date of 24 months following the date of manufacture. Ciprofloxacin hydrochloride ophthalmic ointment should be stored at 2-25 °C. Ciprofloxacin hydrochloride and hydrocortisone otic suspension should be stored in light-resistant containers below 25 °C; freezing should be avoided. Ciprofloxacin hydrochloride and dexamethasone otic suspension should be stored at 15-30 °C and protected from light; freezing should be avoided.

Ciprofloxacin hydrochloride tablets should be stored in tight containers at a temperature <30 °C. The drug should be protected from intense uv light. Ciprofloxacin microcapsules for oral suspension & the diluent provided by the manufacturer should be stored at <25 °C & protected from freezing. Following mixture with the diluent, ciprofloxacin oral suspension should be stored at <30 °C & protected from freezing, & is stable for 14 days when stored at room temperature or in a refrigerator.

The compatibility of 10 mg/ml ciprofloxacin injection in 0.9% sodium chloride and 5% dextrose soln were /mixed/ with other injectable drugs, including amikacin sulfate, aminophylline, clindiamycin phosphate, gentamicin phosphate, tobramycin sulfate and metronidazole ... soln ... were stored for up to 48 hr at room temperature and under refrigeration. Eight hr after amikacin was mixed with ciprofloxacin in sodium chloride soln and refrigerated, the drug concn was 89% of the original. Admixtures of the precipitate formed immediately whenever ciprofloxacin was mixed with aminophylline or clindamycin. /Results indicate/ that ciprofloxacin was incompatable with aminophylline and clindamycin, and that its compatibility with amikacin depended upon the vehicle and storage temperature.

... The physical and chemical compatibilities of ciprofloxacin lactate infusion with other commonly used iv admin drugs /was investigated/ Ciprofloxacin lactate injection in a commercially available concn of 2 mg/ml was mixed with 15 iv drugs during a simulated Y-site injection. Of the 15 drugs /examined/ , only heparin, furosemide and teicoplanin were found to be incompatible with ciprofloxacin. ... /Ciprofloxacin lactate/

Positive

3.1

2.7

Agilent XCT

Electrospray ionization

formic acid (5.3nM)

6.16

8.62

6.25

6.09

pKa = 6.09 (carboxylic acid group); pKa = 8.74 (nitrogen on piperazinyl ring)

This chemical does not meet GHS hazard criteria for 64.7% (66 of 102) of all reports.

H412 (26.5%): Harmful to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

P273, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 102 reports by companies from 11 notifications to the ECHA C&L Inventory.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ciprofloxacin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ciprofloxacin hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Ciprofloxacin hydrochloride/

Extensive pharmacologic & clinical development of quinolone antimicrobial agents has resulted in improved antimicrobial activity, pharmacokinetic features, toxicity, & drug-drug interaction profiles. Nalidixic acid & other early quinolones had limited use due to poor pharmacokinetics, relatively narrow antimicrobial spectrum of activity, & frequent adverse effects. Beginning with the development of fluoroquinolones, such as norfloxacin & ciprofloxacin, in the 1980s, the agents assumed a greatly expanded clinical role because of their broad antimicrobial spectrum of action, improved pharmacokinetic properties, & more acceptable safety profile. Although the pharmacokinetics & efficacy of the drugs have improved significantly, a major area of continued emphasis is to further reduce the frequency & severity of adverse events & drug-drug interactions. Older agents such as ciprofloxacin & ofloxacin are still extensively prescribed, but the focus of this article is on the newer fluoroquinolones (levofloxacin & other drugs that have been approved or have been under investigation since approx 1997).[Fish DN; Pharmacotherapy 21 (10 Pt 2): 253S-272S (2001)]

Ciprofloxacin hydrochloride conventional tablets should be stored in tight containers at a temperature less than 30 °C, and protected from intense UV light. Extended-release tablets containing ciprofloxacin hydrochloride and base (Cipro XR) and extended-release tablets containing ciprofloxacin hydrochloride (ProQuin XR) should be stored at 25 °C, but may be exposed to temperatures ranging from 15-30 °C. Ciprofloxacin microcapsules for oral suspension and the diluent provided by the manufacturer should be stored at less than 25 °C and protected from freezing. Following mixture with the diluent, ciprofloxacin oral suspension should be stored at less than 30 °C and protected from freezing, and is stable for 14 days when stored at room temperature or in a refrigerator.

Ciprofloxacin for oral suspension: Prior to reconstitution, store below 25 °C (77 °F). Protect from freezing. After reconstitution, store below 30 °C (86 °F). Protect from freezing. The suspension is stable for 14 days when stored in a refrigerator or at room temperature below 39 °C or 86 °F.

Ciprofloxacin tablets USP: Store below 30 °C (86 °F) in a well closed container.

Ciprofloxacin injection USP: Store in a cool place between 8 and 15 °C (46-59 °F) or at controlled room temperature (between 20 and 25 °C (68 and 77 °F). ... Protect from light and freezing.

Store in tight, light-resistant container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity.

Wear approved respiratory protection, chemically compatible gloves and protective clothing. Wipe up spillage or collect spillage using a high efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labelled container for disposal. Wash spill site.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

Engineering controls such as exhaust ventilation are recommended.

As with all dry powders it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.

As a general rule, when handling USP Reference Standards avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Respiratory Protection: Use a NIOSH-approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. In the event that a respirator is not required, an approved dust mask should be used. Gloves: Chemically compatible. Eye Protection: Safety glasses or goggles. Protective Clothing: Protect exposed skin.

The concn of ciprofloxacin in breast milk .. was measured following maternal admin of oral ciprofloxacin hydrochloride at a dose of 500 mg/day beginning three months after delivery for the treatment of episiotomy infection in a 32 yr old /female/. The infant was breast fed 8 hr after the last dose ... and milk samples were /drawn/ 2 hr 40 min latter. ... The breast milk concn was 0.98 mcg/ml. ... /Ciprofloxacin hydrochloride/

The concn of ciprofloxacin in mother's and infant's serum was measured following maternal admin of oral ciprofloxacin hydrochloride at a dose of 500 mg/day beginning three months after delivery for the treatment of episiotomy infection in a 32 yr old /female/. The infant was breast fed 8 hr after the last dose ... and blood samples were /drawn/ 2 hr 40 min latter. ... The mother's serum concn was 0.21 mcg/ml. ... The infants serum concn was undetectable.

Ciprofloxacin hydrochloride is rapidly and well absorbed from the GI tract following oral administration, and undergoes minimal first-pass metabolism. The oral bioavailability of ciprofloxacin administered as conventional tablets is 50-85% in healthy, fasting adults, and peak serum concentrations of the drug generally are attained within 0.5-2.3 hours. Peak serum concentrations and area under the serum concentration-time curve (AUC) increase in proportion to the dose over the oral dosage range of 250-1000 mg and are unaffected by gender. Following oral administration of a single 250-, 500-, 750-, or 1000-mg dose of ciprofloxacin as conventional tablets or oral suspension in healthy, fasting adults, peak serum concentrations average 0.76-1.5, 1.6-2.9, 2.5-4.3, or 3.4-5.4 ug/mL, respectively; serum concentrations 12 hours after the dose average 0.1, 0.2, 0.4, or 0.6 ug/mL, respectively. In adults, oral administration of 500 mg of ciprofloxacin as conventional tablets every 12 hours results in mean peak or trough serum concentrations at steady-state of 2.97 or 0.2 ug/mL, respectively. /Ciprofloxacin hydrochloride/

Serious and fatal reactions have been reported in patients receiving concurrent administration of ciprofloxacin and theophylline. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar serious adverse effects have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.

... The effects of aluminum hydroxide ... and calcium carbonate ... on the bioavailability of ciprofloxacin /was determined in/ ... a 3 way randomized, crossover study was concluded in 12 healthy male volunteers (ages 21-45 yr) that consisted of 3 treatments: 750 mg ciprofloxacin alone, 750 mg ciprofloxacin with 3.4 g calcium carbonate or 1.8 g aluminum hydroxide admin 5 min before ciprofloxacin. The relative bioavailability of ciprofloxacin was reduced to 60% and 15% of control values when given with calcium carbonate and aluminum hydroxide, respectively. ... It was concluded that antacids containing either aluminum or calcium should not be given concurrently with ciprofloxacin.

Ciprofloxacin, given to a patient successfully treated with methadone for more than 6 yrs, caused profound sedation, confusion, & respiratory depression. We suggest that this was caused by ciprofloxacin inhibition of CYP1A2 & CYP3A4 activity, 2 of the cytochrome p450 isozymes involved in the metab of methadone.

Synergism does not occur in vitro when ciprofloxacin is used in conjunction with vancomycin against Staphylococcus epidermidis, S. aureus (including oxacillin-resistant S. aureus), Corynebacterium, or Listeria monocytogenes.

For more Interactions (Complete) data for CIPROFLOXACIN (35 total), please visit the HSDB record page.

Ciprofloxacin like other fluoroquinolones is associated with a low rate (1% to 3%) of serum enzyme elevations during therapy. These abnormalities are generally mild, asymptomatic and transient, resolving even with continuation of therapy. More importantly, ciprofloxacin has been linked to rare, but occasionally severe and even fatal cases of acute liver injury. The time to onset is typically short (2 days to 2 weeks) and the presentation is often abrupt with nausea, fatigue and abdominal pain, followed by dark urine and jaundice. The pattern of serum enzyme elevations can be either hepatocellular or cholestatic; cases with the shorter times to onset usually being more hepatocellular with markedly elevated ALT levels, and occasionally with rapid worsening of prothrombin time and early signs of hepatic failure. The onset of illness also may occur a few days after the medication is stopped. Cases with a cholestatic pattern of enzymes may run a prolonged course, but are usually self-limiting. Nevertheless, chronic cholestasis and vanishing bile duct syndrome have been reported with ciprofloxacin and other fluoroquinolones. Finally, the enzyme pattern can be initially hepatocellular and then evolve during the course of illness from a hepatocellular into a mixed or cholestatic pattern. Many (but not all) cases have had allergic manifestations with fever, rash and eosinophilia. Autoantibodies are usually not present.

TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 61,000(2), indicates that ciprofloxacin is expected to be immobile in soil(SRC). The pKa values are 6.09 for the carboxylic acid group and 8.74 for the nitrogen on the piperazinyl ring(3); at pHs greater than 6.09, the acid will be primarily dissociated and at pHs less than 8.74, the nitrogen will be primarily protonated. Volatilization from moist soil is not expected because the compound exists as an ion and ions do not volatilize. Ciprofloxacin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.8X10-13 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Using the OECD closed bottle biodegradation study, 0% degradation over a 40-day incubation period was observed(5), indicating that biodegradation is not an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), a Koc value of 61,000(2) indicates that ciprofloxacin is expected to adsorb to suspended solids and sediment(SRC). The pKa values are 6.09 for the carboxylic acid group and 8.74 for the nitrogen on the piperazinyl ring(3); at pHs greater than 6.09, the acid will be primarily dissociated and at pHs less than 8.74, the nitrogen will be primarily protonated(SRC); therefore, volatilization from water and moist soil surfaces is not expected to be an important fate process. According to a classification scheme(4), an estimated BCF of 3(SRC), from its log Kow of 0.28(5) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Using the OECD closed bottle biodegradation study, 0% degradation over a 40-day incubation period was observed(7), indicating that biodegradation is not an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ciprofloxacin, which has an estimated vapor pressure of 2.8X10-13 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase ciprofloxacin may be removed from the air by wet or dry deposition(SRC). Ciprofloxacin in aqueous solution is susceptible to photodegradation(3), suggesting that the compound may be susceptible to direct photolysis by sunlight(SRC).

Adverse effects are mild at therapeutic doses and are mostly limited to gastrointestinal disruptions such as nausea and diarrhea. The serious adverse effects of ciprofloxacin include prolonged QT interval, hyper or hypoglycemia, and photosensitivity. Rare interactions include drug-induced bullous pemphigoid.

The concn of ciprofloxacin in breast milk .. was measured following maternal admin of oral ciprofloxacin hydrochloride at a dose of 500 mg/day beginning three months after delivery for the treatment of episiotomy infection in a 32 yr old /female/. The infant was breast fed 8 hr after the last dose ... and milk samples were /drawn/ 2 hr 40 min latter. ... The breast milk concn was 0.98 mcg/ml. ... /Ciprofloxacin hydrochloride/

Ciprofloxacin is excreted in human milk.

The elimination half-life of ciprofloxacin ranges from 3.3 to 6.8 hours in the elderly compared with three to four hours in younger persons. There is limited evidence suggesting ciprofloxacin excretion in breast milk.. Clinical data indicate no significant evidence of osteoarticular toxicity in newborns and children. In these studies, the drug exposure of neonates and children was at much higher doses compared to children whose exposure was via breastfeeding.

The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, strand supercoiling repair, and recombination.

/AQUATIC SPECIES/ The effects of mecillinam, trimethoprim and ciprofloxacin, antibiotics used in the treatment of urinary tract infections, on the aquatic environment were assessed. Mecillinam and ciprofloxacin were both readily biodegradable (primary degradation) in activated sludge, whereas trimethoprim persisted. The toxicity of these antibiotics towards sludge bacteria, a green alga, a cyanobacterium, a crustacean and a fish were investigated; both mecillinam and ciprofloxacin were highly toxic to the cyanobacterium Microcystis aeruginosa (EC50 in the range 5-60 ug/L). Risk characterization for the aquatic environment was performed for the three compounds by calculating the predicted environmental concn (PEC) and the predicted no-effects concn (PNEC). A PEC/PNEC ratio of <1 indicates that, with the present pattern of use, no environmental risk is expected. PEC/PNEC ratios of <1 for present usage in Europe were found for mecillinam and trimethoprim whereas a PEC/PNEC ratio >1 was found for ciprofloxacin.

/AQUATIC SPECIES/ The present study investigated the growth inhibition effect of the fluoroquinolone antibiotics enrofloxacin and ciprofloxacin on four photoautotrophic aquatic species: the freshwater microalga Desmodesmus subspicatus, the cyanobacterium Anabaena flosaquae, the monocotyledonous macrophyte Lemna minor, and the dicotyledonous macrophyte Myriophyllum spicatum. Both antibiotics, which act by inhibiting the bacterial DNA gyrase, demonstrated high toxicity to A. flosaquae and L. minor and moderate to slight toxicity to D. subspicatus and M. spicatum. The cyanobacterium was the most sensitive species with median effective concentration (EC50) values of 173 and 10.2 ug/L for enrofloxacin and ciprofloxacin, respectively. Lemna minor proved to be similarly sensitive, with EC50 values of 107 and 62.5 ug/L for enrofloxacin and ciprofloxacin, respectively. While enrofloxacin was more toxic to green algae, ciprofloxacin was more toxic to cyanobacteria. Calculated EC50s for D. subspicatus were 5,568 ug/L and >8,042 ug/L for enrofloxacin and ciprofloxacin, respectively. These data, as well as effect data from the literature, were compared with predicted and reported environmental concentrations. For two of the four species, a risk was identified at ciprofloxacin concentrations found in surface waters, sewage treatment plant influents and effluents, as well as in hospital effluents. For ciprofloxacin the results of the present study indicate a risk even at the predicted environmental concentration. In contrast, for enrofloxacin no risk was identified at predicted and measured concentrations.

/AQUATIC SPECIES/ The effects of trichloroisocyanuric acid (TCCA) and ciprofloxacin (CPFX) on the freshwater alga Chlorella vulgaris were assessed by toxicity bioassays and by the values of biomarkers in phase I and phase II. The biomarkers included growth rate, concentration of chlorophyll a, activities of 7-ethoxyresorufin-O-dealkylases (EROD), glutathione S-transferase (GST), catalase (CAT), and total glutathione (GSH). Ciprofloxacin was a weaker growth inhibitor than TCCA but, at a concentration of >12.5 mg/L, decreased the growth of C. vulgaris. Concentration of chlorophyll a showed a similar trend. The 96-hr median effective concentration (EC50; i.e., 50% reduction in growth relative to the control) of CPFX was 20.6 mg/L. ... Ciprofloxacin and TCCA affected the phase I and phase II enzyme activities differently. On exposure to CPFX, both EROD and GSH decreased at low CPFX concentrations (<5.0 mg/L) and increased at high CPFX concentrations (>12.5 mg/L), and CAT and GST exhibited induction at low concentrations and inhibition at high concentrations. ...

/FIELD STUDIES/ ...Outdoor aquatic microcosms /were exposed/ to combinations of ibuprofen (a nonsteroidal anti-inflammatory drug), fluoxetine (a selective serotonin reuptake inhibitor), and ciprofloxacin (a DNA gyrase-inhibiting antibiotic) at concentrations of 6, 10, and 10 ug/L, respectively (low treatment [LT]); 60, 100, and 100 ug/L, respectively (medium treatment [MT]); and 600, 1,000, and 1,000 ug/L, respectively (high treatment [HT]). ...Effects were observed in the MT and HT. Fish mortality occurred in the MT (<35 days) and in the HT (<4 days). Phytoplankton increased in abundance and decreased in diversity (number of taxa) in the HT, with consistent trends being observed in the MT and LT. Zooplankton also showed increased abundance and decreases in diversity in the HT, with consistent trends being observed in the MT. Multivariate analyses for zooplankton and phytoplankton suggested interactions between these communities. Lemna gibba and Myriophyllum spp. showed mortality in the HT; growth of L. gibba was also reduced in the MT. Bacterial abundance did not change in the HT. All responses were observed at concentrations well below the equivalent pharmacologically active concentrations in mammals. Although the present data do not suggest that ibuprofen, fluoxetine, and ciprofloxacin are individually causing adverse effects in surface-water environments, questions remain about additive responses from mixtures.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ciprofloxacin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ciprofloxacin hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Ciprofloxacin hydrochloride/

S01AE03

J - Antiinfectives for systemic use

S - Sensory organs

S - Sensory organs

S - Sensory organs

QS - Sensory organs

Ciprofloxacin is a second generation fluoroquinolone that is active against many Gram negative and Gram positive bacteria. It produces its action through inhibition of bacterial DNA gyrase and topoisomerase IV. Ciprofloxacin binds to bacterial DNA gyrase with 100 times the affinity of mammalian DNA gyrase. There is no cross resistance between fluoroquinolones and other classes of antibiotics, so it may be of clinical value when other antibiotics are no longer effective. Ciprofloxain and its derivatives are also being investigated for its action against malaria, cancers, and AIDS.

Ciprofloxacin acts on bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Ciprofloxacin's targeting of the alpha subunits of DNA gyrase prevents it from supercoiling the bacterial DNA which prevents DNA replication.

The mechanism by which ciprofloxacin's inhibition of DNA gyrase or topoisomerase IV results in death in susceptible organisms has not been fully determined. Unlike beta-lactam anti-infectives, which are most active against susceptible bacteria when they are in the logarithmic phase of growth, studies using Escherichia coli and Pseudomonas aeruginosa indicate that ciprofloxacin can be bactericidal during both logarithmic and stationary phases of growth; this effect does not appear to occur with gram-positive bacteria (e.g., Staphylococcus aureus). In vitro studies indicate that ciprofloxacin concentrations that approximate the minimum inhibitory concentration (MIC) of the drug induce filamentation in susceptible organisms; high concentrations of the drug result in enlarged or elongated cells that may not be extensively filamented. Although the bactericidal effect of some fluoroquinolones (e.g., norfloxacin) evidently requires competent RNA and protein synthesis in the bacterial cell, and concurrent use of anti-infectives that affect protein synthesis (e.g., chloramphenicol, tetracyclines) or RNA synthesis (e.g., rifampin) inhibit the in vitro bactericidal activity of these drugs, the bactericidal effect of ciprofloxacin is only partially reduced in the presence of these anti-infectives. This suggests that ciprofloxacin has an additional mechanism of action that is independent of RNA and protein synthesis.

Ciprofloxacin usually is bactericidal in action. Like other fluoroquinolone anti-infectives, ciprofloxacin inhibits DNA synthesis in susceptible organisms via inhibition of the enzymatic activities of 2 members of the DNA topoisomerase class of enzymes, DNA gyrase and topoisomerase IV. DNA gyrase and topoisomerase IV have distinct essential roles in bacterial DNA replication. DNA gyrase, a type II DNA topoisomerase, was the first identified quinolone target; DNA gyrase is a tetramer composed of 2 GyrA and 2 GyrB subunits. DNA gyrase introduces negative superhelical twists in DNA, an activity important for initiation of DNA replication. DNA gyrase also facilitates DNA replication by removing positive super helical twists. Topoisomerase IV, another type II DNA topoisomerase, is composed of 2 ParC and 2 ParE subunits. DNA gyrase and topoisomerase IV are structurally related; ParC is homologous to GyrA and ParE is homologous to GyrB. Topoisomerase IV acts at the terminal states of DNA replication by allowing for separation of interlinked daughter chromosomes so that segregation into daughter cells can occur. Fluoroquinolones inhibit these topoisomerase enzymes by stabilizing either the DNA-DNA gyrase complex or the DNA-topoismerase IV complex; these stabilized complexes block movement of the DNA replication fork and thereby inhibit DNA replication resulting in cell death.

... Ciprofloxacin is cytotoxic to a variety of cultured mammalian cell lines at concn that deplete cells of mtDNA. The IC50 values for ciprofloxacin varied from 40-80 ug/ml depending on the cell line tested. Cytotoxicity required continuous exposure of cells to drug for 2-4 days, which corresponded to approx three or four cell doublings. Shorter times of drug exposure did not cause significant cytotoxicity. In addition, cells became drug resistant when they were grown under conditions that bypassed the need for mitochondrial respiration. Resistance was not due to a decr in cellular drug accumulation, ... /indicating/ that ciprofloxacin cytotoxicity is caused by the loss of mtDNA encoded functions. Analysis of mtDNA from ciprofloxacin treated cells revealed the presence of site specific, double stranded DNA breaks. ... Exonuclease protection studies indicated that the 5'-, but not the 3', ends of the drug induced DNA breaks were tightly associated with protein. These results suggest that ciprofloxacin may be causing cytotoxicity by interfering with a mitochondrial topoisomerase II like activity, resulting in a loss of mtDNA.

Fluoroquinolones prolong the QT interval by blocking voltage-gated potassium channels, especially the rapid component of the delayed rectifier potassium current I(Kr), expressed by HERG (the human ether-a-go-go-related gene). According to the available case reports and clinical studies, moxifloxacin carries the greatest risk of QT prolongation from all available quinolones in clinical practice and it should be used with caution in patients with predisposing factors for Torsades de pointes (TdP).

The average half life following a 250mg oral dose was 4.71 hours and 3.65 hours following a 100mg intravenous dose. Generally the half life is reported as 4 hours.

The serum elimination half-life of ciprofloxacin in adults with normal renal function is 3-7 hours. Following IV administration in healthy adults, the distribution half-life of ciprofloxacin averages 0.18-0.37 hours and the elimination half-life averages 3-4.8 hours. The elimination half-life of the drug is slightly longer in geriatric adults than in younger adults, and ranges from 3.3-6.8 hours in adults 60-91 years of age with renal function normal for their age. Based on population pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life of ciprofloxacin in children is approximately 4-5 hours. In patients with impaired renal function, serum concentrations of ciprofloxacin are higher and the half-life prolonged. In adults with creatinine clearances of 30 mL/minute or less, half-life of the drug ranges from 4.4-12.6 hours.

t1/2 for ciprofloxacin- normal: 4 (hr), anephric: 8.5 (hr) /from table/

Ciprofloxacin is primarily metabolized by CYP1A2. The primary metabolites oxociprofloxacin and sulfociprofloxacin make up 3-8% of the total dose each. Ciprofloxacin is also converted to the minor metabolites desethylene ciprofloxacin and formylciprofloxacin. These 4 metabolites account for 15% of a total oral dose. There is a lack of available data on the enzymes and types of reactions involved in forming these metabolites.

The drug is partially metabolized in the liver by modification of the piperazinyl group to at least 4 metabolites. These metabolites, which have been identified as desethyleneciprofloxacin (M1), sulfociprofloxacin (M2), oxociprofloxacin (M3), and N-formylciprofloxacin (M4), have microbiologic activity that is less than that of the parent drug but may be similar to or greater than that of some other quinolones (e.g., M3 and M4 are comparable to norfloxacin for certain organisms).

Hepatic. Four metabolites have been identified in human urine which together account for approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. Route of Elimination: Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug. Half Life: 4 hours

5E8K9I0O4U

CIPROFLOXACIN

Established Pharmacologic Class [EPC] - Fluoroquinolone Antibacterial

Chemical Structure [CS] - Fluoroquinolones

Mechanisms of Action [MoA] - Cytochrome P450 1A2 Inhibitors

Ciprofloxacin is a Fluoroquinolone Antibacterial. The mechanism of action of ciprofloxacin is as a Cytochrome P450 1A2 Inhibitor.

Substances that inhibit the growth or reproduction of BACTERIA.

Compounds that inhibit the activity of DNA TOPOISOMERASE II. Included in this category are a variety of ANTINEOPLASTIC AGENTS which target the eukaryotic form of topoisomerase II and ANTIBACTERIAL AGENTS which target the prokaryotic form of topoisomerase II.

Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP1A2.

A 250mg oral dose of ciprofloxacin reaches an average maximum concentration of 0.94mg/L in 0.81 hours with an average area under the curve of 1.013L/h\*kg. The FDA reports an oral bioavailability of 70-80% while other studies report it to be approximately 60%. An early review of ciprofloxacin reported an oral bioavailability of 64-85% but recommends 70% for all practical uses.

27% of an oral dose was recovered unmetabolized in urine compared to 46% of an intravenous dose. Collection of radiolabelled ciprofloxacin resulted in 45% recovery in urine and 62% recovery in feces.

Cirpofloxacin follws a 3 compartment distribution model with a central compartment volume of 0.161L/kg and a total volume of distribution of 2.00-3.04L/kg.

The average renal clearance after a 250mg oral dose is 5.08mL/min\*kg. Following a 100mg intravenous dose, the average total clearance is 9.62mL/min\*kg, average renal clearance is 4.42mL/min\*kg, and average non renal clearance is 5.21mL/min\*kg.

Based on population pharmacokinetics, bioavailability of ciprofloxacin oral suspension in children is approximately 60%. Following a single oral dose of 10 mg/kg of ciprofloxacin given as the oral suspension to children 4 months to 7 years of age, the mean peak plasma concentration was 2.4 ug/mL. There was no apparent age dependence and no increase in peak plasma concentrations following multiple doses.

When extended-release tablets containing ciprofloxacin hydrochloride (ProQuin XR) are administered with food, approximately 87% of the drug is gradually released from the tablet over a 6- hour period. When administered following a meal, peak plasma concentrations are attained approximately 4.5-7 hours after the dose. Bioavailability is substantially lower if ProQuin XR tablets are given while fasting. In healthy adults receiving ProQuin XR extended-release tablets in a dosage of 500 mg once daily given following a standardized meal, peak plasma concentrations at steady state (day 3) average 0.82 mcg/mL and are attained 6.1 hours after the dose. /Ciprofloxacin hydrochloride/

MEDICATION

Use (kg) in Switzerland (2009): >2500

For the treatment of the following infections caused by susceptible organisms: urinary tract infections, acute uncomplicated cystitis, chronic bacterial prostatitis, lower respiratory tract infections, acute sinusitis, skin and skin structure infections, bone and joint infections, complicated intra-abdominal infections (used in combination with metronidazole), infectious diarrhea, typhoid fever (enteric fever), uncomplicated cervical and urethral gonorrhea, and inhalational anthrax (post-exposure).

Condensation of 2,4-dichloro-5-fluorobenzoylchloride with diethyl malonate by means of magnesium ethoxide in ether gives diethyl 2,4-dichloro-5-fluorobenzoylmalonate, which is partially hydrolyzed and decarboxylated with p-toluenesulfonic acid-water, yielding ethyl 2,4-dichloro-5-fluorobenzoylacetate. Condensation of this with triethylorthoformate in refluxing acetic anhydride affords ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxyacrylate, which is treated with cyclopropylamine in ethanol to give ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-cycloporpylaminoacrylate. Cyclization with NaH in refluxing dioxane then yields 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, which is finally condensed with piperazine in hot DMSO to yield ciprofloxacin.

Table: Ciprofloxacin Preparations [Table#6556]

Table: Ciprofloxacin and Ciprofloxacin Hydrochloride Preparations [Table#6557]

Table: Ciprofloxacin Lactate Preparations [Table#6558]

Table: Ciprofloxacin Hydrochloride Preparations [Table#6559]

For more Formulations/Preparations (Complete) data for CIPROFLOXACIN (8 total), please visit the HSDB record page.